The Sentient Cell

Advanced Praise for The Sentient Cell: The Cellular

Foundations of Consciousness

The perfect book for any scientifically curious individual seeking updates to research on my favourite
subject in all the world—the intelligent living cell.
Brian J. Ford
President Emeritus
University of Cambridge Society for the Application of Research (UK)

The most comprehensive vision of post-neo-Darwinian biology to date. Life is not about genes and digital
information codes. Life is about sentience, consciousness, mind, and intelligence. The building blocks of
sentience and consciousness are cells. A landmark book that heralds a welcome paradigm shift in biology.
Predrag B. Slijepčević
Department of Life Sciences, Brunel University London (UK)

In 20 years of researching biological cognition in unicellular organisms I have studiously avoided what I
call the ‘C-word’, consciousness. The Sentient Cell has made me thoroughly reconsider my reticence. It is a
remarkable book that exposes the standard model of consciousness for the early 19th-century relic it is,
providing abundant empirical evidence of why it should be supplanted. An excellent introduction to a
necessary conversation that will unfold over the coming decades and which sits squarely on the right side of
history. Vive la révolution!
Pamela Lyon
University of Adelaide (Australia)

There are few questions as fascinating, far-reaching, and impactful as the emergence of multiscale minds
from the competencies of physico-chemical systems. This highly thought-provoking book addresses the
continuity of life and diverse intelligence across evolution, physiology, and behaviour. An engaging tour of
ideas essential for understanding our nature and our biological, artificial, and hybrid futures.
Michael Levin
Vannevar Bush Professor
Biology Department, Tufts University (USA)

Tackles head-on and without apology the ultimate question: what are the very foundations of sentience and
how did it spread throughout the tree of life? Leave aside any deep-rooted, human-centred prejudices, and
fasten your seat belt. Be humble, the woven expertise on display is well worth the ride!
Paco Calvo
Minimal Intelligence Lab, University of Murcia (Spain)

This new book presents a sentient, dynamic, eternal boundary, dividing and defining the inner and outer
world of cells, translating and interpreting between both, steering their evolution and supplying meaning to
life.
Anton Markos
Department of Philosophy and History of Science, Charles University (Czech Republic)
Although the view that all organisms possess consciousness is widespread, it is rarely discussed, let alone
defended by Western academics. The Sentient Cell champions the position that all life is sentient, exploring
even its most controversial consequences, including plant consciousness and its ethical implications. The
book is consistently provocative, erudite, and engaging
Robert N. McCauley
William Rand Kenan Jr. University Professor Emeritus
Center for Mind, Brain, and Culture, Emory University (USA)

In The Sentient Cell, readers are granted an extraordinary view into the sophisticated nature of cells and the
complex tapestry of life. Remarkably, numerous technologies once thought to be recent human inventions
have been in existence for over a billion years, thanks to the clever biomolecular craft of microorganisms.
This book promises to transform the way you perceive the world.
Perry Marshall
Author, Evolution 2.0

With cognition evident at all scales in nature, animals large and small, plants, and unicellular creatures, a
new synthesis of many different scientific fields is necessary to understand how this can occur and what it
might mean in relation to our human consciousness. This collaboration of three eminent scientists from very
different vantage points makes a remarkable leap in our understanding of this complex project.
Jon Lieff, MD
Neuropsychiatrist
Author, The Secret Language of Cells
 The Sentient Cell
The Cellular Foundations of Consciousness

Arthur S. Reber, František Baluška, William B. Miller Jr.

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Preface

This volume is the natural follow-up to Arthur Reber’s 2019 book, The First
Minds: Caterpillars, ‘Karyotes, and Consciousness (TFM). In that earlier work,
the Cellular Basis of Consciousness1,2 (CBC) theory was developed based on a
number of earlier efforts published in a variety of journals between 1997 and
2019 as well as in talks, colloquia, and presentations at conferences. The core
proposition in TFM was that life and mind are coterminous. All organisms, all
species extant and extinct, are sentient. All have an existentially secure
consciousness—without which they would have been evolutionary dead ends,
unable to survive in the chaotic, dangerous environment in which life first
appeared. And, importantly, all forms of sentience, all forms of cognitive
functioning right up to and including those expressed by humans, evolved from
the original expression of consciousness at the birth of life in prokaryotes. The
proposition that all life forms evolved from those first unicellular species is a
widely accepted, foundational principle of the biological and social sciences.
The CBC model simply applies that same proposition to sentience.
What was missing from those efforts was an in-depth exploration of the
underlying biochemical, biomolecular, and microbiological factors that were/are
responsible for creating sentient cells. The reason was simple. Reber lacked the
background, training, and experience in the biological sciences needed for such
an exploration. The obvious route was to reach out to others with the requisite
knowledge and skills. František Baluška had already been on board in the sense
that he was one of the cell biologists to whom Reber reached out for advice
while working on TFM. They had also gotten to know each other as participants
in the Summer Institute on the ‘Other Minds’ problem held at the Université du
Québec à Montréal in June 2018. It was at this conference that the decision to
work together on this book was reached. Their approaches were so similar that
Reber recalls thinking ‘Oh no, he’s giving my talk’ while Baluška was
presenting. Bill Miller, a productive medical researcher and frequent collaborator
of Baluška’s, was the obvious choice to round out the team. We put together a
prospectus and sent it to Oxford University Press, the publisher of TFM and
Reber’s 1993 book. After extensive external reviews, they agreed to publish.
One thing was clear from the beginning. Because we were a bit of a
patchwork team coming from very different scientific backgrounds, we needed
to distribute responsibilities for material that reflected our areas of expertise.
Reber’s degree is in experimental psychology and his primary research focus has
been on cognitive processes, in particular ‘implicit learning’—where knowledge
and skills are learned without explicit knowledge of either the processes or
products of acquisition. Think of how infants learn language and how we all
become socialized and come to learn how to behave appropriately in a culture to
get a feeling for the areas where these processes function. Recently, Reber and
Rhianon Allen edited and wrote parts of The Cognitive Unconscious: The First
Half-Century (2022) in which over 30 scholars review the research in a wide
array of topics that emerged from the early experiments on implicit cognition.
Baluška’s degree is in plant physiology and plant cell biology, focusing on
polarity, cytoskeleton, endocytosis, and vesicle recycling as well as other basic
aspects of biology of cells. He is one of the founders of the sub-field of plant
neurobiology where his insights into the causal role that cognition plays in the
life of plants has become increasingly influential in recent years.
Miller’s original training is in medicine and his interests have long been in
developing novel theories for cellular function that expanded the causal factors
that operate in evolution. He has consistently argued that most contemporary
models of evolution are seriously lacking in explanatory power, primarily
because they focus too tightly on genetic factors and fail to take into account a
host of other variables such as information, choice, epigenetics, the impact of an
error-prone biology, the role of stochastic processes, and, of course, cognition.
What emerged from our collaboration is what we regard as a revolutionary
framework for viewing not just consciousness but a model that offers a
genuinely new perspective on evolution and the nature of life on this planet. We
provide support for a framework that downplays the role of genes by making
clear that epigenetic and senomic elements play critical roles, emphasizes the
importance of information and how it is processed by all living forms, embraces
continuity across life forms, integrates all species into a singular framework, and
provides a theoretical platform to understand how cognitive functions evolved
after putting in its original appearance some 4 billion years ago. Keep in mind
that all life was unicellular for some 2 billion of those years. The implication of
this simple fact is that the terms ‘cell’ and ‘organism’ denoted identical entities, a
point that is often missed when the issues raised by our CBC theory are
contemplated. The organismal, sentient nature of cells, all cells including those
in our human bodies, is still valid. We also recognize that our approach raises a
number of questions that touch on ethical conduct and moral behaviour. These
are discussed at length in Chapter 12.
 Unlike virtually all other approaches to the broad topic of consciousness, we
begin with the simplest species, with the first appearance of life, and examine
the development and progression of cognitive functions across the evolutionary
tree. We go into some detail outlining why the decision on the part of other
scientists and philosophers to begin the explorations with Homo sapiens was a
tactical error.
Will we convince others? We do not know, of course, but we hope that, as the
advantages of taking the CBC model as the framework for an encompassing
narrative of evolutionary biology become understood, we will see a paradigm
shift. Amusingly, all of us have had the opportunity to present our views to
various groups. A pattern has emerged—a predictable one. Groups of intelligent,
curious laypersons generally respond to our insistence that life begins with
intelligence with comments like, ‘Now that’s interesting. I hadn’t thought of it,
but it does make sense.’ Cognitive scientists and neuroscientists tend to listen but
question and most conclude that our position is a bridge too far. Philosophers, in
particular philosophers of mind, typically think we have lost ours. But some cell
biologists, ones who study bacteria and botanists with close ties to the plant
neurobiology sub-field who examine the cognitive nature of plant life, respond
with ‘Well, duh. Of course.’
We rather like the recent move in many scientific journals to outline who was
responsible for what. Here is ours. Reber undertook writing the initial drafts of
the Prologue and Chapters 1, 2, 12, and this Preface. Parts of Appendix I were
imported from TFM (with modifications and, of course, permission) and updated
by Reber. Baluška wrote the first drafts of Chapters 4, 5, 6, 10, and 11 and
coordinated with Miller in compiling the glossary in Appendix II. Miller took on
responsibility for Chapters 3, 7, 8, and 9. Everything, of course, was read, edited
by others, sent back, rewritten, edited again, and fine-tuned based on the
feedback. It all went remarkably well with virtually never a harsh word or
serious disagreement about how a topic or issue was being handled. Even more
remarkable, the volume was completed within the initial time frame. It is
possible to pull this off when you have such respect for each other.
We do need to warn readers that some of the material, especially in the
chapters that focus on the underlying biomolecular processes that ‘create’
sentience, can be a bit technical. Consult Appendix II when needed. We tried to
tone down the presentation where we could but, of course, did not want to do
violence to the science. The natural processes that occurred when ‘chemistry
made biology’ as Addy Pross, an evolutionary biochemist, put it, was certainly
not easy and the even more complex one of prokaryotes making eukaryotes was
even more so—as the timeline reveals. It would be unwise to assume that it all
could be expressed without the technical details.
Our backgrounds and current scientific efforts can be found in our web pages
and other Internet locations.
For Reber:
https://psych.ubc.ca/profile/arthur-reber/
https://en.wikipedia.org/wiki/Arthur_S._Reber
For Baluška:
https://www.thethirdwayofevolution.com/people/view/frantisek-baluska
http://ds9.botanik.uni-bonn.de/zellbio/AG-Baluska-Volkmann/
For Miller:
https://humansandnature.org/william-b-miller-jr/
https://williammillermd.com

1 A note of appreciation and apology to Lynn Margulis and Pamela Lyon whose important papers
(Margulis, 2001 and Lyon, 2015) were respectively titled ‘The conscious cell’ and ‘The cognitive cell’. We
borrowed their approach here but note that our title has the advantage of being alliterative.
2 Before we begin our deep dive into the origins of minds, a word on terminology. Consciousness, in the
words of cognitive scientist George Miller, is ‘a word worn smooth by a million tongues’. Synonyms such
as ‘sentience’, ‘cognition’, ‘mentation’, and a host of others that can be found dotted throughout the
literature have also been similarly worn down to lexicographic nubs. We will not try to define them but,
rather, use them in a folk psychology fashion, as a collation of rough synonyms—rather like they are
handled by the lay public. See Appendix I for an historical overview of relevant terminology and why we
chose this lexicographic route and Appendix II for a glossary of technical terms from micro-biology, plant
neurobiology, and the cognitive neurosciences that are sprinkled throughout the text.
Prologue: Setting the Stage

Introduction
As the title of our compact volume states, our goal is to make sense of the classic
problem of the emergence of sentience, consciousness. A few years ago, the
American Association for the Advancement of Science (AAAS) considered this
to be the second most important unanswered question in science. ‘What is the
universe made of?’ was rated as the most important. Before getting into the
theoretical and empirical details of our approach, we need to make our central
proposition clear. Our view is that sentience, consciousness, self-referential
awareness—whatever term(s) are used, and we will have more to say on
terminology below—is an inherent feature of all living organisms. In over a
baker’s dozen chapters and appendices, we will advance arguments based on
foundational principles of evolutionary biology and provide empirical evidence
from recent research in microbiology to support the proposition. Put simply, life
and sentience are coterminous.
As noted in the Preface, several chapters present the underlying biomolecular
functions of cells. This material is designed to explain the basic cell biology
processes that support cellular sentience and, necessarily, is technical. Appendix
II provides definitions of the technical terms from microbiology. Consult freely.
Philosopher David Chalmers famously dubbed the question of ‘How do brains
make minds?’ as the Hard Problem of consciousness. What these chapters do is
provide the cellular biomolecular answer to the rephrased problem, ‘How do
cells make sentience?’

Lexicography, Language, and Labels

Before embarking on our voyage, we need to confront some lexicographic
issues. There is a good deal of confusion about what core terms like
‘consciousness’ or ‘sentience’ mean or what kinds of cognitive and affective
functions are designated by them. To prevent misunderstanding, we will note
here, at the beginning of our exegesis, that each of these terms will be used
interchangeably and flexibly to emphasize one or another attribute of
consciousness. We will be using these terms, and a variety of synonyms and near
synonyms, in what’s generally known as a ‘folk psychology’ manner—how the
typical intelligent layperson treats them. In Appendix I (which was imported,
with modifications (and permission), from Reber’s 2019 book The First Minds),
we cover the history and manner of use in a variety of overlapping fields and
point out the advantages of the terminological position we’ve taken. We want to
prevent what we see happening in the literature on a regular basis. A paper,
authored by respected scholars, presents behavioural or biomolecular evidence
that supports the notion that a species once assumed to be insentient does, in
fact, possess genuine consciousness. Another paper, authored by equally
respected researchers, criticizes it claiming that what the original authors
identified is not ‘really consciousness’. In the next chapter we review several
instances where this is precisely what happened. We also anticipate that
reviewers of this book will do so as well. It becomes a lexicographic debate, not
a scientific one. Nobody wins and progress is thwarted.
We regard consciousness as a cohesive suite of cognitive and affective
faculties encompassing valenced experiences, self-referencing, self-awareness,
organized information assessment, communication, learning, memory, decision-
making, and preference formation all linked to problem-solving in real-world
settings. When viewed within these defining particulars, all life is sentient life
for all species express these functions to some extent. As we will outline in
Chapter 2, even unicellular species have valenced experiences, learn, form
surprisingly stable memories, communicate meaningfully with each other, and
are capable of contingent decision-making and problem-solving. At all scales,
every form of life is not merely conscious in some vague sense but is specifically
capable of self-referential experiences.
We recognize that our view of life and sentience being coterminous is not the
one generally accepted in the larger field of what philosopher Ned Block calls
‘consciousness science’. The standard paradigm is to treat consciousness as a
feature of relatively sophisticated species, in particular, ones with a nervous
system, and to view human mental life as the ultimate instantiation of it on the
planet. There are reasons why the current paradigm is the dominant one. It has
significant historical, epistemic, and cultural roots and we will discuss them in
later chapters while pointing out the advantages of taking our cell-based
position.

Different Platforms for Sentience

The argument that all but only living organisms are sentient and exclusively so,
has, of course, an important implication: artificial entities, computers, robots,
and digital computational devices are not conscious in the biological sense and,
almost certainly never will be. We appreciate that it may not be wise to proclaim
that something that intelligent people can imagine is possible, is impossible (that
is why we put the ‘almost’ in there). We are not dogmatic—but we are empirical.
If evidence for sentience expressed by an artificial intelligence (AI) based on
digital operations is presented, we are more than willing to change our minds.
We are appreciative of the fact that computing devices have been assembled by
humans in just the last hundred years or so and AI, as a field of research, has
only been around for a few decades. Living systems are the products of
biological evolution which has been going on for some 4 billion years. There’s
time for the artificial ones to ‘evolve’.
However, existing artificial systems can hoodwink the unwary. Recently,
Blake Lemoine, an engineer at Google, was part of a team working on a project
called the Language Models for Dialog Applications (LaMDA). The goal of the
project is to design an AI that can engage in realistic conversations with humans
on a wide variety of topics—unlike chatbots3 which are restricted to specific
issues. Ironically, Lemoine became a victim of a sophisticated bit of software
that he helped develop. LaMDA is based on code that uses Google’s
‘Transformer’ neural network and is designed to mimic the ways in which
humans converse with each other. The Transformer platform is now open source
and is widely used to create chatbots for many agencies and businesses. We have
all been in conversations with digital chatbots—though we may not realize it.
They can be quite effective.
After conversing extensively with LaMDA, Lemoine concluded that it was, in
fact, sentient, had emotions, and could empathize with others—in short, that it
had passed the Turing Test4 and was conscious. He sent around an ‘interview’ he
and a colleague had with it as evidence to support his contention. Lemoine
introduces himself on his blog with: ‘I’m a software engineer. I’m a priest. I’m a
father. I’m a veteran. I’m an ex-convict. I’m an AI researcher. I’m a cajun [sic].
I’m whatever I need to be next.’ But he neglected to add ‘I’m credulous’. His
blog does have thousands of followers and his post of the interview went viral.
Predictably, it was picked up by major media outlets which, in several cases,
presented his claims uncritically. Cable shows, including the popular The Daily
Show, then with Trevor Noah as host, had a segment on it—though the credulity
was balanced with comedy.
Google, however, was not amused. Their view of LaMDA is that it is a
sophisticated digital device, an AI, one that does mimic humans in conversations
—provided the necessary information has been fed in. Consciousness is not
considered to be one of its features. LaMDA was trained on real-world dialogue
and a huge database was created over many years by entering snippets of
conversations. The result was an AI that ‘produces a model that can be trained to
read many words (a sentence or paragraph, for example), pay attention to how
those words relate to one another and then predict what words it thinks will
come next’.5 You can, as Lemoine did, ask it what it thought of Les Misérables.
LaMDA responded appropriately and they had an engaging discussion of the
book and the Broadway musical based on it. Then he asked the AI about the
meaning of a Zen koan. This time LaMDA side-stepped the question and its
response was not nearly as smooth and focused. It had, of course, been
previously fed the contents of many conversations, including ones that touched
on Victor Hugo’s masterpiece but not with ones containing information needed
for chatting about koans which are obtuse, calculatingly paradoxical anecdotes
or verbal give-and-takes used in Zen Buddhism to promote spiritual
development.
LaMDA is a fascinating AI but mimicking sentience is not emulating it.
Simulating consciousness is nothing like being conscious. Google put Lemoine
on unpaid leave.
But, for the purpose of this book, our point is straightforward and worth
repeating: life and sentience are coterminous. Life is based on cells,
biomolecular entities of immense complexity. The living element, the biological
component, is the critical factor. As Tufts University biologist Michael Levin has
pointed out, computing devices are made up of inert, individual parts, none of
which has any existential role to play in carrying out computations. It is not until
the device is assembled that it is able to operate as designed. With biological
entities, each part, each cell, and each element within each cell has a role and a
discrete function that can be carried out independently of the Gestalt, the whole.
Levin’s observation is important because it identifies a critical element—
synthetic devices and biological ones are built on wholly different platforms.
Also keep in mind that conscious entities are error-prone, express doubt at an
internal self-referential level, and appraise information using analogue processes.
What is almost never addressed is that humans, above all others, are not entirely
rational. We do clearly stupid things, sometimes out of ignorance or misguided
thought, and sometimes for fun. We do it to attain an internal self-defined,
preferential state. How might that be programmed?
Our guess, which we suspect Levin would agree with, is that if an AI is ever
to become aware, have internal, valenced states graced with a sense of self and
self-awareness, it will be when researchers in the future will have worked out
how to integrate cellular biocomputational processes and functions into their
device. This is not on anyone’s horizon right now, though some (see Schumann
& Pancerz, 2016) are speculating about the possibility and others (Kagan et al.,
2022) are making efforts to integrate living cells into their systems as a way of
achieving synthetic consciousness from the boosting platform of pre-existing
sentience. To date, all functioning AIs are built on digital, informational
platforms while all living organisms are formed on analogue, structural scaffolds
supported by digital nucleotide sequences of RNA and DNA macromolecules.
The difference is more important than many appreciate and is pursued in more
detail in Chapter 8.
The issue of a sentient AI, an artefact that displays human cognition and
emotion, is one of the more vigorously discussed and debated issues among
philosophers, neuroscientists, computationalists, computer scientists, mystics,
and futurists (see Hunt, 1995, for an overview). Not surprisingly, the debate has
a long history crafted by such intellectual luminaries as the elaborately
monikered alchemist, physician, and philosopher Philippus Aureolus
Theophrastus Bombastus von Hohenheim (aka Paracelsus, 1493–1541) who
proposed that an artificial human could be created out of magnetism and sperm
using basic principles of alchemy. There is a statement in Wikipedia6 that
Paracelsus claimed he had actually done this but we could find no evidence for
anything other than the speculation. Rabbi Judah Loew ben Bezalel (1528?—
1609), a revered Bohemian philosopher and mystic, offered a similar proposal—
only his preferred ingredients were clay and an appropriate Talmudic
incantation, which he claimed to have used to create the Golem. Mary Shelly’s
Frankenstein monster was brought to life with electric sparks, then thought to
have a role to play in the emergence of life. These early efforts were, of course,
based on biological principles. The digital age of electronics and computers was
centuries in the future. In an odd way, we celebrate these clever, early
speculations as they did seem to grasp one of our fundamental points: life and its
attendant cognitive, sentient functions are based on biophysical and
biomolecular processes.

Might It All Just Be Computational?

The notion of life and mental states emerging in an artificial entity gathered
steam and adherents beginning in the early 1960s, stimulated by a proposal by
Harvard philosopher Hilary Putnam that the key element in creating
consciousness, experience, and valenced perceptions was computation. If,
Putnam maintained, an artificial entity were to carry out the identical operations
of a human brain, its causal properties and, hence, its internal experiences, would
be identical to ours. In short, you’d have a conscious robot with an existential
mind. The suggestion caught on with a number of philosophers and computer
scientists and led to an enthusiastic programme of research into what became
known as ‘hardware-independent functionalism’, ‘computationalism’, and
several other terms all of which focused on the claim that the functions were the
key not the device carrying them out. As philosopher Jerry Fodor, an early and
enthusiastic promoter of computationalism, was fond of saying, the system could
be made out of string and tin cans but if it carried out the proper causal
computations it would be conscious. It is worth noting that Fodor was Putnam’s
student.
In addition to enthusiastic defences of Putnam’s suggestion, there were
vigorous critiques of it, most notably by philosopher John Searle. Searle’s
arguments were based on a thought experiment, known as the Chinese Room.
There is a fuller discussion of it in Reber (2019) but we can lay out the argument
in simple terms. Inside the room is a person, we will call her Karen, who knows
no Chinese, cannot read it, speak it, or understand it. Karen is, however,
equipped with a set of instructions that can be used to decode written Chinese
and craft written responses. Outside the room are several Chinese speakers who
ask her questions written in, of course, Chinese. When one arrives in her inbox,
Karen consults her code books for how to handle the material and how to
respond to it in Chinese. She dutifully returns the replies to the folks outside the
room who conclude that, clearly, whoever is in the room, is fluent in Chinese.
Searle maintained that this setting is a critique of Putnam’s initial argument since
all the appropriate computations for reading and writing Chinese are being
carried out but there is no comprehension, no meaning. Karen is acting like a
chess-playing robot that can play the game at grandmaster levels without
knowing anything about chess—in fact, without knowing anything at all.
Searle’s argument was subjected to extensive criticism7 and more than a few
philosophers have concluded that not only is it wrong, it has been thoroughly
debunked (see, e.g. Hauser, 1997). While there may be problems with the
Chinese Room argument, it does not mean that computationalism is correct.
Searle’s argument was designed to show that the proposal for a sentient AI was
logically incoherent, that syntax (what Karen’s code books were based on) did
not get you semantics (the meanings the Chinese speakers outside the room drew
from her responses). We note that Searle, whatever the merits of the Chinese
Room Gedankenexperiment are, came to the issue as a philosopher, not as a
computer scientist, not as a social scientist, and certainly not as a cell biologist.
He did not focus on the biomolecular, cellular elements. We agree with Searle’s
conclusions about functionalism and computationalism but for different reasons.
Our claim is that the device carrying out the computations is not only relevant, it
is the critical component. The device must be alive.
We will also note, in passing, that the functionalists got away with a rhetorical
gambit that made resolution of the debate not only difficult, but nearly
impossible. The critics, by attacking Searle’s arguments, succeeded in putting
those taking the anti-computationalist line on the defensive while trying to
counter the anti-Chinese Room criticism. What was left in the dust was that the
burden of proof properly belonged on the hardware-independent functionalists to
show why their position was coherent—not on the critics of computationalism,
whether they took a Searlean line or the biomolecular one we take here. Science
fiction writers, futurists, film makers, and poets can all conjure up robots and
AIs that behave as conscious entities but that does not mean they are possible in
the real world.
Interestingly, there have been a number of recent articles and books critiquing
the hardware-independence view. A common theme in the criticism is that the
existing AIs, ones that can carry out many tasks that appear to be examples of
intelligence including complex undertakings such as identifying the principles of
protein folding, making decisions about appropriate individualized medical care,
creating aesthetically appealing ‘paintings’, predicting the weather, and dealing
with the complex problems of climate change are all domain-specific.8 As
Epstein (2016) and others point out, none of them display ‘general intelligence’
in the sense that the device can function effectively in arbitrary environments.
Note the similarity here with Google’s LaMDA and ChatGPT. The feature the
programmers are working towards is to build an AI that can hold coherent
conversations on any arbitrary topic, provided it has sufficient information
garnered from billions of real-world conversations. And that, of course, is what
humans do. If you know a lot about the cognitive neurosciences you can have
conversations with other knowledgeable people, but if you’re a concert pianist
the back and forth is likely to be like the one Lemoine had with LaMDA when
the topic was a Buddhist koan. It is not going anywhere.
Epstein does a rapid voyage through the history of brain metaphors from the
early theological ones to suggestions from Rene Descartes, George Miller, John
von Neumann, and Ray Kurzweil all of whom put forward one or another
version of the broader claim that ‘the brain is just a ____’—where the blank got
filled out by whatever the insights into human cognition and neurophysiology
were currently the focus of research and theory. All are dedicated to the specific
task at hand while ducking the key issue: human consciousness, intelligence, is
domain general. An AI can play poker and, interestingly, the latest ones do so at
world-class levels. The program Pluribus, developed at Carnegie Mellon
University, consistently wins against up to five opponents, even when all are
professional poker players. But it cannot play chess. Humans can do both.
Epstein’s 2016 article was intriguingly titled ‘The empty brain’ and his main
point was straightforward: brains are not computers. The human brain does not
compute in any way that resembles what digital devices do. For one, it is not
digital. It is analogue in nature and will not be simulated on a digital device. In
addition, living agents are sensitive to the limitations and ambiguities inherent
within sources of available information (Miller, 2018). Further, as we will detail
in later chapters, a cell’s information is a product of its own internal analyses and
is inherently ambiguous and subjective while computer data are digital and
defined by precision. There is no internal self-awareness of the flow of
information within artificial entities.
Moreover, AIs are not embodied. Brains are based on cells, which
neuroscientist and Nobelist Ramón y Cajal discovered well over a century ago
(1894). They live in bodies and are ineluctably intertwined with their
biomolecular functions. Bodies also move, and encounter environments in flux.
Brains provide a central focus for our emotions, feelings, fears, loves,
attractions, repulsions, and, importantly, function in complex social contexts and
cultures. Brains also develop over time and change with experience and, of
course, they age. None of these experiences or processes are, or so we maintain,
possible on non-biological platforms as currently constituted. As Erik Larson
noted in his recent critique of contemporary views of AI, ‘all evidence suggests
that human and machine intelligence are radically different’ (Larson, 2021, p. 1).
We, of course, are extending Larson’s argument to all biological entities. The
sentient functions of individual cells, as will become apparent in the material we
present in the rest of the book, are ‘radically different’ from any algorithm-based
computational system that is instantiated on a digital device.
Although not typically raised in this context, the issue of free will9 also plays
a part in our thinking and, like the other perspectives put forward, argues against
the possibility of sentient entities that are not built on a biomolecular platform.
Our sense of how we live our lives invites the notion that we have free will since
we can, and do, make individual, contingent decisions that are exclusively our
own, as they are based on our obligatory self-generation of all available
information. However, all of biology is an exquisite balance of freedoms of
action and countervailing constraints that manifest themselves at all levels, from
protein configurations and thermodynamic constraints onward to the choices we
Homo sapiens routinely make. Through reiteration, we manifest all of this as our
own mixture of available free will and environmental constraint. Placing free
will into the narrower and more direct narrative of whether or not we are capable
of self-directed choices as opposed to living automatons endowed with an
illusion of self-determination, the answer in our approach is quite plain. Being is
doubt. We live within obligatory ambiguity. Robots do not.
In addition, as sociologist Harry Collins has argued in several places (see
Collins, 2018, 2022), a critical feature of AI research is that it is based on a
model that fails to appreciate that entities that have mental states, consciousness,
have had extensive interactions with others—they have been socialized. An AI,
no matter how sophisticated its computational power, would lack the ‘knowing’
interactions with others that would allow it to function effectively in the real
world. It would not be, as he put it, ‘capable of absorbing knowledge from [its]
social surroundings’. Collins, amusingly, titled his recent book Artifictional
Intelligence.
Recently, a novel approach to computationalism has been put forward by
Swedish mathematician and computer scientist Gordana Dodig-Crnkovic (2022).
Unlike the hardware-independent stance championed by Putnam, she argues, as
do we, that the basis for sentience is biological and sees naturally occurring
objects in terms of information. Essentially, her argument is that the platform for
sentience must be biological info-computational and viewed as self-referential
measurement of information. Her efforts are directed at unpacking the
computational details that cells carry out and identifying the biomolecular
mechanisms responsible. We discuss her analyses of these computational
elements in cellular sentience in more detail in Chapter 9.

Overview
So, to summarize our position, which will be the framework for the remainder of
this volume:
• Life and sentience are coterminous. Unicellular prokaryotes (archaea and bacteria), the original life
forms and their descendants, are sentient.
• All living organisms exist in bodies composed of cells. Their functions and behaviours are intimately
linked with those biomolecular, cellular mechanisms.
• These first unicellular species were spectacularly successful and provide the foundation upon which
all life forms, extant and extinct, evolved.
• A basic principle of biological evolution is that a trait, structure, or function that has significant
adaptive elements is virtually never abandoned or jettisoned but becomes the platform for further
evolution.
• In the absence of evidence that any species or clade ever lost its sentient, affective, and/or social
features, it is reasonable to conclude that cognitive functioning and sociality are essential features of
 all embodied life, including plants.
• The hardware-independent functionalist’s core claim is fatally flawed. An AI, even one able to carry
out the full panoply of cognitive functions of a species, would not have that species’ sentience,
internal perceptions, consciousness, or experience of embodiment. It would not feel. It would be as
dumb as a rock—acknowledging that rocks can play important roles but none of them involve
sentience.

When we begin the elaboration of the arguments we will be making in this book,
the core presumption will be that minds are caused by and only by the
biomolecular functions of living entities, ones based on sentient cells as the
quintessential foundation for all life. Lastly here, we note with amusement that
Putnam, who started this whole gallimaufry, later changed his mind arguing that,
in fact, hardware-independent functionalism was a dead-end and a sentient
computing device is not possible (Putnam, 1999).

3 Chatbots are applications that conduct online conversations through text or text-to-speech. They are
used widely to engage with customers and answer questions that they have about products or issues they
may have with a company and, of course, are used by marketers on what are generally known as
‘robocalls’. The open-source AI, ChatGPT, is uncanny in its ability to answer questions, generate novel
recipes based on a simple request, write essays, and, in ways troublesome to teachers, write term papers.
Like LaMDA, it does stumble over itself when the topic is one it has had little contact with and, of course, it
doesn’t really know anything. In Thomas Nagel’s way of viewing consciousness (Nagel, 1974), there is
nothing it is like to be ChatGPT.
4 British mathematician and computer scientist Alan Turing (1912–1954) was one of the founders of the
field of AI. He maintained that the true test of a sentient AI would be when a human was communicating
with both another human in one room and a computer in another and could not determine which one was
the other human. Many existing AIs can pass a limited version of the test, one where the domain of
questioning is restricted to specific topics. When there are no limits placed on the topics, the artificial entity
is easily identified.
5 For a sense of how LaMDA functions and how the database was created, go here:

https://blog.google/technology/ai/lamda/
6 https://en.wikipedia.org/wiki/Timeline_of_artificial_intelligence#CITEREFMcCorduck
7 The original paper (Searle, 1980) was published in Behavioral and Brains Sciences, an open-
commentary journal, and became the journal’s most influential article. Stevan Harnad, who was then the
editor, wrote an overview of the debate as it played out over many years with a variety of proffered
arguments both pro and con (Harnad, 2001).
8 Searle argued that these kinds of operations were examples of ‘weak AI’. In his framework, they were
based entirely on computations and could solve real-world problems but without emulating consciousness
—which he called the goal of ‘strong AI’. As he noted, one could program a computer with the code that
captured everything known about a swimming pool but no one would get wet. The ‘weak AI’ issue would
be resolved but the ‘strong’ one would still be untouched.
9 Our use of ‘free will’ differs from the way the term is typically used in philosophy, sociology, and
cognitive psychology. Our meaning designates processes in cells where decisions are made based on events
at the membrane and how they are interpreted in the cytoskeleton. We discuss these in later chapters. The
late, highly respected Harvard cognitive psychologist Dan Wegner argued in The Illusion of Conscious Will
(Wegner, 2002) that we don’t really have ‘free’ will. We have ‘constrained’ will. We chose from a limited
number of available actions and the limits on them are quite firm as they are the result of culture,
upbringing, socialization, the current circumstances, etc. We agree—noting that so do cells.
Contents

Abbreviations

1. The Cellular Basis of Consciousness (CBC)

2. It’s Cells All the Way Down
3. What Is Life? The Vitalism–Mechanism Debate and the Origins of
Life
4. Emergence and Evolution of Cells
5. The Structural and Bioelectrical Basis of Cells
6. The Biophysical Basis of Cellular Sentience
7. The Biological Information Cycle: The Terms of Consciousness
8. Genes Are Tools of Intelligent Cells: Biological and Evolutionary
Development in the 21st Century
9. The N-Space Episenome: Life as Information Management
10. Anaesthetics and Their Cellular Targets
11. Plant Sentience: Linking Cellular Consciousness to the Cognitive and
Behavioural Features of Plant Life
12. Issues of Ethics and Morality: Entailments of the CBC

Appendix I: An Exercise in Lexicography: Defining(?) Consciousness

Appendix II: Glossary of Technical Terms in the Biological Sciences
Bibliography
Index
Abbreviations

AI artificial intelligence
ADP adenosine diphosphate
ATP adenosine triphosphate
CBC Cellular Basis of Consciousness
DNA deoxyribonucleic acid
EI* effective information
FUCA first universal cellular ancestor
GABA gamma-aminobutyric acid
ITT integrated information theory
LaMDA Language Models for Dialog Applications
LECA last eukaryotic common ancestor
LUCA last universal common ancestor
PIF pervasive information field
RNA ribonucleic acid
ROS reactive oxygen species
TE transposable element
1
The Cellular Basis of Consciousness (CBC)

The CBC Theory

As noted in the Prologue, our message in this volume is built on a rather simple
but surprisingly fruitful assumption: all life is sentient. Life and consciousness
are coterminous. All organisms have functioning cognitive systems, from the
simplest unicellular prokaryotes and protists to us, Homo sapiens. The model
was dubbed the Cellular Basis of Consciousness (CBC). Details on how and
when the theory was developed are in Reber (2019). We will be using the
abbreviation ‘CBC’ throughout the book.
In a recent paper (Baluška et al., 2022b), we pointed out that in science the
optimal strategy is almost always to begin the explorations with simple systems
and only, over time, as understanding develops, move to more complex ones.
The so-called natural sciences (physics, chemistry, geology, astronomy) followed
this course. Unfortunately, biology and the life and social sciences did not—but
for perfectly understandable reasons. They began with the most complex of
systems, Homo sapiens, and only later looked at simpler, less complicated
domains, eventually reaching down to the prokaryotes and unicellular
eukaryotes.1 One of the themes of this volume will be to explore the problems
that this ordering of empirical and theoretical priorities created and examine how
taking our cellular-based model can resolve many of them.
Before embarking on the voyage, let us be clear about how we are using the
term ‘assumption’. It is not like ‘axiom’, where one uses logical deduction while
attempting to lay out the framework for a formal theory. Rather, we are using it
in a manner similar to how Darwin introduced the principle of natural selection,
Wegener began his explorations of continental drift, Metchnikoff developed his
model of cellular immunity,2 and Pasteur delved into germ theory and
vaccinations. In these, and many other scientific adventures, the theorist simply
assumes that some proposition is true and initiates the investigations using time-
honoured procedures such as examining the database, looking for converging
lines of evidence, digging into the kinds of entailments the assumption suggests,
running experiments, and engaging in discussions and, invariably, disputes with
others who may have a different perspective on the issues at hand. And that is
what the rest of this book will be about. We will look at the theory itself and,
importantly, outline its various entailments. As we will see, the assumption that
all life is sentient life and that the building blocks are individual conscious cells
has far-reaching implications.
It will also put biology and the life and social sciences on a novel footing
where the framework within which research is carried out necessarily changes
and the current format no longer applies. As we will argue in several places,
there are good reasons to suspect that the conceptual framework within which
the life sciences currently operate has reached a critical juncture. The
explanatory power of contemporary models and theories has reached its end-
point, or is very close to it. Novel approaches, new theoretical frameworks, are
needed and it is almost certainly the case that they are going to have to be
interdisciplinary. Israeli chemist Addy Pross maintains that a mature biology is
going to have to be integrated into a larger conceptual structure that incorporates
physical and organic chemistry. In his important 2016 book, he asks the question
that lies at the nexus of these disciplines: ‘When and how did chemistry produce
biology?’ What is needed is a new scientific agenda, one that focuses on getting
a deeper look at the events that took place at the birth of life in the prebiotic soup
—that point when physics and chemistry ‘produced’ biology, where inert, non-
living molecules combined and coordinated their actions and living, sentient
cells emerged.

The Standard Model in the Field of Consciousness Studies

We are under no illusions or delusions. We understand that the CBC model is an
outlier in the broad field of consciousness studies—and it is broad,
encompassing the biophysical sciences, cognitive psychology, cognitive
neurosciences, and philosophy, in particular the philosophy of mind. The
generally accepted stance, the Standard Model of Consciousness, is that
consciousness, sentience, is a property of biomolecularly complex eukaryotic
species—those that have evolved a nervous system. In this approach, the
presumption is that unicellular species are not sentient and that their complex
behaviours3 are the result of automatic, genetically encoded, biochemical
processes that spin themselves out devoid of feelings, of consciousness, or even
valenced perceptions or preferences. In philosopher Daniel Dennett’s trenchant
phrase, there is ‘competence without comprehension’. The classical argument is
that, at some point in evolution, a sufficiently complex species or clade emerged
that possessed self-referencing functions and was aware of itself and its
surrounds. Variations on this approach to the origins of conscious minds can be
found in one form or another in a variety of recent books and papers including
those by Colin Barron and Andrew Klein (2016), Antonio Damasio (2022),
Daniel Dennett (2017), Todd Feinberg and Jon Mallatt (2013), Simona Ginsburg
and Eva Jablonka (2019), Tam Hunt and Jonathan Schooler (2019), Tam Hunt,
Marissa Ericson, and Jonathan Schooler (2022), Joseph LeDoux (2019), and Ogi
Ogas and Sai Gaddam (2022).
All assume that a nervous system is a prerequisite for an existential
consciousness—although none present a coherent argument why this should be
the case. They all do, however, have extensive discussions of how having a
nervous system allows for a variety of new functions to emerge. LeDoux, in
particular, presents extensive analyses of the neurological mechanisms that
modulate and control cognitive functions in a variety of species, in particular
humans.4 It is, of course, true that once nervous systems and brains evolved they
were accompanied by dramatic changes in behaviours but, and this is important,
there have been a large number of functions that evolved and dramatically
altered life on the planet. Multicellularity, warm-blooded metabolism,
respiration, photosynthesis, a vertebra, and legs come to mind and there are
many others. But each built on earlier, existing biological platforms. We have yet
to encounter a solid argument that supports the proposition that consciousness is
dependent on an organism having a nervous system. A nervous system changed
how consciousness was instantiated but it did not create it.
Worse, as noted elsewhere (Reber, 2019), the current standard model is
saddled with an emergentist’s dilemma—a problem that, surprisingly, none of the
authors of the cited books seemed to recognize. If the claim is that a particular
species, in virtue of evolving some trait or feature like a nervous system,
suddenly became conscious while the ones from which it evolved were not, there
is an obligation to at least take a shot at speculating what biomechanism(s)
accompanied this novel transformation. We have yet to see any effort on the part
of those who argue that a nervous system is a necessary and sufficient feature for
a species to be conscious to explain how this miraculous shift took place. We
appreciate, of course, that we have our own ‘emergentist’s dilemma’—but it is
more tractable than the others. It is surely going to be a lot easier to identify the
mechanism(s) that make prokaryotes sentient than those that emerged in insects
(Barron & Klein, 2016), crustaceans (Birch et al., 2021), corvids (Nieder et al.,
2020), and cephalopods (Godfrey-Smith, 2016), or why an ‘unlimited
associative learning’ mechanism (Ginsburg & Jablonka, 2019), or a cluster of
modules based on neural nets (Ogas & Gaddam, 2022) should do the trick.
We’ve made some recent excursions into this domain (Baluška et al., 2021b,
2022b) and will dig deeper into the issue in later chapters. Spoiler alert: the
candidate mechanisms currently under consideration involve processes that take
place in the cell’s cytoplasm and the excitable cell membranes which, for those
who have not explored this domain of cell biology, are remarkably complex,
intricate structures with a truly stunning array of functions.
These other avenues became the industry standard for a rather simple reason.
When philosophers and scientists began explorations of consciousness, the focus
of their attention was us, Homo sapiens. We knew we were conscious. We
understood that it was a distinctly complex cluster of mental experiences,
functions, and processes. There was no need for speculation or existence proofs.
All we had to do was to stop and think and voila, there it was—consciousness,
self-hood, a mind, precisely as Descartes famously quipped. This initial focus on
human sentience had obvious consequences, among the most important was that
it laid out reasonable guidelines for how to approach the topic and identified the
protocols to employ. Begin by identifying behaviours that are diagnostic of
human consciousness and uncovering the underlying neural structures and
pathways that modulate and control them. Once there is a decent understanding
of both, examine the evolutionary tree for homologues and analogues of the
behaviours and underlying neurocognitive structures. As noted, this research
strategy has been employed for decades and has led to a crazy-quilt array of
conclusions about when in speciation consciousness first appeared. They all,
perhaps not surprisingly, contradict each other.
Human consciousness, the Homo sapient mind, has been viewed as the
pinnacle of cerebral functioning—and rightly so. No other species even gets
close to our capacity for creative thought, introspection, ruminative emotions,
self-reflection, language, art, and the scores of other sentient talents we have. In
more recent approaches, where the focus has been on the neurocognitive and
philosophical issues, the most asked questions have been ones like ‘How does
the brain make the mind?’ and ‘How can mere biomolecular “stuff” create
thoughts, feelings, ideas?’ This question has been immortalized by philosopher
David Chalmers who put it forward as the ‘Hard Problem’ of consciousness
(Chalmers, 1996). Chalmers, unhappily from our materialist, reductionist
perspective, decided there was no possible answer to be had in what we will call
‘ordinary’ biochemical frameworks. He retreated into dualism, assuming that the
mental was just made up of other kinds of stuff and should be dealt with
separately from effects caused by ordinary matter. We do not condone this move
but understand how taking a philosophical approach to the matter of
consciousness could lead there. In his latest work, Chalmers dives provocatively
into virtual reality—a topic far removed from our interests here but others are
welcome to pursue it. Whether you agree with him or not, Chalmers’ work is
uniformly creative and thoughtful.

Some Views Almost in Line With the CBC

There are others who have staked out positions with regard to unicellular life
that are closer to ours—some in the past such as William James, others more
recently. James, in his justifiably famous 1890 work Principles of Psychology,
opined that a conscious cell was the only position that was not self-contradictory
because what cells were able to do just seemed to reflect sentience. However,
after struggling with this proposition, he eventually abandoned it on the grounds
that if each cell were conscious, multicellular organisms, like us, would have a
mosaic of individual sensations and feelings—and that did not fit with our
introspections, our sense of self which was singular. We will deal later, in
Chapter 4, with this, the so-called binding problem. But, importantly, as British
researcher Jonathan Edwards noted, there is an even more basic problem within
the one James was concerned with. Edwards pointed out, correctly, that the
binding issue was present in the actions of individual cells. As he put it, ‘a bound
conscious experience is a property of an individual cell, not a group of cells.
Since it is unlikely that one specific neurone is conscious, it is suggested that
every neurone has a version of our consciousness, or at least some form of
sentience’ (Edwards, 2005). We read that statement as a willingness to go along
with the basic premise of the CBC.
There are coherent models that provide tantalizing insights into how
multicellularity evolved and how eukaryotic species maintain a singular
sentience, a coherent identity, and do not experience a medley of conflicting
internal representations. We have touched on this issue elsewhere (Reber, 2019;
Miller et al., 2020b; Baluška et al., 2021b) and will address it in more detail in
Chapter 4. To anticipate the discussion, recognize that each cell in a multicellular
organism still has its own experiences and sentience but it is its sentience. It is
not shared with other cells. Rather, each cell responds appropriately to events
and communicates with other cells. It is the assembly of all the cells involved in
the circumstances that is captured and represented as the experience of the
individual. James’s concerns about a jumble of experiences contributed by each
cell is not a real problem.
 In his 2009 book Wetware: A Computer in Every Cell, British biologist Dennis
Bray toyed with the notion that individual unicellular species such as amoebas
display behaviours and processes that appear to be reflective of internal, felt
states such as a sense of nutrient deficit (hunger), a need to explore the
environment (curiosity), and a motivated reduction in metabolic functioning
(fatigue). He also emphasized the extreme complexity of individual cells and
living unicellular organisms. But he demurred on the key issue of cellular
sentience: ‘single cells are not sentient or in the same way that we are’. The
‘same way’ hedge is, of course, where the problem lies. In the CBC model,
sentience is viewed as a continuum so, yes, there will be countless shifts in the
‘ways’ in which each species experiences their individual conscious states. But
we view them, as noted, not as individual ‘types’ but as ‘tokens’ of an underlying
type. The issue may have more to do with terminology than with science. It does
not feel like a stretch to read Bray as supportive of the core assumption of the
CBC.5
We’ve seen this kind of lexicographical confusion in other contexts.
Neuroscientist Antonio Damasio recently acknowledged that the descriptions of
prokaryote behaviour outlined in Reber (2019) and the follow-up discussions of
even more sophisticated functions (Reber & Baluška, 2021) are suggestive of
sentience (Damasio, 2022). But he criticized the use of the term ‘consciousness’
for them—which makes the different perspectives here feel more like an issue of
terminology and not one where there are disputes over basic biomolecular
processes. The term ‘consciousness’, is, in the general literature in the cognitive
neurosciences and philosophy of mind, so tightly linked with human mental
states that it is difficult to pry it away from being semantically tied to Homo
sapient cognition. This lexicographic tie is unhelpful as it tends to make
researchers and philosophers sceptical of the CBC. They acknowledge the data
for prokaryote cognition but do not want to call it ‘cognition’. They agree with
the remarkable functions of bacteria that are strongly suggestive of sentience but
do not want to say they have an existential ‘consciousness’. They appreciate the
evolutionary biological arguments of the CBC but shy away from concluding
that all life is sentient life. It makes our goal of changing the framework within
which the field of consciousness science operates a lot harder to do. These
lexicographic confounds are reviewed in Appendix I.
A recent stance is that taken by South Asian researchers Contzen Pereira and
J. Shashi Kiran Reddy who have argued that indeed, all life forms are sentient,
including unicellular species. They identify quantum mechanical processes as
responsible and argue that the operations in the cytoskeleton that cause sentience
are based on what they call ‘quantum consciousness’. Their approach is
reflective of the position of British mathematician Roger Penrose and American
anaesthesiologist Stuart Hameroff who have put forward a theory based on
quantum mechanics and space-time geometry—one that identifies biophysical
functions within the microtubules of individual cells as the processes that create
consciousness (see Hameroff & Penrose, 2014, for an overview). Pereira and
Reddy’s work has a distinctly mysterian element to it as they link conscious cells
with the existence of a soul, the utilization of ‘cosmic’ energy, and integrate their
position into a fully panpsychic framework. For details see Pereira (2015),
Reddy and Pereira (2016), and Reddy (2017).
Lynn Margulis famously penned a paper in 2001 titled ‘The conscious cell’ in
which she made the case that the unicellular organisms that combined, via
symbiogenesis, to produce the first eukaryotic species were already conscious
entities. In this paper she also noted that ‘Nothing … has ever been lost without
a trace in evolution’. Indeed. As noted earlier, this is a fundamental principle of
evolution and we will discuss it in more detail as it forms one of the keys that
gives the CBC theory much of its considerable explanatory power.
Vic Norris, at the University de Rouen (France), specifically used the term
‘qualia’ to refer to the subjective experiences that he assumes are a fundamental
aspect of prokaryote life (Norris, 2021). As the term ‘qualia’ is typically used in
the philosophy of mind to refer to the basic sensations of human mental life,
Norris’s position reflects the key principle that there is continuity in mental life.
Like Margulis, he notes that nothing of significance to life is lost in evolution.
A few years back, Pamela Lyon, an American–Australian natural philosopher,
reviewed the evidence for sentience in prokaryotes. Amusingly, she self-
consciously (personal communication) ‘cribbed’ the title of the paper from
Margulis. Instead of the ‘conscious’ cell, she called it the ‘cognitive’ cell (Lyon,
2015). The paper is a thorough review of the research on how bacteria adapt to
the constantly shifting environments they evolved in and still inhabit. She
concluded that bacteria have what she called a large and effective ‘cognitive
toolkit’ that enables them to navigate their complex, ever-changing world. She
also noted, importantly in our view, two disconnects between cell biologists and
cognitive neuroscientists. One is a lack of appreciation of the range of functions
in unicellular species on the part of cognitive neuroscientists who, because they
focus on species with nervous systems, often fail to appreciate how sophisticated
the life of prokaryotes is and tend to downplay the richness and complexity of
unicellular cognitive processes. The other is a tendency to ignore evolutionary
biology and, as a result, miss the point that these sentient functions form the
foundation for the cognitive processes of more complex species.
We agree. We have had experiences that reflect these disconnects. We have all
made formal presentations to groups of cognitive scientists and neuroscientists.
We invariably encounter resistance to the CBC model, to our use of basic
principles of evolutionary biology as a general framework, and to the empirical
evidence itself. Despite the large and growing database that supports prokaryote
sentience and despite the continuity of form and function that underlies
evolution, the evidence is either doubted or interpreted as mere automatic
behaviours that occur without underlying conscious experience or feeling. One
of us has also presented the CBC model to philosophers. It was not pretty. There
was uniform derision and outright hostility to the very notion that a cell could
have qualia, experiences, preferences, and valenced perceptions.6
Brian Tomasik, currently associated with the Center on Long-Term Risk
(London, UK), compiled an overview of the various suggestions in the literature
that point to unicellular consciousness. The list of individual researchers and
philosophers who have either made clear that the evidence for cognition in
unicellular organisms is convincing or that they are open to being persuaded is
long and contains many highly respected scholars. See Tomasik (2017) for the
link to his webpage.
American biochemist J. A. Shapiro published a remarkable little paper where
he noted that he now understands enough about the evolutionary capabilities of
bacteria to conclude that we are required to ‘recognize that even the smallest
cells are sentient beings’ (Shapiro, 2007). More recently, in a paper titled ‘All
living cells are cognitive’, he re-emphasized this perspective, noting ‘Without
that cognitive capacity, they could not obtain nutrition essential for growth,
survive inevitable ecological changes, or correct accidents in the complex
processes of reproduction’ (Shapiro, 2021).
English–Spanish philosopher Rupert Glasgow put forward the notion of
‘minimal selfhood’ based on an intrinsic reflexivity that operates independently
of a nervous system and which he regards as the roots of consciousness. In his
2018 book he argues that it ‘makes sense’ to grant an elementary consciousness
to single-celled organisms such as amoebae and dinoflagellates and ‘some
simpler animals’. We note that the two species identified are eukaryotes and he
was unclear about whether those ‘simpler animals’ included prokaryotes.
Biologist Michael Levin, who directs the Allen Discover Center at Tufts
University (Medford, Massachusetts, USA), is clearly in line with our CBC. In a
recent paper, he focused on the ways of evaluating sentience in beings of
‘unfamiliar provenance and composition’. He specifically referred to the field of
‘minimal cognition’, where the emphasis is on the primitive versions of
cognition in species like prokaryotes, protists, and plants (Levin, 2022).
There are others who take a similar stance but, as Lyon noted, they often
acknowledge that, while unicellular species are capable of highly competent
actions, they are not necessarily accompanied by internal valenced states, states
with preferences. As noted at the outset of this section, the CBC is not the
Standard Model of Consciousness, even among those whose research is easily
interpreted as evidence of sentience.

The Evolutionary Principle of Stability: Keep What Works

As noted above and in the Prologue, there is an important general principle in
evolutionary biology which shores up our core assumption and forms the
foundation for our view of cognitive functions across the evolutionary tree:
Traits, forms, and functions that evolve and have adaptive value, Darwinian fitness, are virtually never
entirely lost.7 Rather, they become the basis for other traits, forms, and functions to evolve from them
in what’s best thought of as evolutionary creativity. (Jacob, 1977; Miller, 2016a)

As this process accelerates over geological time, the foundational forms become
ever more firmly set in the functions and processes of every species. In short,
consciousness, sentience, is not only an inherent feature of every species, it is as
deeply encoded in the species’ genetic make-up as the biomolecular processes
that breathed life into it.
An intriguing aspect of this principle is that plants should be sentient. The
flora of the planet all evolved from an endosymbiotic event involving unicellular
organisms. In an earlier work, one of us contemplated this possibility (Reber,
2019) but, after a quick overview of the issue, remained agnostic. In the years
since and after a more careful examination of the empirical and theoretic
literature, the proper outcome was reached and, like any good scientist, a mind
was changed. We will present a thorough overview of the issue of plant
sentience in Chapter 11 and conclude that, however unlikely it may appear to
those who have not seen the evidence, plants are, indeed, sentient. We will also
discuss, as dispassionately as possible, the various ethical concerns that such a
conclusion raises in Chapter 12.
An effective heuristic is to think of evolution as forming a metaphoric
pyramid where the early-appearing traits are integral parts of the base and later
emerging ones build on them. The ones that make up the base tend to be stable;
their biochemical and genetic functions support those that evolved later.
Continuity is the theme as the newer characteristics emerge, not de novo, but
formed using those traits and characteristics from the ‘layers’ that evolved
earlier. The later-emerging traits typically show greater variability and larger
differences among individuals, species, and clades.8 The obvious implications
are straightforward: (a) sentience, consciousness, should be viewed as a
continuum, where each emerging variation creates a new variation on mental
expression that, (b) is one that has its evolutionary foundations, its roots, in the
functions and forms expressed in the species that preceded it. As noted, human
consciousness thus becomes a token of a singular type—as are bonobo
consciousness, raven awareness, jellyfish sentience, Venus flytrap sensitivity,
and pine tree cognition. This principle is going to play a large role in the
exegesis and, as we will see, differentiates the CBC from virtually all the other
models of origins of consciousness that have been introduced in recent decades.
See Reber and Baluška (2022) for a discussion of how approaches that focus on
the discontinuities over the various species, clades, and families differ from the
CBC and what the consequences of these two strategies are in terms of overall
framing.

Wherever You Look

But, back to the various approaches to the emergence of minds. Because most
contemporary theorists begin with human consciousness, there are, as we noted
above, but two ways to establish a research programme. In one, you begin
working to identify the underlying neural mechanisms that modulate and control
the various ways in which consciousness is instantiated in Homo sapiens. Once
you have a reasonable sense of what structures, pathways, and centres are
responsible, you begin a backward search through the evolutionary tree looking
for the most ancient species that have those neural systems, or homologues of
them—the ones that could have functioned as the platform for future evolution.
In the other approach, a similar analysis is carried out but with the focus on the
cognitive processes and behaviours that can be argued are analogues of human
sentient functions. Some of these research programmes are aimed at trying to
identify the species or clades in which consciousness first evolved. Others focus
on specific species or phyla in order to ascertain whether they display an
existential consciousness—in these, the question of whether these species were
the first genuinely conscious ones is typically not broached.
Elsewhere, we reviewed the results of these parallel programmes (Reber,
2019; Baluška & Reber, 2020). The findings have been very impressive. Scores
of researchers in biology, zoology, neuroscience, psychology, anthropology, and
sociology have produced a rich and compelling picture of the remarkable
behaviours of a vast array of species and have uncovered an impressive range of
neurological structures and functions that modulate and control them. We are
strongly supportive of this research and herald the findings. But the goal, that
such systematic investigation can lead to identifying conclusively the species or
clade in which consciousness first emerged, has been elusive. In fact, what it has
produced is a rather amusing outcome simply because the researchers and
laboratories that have pursued these two methodological avenues have tended to
focus on particular species. Entomologists work with insects. Avian experts with
birds, in particular corvids and parrots. Marine biologists have studied a host of
species including, importantly, cephalopods. Primatologists have explored the
behaviours and brains of various species of monkeys and apes. What they have
concluded is that the existence and/or origins of consciousness are in the species
they study. From the CBC perspective, this outcome was inevitable because
consciousness was always there—all that was needed was a close look.
A classic example is the paper by Nieder and colleagues (2020) who found
that corvids (passerine birds like crows and ravens), despite lacking a layered
cerebral cortex, behave in a visual detection task in a manner that ‘is an
empirical marker of avian consciousness’. Moreover, they noted that the birds’
neuronal responses displayed a two-stage process that they maintained is
diagnostic of cognitive processing. Their conclusion was that a ‘sensory
consciousness’ arose independently of mammals. Nieder et al.’s findings are
coordinate with the research of many others on corvids. Weir et al. (2002)
reported tool-making in New Caledonian crows. Kabadayi and Osvath (2017)
showed that ravens plan for the future and display impressive self-control.
Müller et al. (2017) reported that ravens not only can recognize individual
human faces, they can hold a grudge. Their study involved a ‘bartering game’
where a raven’s unpalatable bread could be traded for highly preferred cheese.
One experimenter cheated—took the bread but ate the cheese. Afterwards the
raven would not play the game with that experimenter and refused to do so a
month later. Another raven, who merely watched the episode, also refused to
play the game with the ‘cheating’ human.
Nieder et al.’s (2020) report is a classic example of how these two lines of
research are being carried out and how they fit into the overall research strategy
that has dominated the field. It was published in the prestigious interdisciplinary
journal Science and the editors considered it sufficiently important to have a
separate ‘blurb’ on it which had this passage:
Humans have tended to believe that we are the only species to possess certain traits, or abilities,
especially with regard to cognition. Occasionally, we extend such traits to primates or other mammals
—species with which we share fundamental brain similarities. Over time, more and more of these
supposed pillars of human exceptionalism have fallen.
We have no issue with the last sentence. We simply repeat our core argument:
any attempt to exclude consciousness from any living organism, including cells,
will eventually fail.
Jonathan Birch and colleagues (2020) presented an overview of these research
programmes with multiple species in an effort to answer the question ‘How does
consciousness vary across the animal kingdom?’ They provided five ‘key’
dimensions of consciousness9 that they argue are diagnostic: (a) perceptual
richness, (b) evaluative richness, (c) integration at a time, (d) integration across
time, and (e) self-consciousness. It is fairly obvious that they are introducing a
rather subjective notion of ‘richness’ that we, frankly, have no idea how to
ascertain or measure but it is clear that they are following the standard game
plan. These are all features routinely associated with human consciousness and
the scan of the evolutionary tree they provide is based on empirical evidence for
each aspect of mental life using both behavioural and neurological data. But,
critically, they only examined the evidence for sentience in birds, fish,
cephalopods, and mammals. They find support for each of their dimensions and,
not surprisingly, with varying degrees based on a host of factors. In their words:
Our five dimensions of animal consciousness vary across and within species. Instead of thinking about
variation between species in terms of levels of consciousness, we should think about multidimensional
consciousness profiles.

Hunter (2021) is in agreement with this approach and, like Birch and colleagues,
maintains that ‘the emergence of consciousness’ is slowly coming to be
understood as ‘research on animals yields insights into how, when, why
consciousness evolved’.
Overgaard (2021) undertook a similar effort to establish conditions under
which one could conclude that species other than humans could be considered to
possess consciousness. His primary focus was insects arguing that, because their
nervous systems were so different from mammals, identifying consciousness in
these species would be particularly important. We will not go through the
struggles he encountered trying to make sense of the literature on the origins of
minds but we would like to quote from the paper’s final paragraph and note how
his approach reflects the problems that accompany research carried out using the
standard model. When you start with humans and work your way through the
tree of evolution you are invariably going to end up here:
In conclusion, we have no direct evidence of consciousness in insects. Furthermore, for principle
reasons, we will never be able to obtain direct measures of the presence or absence of insect
consciousness. … It appears that the center of the battleground is whether specific neural substrates—
 observed in humans—are considered necessary for consciousness. If the answer to this question is
positive, insect consciousness seems unlikely.

There are others who have been a bit bolder. Barron and Klein (2016) focused
their explorations on insects, examining both behavioural and neurological
evidence. They concluded, unlike Overgaard, that there is unambiguous
evidence that insects have subjective experiences, what they dubbed an
‘egocentric representation’ of the environment. They also argued that integrated
structures in the insect midbrain are ‘sufficient to support the capacity for
subjective experience’. They noted that neurological analyses identify the critical
role of the midbrain in humans by integrating experiences of bodily
representation with movement through the environment (Merker, 2005, 2007)—
and that analogous structures in insect midbrain modulate similar functions.
Not surprisingly, there was immediate pushback. Brian Key and colleagues
challenged Barron and Klein’s neuroanatomical analysis claiming that their
characterization of the insect brain was flawed (Key et al., 2016).10 Adamo
(2016) argued that Barron and Klein’s analysis was not really focused on
consciousness because they defined it so narrowly that the evidence they
presented would also apply to robots. Adamo’s conclusion was that their work
was interesting but did not provide any insight into the origins of minds. But,
despite Barron and Klein’s efforts to find evidence for sentience in insects, they
had no intentions of pushing the envelope towards the position of our CBC
model. As they put it, ‘consciousness also gives out somewhere. Plants do not
have it. It would be surprising if jellyfish did.’ We suspect they are not in support
of our cellular-based approach.
Barron and Klein’s analysis also led them to conclude that consciousness first
emerged during the Cambrian ‘explosion’, a period of extensive speciation.
Others, such as Ginsburg and Jablonka (2019), agree on the time frame but for
different reasons. Rather than focusing on neurological and behavioural data,
they argued that the full expression of consciousness required the evolution of an
‘unlimited associative learning’ process, one that was capable of forming
associative links between arbitrary stimuli and events and not tied to specific
aspects of the environment. In their view, earlier forms of learning such as those
observed in species that lack a nervous system are not diagnostic of
consciousness. They refer to these earlier epistemological systems as being
‘nutritive/reproductive’ and assume they operate without awareness, subjectivity,
or preferences.
Chittka and Wilson (2019) reviewed the literature on bees covering a rather
impressive array of cognitive skills including showing foresight in honeycomb
construction, the ability to learn to transport objects like small balls, and,
fascinatingly, solving the ball-moving task after merely watching other bees
perform it. This latter finding is particularly intriguing as the bees distinguish
ball-moving by other bees from instances where no bee is present. If the bees
watch the ball-moving when it was carried out by using magnets under the
apparatus, the bees did not try to move it. Chittka and Wilson also reported on
studies showing that bees can form visual images and anticipate upcoming
events. They conclude that ‘some insects qualify as conscious agents, with no
less certainty than dogs or cats’.
Howard et al. (2022) reported that bees can learn parity, to distinguish
between displays with an odd number of objects from those with an even
number. The displays were composed of four geometric shapes and were
arranged in a random fashion so that the only reliable cue was numerical parity.
In addition to learning the odd versus even task, they generalized it. The original
training used from one to ten objects. When tested with displays of 11 and 12
objects, the bees made appropriate categorization responses. Howard et al. do
not directly confront the question of bee consciousness but they noted that their
study is the first to show parity in any non-human species.
Another phylum that has attracted interest is the cephalopods, in particular
octopuses and occasionally cuttlefish. Australian philosopher of science Peter
Godfrey-Smith’s 2016 book provides a thorough and fascinating overview of the
cognitive functions of cephalopods, concluding that not only are they sentient
but it is likely that this phylum is where consciousness first emerged. Recently,
Ponte et al. (2022) reviewed the large literature on the issue of consciousness in
invertebrates and, like Godfrey-Smith, concluded that cephalopods, in particular
the common Octopus vulgaris, are sentient. Ponte et al. used English biologist
Donald Broom’s (2014) five ‘essential features’ of consciousness: (a) evaluation
of the actions of others, (b) a memory of one’s own actions and their
consequences, (c) being able to assess risks and benefits, (d) some degree of
awareness, and (e) experiencing affective states. Note that these features have
some overlap with those identified by Birch and colleagues (above). However,
unlike Birch, in Broom’s view any species that displayed at least one feature
should be considered sentient. In Chapter 2, where we examine the behavioural
repertoire of the prokaryotes, it will become clear that these ur-life forms,
archaea and bacteria, display all of Birch’s and Broom’s criteria for having a
mind.
One more example of how this research strategy plays itself out is the recent
work with crustaceans, much of it carried out by philosopher Jonathan Birch of
the London School of Economics (London, UK) and collaborators (Birch et al.,
2021; Crump et al., 2022). In Birch et al. (2021) they extended earlier analyses
(discussed above) and developed a list of eight criteria that they felt captured
what defined sentience, with a specific focus on the capacity to feel pain and
stress. They reviewed over 300 published papers on the issue and concluded that
crustaceans are sentient, feel pain, and show negative reactions to stress.
Interestingly, the final report convinced the government in the UK to declare
decapod crustaceans (shrimp, lobsters, crayfish, and hermit crabs) and
cephalopod molluscs (squid, octopuses, and cuttlefish) as sentient species and to
include them in the national Animal Welfare (Sentience) Bill. These species are
now covered by the various regulations in the UK that are designed to minimize
pain and suffering and promote animal welfare in commerce. The report did not
come to any determinations with regard to the origins of sentience, only that
crustaceans are.
Some 50 years ago, philosopher Thomas Nagel penned one of the most cited
works in the philosophy of mind: ‘What is it like to be a bat?’ (Nagel, 1974). The
paper was a critique of mechanism and reductionism and his answer was that we
will never know—and one of the reasons was because of what is known as the
‘first-person’ problem, that the only mental states we can be certain of are our
own. Conclusions about sentience or consciousness in others, independent of the
species, is just speculation and fatally, in his assessment, cannot be either
demonstrated or falsified. But independent of Nagel’s larger concerns (which
show up in a variety of his works), the ‘what is it like’ question continues to be
routinely asked when other species are the topic. The standard parsing of it is
that one can conclude that a species has an existential consciousness when there
is compelling evidence that there is something it is like to be a member of that
species. The conclusion that each of the various research programmes we have
discussed here is, ‘Yes, there is something it is like to be a bee, a crab, octopus,
or raven.’ In Chapter 2, we will present the evidence that points to the conclusion
that ‘There is something it is like to be a bacterium.’
Interestingly, despite these converging lines of evidence and argument, there
remains a stubborn lack of agreement in the broader field of consciousness
studies. An interesting example is the position of British psychologist Euan
Macphail who is of the opinion that consciousness requires the capacity to
develop relationships of ‘aboutness’ or ‘intentionality’. German philosopher
Franz Brentano11 introduced this concept to refer to the ability to mentally
represent objects, events, properties, and states of being in the environment, to
have mental states that are ‘about’ that which is external to the person. In
Macphail’s view, an existential consciousness is built around aboutness and
requires language. Only humans with language have genuine conscious states.
Children are not fully conscious until they have acquired language,
intentionality, and can differentiate self from non-self (Macphail, 1998). Our
stance, as we will see in Chapter 2, is that the unicellular species express
compelling evidence of intentionality.
Finally here, if any readers are interested in exploring these issues further, we
recommend the relatively non-technical work that is routinely published in the
online journal Animal Sentience edited by Université du Québec à Montreal
psychologist, Stevan Harnad. The journal operates on an open peer commentary
model. Articles are peer reviewed and, after being published, other scholars and
researchers are welcome to submit commentaries, which are themselves peer
reviewed. This strict vetting process gives readers assurance that the work is
solid and the evidence is compelling.12 The original authors typically reply to the
various comments. Many of the issues raised in this chapter are discussed there
and the exchanges can be lively. Interestingly, authors of the original target
article will often identify individuals they would like to receive comments from.
The Crump et al. (2022) paper cited above on the criteria for determining which
species are sentient was published in Animal Sentience and the authors
specifically asked one of us to respond. We did so in a collaborative commentary
(Reber et al., 2022).

1 There are good reasons for treating the earliest appearing eukaryotes as multicellular although the
outward appearance of many species such as amoebas invited the initial assessment that they were
unicellular. This issue is discussed in Chapter 4 where we explore the evolution of eukaryotic life.
2
Russian–French biologist Ilya Metchnikoff’s (1845–1916) work on phagocytosis led to the modern
science of immunology. In 1908 he was awarded the Nobel Prize in Physiology or Medicine for it. We will
discuss the pivotal role of immunological competence and its relationship to consciousness in later chapters.
It is important in appreciating the subtle but critical ways in which self-referential cells handle information
and make decisions.
3 Which, as outlined in Chapter 2, include a variety of cognitive processes and functions such as
valenced perception, feeling, developing preferences, associative learning, pattern learning, forming stable
memories, decision-making, directed locomotion, social interaction, and meaningful communication. The
range of behaviours that prokaryotes routinely carry out is remarkable and far more sophisticated than is
generally recognized. The biomolecular structures and processes of these unicellular species are also far
more complex and rich than most appreciate. These will be examined later, in Chapters 4, 5, and 6.
4 LeDoux’s book was the subject of a special issue of Philosophical Psychology to which two of us

contributed a commentary (Reber & Baluška, 2022). Not surprisingly, we focused on the CBC and how, in
our opinion, LeDoux’s arguments would actually be strengthened by recognizing that all cells are sentient.
5 He has confirmed this shift in his thinking (personal communication).
6 Also, adding a balancing note here, in other talks we have given to groups of laypersons without
backgrounds in biology or philosophy (Humanities Department Colloquia, Elder Colleges, Fulbright
Programs) the most frequent response was a nod, a tilt of the head, and a version of ‘Hmm, I hadn’t thought
of that. But it does make sense.’
7 In the rare cases where a trait is jettisoned, it is because the loss was adaptive. As Nishimura et al.

(2022) recently showed, shedding the vocal fold membranes present in all non-human primates simplified
the anatomy of the vocal system and, critically, reduced the chaotic irregularities typical in the sounds
produced by other primates. The simplified vocal apparatus allowed humans to produce the full
phonological spectrum that led to the evolution of language.
8 This pyramidal model has a formal structure which we do not need to go into here but, for the curious,

it is described in Shank and Wimsatt (1988) and Reber (1993).

9 More recently, Birch and his colleagues expanded on their criteria and focused their explorations of

animal consciousness to crustaceans. This work is discussed below.

10 Key has been a central figure in the ongoing debate over whether fish feel pain. We will take a longer

look at this issue in Chapter 12.

11 Brentano (1838–1917) viewed intentionality as the factor that distinguished human minds from all
other objects. Only humans, in his view, could form such mental representations. He was a fascinating and
influential thinker with deep concerns over moral and ethical issues. Ordained a priest, he ‘defrocked’
himself twice. Once over his profound disagreement with the Church over the issue of papal infallibility and
again when he married. At the time, the Austro-Hungarian empire did not permit married priests to hold
university professorships even if they had resigned their ordination. He was allowed to continue at the
University of Würzburg, Germany, but only as a docent and not a professor.
12 We approve of Harnad’s peer-review procedures as they conform with most responsible scientific

outlets. Unfortunately, in recent years the sciences have been flooded with ‘junk’ journals and ‘predatory’
ones. The ‘junk’ journals do not send the submissions out for review by experts but generally publish any
paper sent in. The ‘predatory’ ones follow the same unscholarly protocols but charge outrageous fees, often
several thousands of dollars (US). If a reader stumbles across an article from one of these, it is difficult to
impossible to know whether the work is serious, the data real, and the findings replicable—particularly
because the publishers typically give the journal prestigious-sounding names that make the reader think
they are respected in the field. All three of us are routinely sent ‘invitations’ to publish our work in them.
Our ‘delete’ buttons are all getting work-outs.
2
It’s Cells All the Way Down

Introduction
The title of this chapter is stolen from an old joke that (old) philosophers like to
tell—and one of us almost qualifies. It goes like this:
A young man, searching for the answer to a question that has bothered him for a long time, climbs high
into the Andes to probe the mind of an ancient shaman, known for his knowledge of all things.
‘What, Sire’ he asks the wizened one, ‘keeps the Earth stable, fixed in the heavens? Why does it not
fly wildly about in the cosmos or fall into a black nothingness?’
‘Ah grasshopper’, the shaman says, nodding sagely. ‘It is because it rests upon the back of a great
turtle.’
‘Interesting. Thank you Sire. I will contemplate …’ says the young man. He walks away, but only a
few steps. He turns and says, ‘I’m sorry Master, there still appears to be a problem. What keeps the
turtle from simply falling into the abyss?’
‘Because, my child, it sits upon the back of an even greater turtle.’
‘But …’ and that’s all he gets out.
The shaman narrows his eyes and says, ‘Look, young whippersnapper, it’s turtles all the way down.’

And so it is—but with cells. All life is built on, by, and with cells. As we argued
in Chapter 1, those cells are all sentient entities with experiences, internal
representational states, valenced perceptions, and feelings. The rest of this
chapter is devoted to an exploration of the literature that supports this, the core
message of the CBC: life and sentience are coterminous.

The Time Frame

Before exploring the evidence for the CBC, it will help to have a temporal
framework for when life first appeared and evolved. The estimates vary but most
peg the appearance of the last universal common ancestor (LUCA) at between
3.9 and 3.5 billion years ago (Betts et al., 2018)—although Papineau et al.
(2022) recently presented evidence suggesting that the first cells may have
appeared 4.28 billion years ago. Pushing back the timeline nearly a billion years
is a significant claim. We await follow-up research. Part of the difficulty in
establishing a clear timeline is that single, non-colonial cells do not leave
microfossils. The evidence comes from microbial mats that had grown large
enough to leave their mark in the fossil record. The very first prokaryotes were
social and readily formed colonies so the evidence from the microbial mats is
likely to be proximate to the first cells. This colonial feature of early prokaryotic
life is important and we will look at it more closely in Chapter 3.
While there are various estimates on when the Earth’s environment had
settled, water had accumulated, and it had reached a biofriendly state, the most
common assumption is that this occurred some 4.3 billion years ago. It took,
based on the dating of the LUCA, somewhere between 1 billion and 100 million
years to solve that first puzzle, bringing together the materials needed for, as
biochemist Addy Pross put it, ‘chemistry to produce biology’. For the next
roughly 1.5 billion years all life on Earth was unicellular. The only living forms
were the domains of bacteria and archaea—living along with viruses. The
question of whether viruses are truly alive is a complex one. We have discussed
this issue elsewhere (Miller et al., 2023) and touch on it in Chapter 3. The first
eukaryote appeared some 2 billion years ago. In short, solving the
multicellularity problem took a lot longer than the initial problem of cobbling
together the materials for the appearance of unicellular life. The first eukaryote
cell was the result of a larger prokaryote absorbing and incorporating a smaller
one, a process known as endosymbiosis. There are more than a few theories
about the details of this event, though recent genetic analyses suggest that at
least one of the two cells was archaea (Mattiroli et al., 2017).

Various Proposed Criteria for Consciousness

As we noted in Chapter 1, several researchers have put together what they
maintain are the behaviours or functions that are diagnostic of consciousness.
Here are three examples:
Broom (2014):
• evaluation of the actions of others
• a memory of one’s own actions and their consequences
• being able to assess risks and benefits
• some degree of awareness
• experiencing affective states.
Klein and Barron (2016):
• integration of information from sensory inputs
• access to memories
• interoception
• monitoring feedback.
Birch et al. (2020):
• perceptual experiences
• evaluative experiences
• integration of information at a point in time
• integration of information across time
• self-consciousness.

There is considerable overlap, which is appropriate since, in principle, they are

all focused on the same topic. There is also the inescapable feature that these
criteria were developed by researchers who began with human mental life and
then worked back through simpler species trying to determine which were
sentient. Klein and Barron were, as noted earlier, specifically looking for
evidence of consciousness in insects. Both Broom and Birch and colleagues
were examining the evidence for sentience in other species with a focus on the
issue of animal welfare. But, despite these differences in approach and
motivation, the one thing that is fascinating is that all of these behaviours
considered to be clear markers of an existential consciousness are, in fact, found
in unicellular bacteria, archaea, and eukaryotes.1 The rest of this chapter is
devoted to a review of the relevant literature.2
As Pamela Lyon noted, cognitive scientists and neuroscientists have largely
ignored the work on prokaryotes and unicellular eukaryotes and are generally
unaware of just how sophisticated their behaviours are (see her overview of
prokaryotic function; Lyon, 2015). The result, as noted in Chapter 1, is a field
dominated by a standard operating position—one that assumes that whatever it is
that these ‘simple’ species do is the result of insentient genetic programmes that
operate without feelings or internal, experiential states. This stance has led the
field of consciousness studies to its current muddled state. In this chapter we
review the literature on the ‘conscious cell’ (Margulis, 2001) and the ‘cognitive
cell’ (Lyon, 2015) that lies at the heart of the CBC. As we will see, prokaryotes
and unicellular eukaryotes are rather remarkable organisms with a wide array of
behaviours, all of which are clear manifestations of sentience. They:
• have elaborate sensory systems
• have valenced perceptions
• learn a variety of tasks
• form stable memories
• anticipate upcoming events
• make decisions
• process information and form preferences
• display motivated locomotion
 • have temporal awareness, bio-clocks
• communicate within and between species
• cooperate with each other
• compete with each other
• are capable of computation
• trade resources
• exhibit sociality.

Not quite the sorts of things one expects to see in insentient species.

Unicellular Sensory and Perceptual Systems

The cell membranes of bacteria and archaea are covered with literally thousands
of chemoreceptors. It has been known for decades that prokaryotes are sensitive
to a rich array of events in the environment including temperature gradients,
light levels, electromagnetic stimuli, the passage of time, the identity of specific
nutrients, pH levels, the concentration of solutions (osmolarity), other bacteria
(using quorum sensing to form colonies), the presence of amino acids, waste
products from other organisms, and toxic objects in the environment.
Critically, these sensory functions are valenced. The positive and negative
elements are experienced and evaluated which is why we used both ‘sensory’
and ‘perceptual’ in the heading for this section. The former is generally used to
refer to the detection of stimuli and events, the latter for forming interpretations
of that which was sensed. Hearing a series of notes played on a violin is
‘sensing’. Recognizing that they are a pleasing, familiar melody is ‘perceiving’.
Since prokaryotes routinely make decisions based on the positive and negative
aspects of objects and events, it is clear that they have well-developed perceptual
processes that are the source for making decisions and forming preferences
based on what was sensed (Miller, 2013). They do not simply detect that the
temperature has risen to potentially dangerous levels, they actively swim away
into cooler waters—which they know are cooler because they have a memory of
the prior temperature to compare it with. If they make contact with an acidic
molecule, they experience it as a negative object and withdraw.
Escherichia coli, and other species of bacteria, travel by two means. Rotating
their flagella allows them to move forward in a linear swimming motion and
random tumbling. As Berg and Brown (1972) showed over 50 years ago, they
can detect the presence of positive conditions and move forward using a ‘biased
random walk’ and change directions when sensing that things are taking a turn
for the worse. Miller et al. (2021) pointed out that these kinds of chemotaxic
sensory systems are adaptive and essential for unicellular species to be able to
navigate environments that are in constant flux and ambiguous in the nature of
the information provided. Bruni et al. (2017) showed that E. coli deal with these
constantly changing environments by using voltage-induced calcium flux to gain
information—a mechanism that is highly similar to one used in the sensory
neurons in vertebrates. Again, we refer back to the ‘pyramidal’ model of
evolution discussed in Chapter 1. If something works, it remains part of the
ongoing process of evolution and forms the basis for future traits and functions.
The calcium flux mechanism has been around for a very long time.
The laboratory of Swiss biologist Alexandre Persat recently reported that, in
addition to using chemosensory processes to navigate their world, at least one
species of bacteria (Pseudomonas aeruginosa—a multidrug-resistant pathogen)
also evolved a sense of touch based on mechano-tactical functions (see Kühn et
al., 2021, for details). They make motility decisions by literally feeling their way
across surfaces and make movement decisions based on the relative stiffness of
the surface.
An amusing but effective sensory experience in bacteria is their ability to
detect and respond to, what the scientists at Tufts University called the ‘funky’
smells of the volatile gases produced by the fungi that are responsible for
ripening cheese (Cosetta et al., 2020). Their report noted that this bacterial skill
is likely to have commercial value in the cheese-making world.
Cyanobacteria are sensitive to the passage of time and have circadian clocks
that use bioelectric mechanisms to sense the environment and, literally,
anticipate regularities in the physical environmental cues such as light and
temperature and use this information to make appropriate adjustments in
molecular function (Baluška & Reber, 2021b). Cyanobacteria are also
photosynthetic and were critical in the evolution of plants. We will have more on
the fascinating moment in evolution when a cyanobacterium merged with an
alpha-proteobacterium and the first chloroplast appeared. There are reasons for
thinking that this endosymbiotic event occurred exactly once in the late
Precambrian era—roughly 1 billion years ago (though there are questions about
the date)—and that all plants evolved from it.
There are dozens of additional reports of sensory and perceptual experiences
in unicellular species but these are sufficient to make the case. Prokaryotes
sense, experience, feel, and use these internal representations to drive decisions,
motivate actions, and influence the formation of preferences. These mechanisms
are complex and have a comparative basis to them. In addition to sensing and
processing information, cells must also be tuned to their own internal, metabolic
conditions. They have to be aware of a nutrient deficit to move towards a food
source, and note internal temperature to find the way to comfortable temperature
gradients in the surrounding environment. They need to be able to navigate a
complex, changing environment in order to find the metabolic ‘niche’ that
promotes survival. German microbiologists Tobias Schweinitzer and Christine
Josenhans (2010) reviewed the literature on sensory systems in unicellular
species based on processing some form of energy and found that they are so
widely employed by so many different species that they termed them ‘global’.

Learning: Adaptive, Avoidant, Navigational, and Pattern

All unicellular species learn. We will take a look at four examples noting that
they are associative in nature. That is, the learning consists of forming links
between stimuli and responses. In Chapter 1 we noted that one of the criteria for
consciousness cited by Ginsburg and Jablonka (2019) was an ‘unlimited
associative learning’. They did not, however, grant sentient states to prokaryotes.

Adaptation
Cells must have the ability to adapt to the ongoing, chaotic, external
environment. The standard picture, based on early work by Jacob and Monod
(1961), had been that regulatory networks evolved to establish effective gene
expression states for commonly encountered environmental changes. In short,
the mechanisms were assumed to already be in place as the result of
evolutionary pressures. Until recently, it was not known how cells would react
when confronted with unfamiliar environments, ones that are not in their
evolutionary history. Saeed Tavazoie’s laboratory at Columbia University (New
York, USA) explored this issue recently and found that cells can, indeed, adapt
successfully to new and potentially lethal environments. In their studies,
metabolic functions were modified so that cells were unable to make the changes
in gene expression that would normally occur when levels of a particular ligand
reached dangerously high levels. Rather than succumbing, the cells carried out
stochastic adjustments in metabolic function by randomly increasing or
decreasing relevant gene expression. The ones that worked, which were effective
in promoting survival, were reinforced and, over time, optimal levels of gene
expression were established without genetically predetermined pathways. In
short, cells learn to tune metabolic functions to adapt to novel, challenging
circumstances (see Freddolino et al., 2018, for details).
Yang and Tavazoie (2020) recently reported a similar finding with yeast cells
(Saccharomyces cerevisiae) exposed to ethanol at levels that crossed what they
called the ‘lethality threshold’. Since simple alcohols were not present in the
original environments of yeast, the normal environmental stress response would
not be activated. Nevertheless, over generations, the yeast cells developed an
adaptive compensatory gene expression reprogramming mechanism—one that
was sufficiently successful that enabled them to not only survive, but display
growth rates that were indistinguishable from control cells.

Avoidance
One of the earliest studies was carried out by American biologist H. S. Jennings
who reported an instance of sophisticated avoidance learning in a sessile ciliate
Stentor roeselii (Jennings, 1906). Jennings dropped an aversive dye into S.
roeselii’s trumpet-shaped intake funnel. The response was a classic escape
response as S. roeselii bent over and shook the particles out and retracted its
cilia. After several additional administrations, S. roeselii contracted so that the
dye did not enter the funnel—a classic avoidance response. After a time, S.
roeselii uncoiled and its cilia returned to their normal functions. Jennings then
reintroduced the dye—which was just too much for S. roeselii. It tore itself loose
from its perch, swam away, and reattached elsewhere—an even more complex
avoidance response.
There is an interesting history to this study. In 1967, Reynierse and Walsh
reported that they were unable to replicate Jennings’ findings and the existence
of avoidance learning in the single-celled eukaryotes was widely doubted. It took
another half-century to restore S. roeselii’s reputation. Dexter et al. (2019) noted
that the non-replication was not a real replication for Reynierse and Walsh used a
different species, S. coeruleus. Dexter, along with colleagues at Harvard and
Dartmouth, ran a series of trials with S. roeselii designed to mimic Jennings’
procedures and reproduced the original findings. The organism engaged in the
four stages of bending, ciliary retraction, contraction, and detachment first
reported by Jennings. In the same year Trinh et al. (2019) reported an additional
replication. Avoidance learning in a single-celled eukaryote is now broadly
accepted.

Navigational
Audrey Dussutour’s research group in Toulouse reported that slime moulds
(Physarum polycephalum) learn to navigate a pathway between two Petri dishes
that had caffeine or quinine on it, substances that they find aversive. Over
several days they showed significant improvement in their ability to negotiate
the bridge to the dish containing nutrients without coming into contact with them
(see Boisseau et al., 2016, for details). In their report they described the effect as
‘habituation’ which we found misleading. Habituation is a phenomenon where
responses to a particular stimulus diminish over time as attention is no longer
drawn towards it. It is clear that slime moulds know where they are, where they
are going, and learn the safest path to take. It is worth pointing out that
habituation rarely occurs with aversive stimuli. To do so would not be adaptive
—the presence of stressful events and objects may be unpleasant but,
evolutionarily speaking, it is adaptive to pay attention. What the data do imply is
what we have called here navigational learning and is based, like the research
with S. roeselii, on avoidance of aversive circumstances.
Dussutour, in a recent review of the issue of learning in unicellular species,
hedged on whether there is clear evidence for learning in unicellular species
(Dussutour, 2021). The issue here, we suspect, is yet again, more one of
terminology than of empirical evidence. Her laboratory’s titling a paper that
presents evidence of learning as ‘habituation’ suggests that we really need to
clarify the meanings of terms used in the field. See Appendix I for our
lexicographic efforts.
Recently, Kramar and Alim (2021) and Cheng (2022) independently reported
similar findings where P. polychephalum learned to navigate tubes in which food
had been placed at random locations. Interestingly, both reports refer to the
ability to learn and form memories of the location of nutrients ‘intelligent’
behaviour. Neither regarded the effects as ones of ‘habituation’.

Pattern
Israeli biologist Yitzhak Pilpel’s laboratory showed that both E. coli and a yeast
(S. cerevisiae) can learn to ‘foresee’ (their term) events and anticipate their
arrival by initiating metabolic changes prior to their onset. The procedure
consisted of presenting a sequence of two sugars that both species are fond of,
lactose and maltose, one after the other in an alternating pattern, LMLMLM (see
Mitchell et al., 2009, for details). When the next cycle began with maltose,
nutritive uptake was inefficient. Both species had already made adjustments in
gene expression designed to maximally absorb the anticipated lactose.
Interestingly, Mitchell et al. were able to extinguish the pattern of shifting gene
expression by presenting an ongoing series of lactose without changing to
maltose.
Similar findings where the stimulus modifications were in temperature were
observed with E. coli by Saeed Tavazoie’s laboratory. They raised the bacteria in
environments where the temperature was shifted from relatively cool to warm
and back again, repeatedly (details are in Tagkopoulos et al., 2008). Over several
generations the bacteria learned to shift gene expression to anticipate the next
temperature change.
In a recent paper, Australian neuroscientist Brett Kagan and colleagues
reported that neurons in a Petri dish (what they call the ‘DishBrain system’)
learned, in a surprisingly short period of time, to play the classic arcade game
‘Pong’ (Kagan et al., 2022). As they put it, ‘Using the DishBrain system, we
have demonstrated that a single layer of in vitro cortical neurons can self-
organize activity to display intelligent and sentient behavior when embodied in a
simulated game-world’. For the DishBrain cells, their self-organization was
directed, by definition, towards states of collective preference, that is, one
collective state over another. However, we need to point out that, despite their
findings, Kagan and co-authors cling to the standard model and state that they
regard the cells in DishBrain as being ‘intelligent’ but not ‘conscious’. From the
CBC perspective, of course, we view this to be more of a terminology issue than
an existential one. Their DishBrain cells are as sentient as any.
These findings also fit with the recent discovery that xenografts taken from
human neural tissue thrive on rat cortex, indicating that they sense their new
environment, rapidly self-engineer required internal adaptations to participate
with other neurons, associate with them through collaboration, cooperation, and
trade resources. Put simply, they function as participant multicellular co-
engineers, and are capable of individually contributing to the entire brain output,
showing that they retain their own self-identity (Revah et al., 2022).

Memory
Let us start this section by noting that whenever you have organisms that learn,
you are, necessarily, going to have ones with the capacity to establish memories
of what has been acquired. Without forming stable memories, the task would
have to be learned anew each time the circumstances or those close to it re-
occurred. Learning without memory is clearly non-adaptive, even for the
simplest of organisms. Interestingly, Robert Macnab and Daniel Koshland
presented evidence for memories in bacteria over a half-century ago. But they
shied away from using language that would make it seem like bacteria displayed
genuine cognitive functions. They put memory in scare-quotes (it appeared as
‘memory’) or qualified it as ‘memory-like’ (Macnab & Koshland, 1972).
Since we have already reviewed a number of experiments showing that
prokaryotes and unicellular eukaryotes learn in a variety of circumstances, it
should be obvious that they have parallel memorial functions. The bacterium that
learned to move out of an environment that has grown uncomfortably warm has
to be able to recall the temperature of the surroundings it left in order to
determine whether the one it travelled into has positive valence. If not, it will
move on again. The slime moulds that learned to navigate a ramp with caffeine
and quinine must be able to recall the location of the aversive acids in order to
travel safely over the bridge to the dish with nutrients. With this in mind, the
following sections deal with some of the details of the memory systems of
unicellular species.

Time Frame
Most prokaryote memories are short term, lasting usually less than a minute,
some as short as 3 or 4 seconds. Their function, as noted, is to keep track of the
current state of their environment so they can make appropriate decisions with
regard to changes in ambient temperature, concentrations of nutrients, and
presence or absence of toxic substances. In these normal environments there
would be little gain to establishing long-term memories. In other circumstances,
longer-lasting memories are created, in particular those that are based on
alterations in gene expression. Swiss biologists Roland Mathis and Martin
Ackermann (2016) showed that a sessile bacterium, Caulobacter crescentus, can
establish memories that last up to 2 hours which, in the lifespan of a bacterium,
is a near-eternity.
Cell division in C. crescentus is asymmetric with the stalked ‘mother’ cell
remaining attached to its spot while the motile ‘daughter’ cell swims away to
find another perch. Before cell division, Mathis and Ackermann introduced an
aversive, concentrated salt solution which, previous research had shown, results
in shifts in gene expression as a protective measure. Then, after the daughter
cells relocated, they reintroduced the toxic salt solution. Death rates were much
higher among the daughter cells that swam away to a presumably safe location
than in the sessile mother cells who remained. The mother cells had established a
memory of earlier events and displayed a readiness to make appropriate
metabolic shifts should the salt solution return. Those that relocated did not.
Importantly, both groups of cells had identical genes.3

Immunological Memory
Bacteria and other prokaryotes routinely establish memories based on
immunological functions. Invasion by a virus or a strand of nucleic acid (a
‘plasmid’) initiates a sequence of responses by the cell. It uses a protein, known
as Cas9, to snip out a piece of the invader’s genetic material and insert it into
their own DNA. The resulting modification of their genome functions as a
memory of the identity of the invader and the cell is better prepared for coping
with any future occurrences. This procedure is, of course, the basis for CRISPR,
the revolutionary gene-editing technique. Jennifer Doudna and Emmanuelle
Charpentier may have won the Nobel Prize in Physiology or Medicine for their
brilliant work with CRISPR but the technique was invented by prokaryotes
several billion years ago.
Of interest is the question of the precise biomechanisms used to establish what
is, essentially, a lasting representation of events that occurred, or behaviours that
were carried out. Biologists Josep Casadesus and Richard D’Ari at the
University of Seville, Spain, pointed out that there are, in fact, several distinct
ways to encode and hold information (Casadesus & D’Ari, 2002). Some are
basically genetic in that a heritable function, encoded in DNA, is established
based on experience. The result is a modification of the organism’s genome to a
different pattern of gene expression based on the specifics in the stimuli to which
it has been exposed. The results of Pilpel’s and Tavazoie’s laboratories on
anticipation and pattern learning discussed above are based on this
biomechanism as are those that utilize the CRISPR technique. Casadesus and
D’Ari described these processes as ones that ‘lock in’ the change as it is carried
onto future generations. Other techniques for forming memories are based on
modifications in cellular functions that deal with repeated events or actions and
are not heritable. This knowledge dies with the organism that learned and
encoded it.

Decision-Making
Many of these findings on pattern learning and memory can be traced back to the
early work of French biochemist Jacques Monod carried out in the 1940s. In a
series of seminal experiments, he provided E. coli with glucose (preferred) and
lactose (nutritious but non-preferred). He observed distinct pauses in the growth
of the colony at those points where all the glucose was consumed and only
lactose remained. The reason for the pause, Monod discovered, turned out to be
one of the most important early findings in cell biology. When glucose was
abundant, E. coli simply turned off the gene expression functions that increased
their ability to metabolize lactose and needed time to make metabolic
adjustments to efficiently metabolize lactose. Literally hundreds (perhaps
thousands) of studies (like those described above) sprung from this finding for
which Monod was awarded the Nobel Prize.
The focus of much contemporary research is on the molecular basis that cells
use to ‘decide’ to switch gene expression (and, yes, ‘decide’ is the term used in
the field). Brandeis University (Waltham, Massachusetts, USA) biophysicist
Jané Kondev reviewed the several theoretical gene expression models for how
well each handled the data in the diet-selection studies (Kondev, 2014). He had a
section with the provocative heading ‘Does E. coli have free will?’ in which he
concluded:
The result is a population of cells that, although genetically identical [to another], may behave quite
differently. It is as though each E. coli cell is free to choose between two diets, glucose or lactose,
unencumbered by its genes or the environment. Experiments … reveal the molecular nature of that
‘free will’ and trace it to the stochastic expression of E. coli genes.

Kondev’s primary interest is mathematical modelling and, as we saw in our

earlier review of the work in Saeed Tavazoie’s laboratory, the notion of a
stochastic ‘choice’ and the feedback from the one made is a powerful one. The
stochastic feature allows for multiple options and the decisional distributions
emerge when ‘free’ or unconstrained choices are made. In their approach to this
issue, the circumstances that are present when the bacteria choose can be
artificial or organic. It does not matter because they are looking for general
mechanisms, ones which operate when the environment changes no matter what
the factors of change are. Whether Kondev’s ‘free choice’ is something that falls
under the philosophical umbrella put up by Daniel Wegner is far from clear,4 but
his point is made. When an organism, even a unicellular bacterium, is able to
choose among alternative modes of action, it surely falls within the folk
psychology sense of ‘free will’.

Communication
Prokaryotes are highly social and readily form collectives known as microbial
mats and biofilms. The former are laminated sheets found mostly in aquatic
settings, can be up to a centimetre thick, and are held together by sticky
extracellular substances. Biofilms are only a few layers in thickness and form on
surfaces, commonly on boat hulls and, of course, teeth. Their biomolecular
structures and functions are well known as are the critical roles they played in
evolution. But here we are concerned with their cognitive functions which
include the ability of cells to communicate with each other based on what is
known as quorum sensing or quorum signalling.
As a bacterial colony forms, cells interact with each other by releasing
molecules that have signalling functions that provide critical information to the
rest of the collective enabling them to control gene expression and respond
appropriately to population density.5 When a colony like a biofilm reaches a
certain size, population density issues can arise. Cells on the periphery, the outer
surfaces, are in a nutrient-rich environment but are also exposed to its toxins,
antibiotics, and predators. Those in the interior are in a more protected location
but often are faced with lower levels of nutrients. In fact, if the number of cells
on the periphery becomes too large, the inner cells could literally starve to death
—which would leave the colony at risk from all sides. To prevent this
catastrophic event, the cells in the interior secrete a molecule that signals to the
rest of the colony their state of caloric distress. The cells on the periphery
respond by adjusting metabolic functions, reducing cell division rates, and
decreasing the uptake of nutrients which allows sugar molecules to flow inward.
Once nutrient levels in the interior are back to normal, a different biomolecular
signal is emitted that says, in essence, ‘We’re okay now’, and the outer cells
resume normal activity. When nutrient levels in the interior drop again, as they
must, the phase-cycling repeats and will continue to do so for as long as the
collective lives.
In the event that the biomass has grown large and is made up of different
species (as it often is), the form of communication changes and the interior cells
shift over to releasing potassium ions. These positively charged wave-like
signals travel throughout the collective and have the same effect in
communicating to the outer layers the need for them to make adjustments in
function.6
This elaborate communication network is also seen operating between two
separate bacterial colonies. Gürol Süel and colleagues at the University of
California, San Diego (USA) allowed two collectives of the bacterium Bacillus
subtilis to develop in the same Petri dish and carefully controlled the nutrient
levels in their shared environment. When nutrient levels dropped in the area of
one collective, the potassium release mechanism was engaged, travelled through
the dish’s medium, and alerted the other of their distress. The response was a
primitive form of what can only be called altruism.7 The well-fed colony
lowered molecular functions, reduced cell division, and reduced nutrient uptake
until the first collective released another molecule saying they had recovered
(see Prindle et al., 2015, for details). Süel’s laboratory referred to this as ‘time
sharing’ and Humphries et al. (2017) observed it taking place between different
species.
Süel and colleagues’ work showing cooperation and ‘time sharing’ of nutrients
is fascinating and has been replicated by other laboratories, including biologist
Kevin Foster’s group (Sharp & Foster, 2022) at the University of Oxford (UK).
However, they have also reported competition among bacterial colonies, in
particular when they are of different species (Palmer & Foster, 2022). The
situation is, as their recent work shows, more complex than originally thought.
Since these bacteria normally live not in Petri dishes but in hosts, it is becoming
increasingly clear that the host microbiome also plays a role. Depending on how
it interacts with the several bacterial species, either cooperation or competition
can result (Bentley et al., 2022). Foster is optimistic about the possible medical
role of the discovery of competition among different species of bacteria. It hints
at the possibility of developing ways of dealing with bacterial infections without
the need for antibiotics.

Temporal Awareness—Bio-Clocks
Virtually every cell has a circadian bio-clock. We view them as inherently
cognitive for the simplest of reasons. They provide information that can be used
to anticipate the regularities in physical environmental cues such as light and
temperature. Recent discoveries have revealed their deep cellular basis. The
original view of circadian clocks in humans and animals was that they are
controlled by cerebral processes and needed neural systems to function.
However, more recent studies revealed that organs, tissues, and individual cells
are running lower-level, semi-autonomous clocks based on individual cellular
temporal mechanisms that are sensitive to light levels. In fact, it is even a more
complicated issue than just our own cells. Our biorhythms interlink along
complex communicating, metabolic pathways between our body cells and our
constituent microbiome, with significant effects on satiety, sleep cycles, and
even obesity (Rácz et al., 2018).
Keep in mind that photosynthesis, the basis for redox-based circadian clocks,
was ‘invented’ by ancient cyanobacteria some 2.7 billion years ago. Following
the logic of the CBC model, this novel sensitivity to light levels was instantiated
in cells that were sentient and had a rich sensory system in place. The logical
entailment is that all three phenomena (the fundamental sentience of the CBC
model, the first circadian clocks, and membrane-based electron transfers) are
inherently interlinked. Biomolecular details are in Baluška and Reber (2021b),
Edgar et al. (2012), Loudon (2012), and the issues are explored further in
Chapters 5 and 6.

Fatigue
Do bacteria sleep? This is a reasonable question to pose, particularly in light of
the existence of circadian clocks. One of the elements of life is the role of down
time, taking a break allowing the organism time to recover, re-establish normal
metabolic functions, and repair cellular damage. The best evidence to date
suggests that the answer is probably not—if we regard sleep as a state with
specific neural features marked by shifts in electroencephalograms and with
distinct phases like rapid eye movement (REM) sleep that we see in species with
nervous systems.
But something like sleep in bacteria may be based on a different biomolecular
foundation. As noted, bacteria are sensitive to shifts in ambient light levels and
show circadian rhythms. Of the prokaryotes, the most studied are the
cyanobacteria. Susan Golden and her colleagues at the University of California,
San Diego have shown that the cyanobacterium Synechococcus elongatus shifts
gene expression rates and physiological processes in response to cycles of light
and dark (see Boyd et al., 2016, for details). As noted above, cyanobacteria
invented photosynthesis and used it to generate energy. They are also the species
presumed to have been involved in the chimerical event that occurred some 1.7
billion years ago when the first precursors of the plant kingdom evolved. We will
have more to say about this singular occurrence in Chapter 11 when we look
more closely at sentience in plants. Whether these cyclical modifications in
biomolecular functions is anything like ‘sleep’ and whether S. elongatus is in a
more quiescent state during certain phases of its circadian clock are still
unknown. However, there is evidence for quiescence as quasi-sleep at scale. That
bacterial quiescent state corresponds to a sharp decrease in metabolic turnover,
reproductive rate, and intercommunication.

Summary
We consider these empirical findings to be persuasive and support the original
assumption of the CBC: life and sentience are coterminous. All but only living
organisms are conscious and have valenced experiences. But, of course, not all
agree. As we have noted in more than a few places, the position taken by the
CBC is not the standard one in the field—and the situation is not simple. Most
researchers in microbiology know the literature and are not only comfortable
with our stance but are in general agreement with it—and, in many cases, took
similar stances long before we published our work. And, as we noted earlier,
many cognitive scientists and neuroscientists are also aware of much of these
data, as are many philosophers who have explored the realm of the prokaryotes.
But they are reluctant, for a variety of reasons, to acknowledge the core principle
—and several of those reasons stand out.
One is based on a model that argues that these behaviours, while exhibiting a
remarkable array of functions, are not accompanied by an existential
consciousness. They are, so the argument goes, merely robotic processes, driven
by genetic factors, and they spin themselves out without awareness, experience,
sentience, or a sense of self. There is, in Dennett’s phrase, ‘competence without
comprehension’. We think this argument is wrong, deeply and profoundly
wrong. It is not wrong like a messed-up sum, but a wrongness that has deflected
the field of what philosopher Ned Block likes to call ‘consciousness science’ off
its proper scientific course. Virtually every recent book on the evolution of
minds that we cited in earlier material puts forward one or another version of it.
When stripped bare, this position gains nothing in explanatory power and is rife
with philosophical and evolutionary biological difficulties.
Let us ask a not-unreasonable question: what could the evolutionary
foundation for such a range of adaptive functions be? If each is gene-driven, it
means that there would have to have been a stunning array of independently
evolved genetic foundations—one for each sensory system, another for
interpreting and perceiving what was detected, another for feelings (which, of
course, would not really be felt), others for the various forms of learning,
additional ones that would establish memories of each acquisitional experience,
at least two different ones for communication, yet another for quorum sensing, a
separate one for processing temperature gradients, distinguishing different
nutrients, directing motility, making decisions about where to relocate, and when
to shift gene expressions. It simply makes no sense and, worse, there is no
evolutionary mechanism that could create such a stunning array of functions in
an organism that is supposedly dumb as a post—especially in the chaotic pre-
biotic environment where change, flux, and variation was a staple of the world,
and still is. Trying to explain the behaviours of single-celled species as a
collection of separate, genetically determined, mindless actions is messy,
cumbersome, and unlikely in the extreme. But, toss in the core assumption of the
CBC, a palpable sentience, and everything falls neatly into place. We claim
William of Occam’s crown. We also conclude that ‘there is something it is like to
be a prokaryote’. We may not know ‘what’ that is but we are certain that we
know ‘that’ there is.
Second, assuming these kinds of mindless, robotic systems did somehow
evolve independent of sentience does not help for the simplest of reasons. It
provides no additional explanatory power over the CBC position. And, worse,
you are back skewered on the pike of the emergentist’s dilemma. If the argument
is that sentience was not an inherent feature of even the simplest unicellular
species, you have a fundamental responsibility. You need to present a coherent,
scientifically testable model that explains how, when, and in what species
phenomenal experience, sentience, a mind, first appeared. That, as we have seen,
is one tough nut to crack. And, we will repeat yet again: none of the researchers
who have taken this position has even acknowledged, let alone attempted, to
solve this problem.
Third, taking the CBC stance frees us up from a creeping mysterianism that
several scientists and philosophers have recently embraced. Here is an extended
quote from a recent book one of us wrote that tried to deal with the issue (Reber,
2019):
In this world of the new mysterian, the explanatory gap is somehow made real and unbridgeable, the
impossibility of matter making mind taken as an epistemic inevitability, accepted as gospel, embraced
as truth without evidence. The Hard Problem gets turned into the Impossibly Hard Problem or the
Hardest Problem of All.
The Cellular Basis of Consciousness approach saves us from these kinds of mysterian notions. It opens
another empirical path to wander down but it’s one that has a well-defined goal at the end: uncover the
biochemical, molecular processes that first emerged in the simplest life forms that produced the
emergence of sentience. After that, it’ll just be more evolutionary biology, something we do quite well.

Now it is time to take on the real challenges, the first of which will be to
examine the Vitalism–Mechanism debate and look at what we know about the
origins of life.

1 As noted above, the earliest eukaryotes resulted from an endosymbiotic merging of two prokaryotes.
Although their physical form is that of a unicellular species, there are good reasons for treating them as
multicellular (see Chapter 4 for further discussion of this oft-neglected point). However, we will include
them in this chapter as they display a host of behaviours and functions that are further evidence of cognitive
processes in relatively simple species.
2 Some of which was discussed previously in Baluška and Reber (2021), Baluška et al. (2022b), and

Reber (2019).
3 The role that genes play in these adaptive learning and memory functions is complex. We discussed the
issue in Baluška and Reber (2022) and present more detail on it in Chapter 11.
4 Wegner’s 2002 book The Illusion of Conscious Will is an unpacking of the notion of will that argues,
persuasively in our minds, that we don’t have anything like what the average layperson thinks of as ‘free
will’. What we do have is a more mundane but more understandable range of things we can choose to do, or
not, under the momentary circumstances. We have, in short, the capacity for choice but it is far from ‘free’
and, ultimately, the notion of ‘will’ is best handled metaphorically. The issue of course, is far from resolved
(see Baggini, 2005).
5 In passing, it is worth noting that quorum sensing is also used by more complex species including the
hive insects like bees and termites to make decisions about when a nest has exceeded its optimal size and
should split.
 6 The details of these communicative processes can be found in Beagle and Lockless (2015) and more on
quorum sensing is in Schertzer et al. (2009).
7 This is an interesting issue and we will discuss it further in Chapter 12. The reason we are calling it

altruism is because it has the two key features typically identified: (a) the response increases the well-being
of others while (b) it puts the individuals making it at risk. Note that the Humphries et al. (2017) finding is a
classic case of non-kin altruism.
3
What Is Life? The Vitalism–Mechanism Debate and
the Origins of Life

What Is Life?
Anyone delving into the definition of life will make a disquieting discovery.
There is no established consensus. Enthusiastic scientific arguments are
presented on both sides of that contentious debate, and despite our best efforts,
there are no unambiguous answers.
Arguably, the most influential contribution to this topic was in 1944 by the
Austrian-Irish Nobel Prize-winning physicist Erwin Schrödinger in his seminal
publication What Is Life? In that compact volume, Schrödinger placed life in
terms that make physicists quiver, declaring it to be a special case, defying the
second law of thermodynamics. The second law governs the relationship
between physical order and disorder, generally represented within the framework
of entropy. In an open system, the total disorder of that system must increase
over time as increased entropy. Life is exceptional since it seems to contravene
the second law as an ordered state that never reaches equilibrium. Consequently,
life is a singular physical state. Schrödinger argued that life was defined by this
relative ‘negentropy’ between the external physical world and living organisms,
constituting a state of greater structural ordering, opposing otherwise universal
entropic expansion.
In the decades beyond Schrödinger’s revelatory insight, considerable progress
in cellular biology has steadily accrued with our burgeoning knowledge of the
internal complexities of competent cells. Pertinently, there is an increasing
realization that entropy is interconvertible with information (Brillouin, 1951).
From this equivalency, a few particular characteristics of life come into focus.
Life is an ordered (entropic) state where information (as an entropic
equivalency) has meaning. Crucially, for this conjunction to occur, cellular
consciousness must be present. Further, that essential ordered internal state relies
on the membranous physical boundary that circumscribes all living cells. The
dependence of life on a competent boundary system can now be readily
explained. That membranous boundary is the gateway for the flow of
information into all cognitive cells as a foundational aspect of its information
management system, whose particulars will be discussed in Chapter 7.

How Did Life Begin?

If the definition of life is elusive, scientists must surely know how life began.
Yet, this, too, remains an enigma, stumping even the foremost experts. In 1981,
Francis Crick, the co-discoverer of the DNA helix and a Nobel Prize winner,
declared his puzzlement, ‘An honest man, armed with all the knowledge
available to us now, could only state that in some sense, the origin of life appears
at the moment to be almost a miracle, so many are the conditions which would
have had to have been satisfied to get it going’ (Crick, 1981). Paul Davies, a
perceptive Professor of Physics at Arizona State University, USA, offered this
assessment in 1999: ‘Many investigators feel uneasy stating in public that the
origin of life is a mystery, even though behind closed doors they admit they are
baffled’ (Davies, 1999). It remains true still.
Although the exact thresholds that separate the animate from the inanimate
remain uncertain, some progress has been made over the decades, establishing
those elements considered essential to its formation and directly relating to how
complex life on the planet is constructed. Some aspects of the origin of life have
achieved a consensus. Nearly all scientists agree that life began as cells. The
eminent scientist and essayist Lewis Thomas summed up this perspective:
The uniformity of the earth’s life, more astonishing than its diversity, is accountable by the high
probability that we derived, originally, from some single cell, fertilized in a bolt of lightning as the
earth cooled. It is from the progeny of this parent cell that we take our looks; we still share genes
around, and the resemblance of the enzymes of grasses to those of whales is a family resemblance.
(Thomas, 1978)

Many scientists have postulated a ‘primordial soup’ where life-granting

processes might have been stimulated some 4 billion years ago. A Soviet
biochemist, Alexander Oparin, believed that atmospheric oxygen would have
prevented the synthesis of the requisite organic compounds, insisting that life
needed an anoxic period, as a ‘primeval soup’ of organic molecules for the
development of spontaneous life (Deamer, 2020). A pioneer of crystallography
and molecular biology, John Desmond Bernal, theorized that spontaneous life
required three stages: the appearance of biological monomers, the subsequent
development of biological polymers, and the final evolution of molecules to
cells. These polymers were crucial since they demonstrate the inherent property
of self-replication.
Scientific investigations have revealed that specific properties of organic
molecules are necessary for life. Organic molecules exhibit chirality, referring to
the non-superimposable three-dimensional forms as mirror images of one
another and either right- or left-handedness. For unknown reasons, biological
systems are homochiral: amino acids are left-handed, and nucleotides and sugars
are right-handed. In typical chemical reactions, the mixture is generally fifty-
fifty. Some astrobiologists have postulated that the existence of earthly
homochirality is evidence of an extraterrestrial origin for biological molecules,
since it is so otherwise exotic on Earth. Curiously, examinations of meteor
samples have found amino acids like alanine occurring much more frequently in
their levo form, and sugars that are much more common in a dextro form.
One of the major problems with all origin of life theories is that autocatalysis
(increasing the rate of a chemical reaction by one of its products) is essential to
life. In 1993, the physician and theoretical biologist Stuart Kauffman proposed
that life arose from autocatalytic chemical networks, as combinations of the
amino acid adenosine, an appropriate ester like a pentafluorophenyl ester, and an
autocatalytic adenosine triacid ester. This potent mixture stimulated a
prototypical, molecular form of natural selection (Kauffman, 1993). Although an
attractive theory as it could account for the self-organization and the proto-state
required for self-replication, it suffers from some significant deficiencies. For
any biological process to proceed at a living rate, enzymes are required, and their
origin must also be explained. Secondly, the presumption that life originated
through a process of competitive natural selection is ill-supported since life is
sustained much more by cooperation rather than competition (Miller, 2016a;
Miller et al., 2020a).
How then might life have been triggered to include its unique combination of
molecules and processes? There is no shortage of highly intricate theories. Since
this issue remains as clouded today as ever, it is only natural that a welter of
competing hypotheses have blossomed to fill the knowledge vacuum:
1. Electric sparks might have generated just the correct amino acids or sugars. Volcanic clouds in the
early atmosphere might have held methane, ammonia, and most amino acids that are the basic
chemicals of life, and this ‘stew’ could have led to the self-replication essential for life on Earth
(Ignatov & Mosin, 2014). This path satisfies the need for self-replication but says little about the
other requisite of self-organization.
2. Pools of condensed and cooled thermal vapours might have started life. A 2012 study at the
University of Osnabruck in Germany claimed that adding a type of clay to a mixture of fatty acids
yields a form of membranous vesicle formation that could lead to the spontaneous self-assembly of
 nucleotides, forming RNA on an early anoxic Earth (Mulkidjanian et al., 2012).
3. Scottish organic chemist Alexander Graham Cairns-Smith offered allied ‘community clay’ theory,
indicating that clay minerals could have constituted an appropriate scaffolding for life and catalysed
RNA formation (Cairns-Smith, 1971).
4. Others have championed a ‘chilly start’ hypothesis (Miyakawa et al., 2002). Ice might have covered
nearly all of the planet 4 billion years ago since the sun was less luminous than today. Life might
have been able to form under this extremely thick layer of ice because the required molecules would
have been protected from harmful ultraviolet radiation, giving them more time to stabilize and
potentially self-replicate.
5. At the opposite extreme, the ‘deep-hot biosphere’ model, first proposed by Thomas Gold 30 years
ago, suggested that life did not begin on Earth’s surface (Colman et al., 2017). Instead, life formed
below the surface where even today, microbes with exotic chemistries thrive, with some even using
radioactive substances as their energy source.
6. Planetary thermocycling might have done the trick. Life needs an energy source and planetary
thermocycling might have triggered thermosynthesis, beginning a process akin to fermentation
(Muller, 2005). Protocells might have formed in an energetic convection from a volcanic hot spring,
aggregating molecules, stimulating self-organization, and encouraging the heat dissipation, a critical
attribute of life.
7. Some origin-of-life scientists insist that ‘life’s a beach’. The ‘radioactive beach’ hypothesis
postulates that life began in tidal pools where energy-producing radioactive elements might have
aggregated and become the energy source for living catalysis (Bywater & Conde-Frieboes, 2005).
8. Possibly, life is all about entropy. Karo Michaelian at the National Autonomous University in
Mexico proposes that any robust model of life must account for it as an irreversible thermodynamic
process (Michaelian, 2022). Living organisms dissipate energy, equating to entropic production.
Conceivably, that entropy production should not be viewed as incidental to life but as its exact
purpose and reason for existence. Accordingly, DNA and RNA were formed for the specific purpose
of energy dissipation to serve basic thermodynamic processes. Although this theory might seem
attractive to physicists, it subtracts the life out of life for biologists.
9. A very popular theory champions life’s origin in deep submarine hydrothermal vents where copious
hydrogen-rich molecules spew at or near the sea floor (Martin et al., 2008). Theoretically,
congregations of these molecules in rocky nooks might have provided catalytic minerals for critical
molecular reactions.
10. For many scientists, biology is all about genes. Naturally, many assume that life arose first from
genetic material, either forming spontaneously here on Earth or arriving via panspermia (Line,
2007).
11. Other scientists disagree, insisting that metabolism had to come first. In the 1980s, Günter
Wächtershäuser and Karl Popper proposed an ‘iron-sulphur world–metabolism-first’ model
(Wächtershäuser, 1988). Energy for the origin of life derived from sulphides of iron and other
minerals such as pyrites, released by reduction and oxidation reactions of metal sulphides to yield
organic molecules, including polymers. These molecules became the basis for an autocatalytic chain.
Theoretically, this reaction set provided the environment in which RNA replication could emerge.
12. The ‘zinc world’ hypothesis extends the iron-sulphur and hydrothermal vent models (Mulkidjanian
& Galperin, 2009). Fluids with high levels of hydrogen sulphide could have flowed from
hydrothermal vents and reacted with cold water to precipitate zinc sulphide, which has the unique
ability to store radiation energy such as ultraviolet light. This reaction energized the initial stages of
photosynthesis, leading to informational and metabolic molecules.
13. The ‘RNA world’ hypothesis recognizes that DNA needs proteins to form, but the formation of
proteins requires DNA. How could one exist without the other? The answer might have been RNA
which stores information just as DNA does, serves as an enzymatic catalyst (ribozyme) as an
intermediary in the expression of genetic information, and was likely present on early Earth (Alberts
 et al., 2002). Although an attractive alternative, one major problem looms. How did RNA form?
14. The ‘lipid world’ or graded autocatalysis replication domain (GARD) model has no initial
requirement for DNA or RNA to jump-start life. In this scenario, the first self-replicating entity was
lipid-like (Lancet et al., 2018). For example, phospholipids form lipid bilayers if agitated in water
and these micelles are very similar to simple membranes. Further, lipid molecules exhibit hysteresis,
a physical property where molecular conformations lag behind the changes affecting them. This
effect can be considered a primitive type of information storage and memory. In theory, these could
have evolved into bioactive polymers and initiated a self-replicating cycle.
15. As might be expected, a mixture of many of these have been combined in to a synthesis, now dubbed
the ‘multiple genesis’ hypothesis. The justification is that early Earth chemistry might have been
substantially different than it is now and would have gone through many stages, each of which might
have had a developmental impact on the emergence of life. Some of these crucial, early chemical
compounds might have been subsequently expunged and no longer exist. For example, early life
might have been based on arsenic instead of phosphorous. Modern extremophile microbes and their
exotic chemistries offer a potential template for these differences. Indeed, it may not have been
necessary for any highly complex molecules such as RNA to be present to produce life. In the
‘simply beginnings’ scenario, life began from small, simple molecules, each interacting with others.
Alternatively, there might have been different nucleic acids preceding preceded RNA, the so-called
‘pre-RNA world’ scenario.
16. Some researchers believe that the origin of life depended on viruses, as a ‘virus world’ hypothesis
(Kostyrka, 2016). Although viruses are presumed to have emerged from cells since they require
cellular machinery to replicate, the discovery of giant viruses, such as Mimivirus, with more than
1000 genes, has stirred intense debate (Claverie et al., 2006). This virus is so large that amoeba will
mistake it for its typical bacterial meal. Pertinently, these giant viruses contain genes for their own
replication, can manufacture a few proteins, and can even repair DNA. Pandoravirus is even larger
and has over 2500 genes, an astounding number when considering that our human complement is
approximately 22,000. If true, we not only share a LUCA cell but an additional common
denominator from a ‘deep viral’ past.

Evolutionary biologist Eugene Koonin (2007) focuses on the intractable obstacle

within the RNA world hypothesis, which applies analogously to all other
theories. Despite many experimental efforts, there is no actual evidence of how
replication and translation began. Furthermore, and critically, there is no
knowledge of where RNA replicase came from, which is necessary for the
translation system that continues beyond it. So, the origin of the core biological
processes remains unanswered. Even if there was an RNA beginning, the origin
of the essential catalytic enzymes that life requires remains a mystery.

The Vitalism–Mechanistic Debate

Since the beginning of humankind, philosophers and scientists have sought
solutions to the riddle of life’s origin, either by direct observation or through
metaphysical approaches. The ancients believed that life came from non-life
since it corresponded so closely with what they could readily observe. For them,
abiogenesis was obvious (Sheldon, 2005). To the unaided eye, maggots simply
appear on rotting meat, representing the spontaneous generation of life from
non-life. Indeed, this was obvious to Aristotle. After all, flies could be directly
observed arising from putrid matter, and undoubtedly, frogs emerged de novo
from slime. The ancient Greeks agreed about the validity of abiogenesis and
accounted for the varieties of living forms through ‘heterogenesis’. For example,
bees came from flowers, not putrid waters.
The belief in spontaneous generation was so ingrained that it persisted for
over 1500 years. Even Leeuwenhoek’s first microscopic observations of
microbes in 1665 was initially interpreted as strengthening that concept since it
was believed that microorganisms could not reproduce. It was not until the
inspired experiments of Louis Pasteur that the concept of spontaneous generation
was replaced by biogenesis—life must issue from prior life. Pasteur recognized
that his germ theory would never be fully accepted as long as the belief in
spontaneous generation persisted. He devised a simple experiment, putting beef
broth in a long-necked flask, and boiling it to sterilization (Gillen & Sherwin,
2008). If the sterilized broth was never exposed to air, it remained unchanged
and lifeless. If exposed to air, it became turbid, indicating microbial
contamination.
Although Pasteur settled that debate, he raised others. How might first life
have arisen? One possibility source gained broad initial credence as a theory of
panspermia; life originated elsewhere beyond the planet, coming from another
cosmic location. Darwin disagreed and favoured another interpretation, famously
opining in an 1871 letter to Joseph Dalton Hooker. According to Darwin, life
may have begun in a ‘warm little pond, with all sorts of ammonia and
phosphoric salts, lights, heat, electricity, etc. present, so that a protein compound
was chemically formed ready to undergo still more complex changes’ (Damer,
2016). However, for life to take hold in this manner, two possibilities loom. Is
‘life’, ‘mind’ or ‘consciousness’, resulting as a type of special vital spark
(vitalism), as a ‘vis essentialis’ or ‘élan vital’ that extends beyond materialism?
Or alternatively, can life’s essence be reduced to a series of discernible
materialistic/energetic steps (Masi, 2022)? In other words, is reality ‘mind’ or
‘consciousness’ rather than structural matter?
Indeed, this debate has ancient roots in metaphysical vitalism (Masi, 2022).
Plato and Aristotle had supposed the presence of an immanent life force,
regarded as the soul by Aristotle. The Greek surgeon, physician, and philosopher
Galen (129–210) believed in ‘pneuma’ as an essential life spirit, a concept that
continued through the Middle Ages (Masi, 2022). The French biologist and
evolutionist Jean-Baptiste Lamarck insisted on the existence of a life-power that
conjoined with an inner adaptive force, marrying well with his theory of
adaptive evolution (De Klerk, 1979). For many scientists, such as the eminent
French physiologist Claude Bernard (1813–1878), it seemed impossible to
reduce life to a sum of its parts (Masi, 2022). Life was uniquely intricate,
constituting an entirely integrated whole, defying reduction. However, some
insisted that this essence need not be metaphysical and might be perhaps
conceived as a vital physical process, such as Bernard’s homeostasis.
These latter ideas carried substantial weight within the scientific community.
Eventually, they gave rise to a scientific neovitalist movement, initially
spearheaded by German embryologist Hans Driesch (1867–1941). This form of
vitalism was believed by many eminent scientists of that era and earlier,
including Pasteur (Miller, 2013). Based on observations of the development of
sea urchin embryos, Driesch proposed a reinvigoration of Aristotle’s entelechy
as an inner vital animating and self-organizing living force (Masi, 2022). This
movement enjoyed fleeting popularity but was quickly eclipsed with the
rediscovery of the long-forgotten records of Mendel’s pea plant genetic
experiments by botanists Hugo de Vries and Carl Correns in 1900. From that
time forward, vitalism has been discounted as a relic of a former age, tainted by
quasi-religious metaphysical convictions rather than based on scientific evidence
(Bowler, 2003).
Since 1930, a mechanistic view of life as a living machine has dominated the
life sciences. This duelling mind–body dualism stretches from Descartes’ 17th-
century declaration of animals as ‘automata’, that he formalized into his
mechanical philosophy to explain life (Gorham, 1994). Indeed, the current
academic sentiment about the lack of merit of vitalism and derivatively, the
categorical rejection notion of any purposeful direction to biological and
evolutionary development, has reached such a pejorative that any belief in living
purpose or a non-mechanistic approach to living processes is equated with
superstition and immature reasoning. In 2010, Finnish psychology researchers
studied vitalistic causality in children and adults (Lindeman & Saher, 2007).
They concluded that attributing purpose to objects or explaining biological
processes in terms of intentionality that might be centred within constructive
energetic forces was a common characteristic shared by naive children and
superstitious adults. For them, vitalistic thinking was an obvious example of
ontological confusion and unmitigated superstition, equating with belief in the
supernatural and childish fantasies.
However, there are some scientists who rigorously insist otherwise. Living
organisms are not mechanical machines. Theoretical physicist Stuart Kauffman
maintains that planetary biology has a set of identifiable living principles that are
not in strictly mechanical conformity with known laws of physics (Kauffman,
2000). Others agree that living self-organization and its apparent purposeful
agency lies outside the boundaries of our current understanding of the physical
sciences (Szent-György, 1972; Prigogine & Stengers, 1984; Gómez-Márquez,
2020).
In our contemporary era, this debate has achieved a new differentiating
plateau that clarifies the separation between living entities and mechanical ones.
That difference is that life is information based in ways that do not match how
information is processed in computers and machines. Consequently, as physicists
Sarah Walker and Paul Davies declare, life exists within parameters where ‘new
principles and potentially even physical laws are necessary’ (Walker & Davies,
2017).

There Are Rules of Life

Although we do not have the precise answer to how to define life or how it
arose, some rigorous parameters of living processes can be readily identified that
determine how life is comprised. Despite all other uncertainties, two critical
living essentials are paramount. First, it is not productive to consider life in
terms of a ‘noun’ as a particular assemblage of matter in a strict order. Instead,
life is a ‘verb’ as a dynamic, ongoing, energetic process (De Loof, 2015; Miller,
2020a). Second, life is coterminous with consciousness, and everything in
biology and evolution are defined by that cognitive cellular endowment (Miller,
2016a; Baluška & Reber, 2019; Reber, 2019). Crucially, that conscious life is
embodied in the cellular form and has remained so for at least 3.8 billion years.
Further, we know that the explicit direction of the living process is not directed
towards specific forms but is instead a narrative of seeking cellular solutions to
environmental stresses to assure continued cellular equipoise and survival
(Miller, 2018; Miller et al., 2020a). Further yet, conscious life is capable of
sustaining itself by continuously upholding a set of perpetual rules that govern
cellular interactions and grant planetary survival, since evidence indicates that
the same cellular rules have been in place from the instantiation of life forward
(Miller & Torday, 2018).
Current estimates are that life began at least 3.7 billion years ago and possibly
as far back as 4.28 billion years (Papineau et al., 2022). A factor that is often
underappreciated is that this first evidence of life relies on competent
multicellularity for its support. Single cells provide no opportunity for
fossilization unless they have adopted a communal, multicellular form that can
produce metabolic products that leave fossil remnants. Accordingly, first-life
estimates equate with multicellular life. And crucially, this multicellular life
exists through identifiable established rules.
There is no reason to suppose that those foundational rules initiated at the
beginning of life have materially changed in the intervening aeons, since all life
is directed towards sustaining cellular homeorhetic balance and maintaining the
crucial self-referential identity that established first life (Miller, 2019).
Homeorhesis is a dynamic system that returns to a prior trajectory, standing apart
from homeostasis, which is a system that returns to a particular state. Cells are
flux agents that maintain states of preferential flow and are never in equilibrium.
Cells sustain their preferential homeorhetic equipoise through the defining
cellular properties of chemiosmosis and relative negentropy versus the external
environment (Torday & Rehan, 2012). Life’s living requirement thereby imposes
the need for an external membranous boundary that permits those life-defining
properties.
What are those further perpetuating biological properties that assure that
planetary life thrives? Foremost among these is cooperation. Life willingly
cooperates with other life. The reason is that life is an informational interactome
and, as will be explained in a later chapter, the cooperative assessment and
sharing of information improve its validity (Miller, 2018). Multicellularity is the
biological expression of this imperative, further impelling collaboration,
cooperation, co-dependence, and generally mutualizing competition (Miller et
al., 2019). Consequently, most cells survive by freely trading resources across
scales. Cancer cells do not, which is their pathway to competitive cellular
destruction.
Cognition/consciousness/sentience weld these cellular ‘rules of the road’ into
biochemical biological expressions. Consequently, two further crucial attributes
of life can be readily identified. First, all cellular life proceeds through cell–cell
communication (Torday & Rehan, 2012) since critical environmental
information must be shared to assure individual cellular self-protection (Miller et
al., 2020b). And second, since survival is dependent on conscious, contingent
cellular decisions, life is problem-solving (De Loof, 2015; Miller, 2016a). Of the
greatest importance, at the scale of cells and even for ourselves, problems are
solved through collaboration. Consequently, life and its origins is much more
about symbiosis than neo-Darwinian competition (Chapman & Margulis, 1998;
Villarreal & Ryan, 2018).
Within this overarching framework, other cellular prerequisites beyond
sentience can be identified. Chief among these are the principles of
complementarity and recursion. Complementarity, as a fundamental principle by
which ‘apparent’ opposites unify, was first formulated at the molecular level by
Linus Pauling and Max Delbrück as a intermolecular force, and then extended to
the cognitive frame by Howard Pattee (see Miller et al., 2019; Baluška et al.,
2022b). Although this unification is also a feature of quantum systems, it equally
applies to living cells in which information has both a presenting value and a
hidden implicate order, the importance of which we will review in a later
chapter. Complementarity underscores our living system since cells actively
sustain themselves and cooperatively maintain an entire multi-trillion cellular
organism and its critical balance, which might otherwise represent a concurrence
of opposites (Kafatos, 2014).
Recursion is crucial to sentient cells, enabling the individual cellular
assumption of ‘as here, so elsewhere’. Collaborative life depends on this
sensibility so that groups of self-referential cells can react to information in self-
similar patterns (Miller et al., 2019). This fundamental principle assures that
differentiated cells as constituents of individual organs remain attuned to one
another, following the essential patterns of reiterative self-similarity, mosaic
formulation, and fractal reiterations (Kafatos, 2014). All macro creatures are
examples of recursion across all scales as the basis of common cellular
understanding and effective cell–cell communication. Indeed, the principle of
recursion is unarguable. We reproduce to yield self-similar organisms.
Both complementarity and recursion are elemental biological attributes
upholding life-sustaining sentience. Both are served by the additional critical
principle of reciprocation that underscores all multicellular life, either as
holobionts or microbial biofilms. All these co-linked processes are crucial to
melding the subjective states of self-referential cells to enable seamless
multicellular collaborative organisms that can further reiterate into complex
living societies and planetary ecosystems (Baluška & Mancuso, 2021; Frank et
al., 2022).
Beyond these specific elemental tenets guiding all planetary life, there is an
additional set of rules that govern cellular life so that cells can constructively
engineer solutions to environmental stresses (Miller, 2016a; Miller et al., 2019,
2020a). Certain laws are absolutely implicit to all the biological activity. Cells
uphold the law of sentience as agency, cognition, and communication.
Furthermore, there would be no evolutionary timeline without the law of
biological continuity which represents the drive for reproduction, leading to
evolutionary space-time. These all link to the principle of biological learning
and memory, which is dependent on the principle of biological ordering (as
living negentropy).
As will be fully explained in a later chapter, all multicellularity is driven by
concordant cellular engineering. Consequently, complementarity, recursion, self-
similarity, and fractal reiterations as mosaic formulations are forces that impel
self-consistent biological forms. In toto, these co-linking rules comprise a
dominating principle of biological attraction as an innate, spontaneous drive for
mutual association (Agnati et al., 2009). This principle is best conceptualized as
a cohering biological ‘attractive’ field that energizes the merger of biological
entities into greater degrees of complexity. Accordingly, the principle of
biological attraction underscores the effective measuring assessment,
communication, and deployment of information from environmental cues that
can be carried into discrete biological expression. The attraction between male
sperm and female oocytes that perpetuate multicellular eukaryotic survival is its
further manifestation.
The law of survival (self-repair and self-preservation) corresponds with this
attractive field, enabling organisms to flexibly confront a wide range of
environmental confrontations (Baluška et al., 2022b). Together, these two
dominating living principles (attraction and survival) constitute a form of
cellular glue that motivates the intimate partnerships among cells of many types
with varied genomes to survive as a group, yet energetically maintain individual
states of homeorhetic preference.
This cognitive-based energetic confluence supports the life-enabling stable
non-equilibrium principle, first established by Ervin Bauer (1935) as a defence
of cellular homeostasis. According to the non-equilibrium principle, an
energetically open system is capable of sustaining stable equilibrium separate
from the external environment. To support this principle, the cellular membrane
acts as a biological Maxwell’s demon, decisively contributing to the intelligent
cellular maintenance of preferential homeorhetic cellular flux to consistently
contradict the second law to maintain every cell as a relatively negentropic state
(Baluška et al., 2022b).
None of these foundational principles would be lasting absent one further and
all-encompassing determinant. The physicist Walter Elsasser, renowned for
explaining Earth’s magnetism, contributed mightily to biology by propounding
the principle of constraints (Elsasser, 1981). The living reality of all biological
states is that they exist as a superposition of possible outcomes before any
biological expression. Indeed, this is the essence of conscious contingent
decision-making, enabling cellular problem-solving and determining whether
cells will expend the necessary energy to engage in cell–cell communication. As
Elsasser declared, biology is not founded upon mathematical rules. The choices
that living organisms make within the vast reservoir of potential states are acts of
creativity. However, notably, these can only exert their influence through
reiterating constraints as well as liberties. Effective constraints reiterate
throughout living systems, extending from thermodynamic limitations to
restrictions on protein configurations to imposed physiological limits.
Consequently, biology exerts constraints at every level, reinforced through the
principles of recursion and recursive self-similarity.
However, none of these principles could have exercised their mandated
influence over biological space-time absent yet for a further crucial cellular
principle. In order for life to have successfully perpetuated for nearly 4 billion
years, it is necessary for life to conform to the principle of optimality (Helman,
1986). This dynamic principle was originally identified by Richard Bellmen to
identify the best architectural features for computer program design. The optimal
path occurs when the initial conditions and control variables established within
the first initiating period and solving the first set of problems is followed within
all subsequent decisions as solutions to succeeding sub-problems. All computer
architecture and derivatively, living systems, are mandated to remain in
conformity with first solutions. Accordingly, the state that resulted from the first
solution must always be considered to maintain an optimal subsequent trajectory.
Notably, with respect to cellular life, decisions are choices, and those choices
must perpetually adhere to the life-sustaining rules that began at the very
beginning of life’s trajectory, including any foundational quantum states
(Igamberdiev & Shklovskiy-Kordi, 2017). This specific living principle explains
why all multicellular organisms without exceptions must undergo an obligatory
recapitulation through a unicellular zygotic stage for sexual reproduction (see
further discussion of this principle in Chapter 8).

Is There Minimal Life?

We have already established that the origins of life and its exact definition
remain a mystery, but can a precise threshold of life be established that might
give us a clue about the interface between the animate and inanimate?
Unfortunately, even here, the evidence is still incomplete. Confoundingly, some
molecules behave in such complex ways that it is possible to entertain that they
are living subsets within conscious cells. Those same clouded particulars equally
apply to viruses. One such ‘in-between’ molecule is the vital protein, mTOR, the
mammalian target of rapamycin. Rapamycin is a naturally derived compound
that blocks fungal cell division, originally discovered in a microbe on Rapa Nui
(Easter Island). Mammals produce a competitor molecule and another specific
protein, mTOR, which is the target of both rapamycin and that competitor (Lieff,
2020). In its human form, mTOR can accomplish some startling things,
exhibiting an astonishing range of effects on crucial cellular processes. By
sensing nutrients, energy, and oxidation pathways, mTOR participates in the
manufacture of proteins by signalling messenger RNA and ribosomes and is
necessary for the proper function of the cytoskeleton of the cell. How might one
molecule control such a vast array of processes, assess nutrients, oxygen, and
energy, and even contribute to the remodelling of the developing human brain?
In some ways, mTOR behaves like a brain itself, integrating many highly
complex processes and making a wide range of simultaneous decisions. So, is
mTOR independently alive? Does it have ‘mind’? That has yet to be
conclusively decided.
Aside from single molecules, the plasma membrane and the variety of highly
intricate intracellular structures, such as the nuclear envelope, centrosome, and
the cytoskeletal microtubules, can all act independently or as part of a distinctly
choreographed integrated whole, raising the possibility that each independently
possesses a minute nanobrain or ‘mind’ (Baluška et al., 2021b). Moreover, the
extraordinary competence of ribosomal r-protein networks, displaying
remarkable architectural and functional resemblances to simple nervous systems,
suggests that their role in information processing can also be considered a type
of nanobrain (Timsit & Grégoire, 2021).
Viruses demonstrate surprisingly competent behaviours, perform complex
intracellular tasks, and actively deceive cells. Viruses can cooperate, exhibit
contingent behaviours, communicate, share resources, and even associate
together in assemblies that resemble social interactions (Diaz-Munoz et al.,
2017). These actions are so convincing that an entirely new field of
sociovirology has recently developed. Consequently, are viruses alive? Certainly,
they behave as if they are, at least within cells. For now, it remains uncertain.
However, it is clear that viruses are sufficiently life-like to co-partner with cells
for both collaborative and competitive ends. If not exactly alive, they should be
considered a liminal form of life whose living expression is context dependent
(Miller et al., 2022).

Biology for the 21st Century

It would seem that 60 years after Erwin Schrödinger wrote his book ‘What is Life?’ we should be
able to answer the question. However, Nature never ceases to challenge the limits of our
imagination.
M. Y. Galperin (2005, p. 149)

The explicit gap separating the living from the non-living cannot be bridged
solely by genetic expression since genes are tools of cells and are inert outside
them (Miller, et al., 2020a). Based on many decades of research, we have learned
that life is defined more by its processes than its molecules. Masi (2022)
considers life as ‘anything capable of metabolizing, eating, excreting,
maintaining homeostasis, growing, adapting and responding to the environment,
reproducing, and evolving’. For most scientists, the capacity to evolve is
regarded as the single most important living attribute. In the search for cosmic
life, NASA has elevated the capacity for evolution, proclaiming it the central
feature in its search for extraterrestrial life. Their definition derives from Carl
Sagan’s vision of life as a ‘self-sustaining chemical system capable of evolution’
(as quoted by Masi, 2022). Current research affirms that this definition is
entirely insufficient.
Although, the origin of life is unknown, it is certain that it was coincident with
the inception of self-referential consciousness. Necessarily, that conscious life
exerted its obliged rules to establish and maintain its living foothold. Through
these perpetual cellular rules, we are the inheritors of an immense succession of
self-referential cellular self-similar reiterations, which have enabled our form of
life, level by level.
Part of the defining problem in the study of life’s origins is an affliction
specific to our modern era. The complexities of every scientific discipline are so
overwhelming that each is relatively segregated from others. Accordingly,
obtaining consensus within one scientific field or cobbling a cross-disciplinary
synthesis imposes natural academic barriers. For instance, in his rewarding book
What Is life?, Nobel Prize-winner, geneticist, and biomedical expert Sir Paul
Nurse emphasizes our need for a modern cell theory in biology. That theory
should concentrate on the endowed properties shared by all living organisms,
focusing on their competent linkages that enable living organisms to evolve and
remain concurrently separate from and connected to the environment (Nurse,
2020). This perspective views life as a propulsive, living process. In contrast, the
Harvard Origin of Life project, which includes the exceptional mathematician
Martin Nowak, declared that ‘life is an engine propelled by evolution’
(Humphries, 2013). For Nowak and colleagues, evolution is governed by precise
mathematical principles. Indeed, in this framework, evolution is not just an
attribute of the living process but is its primary definition, reiterating through
combinations of sequences at successive molecular levels (Nowak, 2006). For
them, like Sagan, the key drivers of life are evolution and natural selection,
which naturally constitute its best definition.
Our approach here, driven by the CBC model, insists otherwise. Life is not
propelled by evolution or natural selection. Instead, life is galvanized by the
consciousness that resides in all living things. Sentient entities communicate and
problem-solve to meet environmental proscriptions (Miller, 2016a, 2018;
Baluška & Reber, 2019). This is the timeless living mission of cells. How is a set
of problem-solving solutions to environmental stresses communicated? That is
heredity in all its forms. Evolution results from this chain of processes that
proceeds through self-referential living choices, not the reverse.
We have learned that the basic cell is a complex enactment of physical
properties into a reproductive, entirely ‘organized whole’ as an entrainment of
physics, utilizing basic minerals and organic molecules (Ho, 1994). These
building blocks may be common in nature, but to join them into living systems
requires lipid membranes, sugars, genes, and calcium—all meeting in a
compatible forum in which reciprocating combinations can seamlessly merge.
How that happened, and its precise order, is yet unknown. Yet, the fundamental
alloying force can now be identified. Self-referential cognition prompts
biological and evolutionary development.
We regard that recognizing organisms as an ‘organized whole’ is essential to
understanding biology. Indeed, this perspective has stimulated several
generations of biologists and philosophers as a form of materialistic holism,
often categorized as ‘organicism’ and separate from vitalism or mechanistic
reductionism (Gilbert & Sarkar, 2000). The central tenet of organicism is that the
whole consists of its parts but becomes greater than any simple summation of
those components because of emergent interactions. The full functions of those
biological parts are context dependent, and attempting to separately reduce a
component to discrete functions outside its exact context leads to a fundamental
misunderstanding of the whole.
This organic holism is increasingly accepted among biologists since it is
amply supported by contemporary research, so much so that it fuels much of
modern systems biology and the growing interest in emergent self-organization
that underpins contemporary studies of metabolism, physiology, and morphology
(Allen, 2005). Further, materialistic holism has become an integral aspect of
analysing the successful adaptation of organisms within their respective
ecological niches (Emmeche, 2004). From our standpoint, organicism is
attractive as it does not entail any vitalistic mysticism and avoids the blind ends
of standard reductionism. For ourselves, we lay no claim to adherence to any
distinct philosophical movement. On the contrary, our allegiance is non-
philosophical and biologically based. Life is cognition, embodied in the
perpetual cellular form.
We do not yet know how the interface between life and non-life was crossed.
The physicist Walter Elsasser insists the behaviour of organisms cannot be
reduced to simple physicochemical reactions (Elsasser, 1987). He repudiated
‘vitalism’, arguing that the structural complexity of cells is ‘transcomputational’,
with computational complexities extending well beyond any machine metaphor.
Indeed, he declared that the separation between the living and the non-living
represents a ‘no-man’s land of irrationality’ whose intricacies are frankly
unfathomable, mirroring the whole universe.
Whatever the case, we can assert that the explicit point of division between
the animate and the inanimate rests discretely between chemical processes on the
one hand and communication and problem-solving capacity on the other. There
may never have been just one line that was crossed, with life emerging on a
sliding scale to achieve full cellular competence. Some insist that we are making
arbitrary distinctions about what constitutes life. Keep it simple, they assert. Life
should be considered just a reproductive lineage capable of collaborating in
metabolism (Dupré & O’Malley, 2009). In that circumstance, the concept of life
might be appropriately applied to viruses, plasmids, prions, and intracellular
organelles.
What we know with certainty is that life requires biological boundaries since
the living process is as much a product of its constraints as its liberties. However,
once cognition, communication, and problem-solving became entwined within
the cellular compartment, the rest of life can be considered a process of self-
similar reiterations. Each recapitulation from the first instance of cellular
reproduction forward has centred within fundamental cellular principles,
reinforced through the accurate cellular assessment of information, enacted
through cell–cell communication among competent cells, and always directed
towards finding compatible solutions to meet contemporary environmental
stresses. Necessarily then, cells represent an informational interactome (Miller,
2018). All environmental stresses must be internalized so that the three basic
cellular domains can perpetually meet planetary realities (Miller & Torday,
2018). How well have self-referential cells accomplished this? They have
continuously followed their rules for over 3.7 billion years as the planet’s only
perpetual survivors.
Does this dynamic view of life from the first conscious cell forward constitute
vitalism? Surely not in any metaphysical sense. Nonetheless, cellular
consciousness is a verifiable reality. That ineffable quality is our living domain
and we can securely declare that cellular cognition/sentience is the basal impulse
that propels all subsequent biological and evolutionary development. When
correctly viewed within this framework, life becomes a property beyond ‘being’
constituted by material components. Instead, life is a concordant process of self-
referential communication, problem-solving, and collaboration. Vitalism or not,
that planetary gift of consciousness is the central nexus of our continuous
planetary narrative over the billions of years required to yield us. Thus, even if
many answers still elude us, the path towards settling the enduring debate
between vitalism, organicism, or strictly mechanistic reduction can now be
identified. That resolution resides within the identification of those specific
factors that enable the elusive, transcendent quality of living sentience
conclusively separating the animate from the inanimate, which is the mission of
this volume.
4
Emergence and Evolution of Cells

Emergence of First Cells From Ancient Vesicles and Proto-

Cells
Life on Earth has evolved for an estimated 4 billion years. For the first 2 billion
years of that evolutionary span all life was unicellular, including at first archaea,
bacteria, and then eukaryotic protists. The first multicellular organisms emerged
some 2 billion years ago and diverged into three main types: fungi, plants, and
animals (Porter, 2020; Mills et al., 2022). Based on paleontological and
biological studies, our current understanding implies that the most ancient
archaea and bacteria invented all the essential cellular metabolic processes on
which life depends, including respiration and photosynthesis. All current life on
the planet depends on these innovative, primordial processes (Fournier et al.,
2021; Gözen et al., 2022). These initiating primal unicellular prokaryotic
organisms lacked a cell nucleus but still maintained a relatively simple and
stable metabolic repertoire for a long evolutionary span. Through successive
waves of slow, continuous evolutionary novelty, archaea and bacteria became
increasingly metabolically complex, authoring almost all of the metabolic
processes known presently.
The origin of life remains a mystery. Although not the focus of this volume,
there are several speculative proposals based on acellular replicators that might
account for life including the so-called RNA world hypothesis. It is also possible
that life emerged with help of organic compounds brought to the Earth through
impacts of asteroids and meteorites known to contain diverse organic molecules
that could seed life on the Earth (Milshteyn et al., 2019; Oba et al., 2022).
Currently, there seems to be overall agreement that the LUCA resulted from the
pre-LUCA evolution via the first universal cellular ancestor (FUCA). This early
cell evolution was accomplished under anoxic conditions of ancient Earth
(Porter, 2020; Gözen et al., 2022). The most plausible scenario for planetary life
is that spontaneously formed vesicles merged together and generated the first
proto-cells that could become the competent diverse cell populations that are
now present (Tang, 2021; Gözen et al., 2022). These proto-cells perhaps relied
on non-enzymatic metabolic reactions (Muchowska et al., 2020).
How the first vesicles emerged is debated. One possible scenario is that early
micelles as coacervates (small liquid droplets combining two immiscible liquid
phases based on macromolecules with opposite charges or the association of
hydrophobic proteins) became the first vesicles (Donau et al., 2020; Gözen et al.,
2022). It is proposed that the ancient vesicles had an inherent propensity to fuse
together (Donau et al., 2020; Sarkar et al., 2020), thereby representing the
prebiotic system prone to develop into the first proto-cells (Kompanichenko,
2012; Spitzer, 2017), perhaps with the assistance of self-replicated RNA
molecules (Joyce & Szostak, 2018). Important in this respect is the suitability of
ancient vesicles and proto-cells to reach life-specific far-from-equilibrium states
by handling both energy and information fluxes via their limiting membranes,
allowing the contravention of the second law of thermodynamics that permits the
ordered cellular state (Kompanichenko, 2012). This thermodynamic separation
of the intracellular space from the extracellular environment is the most critical
issue for the initiation and continuation of living processes (Morowitz et al.,
1988). Ever since the first excitable plasma membrane was formed, it never
again formed de novo but remained continuous via replication and has been
structurally continuous across 4 billion years of cellular evolution (Fields &
Levin, 2018; Baluška et al., 2022b). Relevant in this respect are recent reports on
coacervate-like synthetic proto-cells (Abbas et al., 2021; van Stevendaal et al.,
2021) which can be spontaneously membranized by amphiphilic silk polymers
(Li et al., 2019; Yin et al., 2022) and induced into communications and
predatory-like proto-cell behaviours (Qiao et al., 2017; Grimes et al., 2021). We
will further discuss the critical role of the ancient plasma membrane with its
dense population of protein macromolecules that are required to handle sensory
information and energy fluxes in Chapters 5 and 6.

Cells Are Based on Biomembranes Charged With Excited

Electrons and Protons
There is a huge diversity in metabolic processes and sensory signalling cascades
which can be illuminated only by bottom-up molecular biology and biochemistry
based on experimental analysis. An often-neglected aspect of cellular life is that
besides biochemistry and metabolism, crucial bioelectric aspects of cellular life
are based on electrostatic phenomena and ionic electrical charge transfers within
and between diverse macromolecules (Derr et al., 2020). Saliently, bioelectricity
and charge transfers are essential for almost all metabolic processes, especially
respiration and photosynthesis invented by ancient prokaryotic organisms and
vital for life. This suggests that life evolved via proto-cells leveraging
bioelectricity generated by ionic transfers across their limiting membranes.
Present-day archaea and bacteria use membrane-based bioelectricity not only for
respiration and photosynthesis, but also for cell–cell communication to facilitate
stress adaptations (McGlynn et al., 2015; Wegener et al., 2015). Devoted protein
complexes push protons across the biological lipid-based membranes associated
with electron donor and acceptor proteins arranged in forms of charge-transfer
chains, allowing the generation of transmembrane proton gradients charging
electrically capable biological membranes (Morowitz et al., 1988; Milshteyn et
al., 2019). Bioelectrically charged membranes are then harnessed to fuel ATP
synthesis via ATP-synthases spanning the membranes and supporting the active
transport of ions (Mitchell, 1961; Kaur et al., 2021). Importantly, biological
membrane bioenergetics is universally valid and conserved across all domains of
life (Sojo et al., 2014), implying that bioenergetics was the first critical feature of
emerging proto-cells allowing the later emergence of the very first cells
(Morowitz et al., 1988; Milshteyn et al., 2019). As will be further discussed in
Chapters 5 and 6, this specific capacity for cellular bioelectricity and
bioenergetics rendered sentient experientiality within ancient cells, facilitating
their survival and spurring their further evolution in an unbroken continuum to
the present.
Cells use redox-based charge transfers to excite their macromolecules,
especially at their biological membranes, allowing the generation of
bioelectricity, based on charged transmembrane gradients and voltage-sensitive
protein flux across ion channels. Besides excited and movable electrons and
protons, diverse reactive molecular species and radicals (derived especially from
oxygen, nitrogen, and sulphur) are similarly relevant (Jones & Sies, 2015;
Santolini et al., 2019). These free radicals are generated as a by-product of most
metabolic processes and actively kept under tight control through complex
networks of molecules and processes. Moreover, most of these short-lived
radical molecules are an inherent part of homeorhetic signalling systems that
maintain stable, preferential cellular states of flux. Homeorhesis represents the
tendency for a dynamic system to return to a prior trajectory after being altered
by a stimulus. Since all cells are in a constant state of dynamic flux, that term
better suits living systems than homeostasis, which implies a stable equilibrium.
These cellular flux states particularly pertain to respiration and photosynthesis,
involving the release of diverse reactive species by both electron and proton
transport processes across biological membranes. Respiration is the much more
ancient process and served as a prototype for the later evolution of
photosynthesis. That later cardinal event allowed ancient cells to gain
independence from Earth-based energy sources and instead, rely solely on the
photon-based energy source of the Sun. In that respect, that transition is
reminiscent of our current attempts to rid civilization of our dependence on the
Earth-based energy sources and oil reserves, making the Sun our major energy
source. For that cellular transition billions of years ago, bacteria and archaea
used energy-converting hydrogenases for efficient redox-driven complexes as
precursors of the contemporary complex I of the mitochondrial respiratory chain
(Mühlbauer et al., 2021; Yu et al., 2021).
CBC theory proposes that the emergence of the very first living cells, enclosed
with an ancient version of the plasma membrane, is coterminous with the origin
of life and consciousness (Reber, 2019; Baluška & Reber, 2019). The cell plasma
membrane allowed active and tight control of the intracellular space and
generated the essential components of organic chemistry, based on diverse
macromolecules, to sustain cellular functions and energy conservation. Survival
of these ancient cells and their predecessor proto-cells would only have been
possible due to cellular self-referential cognition as cell-based sentience. In order
to embark on continuous biological evolution, CBC theory proposes that these
proto-cells/progenotes (Woese, 1998; Di Giulio, 2021), had a minimal version of
proto-consciousness that was sufficient to respond sensitively and effectively to
diverse environmental insults and challenges that were extremely violent on
ancient Earth (Knoll et al., 2016; Korenaga, 2021). Cellular proto-consciousness
was also required to manage the self-reduplication of their myriad macro-
molecules and processes with high levels of complexity during cell division.
Unfortunately, no fossil record of these first cells exists. After some 4 billion
years, we are left only with the educated guesses and constructive speculations
as to the exact capacities of these very first primordial cells. However, one
essential component of this critical transition to a fully capable cell is
incontrovertible. Any living entity must be thermodynamically separated from
the environment in order to generate and maintain internal order that is essential
for adaptations, metabolism, and heredity. All of these were necessary to pass the
Darwinian threshold of the faithful reproduction of structural integrity and
metabolic processes (Woese, 2002, 2004) that is required for continuous
biological evolution.

Ancient Bioelectric and Redox Codes Precede Genetic Codes

in Cellular Evolution
As mentioned, all life is based on charge transfers by excited electrons and
protons. These electrically charged molecules generate dynamic bioelectric
fields, most prominently from biological membranes, but also permeating both
intracellular and extracellular spaces (Santolini et al., 2019; Derr et al., 2020).
These excitable electrons and protons are central to the critical energetic
pathways of cellular respiration and photosynthesis that underlie most metabolic
processes and mechanisms (Zerfaß et al., 2019). All redox networks were
established at the dawn of life with the first, primordial cells which used these
pathways to extract energy and information from their environment (Harel et al.,
2018; Raanan et al., 2018). Ancient cells still lacked a DNA-based genome but
likely used RNA molecules inherited from the hypothetical RNA world for the
long-term storage of biological information. The fact that the three basic
domains of life, archaea, bacteria, and eukaryotes, have homologous RNA
polymerases but different and domain-specific DNA polymerases (Koonin et al.,
2020) implies the later acquisition of DNA as a supplemental information
storage macromolecule (Di Giulio, 2021). Of greatest importance was the
absolute conservation of the crucial bioelectrical and bioenergetic phenomena
based on excitable, mobile protons and electrons inherent within the plasma
membranes of all archaea and bacteria. Consequently, these phenomena are the
ground state for associated cellular sensory perceptions. These are generated first
by the plasma membrane receiving environmental informational stimuli which
generate code-like patterns of charged particles that move forcefully and
meaningfully across the intracellular space stimulating cellular experiences
(Adamski, 2016; Levin & Martyniuk, 2018). This specific chain begins with
transmembrane membrane flows of signalling molecules and ionic transits that
further connect to internal ionic states and integrated cellular receptivity has
been productively described as the ‘senome’ (Baluška & Miller, 2018). The
senome represents the totality of the cellular apparatus to assess and measure
intracellular information leading to its productive deployment (Baluška & Miller,
2018; Baluška & Reber, 2021a). Accordingly, the formation of a fully competent
senomic apparatus is crucial to the emerging sentience of the ancient cells.

Bioelectric and Redox Codes Underlie Cognitive Circadian

Clocks and Cellular Sentience
Cellular life emerged on Earth within its predictable rotations constituting our
day/night cycles. Ancient proto-cells and the first primordial cells, still lacking a
DNA-based genome, evolved their cellular circadian clocks based on their
ancient redox code platforms (Cortese-Krott et al., 2017; Santolini et al., 2019).
Within contemporary cyanobacteria, it is known that their gene transcription-
based circadian clocks are upheld by the ancient redox-based circadian clocks
assembled through integration of oxidation–reduction cycles of peroxiredoxin
proteins (Edgar et al., 2012; Stangherlin & Reddy, 2013). It can be speculated
that emerging vesicles and proto-cells relied on these proto-cellular clocks
generated by their ancient excitable, limiting, competent membranes
productively channelling both energetic and sensory information-based fluxes
(Morowitz, 1978; Wilson & Lin, 1980).
Recently, we have proposed that the cellular evolution of cognitive circadian
clocks was closely linked with the evolution of cellular proto-sentience (Baluška
& Reber, 2021b). Undoubtedly, ancient proto-cells must have co-evolved their
proto-metabolism (Stewart, 2019; Takagi et al., 2020), including their ancient
versions of cellular respiration and photosynthesis, to permit the emergence of
redox-based sentience and cognitive circadian clocks (Rey & Reddy, 2015;
Baluška & Reber, 2021b). Cellular clocks emerged in ancient cells as predictive
circuits allowing cognitive cells to productively cooperate and collaborate to
further cellular evolution. As we will be discussing extensively in Chapter 6, all
electrically charged and redox-based molecules (Cortese-Krott et al., 2017;
Santolini et al., 2019) freely move within the available intracellular space,
generating dynamic and ever-changing plasma-like and cell-wide
bioelectromagnetic fields (Adamski, 2016; Levin & Martyniuk, 2018).

Symbiotic Evolution of Eukaryotic Cells

How the first eukaryotic cells evolved from the ancient prokaryotic cells remains
a puzzle but a substantial amount of theoretical analysis has been done. The
current consensus is that it took about 2 billion years, a period termed the
Lucacene, to evolve the first eukaryotic cells from the conjoining of two
previously separate living prokaryotic unicellular organisms (Mikhailovsky &
Gordon, 2021; Nobs et al., 2022). Why might it have taken so long to evolve the
first eukaryotic cells? It took just 1 billion years or less to evolve the first
prokaryotic cells after the formation of the Earth. From the perspective of the
CBC theory, this long span to reach the eukaryotic cell from the prokaryotic cells
is strictly related to the imposing task of generating unified eukaryotic cell
sentience from several separable prokaryotic cellular sentiences. This complex
topic will be discussed in greater detail below and further in Chapter 6.
However, before we do so, let us initially focus on the so-called multicellular
nature of the eukaryotic cell from the perspective of symbiotic unification of
originally independent unicellular organisms.
For some curious reason, the symbiotic nature of eukaryotic cells contravened
earlier traditional mainstream logic in cellular and evolutionary biology,
preferring its entrenched narrative of evolution by gradual adaptive nucleotide
point mutations to the self-evident saltationist gaps that evolutionary evidence
provides. As a particular example, the concept of a crucial endosymbiosis
enabling the eukaryotic cellular form based on mutual symbiosis was greeted by
ridicule and scientific dissent when first proposed in Lynn Margulis’s 1967
landmark paper, ‘On the origin of mitosing cells’ (Sagan, 1967). This remarkable
paper was rejected by 15 journals, until its ultimate acceptance by the Journal of
Theoretical Biology (Gray, 2017). The strong entrenched preference for
autogenic evolutionary theories had also resulted in the predominant belief that
the eukaryotic nucleus was the product of slow cellular evolution through
gradual remodelling of intracellular membranes and compartments. In order to
keep this autogenic scenario relevant and valid, some inconvenient aspects of the
eukaryotic cell biology were conveniently ignored (Baluška & Lyons, 2021). For
example, the presence of the centrin-based contractile rhizoplast connecting the
basal bodies of microtubule-based eukaryotic flagella with the surface of
eukaryotic nucleus suggests that nucleus and flagella have the same evolutionary
origin (Baluška & Lyons, 2021; Joukov & De Nicolo, 2019). This mysterious
structure is present in numerous sperm cells and many protists including the
green algae Chlamydomonas. As a heritage of this structure, centrin is present in
almost all eukaryotic cells and organisms, having diverse functions related to
calcium-induced contractility. The best explanation for the centrin-based
contractile rhizoplast (Joukov & De Nicolo, 2019) is an endosymbiotic origin,
just as is the case for the origin of the eukaryotic nucleus (Baluška & Lyons,
2021). Endosymbiosis would explain several unique cellular features, including
similarities between nuclear pores and cell–cell channels (Baluška et al., 2004;
Baluška, 2009), which are also incompatible with autogenic theories of
eukaryotic cell evolution.

Multicellular and Archaeal Nature of Eukaryotic Cells

Evolution of the eukaryotic cell still remains mysterious but it represented a
momentous event in cell evolution. All present-day eukaryotic cells, including
all protists, fungi, plants, and animals, trace back to the last eukaryotic common
ancestor (LECA) equipped with a previously evolved microtubular cytoskeleton-
based flagellum (Margulis et al., 2006; Koumandou et al., 2013). That early
competent eukaryotic cell could engage in an ancient version of phagocytosis for
nutrition, resulting in an evolutionary explosion within the eukaryotic cellular
domain of life (Koumandou et al., 2013; O’Malley et al., 2019). As already
mentioned, the Lucacene transition phase from the LUCA to LECA took
approximately 2 billion years which is, obviously, an immense period of time
(Mikhailovsky & Gordon, 2021). That extended duration relates to a vital hurdle
that had to be overcome. For success, it was necessary to set the internal cellular
stage for the accommodation of two different organisms to join together in
endosymbiosis between separate previously competent independent ones. To
effect that merger, all cellular structures, including their membranes, RNA and
DNA polymers, and ribosome-based translational apparatus must have been
made compatible with one another for seamless communication and for the
sharing of information in order to successfully confront environmental stresses.
Most importantly, the immense task of generating a new composite multicellular
self-identity as a unique and novel dual agency had to be devised.
In our recently proposed model of emergence of the LECA, two
fundamentally different archaeal cells merged, with one becoming the combined
cell’s nucleus and microtubular apparatus that was the grafted to the actin-based
cytoskeleton of the resident archaeal host cell. The result was the ‘birth’ of the
contemporary eukaryotic cells with their rich complement of tools in a combined
cytoplasmic space enclosed by one plasma membrane. While the identity of both
these unicellular organisms may never be revealed, there are strong recent
indications that the host archaeal cell was related to the currently discovered
Asgard archaea (Zaremba-Niedzwiedzka et al., 2017; Rodrigues-Oliveira et al.,
2023). In contrast, the identity of the putative microtubular guest cell remains
unknown. The archaeal nature of both merging host and guest cells would
provide some explanation to puzzling issues. For example, it might account for
why archaea, in contrast to bacteria, are not pathogenic to eukaryotes (Borrel et
al., 2020; Jung et al., 2020) although human and plant archaeomes are abundant
(Mahnert et al., 2018; Jung et al., 2020). Furthermore, that association might
have provided the conforming channel that permits archaeal constituents as
productive aspects of the holobionic microbiomes of both plants and animals.

Slow Emergence of Eukaryotic Cells Due to the Cellular

Sentience Binding Problem
The 2-billion-year-long Lucacene period required for the emergence of the first
eukaryotic cells (Mikhailovsky & Gordon, 2021) had previously been very
difficult to explain. From the CBC theory perspective, however, this lengthy
period is logical if cellular cognition and the linked, requisite sentient faculties
of the two archaeal cells were based on different structural cell motility
platforms. In fact, the host cell cytoarchitecture and motility was based on the
actin cytoskeleton whereas the putative guest cell’s conscious sense-awareness
and problem-solving apparatus relied on the microtubuli-based flagella. As will
be further discussed in detail, these two cytoskeletal assemblies are relevant for
cellular sentience and their electrical action potentials are closely related to the
emergence of supracellular organismal sentience in multicellular organisms.
Here we will only briefly introduce the major differences between these two
most ancient cytoskeletal systems of eukaryotic cells. The actin cytoskeleton is
inherently associated with the action potentials (Baluška & Mancuso, 2019) via
its interactions with the plasma membrane based on pulsatile and excitable
contractions with cascading reverberations across the cell to its peripheries
(Staddon et al., 2022; Yang et al., 2022). The actin cytoskeleton is essential for
the exocytosis, endocytosis, and endocytic vesicle recycling, which are all vital
for synaptic cell–cell communication (O’Neil et al., 2021; Wu & Chan, 2022).
Microtubules are primarily associated with and organized by the microtubule-
organizing centres (MTOCs) which are connected with the basal bodies of
flagella and cilia, as well as with the nuclear surfaces in cells lacking these
structures (Baluška et al., 1997). It is very relevant that both the actin and
microtubuli-based cytoskeletal systems represent targets of anaesthetics along
with their excitable membranes (Platholi et al., 2014; Granak et al., 2021).
Notably, all organisms with a modified cytoskeleton and membranes become
insensate after exposure to anaesthetics (Craddock et al., 2017; Hameroff, 2021).
As Christof Koch concluded, consciousness cannot be computed just based on
information. Instead, consciousness is imprinted and built into specific and
dynamic biological structures (Koch, 2018). According to CBC theory, basal
consciousness is generated at the cellular level through the coordination of
multiple internal structures and processes including the macromolecular
assemblies at and around excitable plasma membranes and cytoskeletal
polymers. Since all cells have these essential structures, all cellular beings can be
anaesthetized at all scales, starting with prokaryotic organisms, unicellular
protists, extending to fungi, and all plants and animals, including humans
(Baluška et al., 2016; Kelz & Mashour, 2019).
Consequently, the first eukaryotic supracellular-like organism required a
melding of two hypothetic cellular organisms with two different
cytoarchitectures: one was relying on an ancient version of actin cytoskeleton-
based cellular sentience whereas the second was based on a microtubular
cytoskeleton. These two fundamentally difference cellular sentiences were, at
first, distinct from each other. It can be presumed that this integration took a very
long evolutionary time span. Ultimately, unified eukaryotic cellular sentience
was established and became the new platform for conscious awareness with high
levels of responsiveness linking to greater problem-solving abilities. This higher-
complexity cellular sentience proved to be very competent, energizing not only
an evolutionary burst of creativity leading to a great diversity of protists (Finlay,
2004; Burki et al., 2021; Gooday et al., 2021) but also establishing the proper
ground state for the emergence of fully integrated multicellularity which evolved
into fungi, plants, and animals.
All planetary habitats were affected, including the dark ocean and deep
seafloor that hosts a major part of the Earth biosphere with its huge diversity of
pelagic and benthic protists. This abyssal benthic megafauna is still largely
uncharacterized and some of these protists, such as xenophyophores, reach huge
sizes, up to 24 cm (Gooday et al., 2021). The evolution of true multicellularity
that could lead to holobionts (Niklas & Newman, 2020; Umen, 2014), required
tight integration of cellular informational systems so that individual cells could
seamlessly amalgamate into vast assemblages of trillions of cells of many types
and degrees of specialization (Colizzi et al., 2020). For this threshold to be
reached, intracellular organellar synapses were required to integrate eukaryotic
cells and their organelles (Baluška & Mancuso, 2014). These essential structures
play a central role in the informational and mental integration of the myriad
eukaryotic cells and their companion microbiome that must coordinate to be
fully dextrous holobionts.

Viruses as Key Players in Cellular Evolution Towards Higher

Complexities
Viruses remain mysterious, stimulating an ongoing contentious debate about
their living or non-living status. Similarly, it is disputed whether viruses
preceded cells as part of a putative ancient virus world or if they are an
evolutionary cellular product that somehow escaped from diverse cells. Life as
we understand it is not possible without a lipid bilayer-based excitable plasma
membrane. Consequently, it is more likely that viruses are not alive. However,
viruses do have a competent capsid envelope and exhibit many features that are
attributed to living entities when they gain entrance to cells and co-opt their
internal machinery. Accordingly, it is possible to consider viruses as becoming
‘alive’ inside cellular boundaries. In this scenario, all viruses are semi-living
macromolecules which can escape their birthplace within cells, entering a
dormancy-like inactive stage outside of them much like bacterial spores.
However, for their replication, they must return to cells. In order to infect and
replicate within the cells, viruses manipulate all the cellular macromolecules,
especially their membranes, cytoskeletal elements, and nuclei. In addition, they
induce the formation of synaptic-like adhesion domains for their cell–cell spread
(Baluška, 2009; Bayliss & Piquet, 2018). Although they were originally not part
of neo-Darwinian evolutionary theory, it is clear that they play central roles in
cellular and organismal evolution (Koonin & Wolf, 2012). Viruses act as vectors
of genetic materials and genes among diverse organisms (Gilbert & Cordaux,
2017; Irwin et al., 2022). Moreover, diverse viral-derived elements are relevant
for the evolutionary origins of agency, self, and immunity in all three domains of
life. In this regard, viruses represent a vital intermediary of genetic and
information transfer and communication across the three cellular domains of
Prokaryota, Archaea, and Eukaryota (Miller & Torday, 2018).
Viruses also might play crucial roles in the evolution of the first eukaryotic
common ancestor (FECA) and LECA, contributing meiotic genes, as well as
genes involved in coordinating the cellular and nuclear merger during eukaryotic
gamete fusion, known to predate the emergence of LECA (Ramesh et al., 2005;
Moi et al., 2022). Especially relevant to this process is the viral class II fusogen
HAP2/GCS1 (Brukman et al., 2022), essential for the gamete fusions in protists
(Pinello & Clark, 2022), plants (Valansi et al., 2017), and several other
eukaryotic organisms (Podbilewicz, 2014; Pinello et al., 2017). Recently, it was
discovered that archaeal fusexins are homologous with eukaryotic HAP2/GCS1
gamete fusion proteins (Moi et al., 2022). Viruses manipulate cellular structures
very effectively. They can induce vesicle formation both in and out of cells,
either internalizing within or escaping from target cells. Further, these complex
actions implicate viruses in the evolution of eukaryotic endocytosis and
exocytosis. Interestingly, molecular machinery required for the budding of viral
vesicles out of eukaryotic host cells also impact the final stages of the
cytokinetic cell division (Carlton & Martin-Serrano, 2007; Callistri et al., 2022),
suggesting that ancient viral infections might have been relevant for the
invention of cytokinetic cell division of the eukaryotic cell. Notably too, the
emergence of Eukaryota was not just dependent on viruses. Archaea was crucial
to the emergence of the endosomal sorting complexes required for transport
(ESCRT) complex as part of eukaryotic cytokinesis (Hatano et al., 2022). The
ESCRT protein complexes have an ancient archaeal origin and are essential in
diverse cellular processes including cellular endomembrane organization as well
as for viral intracellular life cycles (Meng & Lever, 2021; Callistri et al., 2022).
The path from primordial proto-cell to competent conscious cellular life was
the combination of lengthy periods of internal cellular adjustment interspersed
with infrequent leaps of evolutionary novelty. Eukaryotic cells, the types of cells
that make up our cellular architecture, are the result of a combination of two
prior independent living forms learning that mutualistic symbiotic
accommodations are their best means of survival. All the internal architectural
complexity of cells are tools of that journey, and honing them required billions
of years. That entire narrative was dedicated to dual perpetual aims. Each cell
acts to uphold its conscious self-integrity by the active, competent, and
continuous assimilation of the external environment and thereby grants their
perpetual planetary dominion.
5
The Structural and Bioelectrical Basis of Cells

Motto: Life is nothing but an electron looking for a place to rest.

Albert Szent-Györgyi (1972)

The Plasma Membrane as a Smart and Excitable Anti-

Entropic Barrier
As we mentioned in Chapter 3, cells are living organisms as open systems,
extracting matter, energy, and information from their environment for their
maintenance and survival in confrontation with a perpetually changing
environment. They export all unwanted material and energy via metabolic
degradation products and heat. The first ancient plasma membrane fully
enclosed an internal space allowing the assembly of concentration gradients
across a proto-version of a competent cellular plasma membrane (Morowitz et
al., 1988; Morowitz & Smith, 2007). Disequlibria across the proto-version of
that plasma membrane allowed the harnessing of energy and material fluxes via
proto-versions of biological Maxwell’s demons, as competent sensors, channels,
and transporters (Binder & Danchin, 2011; Boël et al., 2019). This effective
interface permitted the generation of proto-excitability through electrochemical
ionic gradients and out-of-equilibrium bioelectricity-based metabolism. Cellular
sentience emerged together with cellular proto-metabolism as an inherent feature
of cellular biology at the very beginning of cellular life, allowing ancient cells to
embark on continuous cellular evolution based on cognition and sentience.
Notably, the intelligent anti-entropic actions of the biological version of
Maxwell’s demons densely populating the plasma membrane enabled the control
of energy fluxes that harnessed the plasma membrane excitability that underpins
cellular cognition (Miller et al., 2020a, 2020b), allowing cellular survival and
uninterrupted cellular evolution for more than 4 billion years (Baluška et al.,
2022b). Bioenergetics based on charged ions, free electrons, and reactive species
moving within the intracellular space is an integral part of the tightly linked
senomic apparatus that underlies cellular sentience.

Cellular Bioelectricity Is Based on Charged Ions and Moving

Electrons
Cells are based on bioelectricity because life depends on moving electrons. In
fact, all cells maintain life by effecting redox reactions in biological
macromolecules through the exchange of electrons between electron-donor and
electron-acceptor proteins, typically embedded within biological excitable
membranes. In addition to the most investigated and understood reactive oxygen
species (ROS), underlying both cellular respiration and photosynthesis, there are
other reactive sulphur and nitrogen species which are even more ancient and
relevant for the evolution of life (Cortese-Krott et al., 2017; Kolluru et al., 2020).
Moveable electrons in iron-sulphur cluster-containing ferredoxins appear to go
back to the very origin of life (Lane, 2022; Moran, 2022). As we have already
discussed in Chapter 4, all reactive species interact generating the so-called
redox code (Santolini et al., 2019) as it emerged together with the first cells. This
ancient redox code is associated with a similarly ancient electrome code based
on excitable membranes and the cytoskeleton (De Loof, 2016; Fillafer et al.,
2021). The cellular redox code assembled in the very first cells, emerging from
hypothetical proto-cells. This concurrent emergence would explain why our
metabolic cycles closely couple with our circadian cycles, both sharing deep
similarities (Amponsah et al., 2021; O’Neill, 2021). Intriguingly, a critical role
was played by peroxiredoxins which allowed tight co-evolution of ancient
circadian clocks and emerging metabolism in the very first cells (Edgar et al.,
2012). Oxidation–reduction cycles of peroxiredoxins constitute a universal
molecular player within the circadian rhythms of all three domains of life.
Plasma membrane bioelectricity and its associated highly dynamic actin
filaments are closely integrated via endocytic vesicle recycling (for plants, see
Baluška & Mancuso, 2019; Baluška & Wan, 2021), generating fast bioelectric
signals known as action potentials (Beilby, 2007; Hedrich, 2012). Although plant
action potentials have a slightly modified ionic background, the properties of
action potentials in animals and plants are very similar (Baluška et al., 2021a;
Scherzer et al., 2022). In both animals and plants, action potentials are essential
for the movements of vital organs and the organism as a whole, and further, both
types of movements are blocked by anaesthetics (Baluška & Yokawa, 2021;
Scherzer et al., 2022). We will discuss these issues in Chapter 11.
Integrated Cytoplasmic Matrix: Self-Organized and
Crowded Protoplasm
Cells are composed of numerous biological macromolecules with proteins being
the most numerous and performing the most important tasks. These flow along
metabolic, biochemical, biophysical, and signalling pathways, integrating into
very complex networks that assemble in the cytomatrix-like cellular interior
(Luby-Phelps, 2000, 2013). In several respects, the actions of proteins resemble
cognitive counterparts as their conformations and interactions are tightly coupled
with cellular cognitive faculties inherently linked to cellular sentience (Baluška
et al., 2021b). An excellent example of this linkage are ribosomes, representing
the translational apparatus of cells acting at the interface between their genomes
and proteomes (Timsit et al., 2021). The crowded intracellular micro-
environments, due to dynamically interconnected macromolecules (Rivas et al.,
2004; Foffi et al., 2013), can restrict and disturb cytoplasmic diffusion
(Kwapiszewska et al., 2020). The cognitive potentials of proteins, their
associated macromolecules, and dynamic cytoskeletal polymers (Baluška et al.,
2021b; Timsit & Grégoire, 2021) represent a cell-based molecular interactome
that has been inherited as a structural continuum across several billion years of
evolutionary history, with every successive cell division propagating the
initiating structural and functional features of all the ordered biomolecules that
comprise competent cells (Baluška et al., 2022b).
The dynamic self-organization of these intracellular structures, organelles, and
micro-environments was experimentally documented via vigorous
ultracentrifugation of unicellular organisms such as Euglena. These hardy
microbes remained viable after intracellular stratification of their structures and
organelles, recovering quickly from that stress (Srere, 2000). These robust
survival characteristics suggest that their highly integrated biological macro-
molecules can effectively and rapidly reconstruct ordered networks after
mechanical disturbances. There is a natural limit, however, since that self-
organizational order is lost in both dying or dead cells (Srere, 2000). Therefore,
there must be a highly effective ordering and organizing principle at work inside
cells. Our position is that the previously discussed redox and bioelectric codes
are involved. We will discuss these important issues more deeply in Chapter 6.
The classical biochemical view of the cytoplasm as a bag of enzymes has been
proved to be incorrect. Biochemical processes in cells are spatially organized via
supra-molecular fractal and hierarchically organized complexes as part of
dynamic structural–functional cytoplasmic organization (Aon & Cortassa, 2015;
Schmitt & An, 2017). In cellular evolution, ordered macromolecules are
inherited through structural templating from lineal ancient cells (Baluška et al.,
2023). Spatial assembly of cytoplasmic structures is sensitive to cellular
signalling pathways, linking this process directly to cellular sensory-based
cognition (Reber & Baluška, 2021; Shapiro, 2021). This inherent and dynamic
sensitivity of ordered macromolecules to the environment has been proposed to
act as nano-intentionality representing a type of subcellular proto-mind (Fitch,
2008; Timsit & Grégoire, 2021). The concept of nano-intentionality adroitly
complements the concept of nano-protoplasts as proposed by Gilbert Ling
(2007). We must be aware that the cellular interior of eukaryotic cells is a
crowded, active environment based on colloid-like active emulsions and
electrically charged hydrogels complemented with diverse biomolecular and
cytoskeletal condensates (Charras & Lenz, 2022; Yan et al., 2022). Crowded and
integrated composition helps explain the rather surprising survival of naked
protoplasts released from wounded coenocytic algae (Kim et al., 2014).
An additional feature of intracellular molecular crowding are biomolecular
condensates which are membraneless organelle-like droplets inside the
cytoplasm and present in cell organelles, including the nucleus (Li & Jiang,
2022). These self-assemble by liquid-liquid phase separation into transient
liquid-like droplets. Importantly, recent studies have revealed that the actin
cytoskeleton-based biomolecular condensates orchestrate self-assembly and
actively participate in signalling the cell periphery complexes (Charras & Lenz,
2022; Yan et al., 2022).

Actin-Based Cell Periphery, Sensors, Demons, and

Membrane-Cytoskeleton Adhesions
The cellular periphery in all eukaryotic cells is supported by the dynamic actin
cytoskeleton which is closely connected with sensory signalling initiated through
membrane-embedded proteins. These complexes act as specific sensors,
representing the biological version of Maxwell’s demons (Mizraji, 2021;
Baluška et al., 2023), transducing signals vectorially across the plasma
membrane towards the cytoskeleton. A special role is played by interstitial water
in this connection (Mayer et al., 2006), generating a specific micro-environment
that permits all the plasma membrane-based sensors, receptors, ion channels, and
other biomolecules that handle biologically relevant information to act as the
biological version of Maxwell’s demons (Baluška et al., 2023).
Significantly, the specific nature of interstitial water, known as exclusion zone
water, is sensitive to weak electric and magnetic fields (Rad et al., 2021;
Shalatonin & Pollack, 2022) and acts as a target of both local and general
anaesthetics (Kundacina et al., 2016). The actin cytoskeleton and microtubules
are sensitive to anaesthetics, providing a huge intracellular surface to be
associated with the exclusion zone water (Kabir et al., 2003; Chierici et al.,
2022). Furthermore, other biomolecules are controlled by their hydration shells
in an ultrafast dynamic mode, impacting their structural memories (Elsaesser,
2009; Laage et al., 2017). Bundles of actin filament are sensitive to this
molecular crowding and the resulting electrostatic interactions (Castaneda et al.,
2021), making the whole actin-based cell cortex prone to the perceptions and
amplications of any sensory events effected by the biological version of
Maxwell’s demons.
There are numerous proteinaceous sensors embedded within the plasma
membrane which continuously sense the cellular environment, flexibly changing
conformations and passing this sensory information onwards via bioelectric and
biochemical signal transduction pathways. During these measurements, cells and
their sensors behave as biological versions of Maxwell’s demons, acting as a so-
called Szilard macromolecule engine (Varn & Crutchfield, 2016). They repeat
three-step cycles to extract information from their surroundings through
measurement, control, and erasure. Of these three basic stages, the last one is the
most energetically demanding. Accordingly, this means that these biological
demons are acting in accordance with the second law of thermodynamics.
Moreover, the erasure step also leads to resetting the demon for the next
measurement within the next cycle. The obtained information is used to support
the orderly assembly of macromolecules, representing local islands of low
entropy submerged within a cytoplasmic space of a high entropy (Hoffman,
2016; Varn & Crutchfield, 2016).

Actin-Based Cytoskeleton in Endocytosis and Bioelectricity

of the Plasma Membrane
The bioenergetics of the plasma membrane is closely linked to the inherent
bioelectrical nature of the actin cytoskeleton. Actin filaments support the
electrical propagation of ionic waves (Hunley & Marucho, 2022; Manrique-
Bedoya & Marucho, 2022) along large intracellular surfaces of this ancient
cytoskeletal system with its deep evolutionary origins in archaea (Akıl et al.,
2021). Both actin cytoskeleton and membrane-based bioelectricity are closely
linked to the tight control of pH on both sides of the plasma membrane.
Moreover, action potentials are associated with cell surface deformations which
indicates that bioelectricity is intrinsically linked with both electrostatic and
electromechanical phenomena (Galassi & Wilke, 2021). In order to maintain
physical and structural plasma membrane homeostasis, eukaryotic cells employ
either endocytosis (removal of the excess membrane) or exocytosis (adding
membrane from intracellular vesicular stores). The actin cytoskeleton is essential
for both processes. Advances in our understanding of the evolutionary origin of
action potentials reveal that ancient primordial cells used these fast electrical
signals to connect to vesicular trafficking to safeguard the mechanical integrity
of these ancient cells (Andrews et al., 2014; Brunet & Arendt, 2016).
Endocytosis is essential not only for safeguarding plasma membrane integrity
but also for internalization of the external environment and intercellular
interstitial space, generating intracellular islands of extracellular space within the
cellular interior. This process seems to be unique to eukaryotic cells,
contributing to both cellular heterotrophic nutrition and a significant increase in
the effectiveness of the sensory border between the inside of cells and their
extracellular space. As the limiting membrane of endocytic vesicles and
endosomes is derived from the plasma membrane with its dense population of
bioactive constituents as the biological version of Maxwell’s demons,
endocytosis results in cells which are much better informed about their local
environment compared to cells with less competent membranes (Baluška et al.,
2021b).
In the case of the plasma membrane, an endosomal matrix is assembled from a
diverse populations of recycling endosomal vesicles (Sigismund & Scita, 2018),
supplementing the redox code in the cellular information matrix, thereby
contributing to the vital functions of our recently introduced plasma membrane-
based cellular senome concept (Baluška & Miller, 2018). The senome
complements the genome and epigenome in the trinity of components that
comprise the essential elements of cellular information management systems
(Miller et al., 2020a, 2020b). Of these, only the senome is directly linked with
the external environment via biological versions of Maxwell’s demons
embedded within the plasma membrane and plasma membrane-derived
membranes of endosomes. Therefore, the senome is directly relevant for cellular
cognition and sentience (Baluška et al., 2021b). Sensory signals initiated at the
plasma membrane permeate the whole cytoplasmic space and reach the nuclear
surface (Matzke et al., 2019). Accordingly, the entire senome apparatus actively
participates in the information management system of each cell upstream of any
involvement by the cell’s central genome. Importantly, these molecular-based
biological Maxwell’s demons, especially ion channels and transporters, are
sensitive not only to the external environment but also to bioelectrical charges
within the plasma membrane (Bezanilla, 2018; Hille, 2022).
Bioelectricity-based membranes have been investigated for a long time in
neurons, but this field received an unexpected push from the uncovering of the
biochemical mysteries of cell energy processes based on ATP. Previously, there
was little interest in bioenergetics compared to the study of biological molecules
or genes. While the discovery of DNA was anticipated and celebrated, the
unexpected discovery of oxidative phosphorylation-based chemiosmotic theory
met with a resistant scientific community treating that breakthrough rather like
an unwanted child in the family. Consequently, Peter Mitchell’s illuminating
discovery of a cohering chemiosmotic theory received initial disdain (Prebble,
2001). Mitchell’s revelations went against scientific expectations in the same
way that Margulis’s endosymbiotic theory had. Each took several years before
they were accepted (Mitchell, 1961; Prebble, 2001). Eventually, however, Peter
Mitchell was awarded the Nobel Prize in 1978. Discoveries by other scientists
supporting this new view of bioenergetics were crucial to that acceptance,
including the involvement of membranes, protons and electrons, rotary
ATPases/synthases, and respiratory complexes (Yip et al., 2011; Sazanov, 2015).

Tubulin-Based Cytoskeleton and Centrosomes: From Basal

Bodies to Nuclear Surfaces
In contrast to the actin cytoskeleton, microtubules are widely distributed and
intrinsically associated with the basal bodies of flagella/cilia and the nuclear
surfaces of multinucleated animal, fungal, and most plant cells. The evolutionary
origins of microtubules, centrosomes, and centrioles are tightly linked with the
evolution of the eukaryotic nucleus. In ancient protist cells, the nuclear surface is
anchored via contractile centrin-based rhizoplasts at the basal bodies of cilia and
flagella. Interestingly, sperm cells in animals and lower animals closely resemble
hypothetical protist-like cells. These merged with oocyte-like host cells to
generate the first eukaryotic cell based on integration of two originally
independent cells. Importantly, these two ancient cells were supported by two
different cytoskeletal systems: the actin cytoskeleton-based host cell and the
microtubules/centrin-based guest cell (Baluška et al., 2004; Baluška & Lyons,
2021).

Endoplasmic Reticulum as a Master Organelle Integrating

Other Organelles and Endomembranes
In contrast to the prokaryotic archaea and bacteria, all eukaryotic cells have a
complex system of intracellular organelles and endomembranes. There is a clear
duality in the endomembrane systems in all known eukaryotic cells—the plasma
membrane organizes the outside–inside endocytic membrane flows and the
nuclear envelope-associated endoplasmic reticulum organizes the inside–outside
endocytic membrane flows. The endoplasmic reticulum acts as a kind of master
organelle, making tight membrane–membrane contacts with all other organelles
as well as with the plasma membrane (Mathur et al., 2022). These endoplasmic
reticulum–organelle contact sites not only integrate the intracellular space of all
eukaryotic cells but they also serve as intra-organelle communication platforms
(Jain & Zoncu, 2022; Kim et al., 2022) via intracellular synaptic-like membrane
adhesion domains (Baluška & Mancuso, 2014).

Reactive Oxygen Species–Calcium Waves Within and

Between Cells
The extensive integration of the cellular protoplast is most obvious when
signalling events induce calcium and redox waves that rapidly spread throughout
cells, often continuing externally to enable supracellular connections through
tight synaptic adhesion domains. This feature is well known in neuronal cells,
animal tissues, organs (Yuryev et al., 2016), and plant cells and tissues (Tian et
al., 2020), as well as within their symbiotic chloroplasts (Frank et al., 2018).
ROS represent ancient redox and electrically charged molecules due to their loss
and gain of free electrons that tightly couple to crucial cellular metabolic and
energetic processes such as the Krebs cycle, respiration photosynthesis, and
biological circadian clocks (Pospíšil et al., 2022). All cells actively maintain
ROS homeostasis. Part of their signalling and coding roles is associated with
intracellular and transcellular ROS waves. In both plants and animals, ROS and
calcium waves are tightly integrated with bioelectric action potentials (Lee &
Seo, 2022; Scherzer et al., 2022). Redox code and ROS homeostasis are solidly
linked to ion homeostasis. Interestingly, neurotransmitter-related molecules,
including gamma aminobutyric acid (GABA) and melatonin, play important
roles in this respect (Hardeland, 2022). Both GABA and melatonin represent
ancient signalling molecules (Xie et al., 2022) and were introduced into evolving
eukaryotic cells via bacterial endosymbionts (Reiter et al., 2018; Zhao et al.,
2019).
6
The Biophysical Basis of Cellular Sentience

Cellular Sentience Guides Cellular Evolution and

Communication
The subject of cellular sentience remains outside of mainstream cell biology
despite its strong support by numerous lines of research and observation. One of
the major reasons that this topic maintains its relative orphan status is that our
scientific analysis of sentience started from the wrong end. Most considerations
of sentience begin with the most complex cognitive systems such as the human
brain. In science, one should start with the most simple system and, only after
some understanding of it at that level, approach more complex systems with
greater understanding. There is another significant problem in discussing cellular
sentience. Our most important theory in biology, cell theory, is in permanent
crisis and confuses the biological connections between cells and organisms.
It is a most important point that although there have been nearly 4 billion
years of life on this planet, the first 2 billion years were an exclusive period
where the terms cells and organisms were synonymous. There were only
unicellular organisms and the first eukaryotic cells emerged symbiotically from
several originally independent prokaryotic cells (organisms) about 2 billion years
ago. The fact that any single eukaryotic cell is a multicellular assembly
representing a cells within a cell situation (Baluška et al., 2004a, 2004b) clearly
documents the definitional problems facing a unifying framework (Mazzarello,
1999).
An additional serious problem blocking the acceptance of the primacy of
cellular sentience is the ‘central dogma’ of molecular biology formulated after
the discovery of DNA. Crick’s central dogma states that the information encoded
in DNA sequences represents the only source of biological information within
cells that is relevant for cellular evolution, development, and morphogenesis.
Recently, it has become obvious that transgenerational memory is possible and
represents an often-used pathway, allowing improvements in organismal
adaptations to challenging environment (Klosin et al., 2017). This pathway is
especially useful in plants which use their sessile lifestyle to permit effective
transfer of their sensory stress memories across generations (Byko & Kovalchuk,
2010; Oberkofler et al., 2021). Besides the genome which represents the
sequence-based digital storage medium, the plasma membrane and the
associated cytoskeleton provide a structure-based templating storage medium as
part of the epigenome. A recent study reported that a lipid bilayer membrane
composed of phospholipids, but lacking proteins and any other molecules, was
capable of long-term potentiation and memory storage (Scott et al., 2022).
Cellular sentience supersedes the genome and epigenome, serving as a
repository of flexible long-term memory for cells, and is crucial for
understanding their proper environmental context.
Sentience is an implicit aspect of cellular cognition and memory and essential
for cell survival via contextual decision-making from the very early evolution of
cells. Cell and organism were synonymous terms during the first 2 billion years
of life. All cells ever existing on this planet, including those of multicellular
organisms, have embedded historical memory in their ordered biomolecules.
Especially important in this respect, encompassing cellular existence as
unicellular organismic forms, is their plasma membranes. This type of
membranous historical continuity necessarily became a part of multicellular life,
permitting the cells of all multicellular organisms to act as semi-autonomous
units still capable of seamless coordination through fast, efficient cell-to-cell
communication. This inherent feature of all eukaryotic cells was critical for the
communicative emergence of multicellularity, as well as embryogenesis and the
development of fungi, plants, animals, and humans. Without an understanding of
cells in their historical, organismal, and communicative context, we will not be
able to properly understand archaea, bacteria, protists, fungi, plants, and animals.
Obviously, without that requisite grasp, our understanding of human diseases
and our place in nature will remain compromised.

Plasma Membrane as a Vesicle-Generating Smart Border for

Inside–Outside Dichotomy
The plasma membrane permits the establishment and active maintenance of life
processes by defining the organismal self (inside) from the extracellular space
(outside). This situation is true for all unicellular organisms, but also partially
true for all cells of multicellular organisms. The plasma membrane smart border
performs a sensory analysis of both the outside space via exteroception and the
inside space via interoception. The sensory analysis of the extracellular space via
cellular exteroception generates a cellular representation of that extracellular
space, whereas interoception allows the generation of a robust internal
representation, relevant for the assessment and maintenance of metabolic and
senomic cellular homeorhesis. Both exteroception and interoception are essential
for sentience-based perception of self whereby cells act as conscious agents
capable of problem-solving in their continuous confrontation with their
challenging environment in an appropriate contextual manner (Baluška & Levin,
2016; Reber & Baluška, 2021). In order to survive, cells need to understand
contemporary environmental challenges through both a historical and current
environmental context. Necessarily, cells are historical systems which
continuously generate and retrieve cellular long-term memories and knowledge
of their complete evolutionary narrative and store them in their epigenomes and
genomes to enable cellular problem-solving and prediction (Baluška & Reber,
2019; Baluška et al., 2022b).
Among its many functions, the plasma membrane is a universal vesicle
generator system wherein vesicles are pinched-off from the plasma membrane
extending into the cellular interior and exterior. These events allow structural
and functional homeostatic balance of the plasma membrane, despite a heritage
of turbulent evolutionary phases at the coacervate–protocells stages.
Internalization of small vesicles is known as endocytosis. These endocytic
vesicles can merge together into endosomes, which can themselves pinch-off
vesicles that can later fuse back with the plasma membrane. This process is very
important for neuronal cell–cell communication and these recycled neuronal
vesicles from the plasma membrane are known as synaptic vesicles which can be
released into the extracellular space.
Importantly, the limiting membranes of both intracellular and extracellular
vesicles are each derived from the plasma membrane, and accordingly, all have
relevant features and properties that generate senomic fields. The previously
discussed biological versions of the Maxwell’s demons that populate the plasma
membrane are active in these vesicles, generating mini-senomic vesicular fields
that expand the plasma membrane-based senome both intracellularly and
extracellularly. Consequently, in cells with active endocytosis, such as neurons
and root apex cells, the limiting membranes of endosomal vesicles significantly
magnify the reach and scope of the plasma membrane-based cellular senomic
system. We speculate that the vesicular senomic fields integrate together with the
plasma membrane-based fields to form a robust cell-periphery N-space senomic
field which can interact with those of neighbouring cells in multicellular
organisms.
 Further, these plasma membrane-based senomic fields are complemented in
eukaryotic cells by organelle-based subcellular fields and with micro-senome
fields emanating from diverse macromolecules and cytoskeletal polymers.
Particularly strong senomic fields can be expected to be generated by the nuclear
envelope and endoplasmic reticulum of each cell. The limiting membranes of
these organelles are associated with other critical intracellular participants,
including peroxisomes, mitochondria, and plastids. Most of these organelles
release vesicles into the cytoplasmic space which again support the entire
cellular senomic matrix, allowing cells to communicate and interact together at a
distance which is especially relevant for immunity (Tung et al., 2018; Buzás,
2023) but also plays a role in carcinogenesis (Wortzel et al., 2019; Zho et al.,
2021).
From an evolutionary perspective, it is important to emphasize that there are
three cellular sources of senomic fields in eukaryotic cells. As we have discussed
in Chapter 4, in the endosymbiotic merger that enabled eukaryotic cells, the actin
cytoskeleton-based host cell is represented by the plasma membrane and the
cytoplasm whereas, the tubulin/centrin cytoskeleton-based guest cell is
represented by the nucleus and cilia/flagella. The third cellular source of the
eukaryotic senome is provided by their endosymbiotic organelles, descended
from previously free-living cellular organisms.

The Plasma Membrane-Based Senome Provides the

Biophysical Basis of Cellular Sentience
The plasma membrane is inherently excitable, providing not only the structural
but also the bioelectric boundary of the cellular self (Veech et al., 2002; Oliveira-
Brett, 2017). This feature of the plasma membrane and cell periphery was
discovered, among others, by Ernest Everett Just who studied excitable egg cells
(Just, 1939; Byrnes, 2020). As all cells of an organism derive from a fertilized
egg cell, so all present cells derive from a continuous chain of cell divisions
extending back to the very first cells; they retain semi-independent organismal
heritage and agency even within multicellular organisms (Baluška et al., 2022b).
While the prokaryotic senome is relatively simple, eukaryotic cells assemble a
very complex cellular senome by deploying abundant endomembranes. The most
critical issue for the assembly of the senome and cellular sentience is
maintaining a complete isolation of the intracellular space from the extracellular
environment. As we have discussed earlier, the slow and turbulent evolution of
the ancient proto-plasma membrane surrounding coacervate-like proto-cells was
associated with the very slow emergence of the cellular membrane- and senome-
based sentience, building complexity over time. Accordingly, the most simple
senomes are associated with vesicles which are also abundantly present within
all eukaryotic cells and are considered to be more recent.
With vesicles generated by endocytosis, there is unique inverted topology
since these vesicles enclose what was originally an outside space. This
somewhat paradoxical feature is further complicated in endosomes, known as
multivesicular bodies. In these complex structures, a primary limiting membrane
originates from the cellular plasma membrane which then releases smaller
endovesicles into the lumen of each multivesicular body. By fusion with the
plasma membrane, the interior vesicles of these complex endosomes (vesicular
bodies) are then released into the extracellular space as extracellular vesicles. It
can be expected that all these vesicles contribute to the senomic complexity of
the eukaryotic cell functioning in many capacities including serving as a type of
environmental exploration by the cell. All cells produce extracellular vesicles,
including bacteria and archaea (McMillan & Kuehn, 2021; Buzás, 2023). Such
vesicles represent the smallest senomic units with a wide range of activities
including cell–cell communication and even participating in cancer cell
invasions. Intriguingly, such extracellular vesicles might represent vestiges of
proto-vesicles that preceded hypothetical proto-cells in the evolution of the first
cells. Furthermore, extracellular vesicles play important roles in cancer biology
by changing cell and tissue identities (Gopal et al., 2017; Zhou et al., 2021).
Future studies on the extracellular vesicles circulating between cells will be
essential for our improved understanding of embryogenesis, development, and
cancer. Extracellular vesicles serve as a primary means of inter-kingdom
communication (Cai et al., 2021; Díaz-Garrido et al., 2021). All cells are known
to release extracellular vesicles, including archaea, bacteria, and algae (Liu et al.,
2021; Picciotto et al., 2022), thus, these vesicles have a huge impact on
maintaining cellular ecologies and the entire course of biological evolution.

Membrane-Based Senomic Fields Permeate Cellular Insides

and Radiate Out of Cells
The redox-based homeostasis and excitable bioelectrical capacities of the plasma
membrane generate an extracellular version of the cellular senome that projects
externally for some distance beyond an individual cell. At the present state of
our knowledge, we have limited information about this process. However,
measurements of extracellular electric fields reveal that all cells, including
archaea, bacteria, and all eukaryotic cells in multicellular organisms, generate
bioelectric and biomagnetic fields at their surfaces (Wegener et al., 2015;
Fabricant et al., 2021). These cellular senomic fields (Baluška & Miller, 2018)
integrate into supracellular senomic fields, acting in collective aggregates—N-
space Episenomes (Baluška & Miller, 2018; Miller et al., 2020b). The excitable
plasma membrane not only generates these dynamic biofields but is reciprocally
sensitive to them (Galassi & Wilke, 2021), enabling memories to be stored
(Yang et al., 2020) and communicated (Manna et al., 2020) via dynamic
supracellular senomic fields. For instance, in bacteria, these fields are critical to
the formation of biofilms. Bio-electromagnetic fields extend relatively far
beyond any single cell and can be easily measured online using microelectrodes
(Jaffe & Nucitelli, 1977; Portes & Feijó, 2021). These same fields extend out
from organelles (Matamala et al., 2021; Klier et al., 2022), and can be further
identified around sensoric organs such as leaf traps of carnivorous plants
(Fabricant et al., 2021), and growing root apices (Collings et al., 1992; Masi et
al., 2009). Furthermore, these fields have documented roles in the cognitive
function of animals, including our human brain (Buzsáki et al., 2012; Hales &
Ericson, 2022).
These same fields can aggregate as supracellular bio-electromagnetic fields
helping to explain such phenomena as the so-called peripersonal space which is
meaningful in the social organization of humans and other organisms (Salomon
et al., 2017; Serino, 2019). There may also be other bioavailable field sources.
For example, besides bio-electromagnetic fields, so-called reactive clouds and
oxidation fields might be relevant in explaining many biological phenomena
(Zannoni et al., 2022; Schoemaecker & Carslaw, 2022). We will discuss these
issues further in later chapters dealing with the N-space Episenome.

Macromolecular, Cytoskeleton-Based, Organellar and

Vesicular Senomic Micro-Fields Integrate With the Plasma
Membrane-Based Cellular Senome
Every cellular macromolecule and all polymers are exquisitely dynamic and
sensitive to any signals entering into cells from the external extracellular space.
These also vibrate and oscillate, sending out waves that permeate the entire
cellular senome field, functioning as electromagnetic ripples. Proteins are also
known to represent dynamic and highly flexible structures based on short-range
electron transfers and electrostatic interactions within their structures which are
very sensitive to electromagnetic ripples and vortices in the intracellular
environment (Sjulstok et al., 2015; Tsai et al., 2015). Moreover, contractile
properties of cytoskeletal polymers also generate electromagnetic micro-fields
and are also sensitive to cytoplasmic macro-fields.
As the cytoplasm is a very crowded environment (Ellis, 2001; Knapp &
Huang, 2018), all these senomic sources dynamically integrate into a unified
senomic field whose major source is the excitable plasma membrane densely
populated with the biological version of Maxwell‘s demons including diverse
receptors, sensors, and ion channels. Cytoplasmic crowding is an ancient feature,
typical in small bacterial cells and actively maintained by the cellular activities
within all of the cellular domains (Parry et al., 2013; van den Berg et al., 2017).
Interestingly, as will be discussed in Chapter 11, physical pressure relieves
effects of all known anaesthetics on all tested organisms, suggesting that
cytoplasmic crowding is relevant for the cellular sentience.
As vesicles are enclosed by a plasma membrane-derived smart and flexible
border, their inside spaces can be expected to be permeated with radical
molecular and ionic charge-based senomic vesicular micro-fields as a further
derivative of that main field. Such vesicles contain diverse proteins and RNA
molecules and are internalized by their target cells via endocytosis. It would be
expected that these vesicular micro-senomes would affect the senomes of
adjacent cells and have an impact on collective sentience and action. The
potential range of effects of these small senomic vesicular messengers on the
generation of integrated sentience of multicellular organisms will be discussed
later.
The extracellular vesicle emerges as an important player in innate and
adaptive immunity (Buzás, 2023). Almost all of the diverse cells of the human
immune system produce extracellular vesicles which serve, among other
potential roles, in cell–cell communication in their complex task to discern self
from non-self cells and defend humans and other multicellular organisms from
pathogen attacks. Immune cells producing diverse extracellular vesicles are also
involved in embryogenesis, development, regeneration, and homeostasis of
multicellular organisms (Taubner, 2013; Underhill et al., 2016). Ilya
Metchnikoff’s discovery of the cellular basis of human and animal immunity as
well as of phagocytosis accomplished by amoeba-like motile cells was a unique
advance in cell biology, evolutionary theory, and medicine (Taubner &
Chernyak, 1991; Taubner, 2003). In future, it will be important to explore
senomic micro-fields of extracellular vesicles and their roles in immunity as well
as in embryogenesis, development, regeneration, and homeostasis of
multicellular organisms.
Rotary ATPases as Ancient Bioelectric Macromolecular
Devices Charging Membrane-Based Biological Batteries
The bioelectric drive behind the excitable prokaryotic membranes responsible
for both cellular respiration and photosynthesis are the multi-protein enzymatic
rotary complexes known as ATP synthase (Yoshida et al., 2001; Kühlbrandt &
Davies, 2016). Rotary ATPases are ancient nanodevices that couple the
translocation of protons across membranes to accomplish ATP synthesis or, as in
the case of bacterial F-ATPases, can run in the reverse mode to enable ATP
hydrolysis (Nirody et al., 2020). There are several types of ATP synthases:
prokaryotic A- and F-type ATP synthase (A- and F-ATPase) present in archaea,
bacteria, mitochondria, and plastids (Hahn et al., 2018; Nirody et al., 2020), and
eukaryotic vacuolar ATPase (V-ATPase), which energizes endosomal vesicles,
endosomes, and vacuoles. The complexity of these ancient macromolecular
assemblies capable of electrically charging biological membranes is breathtaking
(Kühlbrandt, 2019). These complexes are composed of more than 22 molecular
subunits (Nakamoto et al., 2008) arranged in a characteristic way by connecting
two rotary motor-like domains (Ro and R1) coordinated via a central stalk
domain (Stewart et al., 2013; Kühlbrandt, 2019). The membrane embedded Ro
motor domain rotates within the membrane plane very fast, acting as a biological
nano-turbine, with one rotation releasing three ATP molecules (Fillingame,
2000). These nano-turbines rotate at astonishingly high speeds of more than 400
rotations per second (Nakanishi-Matsui et al., 2010) and show very near 100%
efficiency (Kinoshita et al., 2000; Saita et al., 2015). Surprisingly, these rotary
ATPases have a common evolutionary origin with the flagellar export apparatus
(Ibuki et al., 2011; Ishikawa et al., 2013).
Besides the membranes of bacteria and archaea (Müller et al., 2005; Grüber et
al., 2014), endosomal and vacuolar membranes are energized via structural and
evolutionarily similar rotary ATPases known as V-ATPases (Collins & Forgac,
2020; Kühlbrandt, 2019). These have crucial roles in ionic and pH homeostasis
of eukaryotic cells with important effects on virtually all aspects of cellular
biology, ranging from cellular respiration and photosynthesis up to neuronal
signalling, synaptic transmission, and cancer cell induction (Ko et al., 2020; Gao
et al., 2022). V-ATPases within endosomal, lysosomal, and synaptic vesicle
membranes also play a central role in phagocytosis and symbiosis (Mills, 2020),
thereby having direct connections to the evolution of eukaryotic cells (Yutin et
al., 2009).
Unique Roles of Interface Water in the Biophysical Basis of
Cellular Sentience
Water represents the major part of cells. However, inside cells, water almost
never exists as pure water. Instead, the cellular interior consists of complex
forms of water due to numerous electrostatic interactions with myriad diverse,
and electrically charged biological molecules and macromolecules (Fayer, 2012;
Ball, 2017). Albert Szent-Győrgi called water the matrix of life (Ball, 2017) and
specific hydrophilic and hydrophobic properties of phospholipids provide the
structural and functional basis for cellular membranes. As already mentioned,
pure phospholipid-based bilayer membranes can store memories via long-term
potentiation phenomena (Scott et al., 2022). These membranes are formed by
self-assembly of a phospholipid bilayer following the basic rules of
thermodynamics for organizing membrane lipids and proteins with associated
cytoskeletal polymers (Nicolson, 2014; Nicolson & Ferreira de Mattos, 2022).
Many unique aspects of life ultimately reflect specific features of water which
are still far from being fully understood. In particular, water situated close to
interfaces with internal macromolecules and polymers, known as interfacial
water, has unique biophysical and biochemical properties (Messori, 2019). This
water has higher viscosity and ordering than pure water, preventing the diffusion
of even small molecules due to its semi-crystalline nature. This interfacial water
was discovered in 1978 (Mollenhauer & Morre, 1978) and later investigated,
especially by Gerald Pollack’s research group (Pollack, 2001, 2013; Kowacz &
Pollack, 2021). Intriguingly, this unique state of water is sensitive to weak
electric fields induced by magnetic fields (Rad et al., 2021; Shalatonin &
Pollack, 2022). An important role in this respect is also played by ATP which is
the most ancient and abundant component of cells (Chu et al., 2022). Besides its
best known role as the cellular energy currency, ATP is also acting with
interfacial water as a biological hydrotrope (Patel et al., 2017; Rice & Rosen,
2017). ATP maintains dynamicity of cellular processes at the nano-level by
preventing macromolecular aggregations in the crowded cellular interior (Bye et
al., 2021; Sarkar & Mondal, 2021).
As discussed by Peter Hoffmann in his excellent book Life’s Ratchet: How
Molecular Machines Extract Order From Chaos (Hoffmann, 2012), water
molecules are electrically charged and electro-negative oxygen molecules bind
electro-positive hydrogen molecules through hydrogen bonds, representing one
of the molecular entropic forces. Importantly, molecular exclusion zones and
molecular assemblies are playing crucial roles in these biomolecular entropic
forces (see Figure 4.2 in Hoffmann, 2012). This is one of the most important
roles of the intracellular biomolecular crowding. We will discuss these topics in
deeper details in Chapter 10 dealing with the cellular targets of anaesthetics.
Electrostatic interactions play a crucial role in dynamic assembly of
electrically charged biological membranes and their association with internal
cytoskeletal elements and polymers of extracellular matrices (Platre & Jaillais,
2017; Ben-Amotz, 2022). Actin filaments and microtubules are particularly
important for intracellular propagation of ionic waves (Hunley & Marucho,
2022; Manrique-Bedoya & Marucho, 2022), which act as some kind of
intracellular neural system. All these bioelectric interactions establish the so-
called cellular electrome (De Loof, 2016) and metallome (Galera-Laporta et al.,
2021), which are part of the senome which acts as a non-genomic system
upstream of the cellular genome in the management of biological information. In
order to correctly understand organisms and living properties, we must turn back
to cells, understand them in their historical context, honour their cognitive
faculties, and, in particular, we must put cells into the proper senomic
framework, correcting the so-called central dogma of molecular biology (Crick,
1970). Of the utmost importance, and quite contrary to conventional thinking,
the primary role in cell biology is played by the cell’s intelligent, competent
biomembranes and their associated bioelectric fields rather than by their genes.

Cellular Electrome and Sensitivity to Extracellular Electric

Fields
Existence of the cellular electrome is strongly supported by the documented
generation of bioelectrical fields around cells and cellular organs that is
associated with the extreme sensitivity of cellular structures and processes to
externally applied electric fields. It is certain that the plasma membrane is the
most ancient cellular structure. Further, all biomembranes of currently living
organisms are directly and structurally linked to an initial primordial proto-
membrane that preceded the DNA-based genome even though most biologists
still consider the genome as the most important cellular system underlying all
subsequent life. This ingrained attitude is partially linked to the central dogma of
molecular biology defined by Francis Crick more than 50 years ago (Crick,
1970). Nonetheless, recent studies clearly document that development,
embryogenesis, and regeneration can be controlled by extracellular electric fields
and that the endogenous electric fields represent a primary bioactive mechanism
regulating organismal morphogenesis (Levin, 2021; O’Hara-Wright et al., 2022).
Thus, the central role of the bioelectric code-based senomic electrome must be
explored through future experimental studies, seeking to better comprehend
those processes that control cellular life, cellular behaviours, and planetary
evolution, ultimately granting material insight into our human living
predicament and the diseases that afflict us.
As in the conclusion of Chapters 5 and 6, cellular sentience is not based on
mysterious vitalistic forces but rather on molecular biophysics based on classical
as well as exotic physics waiting to be explained and understood. As cellular
biophysics underlies cellular biochemistry and current molecular biology, it will
be essential to study cellular biology from nano-scale physical perspectives. We
badly need a fresh new biophysical approach to biology by reconnecting to Max
Delbrück’s insightful analysis from 1949 (Delbrück, 1949; Strauss, 2017).
7
The Biological Information Cycle
The Terms of Consciousness

Developmental biology can be seen as the study of how information in the genome is
translated into adult structure, and evolutionary biology of how the information came to be
there in the first place.
John Maynard Smith (2000)

Introduction
In Chapter 3, the problems of defining life and precisely understanding its origin
were discussed, and the various factors delineating the living process were
reviewed. One intriguing means of exploring how the animate separates from the
inanimate resides in the complex topic of information science. Pertinently, there
is a clear-cut distinction between how computers and machines use information
and how living organisms assess and utilize it. That crux is that all information is
ambiguous in the living state and thereby distinctly unlike the zeros and ones
that constitute computer data.
This critical difference explains several previously unresolved issues in
biological development, including the origin of multicellularity and the role of
the virome in evolutionary biology. Furthermore, it places life in its correct
perspective. The most important aspect of biology is that all cells are conscious,
self-aware, self-referential, sentient agents. Living organisms are not automatons
that receive information from the environment and respond to it automatically
according to a fixed programme. Instead, intelligent cells measure the
information they receive, which is the essence of our biological experience
(Miller et al., 2020a). Cells measure information to assess its meaning and, based
on those measurements, decide whether or not to communicate that information
to other living organisms and deploy its meaningful content as biological
expression (Miller, 2018). Since the living state is dependent on that cellular
measurement of information, it is apparent that life represents an informational
interactome and that the maintenance of cellular integrity and survival is
rigorously dependent on the competency of its information management system.
This chapter will explore this intimately linked cellular chain of events and
explain its further implications.

How Is Information Defined?

At first consideration, most would expect that defining information would be
straightforward. Everybody is familiar with the term. We commonly refer to it
every day and understand what we mean by its meaning in casual conversation.
However, a certain level of rigour is demanded when science deals with any
issue. In scientific terms, that stipulates a search for a consistent meaning of
information that can be methodically measured and compared. There is no
problem with that requirement in general terms. However, as is commonly
affirmed, ‘the devil is in the details’.
As was previously discussed relating to the definition of life, it is surprising
that a general consensus about what constitutes information has proved similarly
elusive. The term ‘information’ can be traced to ancient and medieval texts, but
it was only in the 20th century that any attempts at a formalized definition were
launched, particularly through the work of Claude Shannon (1948) and the
inauguration of the concept of Shannon information. Surprisingly, the Shannon
information concept is not a specific theory of information. Instead, it is a theory
of communication (Schroeder, 2017). Shannon’s formalism provided a
mathematical definition of information designed to solve problems in
communication and engineering, and is particularly suited to computer systems
and the search for optimal coding and robust communication. Shannon
information (entropy) relates to the statistical properties within a given system
and how states between different systems correlate. This definitional stance is
fine for engineering applications but has no direct bearing on the qualitative
aspects of information that we depend on in our everyday discourse, remaining
devoid of semantic intent and independent of its qualitative value (Schroeder,
2017). Consequently, computer scientists and communications engineers view
information in statistical terms and mathematical parameters, and utilize formal
definitions that are highly suitable to specific applications, such as Fischer
information (random variables influenced by unknown parameters), algorithmic
information used in computational programming, or quantum information as a
statistical measure of von Neumann entropy that has direct bearing on
calculating quantum resources (Lombardi et al., 2015).
By design, these approaches to information are closely tailored to discrete
tasks and thus do not match the requirements of a more broadly conceived
definition of information that could better suit the variabilities of biological
systems. Given the sophistication of each of the disciplines within physics and
engineering, the specific definition of information that is employed is dependent
on its application within that discipline. Hence, it is not unexpected that there is
no general cross-disciplinary consensus as to a precise meaning for information
in biology. For example, in computer applications, the term ‘information’
translates into ‘data’ and the language of bits and bytes, where a ‘bit’ is generally
conceived as the minimum data unit that describes a ‘single difference’ in that
application (Farnsworth et al., 2013). Although these definitions are superbly
helpful for designing robots, they do not meet the need of understanding the
nuances of information in living systems.
To better conceptualize living systems, other scientists have undertaken
different approaches. For example, the British physicist David MacKay stated,
‘Every piece of information has the characteristic that it makes a positive
assertion and at the same time makes a denial of the opposite of that assertion’
(Schroeder, 2017, p. 2). Of course, he was a renowned mathematician, and what
seems quite plain to mathematicians and physicists can be difficult for others,
like ourselves, to grasp. However, he was trying to place information into a
formal logic of ‘representation’ that encompasses patterns, pictures, or models,
specifically as concrete forms or abstractions that symbolize an element of
meaningful content corresponding to the structure being considered. Central to
this perspective is the concept of ‘difference’ that can be directly applied to
distinguishing differences between objects of thought.
The polymath and anthropologist Gregory Bateson is generally credited for
offering the broad definition of information that is used most often to describe
biological activities. In his 1972 book Steps to an Ecology of Mind, Bateson
developed a synthetic definition of information based on his work on semiotic
messaging and cybernetics, stating that information is ‘a difference that makes a
difference’ to which he later amended the codicil, ‘in some later event’
(Schroeder, 2017). For Bateson, these differences were crucial to formulating a
‘map’ of the abstract information that the mind constructs. Adding to the work of
MacKay and Bateson, the American philosopher Frederick Dretske offered a
flexible definition of information that is particularly relevant to living systems,
emphasizing that ‘information is a commodity that, given the right recipient, is
capable of yielding knowledge’ (Dretske, 1981).

Biological Information Is Different From Computer Data

In computer systems, data can be readily moved and transferred as binary
functions, characterized by sequences of ‘ones’ and ‘zeros’. However, for
computer data to become information, it must be interpreted, following a pre-
programmed set of instructions. Significantly, there is no assessment of
computer data for qualitative aspects since, by design, it is meant to be precise
and uniform so that computer outputs will be exactly reproducible for each set of
identical inputs.
However, this form of information content is vastly different from information
in the living state. For living entities, all information is ambiguous (Miller,
2016a, 2018; Today & Miller, 2017). Living information has both quantitative
and qualitative aspects, unlike computer data. The differential crux is that living
organisms are cognitive entities and computers are inanimate machine
mechanisms. Machines use digital, binary data and living organisms primarily
use analogue information, although some geneticists regard the genome as a
quasi-digital information system. One way to visualize the critical differences
between these two forms of information is to examine simple waveforms that
differentiate digital data from analogue information (Figure 7.1).

Figure 7.1 Digital data versus analogue waveforms.

 A digital waveform is characterized by a square wave, denoting its binary
character, reflecting discrete orthogonal signals mirroring how digital electronic
circuits instantaneously respond. An analogue waveform is alternatively
depicted as a smooth continuous sinusoidal wave that depicts harmonic
averaging. Consequently, analogue systems are much more susceptible to noise
and are more likely to produce significant errors.
There is a crucial reason for these distinctly different forms of information
profiles between living systems and machines. All living organisms are sentient,
cognitive organisms that must individually evaluate their information to
determine both its quantitative and qualitative measuring value (Miller, 2018;
Miller et al., 2020a). Indeed, it is this living action that specifically separates the
animate from the inanimate. Living organisms have the capacity to discriminate
information content so that physical, informational cues become meaningful
biological information. Most importantly, living organisms are information
dependent and actually participate in creating what that information means.
Moreover, they communicate their qualitative appraisal of that information
abundantly at all scales. For example, the cross communications among bacteria
in biofilms to engage in quorum sensing is so active that it has been described as
chatter (Visick & Fuqua, 2005). However, that communication represents an
information exchange between ‘knowing’ cognitive agents and that ‘knowing’
reflects their sentient appraisal of both information quality and quantity.
Obviously, this is different from computer data analysis since each of these
cognitive players must assess information within their own context and
limitations. Consequently, not only is the information that cells receive
imprecise, but so is all the information they communicate to other living
organisms.
There are several reasons that biological information is ambiguous by
definition. For example, in living systems, neither the sender nor the receiver of
information is necessarily known to one another. Substantial amounts of cell–
cell communication represent a general broadcast, either as a profusion of
bioactive molecules or bioelectrical signalling (Witzany, 2012). Further, any
communication or environmental cues that a cell might receive must travel
through an intervening medium, such as the cellular interstitial spaces, to reach
the cell and deliver its information content.
That transit is a source of information noise because of inevitable
degradations by the intervening media and time delays that are naturally
imposed between the initiation of any information exchange and its reception
(Miller, 2018). Moreover, all cells have an external membrane essential to their
information system as a critical aspect of their senomic apparatus that connects
them to the external environment (Baluška & Miller, 2018). Within this senomic
chain, the cognitive cellular measuring assessment of information and its
eventual contingent deployment directly relates to innumerable interrelationships
within the complex, crowded environment of the cellular interior involving
various organelles, each with their own membranes and the varied components
of the cytoskeleton. All are vital links within the senomic apparatus and are
essential to the process but inevitably contribute additional sources of noise.
Beyond these readily understandable physical sources of error in information
evaluation among cells, another constitutive source directly relates to the fact
that all living beings are self-referential. Self-referential status means that all
organisms are both observers and participants in decision-making processes
(Torday & Miller, 2020). Unlike computers, no two observers or participants are
identical in their internal measuring assessment of information in living
communications. Obviously, as two separate entities, they are not in precisely
the same place at the same time. Consequently, they never receive identical
information inputs. Nevertheless, they react similarly to these minor variances in
information inputs since they are self-similar and are conditionally triggered to
interact with one another. However, information quality takes on differing
characteristics for each of them as separate observer/participants (Miller, 2018).
It is an important point that this observer/participant effect is not merely the
result of their physical separation. Certainly, they both can not occupy the same
space simultaneously. However, there is another pertinent factor at work in a
self-referential framework. There are obliged differences in information
perception and its consequent analysis that stem from variances in the
assessment of thermodynamic variables and quantum phenomena which are all
guided by inherent uncertainty relationships, codified as the Heisenberg
uncertainty principle. In physics, it is not possible to know simultaneously both
the position and speed of a particle, such as a photon or an electron, with perfect
accuracy. The measurement of one variable changes the value of the other.
Consequently, different observers will use their senses to evaluate environmental
cues, some of which are quantum dependent. The result will be inter-observer
variances in the assessment of speed, amplitude, or quantity of experienced
phenomena. This principle applies to all aspects of the cell, including its genome
(Strippoli et al., 2005). Even for our genes, considered by some biologists to
rather closely reflect a digital system, there is never any possibility of knowing
with absolute certainty what the exact composition of the genome is at any
moment in time. As will be covered in Chapter 8, the genome is no longer
regarded as a static repository as it once was. Instead, it is a dynamic
reciprocating partner in cognitive cellular living processes with its own rate of
inherent mutations, insertional mutations, self-generated editing, and epigenetic
impacts. An evaluation at any moment is a snapshot of something in motion that
does not represent an absolute.
Other important, embedded variances in the self-referential information
assessment are unique to the observer–participant context. The most significant
cause of this living effect is characterized as ‘antipodal’ information that offers
insight into how dependent individual observer/participants are on their
circumstances when evaluating environmental cues. Four examples of this type
of antipodal information are worth examining.
The first type views information as a volume, like a sphere with
dimensionality rather than a specific point that would convey higher measuring
value. To conceive this, imagine two observers standing on either of a soccer ball
tossed in the air. Both see a ball, but each sees a different side as it rises and falls
in the air. For each, one side is visible, and the other is hidden. However, for
each, what is ‘en face’ is ‘opposite’ or ‘antipodal’ compared to the other.
Consequently, they might construe differences in meaning exactly what that
soccer ball represents (Tozzi & Peters, 2017). For instance, there might be
painted lettering on one side and not the other, and each would ‘understand’ the
ball differently within their separate observer context. Same ball, different net
self-referential appraisal.
The second type has been categorized as a ‘distinction on the adjacents’
(Marijuán et al., 2015). The term ‘adjacents’ references the obligatory gap
between information reception, its intracellular measurement, and its
deployment. Uncertainties in the measuring value of information can be
narrowed by bringing ‘adjacents’ together. This scenario can be conceptualized
by regarding information content as something like a dimple on a golf ball.
Suppose the information content is imagined as the dimple. In that case, the
uncertain spread of that information can be narrowed if the assessment proceeds
across the diameter of the dimple rather than its circumference, or if the edges of
the dimple can be brought closer together.
A third crucial factor in information assessment is easy to disregard but is still
imperative. There is substantial measuring value to the gaps between ‘bits’ of
information. Notably, these gaps as space between the formal information
content are meaningful and have been dubbed a ‘third state’ of information
(Forshaw, 2016). The third state contributes organizational structure to
information just as pauses between words connote semantic information in
speech or the spaces between the words in this sentence contribute to its ready
understanding.
There is one further highly significant type of inter-observer informational
variability that is often overlooked and specific to the self-referential frame.
Cognitive organisms use information to predict and anticipate. Any absent but
anticipated information is meaningful, as we all know in our lives (Miller et al.,
2020a, 2020b). Significantly, this self-referential form of information is scale
independent since it is experimentally confirmed that even single-celled
microbes can anticipate and predict (Vallverdú et al., 2017).
From this background, we can now discuss two critical living realities driving
biological and evolutionary development among conscious cells. The first is the
presence of a definable information cycle that stimulates the cellular behaviours
that permit multicellularity. The second is why the self-referential frame assures
that any cell’s information is exclusive to itself.

There Is a Crucial Cellular Information Cycle

From the preceding, where the quantity and quality of information constitute the
working parameters of cellular consciousness, it is readily apparent that cellular
life equates with information management (Miller, 2016a; Miller et al., 2020a,
2020b). When that is acknowledged, an understanding of the origin and
persistence of multicellularity representing the dominant form of life on the
planet emerges. That path lies within the mandated properties of the cellular
information management system. Accordingly, given this overarching
framework, it becomes apparent that information has crucial self-organizing
properties in a self-referential framework (Miller, 2018).
As has been emphasized, all the information any cell has is conditioned on its
imprecision. Consequently, all cells must measure any information they receive
to assess its meaning. This prescribed process of the self-assessment of
ambiguous information drives two key features of a biological information
cycle. First, since all cellular cues are ambiguous for the reasons that have been
enumerated, cells have learned that the measuring value of information can be
improved by its collective measurement as the cellular expression of the
‘wisdom of crowds’. Sentient organisms ‘know’ that their individual internal
assessment of information is an imperfect model of their circumstances. How do
sentient organisms cope? They do just as we do ourselves when feeling
conflicted. We ask others for their opinions. This innate tendency is present at all
living scales, including our own. This same obliged impulse forms the basis of
many TV game shows. What do contestants do when asked to respond to a
multiple choice question and have no clue about the answer? They appeal to the
audience for their collective judgement. They even do the same for random
selections. Do I choose door number 1, 2, or 3 to get the best prize? Cells do the
same and exert the ‘wisdom of cells’ to improve their individual assessment of
the validity of environmental cues. Humans and cells instinctively ‘know’ that
they do better following collective judgements and obtain the ‘wisdom of
crowds’ rather than relying solely on their own limited ability to assess
information unless they’re academics who delight in disagreeing with others, as
we do.
Accordingly, the collective assessment of information improves its validity for
cellular decision-making and enabling predictions as effective information (EI*)
(Miller, 2018). Maximizing EI* directly links to improved energy efficiency
since the decision tree towards cellular decision-making is strengthened and the
deployment of its limited resources is improved. This aspect of information
quality and how it relates to informational imprecision has been categorized as
an ‘uncertainty relation’, which in data transmission refers to the number of
independent data points available over time to make the analysis (Gabor, 1946).
Simply put, more independent measurements by self-similar cells mean
narrowing this uncertainty relationship and a higher measuring value for the
information in question.
Importantly, the shared assessment of information is not merely a learned
response by cells. The only requirement to set the cellular information cycle in
motion is the reception of information by any self-referential organism as an
observer/participant. Any information that is received must be measured, and
that process of internal analysis is necessarily work. That work is an obliged
consequence of the cellular internal measurement of information whose analysis
necessarily requires an energy expenditure. That cellular work leaves an
obligatory energetic signature relating to both the quality and quantity of the
information being assessed. In turn, this activity becomes a communication to
any other observer/participant within the same system as an energetic input.
Moreover, that communication, itself, obliges that next observer/participant to
engage in its own self-referential measuring assessment of that communications
informational meaning. This also constitutes work, inevitably delivering a
reiterating signature that becomes yet another communication. The result is an
obligatory, reiterating work channel (Deacon, 2011). This specific obligatory
feature of biological information analysed within a self-referential framework
accounts for multicellularity (Figure 7.2). From the cycle, it becomes apparent
why biological information is inherently self-organizing and all of biology is
information management (Miller, 2018; Miller et al., 2020a).
Figure 7.2 The cellular information cycle.

All cells receive biological information from the environment characterized

by its imprecisions, triggering an obligatory self-referential cellular information
cycle. The reception of information requires its measured internal assessment to
determine its value and meaning for potential communication and deployment.
However, irrespective of that exact measuring value, any internal assessment
involves an expenditure of energy which becomes an obligatory environmental
cue to some other cell (observer/participant). Any cell receiving that cue is then
obliged to assess it, stimulating a further work channel. Cells measure
information together to improve its measuring value as EI*, which translates into
energy efficiencies, the willingness to trade resources, improved cellular
homeorhetic equipoise, and survival. The tightly woven, obligatory cellular
information cycle explains why multicellularity is a dominating form of life on
the planet, either as biofilms or holobionts.
This living imperative is no small matter. It explicitly accounts for all
multicellularity. If cells did not have the ‘knowing’, sentient impulse to
collaborate with other self-similar (recursive) organisms to strive towards better
informational validity through collective measurement, you would not be here.
How strong is this biological imperative? It accounts for the seamless integration
of the tens of trillions of co-dependent microbes that partner with your personal
eukaryotic differentiated cells, enabling you to be a successful reproductive
holobiont. What does this mean in strictly biological terms? All cells, and
derivatively all multicellular eukaryotes as holobionts, such as you, are an
intricately integrated informational interactome.

Your Cells Create Their Own Reality—So Do You

The nature of cellular information assessment has a further crucial entailment
critical to cellular life and yours. Both cells and we create our own realities.
Although, at first consideration, this assertion might seem to lie within the
purview of philosophy and metaphysics, or via a deep dive into consciousness
studies, the correct analysis is directly rooted in our obliged biological context as
completely cell-dependent self-referential organisms.
All individual self-referential, conscious agents are obliged to assess
imprecise environmental cues through their individual tools for information
assessment. Since the only information a cell can have about any external reality
must travel across an outer membrane and be analysed internally, any
information a cell has is internally generated. A cell receives an ambiguous
environmental stimulus and measures it. That is its only real information, as the
self-produced awareness of its measuring value based on its own self-determined
assessment. That is the totality of the information that a cell has. A disturbing
conclusion derives from this inescapable circumstance. There is no such thing as
a completely objective measuring value of any physical information. All our
information is our self-referential creation through self-production (Miller et al.,
2020a). This living reality has been formalized in the concept of info-
autopoiesis, which axiomatically shows that every bit of the information a cell
possesses is the product of its internal self-creation (Cárdenas-García, 2020).
Although cells of like type are self-similar, they are never identical.
Consequently, each cell will have constructed its exclusive interpretation of its
external milieu.
Since we are assemblages of trillions of cells, each producing its assessment
of information content and quality, it is inescapable that we create our own
derivative reality as a summation of our cellular information content. Naturally,
this accounts for the wide range of variances that self-referential organisms,
including ourselves, display towards environmental stresses. Of course, we intuit
this principle since we all acknowledge that we do not feel each other’s
experiences. And further, who among us has not commented at least once about
someone else as we have tried to fathom their contrary opinions or actions and
said with a resigned shake of our heads, ‘They just live in their own world’.
A significant feature of ‘reality’ to a cell is that its interpretation of the
external environment must be conducted through the veil of its own internal
noisy processes. One unquestionable aspect of our living circumstances is that
we are surrounded by noise. That noise is received information that is
instinctively regarded by us as part of a continuous background state, typically
not rising to the level of requiring overt attention. Cells live in a crowded, active
milieu with a flood of molecular and energetic flows. It is mistaken to assume
that a cell only depends on high-amplitude information inputs. Indeed, it is quite
the opposite. Cells rely on all types of inputs, including the continuous
monitoring of their background noise as a further cue to its equipoise. For
example, consider the background, noisy chatter in the jungle. If you were
travelling through it and it was suddenly interrupted, you might interpret that as
consequential information. Perhaps a predator lurks. True, the general run of
these noises seems random, however, there are characteristics of that type of
information that can be put to constructive use. Similarly, when we engineer,
some chance events are seen as a serendipitous boon, helping to solve a problem.
This concept of noise as a useful contributor to biological information
assessment, intermittently representing useful information has been formalized
as the concept of the ‘harnessing of stochasticity’ (Noble & Noble, 2018).
Notably, this is not merely a theoretical concept. Research experiments in
habituation in plants, animals, and even single-celled organisms confirm that the
concept of the ‘stochasticity of information’ is real and context dependent
(Eisenstein & Eisenstein, 2006; Gagliano et al., 2014).
Since it is insisted that life is an informational interactome, articulating a
unified theory of integrated information that can be applied to biology is
desirable, beyond the categorical acknowledgement of its ambiguity. The
relatively recently introduced concept of integrated information theory (ITT) can
be productively applied to the patterns of biological information and
consciousness studies since it focuses on ‘nested discriminations’ (choices)
(Tononi, 2008). In particular, ITT is an attempt to better explain the contentious
issue of qualia (individual and specific subjective instances of conscious
experience, e.g. the taste of wine). In ITT, qualia as subjective experiences
represents integrated information that is internally generated (Tononi, 2004).
Fortunately, the major tenets of ITT apply directly to a cellular approach to
consciousness, placing it on a solid footing of information reception and analysis
(Oizumi et al., 2014). In ITT, conscious is structured. Further, every instance of
an experience is a combination of inherently integrated aspects such that it
cannot be reduced to its individual components. Naturally, consciousness is also
informative. And each instance of an informative experience is exclusive and has
separate particulars compared to all others. All of these particular facets of ITT
relate to cells and their obligatory framework of self-produced information.
What can we glean from this approach to cells and their information-
dependent circumstances? The reason our experiences are individual and
idiosyncratically our own is because it is the same for cells, and we are cellular
beings. Consequently, a theory of mind or consciousness is a cell theory. And
further, every stimulus that impacts the cellular senome constitutes a cellular
experience since all such impacts are highly integrated across the cell.
Consequently, any attempt at undue reductionism, taken outside of the cell as an
‘organized whole’, will lead to a fundamental misunderstanding about the
enigma of consciousness. Albert Szent-György, a Nobel Prize-winner in
Physiology or Medicine, vividly grasped this principle, stating, ‘My own
scientific career was a descent from higher to lower dimension, led by a desire to
understand life. I went from animals to cells, from cells to bacteria, from bacteria
to molecules. … On my way, life ran out between my fingers’ (as quoted in
Gómez-Márquez, 2020).
Cells as Biological Expressions of an Information
Architecture
When we regard our consciousness, it is apparent that we somehow integrate the
myriad environmental cues that our senses provide us to form our experiences
and enable our decisions. Accordingly, the concept that our consciousness is
some form of information management seems intuitively obvious. It is the same
for our cells. Their information management system is based on the exquisite
links across their cellular senome, which enables the cellular measurement of
information (Baluška & Miller, 2018). There is a direct reason for this complex
set of connections. Cells have a senomic information architecture since it
governs their self-production of information, enabling cellular prediction as
inference and anticipation. That architecture seamlessly connects cellular
problem-solving and triggers the cellular communication of information
appraisals to improve the critical deployment of cellular limited resources as
bioactive molecules or energy. Consequently, self-referential cells have a cellular
information architecture as a crucial component of its self-referential information
management system (Miller, 2016a). Our human capacity for abstract thought
and greater engineering prowess must therefore relate to our emergent ability to
juggle more informational uncertainties prior to our contingent decisions to
deploy our own limited energetic resources.
Our cell-based self-referential information management system is sustained by
a fundamental fulcrum. In a self-referential framework, energy as environmental
cues represents self-referential information which obliges communication. Thus,
our world of biological expression, which is exclusively cell-based, relies on
triadic energy–information–communication to propel biological expression
(Miller, 2018). Crucially, that triad links to an impelled work channel.
Multicellularity is the biological expression of that work channel, whose
characteristics will be further described in Chapter 8 that explains the critical
patterns of biological and evolutionary development that have contributed to all
planetary life.
When information assessment is appraised as the epicentre of cellular
consciousness, the intricately coordinated cellular confrontations with
environmental stresses can be appreciated as indicative of a highly attuned
information management system, permitting the orderly assessment,
measurement, communication, and deployment of information by self-referential
cognitive cells. What do cells know? They know that their information is
imperfect and they know to seek others to share information to improve its
quality. Intimately linked to that is the principle of recursion that grants the
knowing of self-similarity, as the sense of ‘as here so elsewhere’ (Kafatos, 2014).
By this means, self-similar, self-referential organisms react to stimuli in
generally concordant patterns, that is, they know together.
Consequently, cells ‘know that they know’, and ‘know that others know’
(Miller et al., 2020a). This is the informational bioactive substrate of
multicellularity that depends on shared information. In this way, self-similar,
self-referential organisms constitutively self-produce their own information, but
can collaboratively cooperate since they share a binding informational motif.
They may not be identical, but they are of like kind. This informational nexus is
the glue that binds multicellular organisms.
How does ambiguous information centre in this narrative? It exists at its
epicentre. The realization that biomolecular processes represent informational
processes is growing (Miller, 2016a; Baluška & Miller, 2018; Miller et al.,
2020a, 2020b; Fields & Levin, 2021; Marijuán & Navarro, 2022). Consequently,
the flow of information is now regarded as central to all biological processes.
Pertinently though, information flow in biological contexts mirrors energy flow
(Miller, 2018; Marijuán & Navarro, 2022). Just as energy must be channelled to
do productive work, the trick in living systems is to control the appropriate flow
of information to permit contingent cellular problem-solving. Accordingly, the
characteristics of information in biological processes are paramount to our
understanding, which can be ascribed to two salient attributes. First, as stressed
in this chapter, all the information that any organism has about itself is
characterized by imprecisions. And second, the heart of living information
management governing its productive flow is cellular sentience.
Within the foregoing, two further conclusions directly ensue. The objective of
cellular measurement is attaining and sustaining a preferential state of
homeorhetic equipoise in continuous confrontation with environmental
variables. However, and unequivocally, the cellular sentient appraisal of its
equipoise is representative of its consciousness. Hence, the primary objective of
cellular measurement clarifies. The cellular information management system is
always directed towards preserving its instantiated consciousness within its
embodied cellular form (Miller et al., 2019). The specific objective of the
cellular measurement of information is to protect its self-referential integrity.
From an information perspective, uncertainty equates with incomplete
information about any relevant information-dependent system (Khrennikov,
2007). That uncertainty is diminished through collective cellular judgement.
Necessarily, cognitive faculties lie at the centre of all discriminating actions.
How might that cognitive capacity of cells be characterized? Self-referential
cells understand that the quantitative and qualitative aspects of their
informational palette have constraints. Necessarily then, cells are measuring
instruments (Miller et al., 2020a). Further, as environmental flux is life’s
condition, all cellular deployments of assets entail prediction and anticipation.
Recent research confirms that single cells can do internal calculations and
predict (Luczak & Kubo, 2021). A direct correlation has been found between the
activity of individual neurons and their ability to accurately predict the validity
of informational inputs, thereby minimizing ‘surprise’ which directly relates to
energy expenditure. Modelling suggests that the exchange of predictions among
individual neurons to aggregated cellular networks that realize more complex
learned predictive patterns, ultimately representing human consciousness
(Luczak et al., 2022). Moreover, pre-existing cellular states and multimodal
perceptions shape cellular decision-making according to their internal states and
external conditions (Kramer et al., 2022).
Less obviously, these same principles hold true for cellular communications
(Miller et al., 2020a). It has been previously noted that any energy expenditure
by a cell becomes a form of communication to others surrounding it. However,
beyond that obligatory type of communication, cells communicate abundantly on
a volitional basis so that they can collaborate. However, each such
communication requires an energy expenditure. Accordingly, the cellular
decision to expend that energy is a prediction. Is it worth the energy
expenditure? All biological and evolutionary development must thereby
represent the entanglement between the real-time cellular ability to assess
conflicting environmental cues to resolve informational ambiguities and
productively deploy cellular resources, either on its own or through collective
action. That explicit gap between cellular environmental assessment of available
information and its deployment to constructively meet environmental
imperatives represents cellular prediction and explains the compulsory role of an
overarching cellular information management system to efficiently manage its
scant resources.
Frankly, none of this is conjectural. If cellular information were perfect, it
would not require measurement, and consequently, a cellular informational
architecture or a cell-centred information management system would be an
unnecessary encumbrance. Perfect information requires no measuring
assessment or any information management apparatus. Instead, cells leverage
imperfect knowledge to sustain homeorhetic equipoise. Significantly, then, the
collaboration, cooperation, co-dependence, and competition that characterize all
multicellularity are the biological expressions of information flow. The driver of
that flow of information is cellular consciousness that enables the productive
predictions which sustain life (Miller et al., 2020a). Saliently, this accurate
perception of cellular dynamics effectively reduces to a single encompassing
biological and evolutionary narrative. Information-dependent cells dwell in self-
referential doubt, and that incertitude drives our living world.
8
Genes Are Tools of Intelligent Cells
Biological and Evolutionary Development in the 21st Century

Introduction
This book is premised on the copious research demonstrating that all cells are
intelligent, problem-solving agents (Ford, 2004, 2009, 2017; Shapiro, 2007,
2021; Lyon, 2015; Miller, 2016a; Reber, 2019; Baluška et al., 2021b, 2022b). As
discussed in Chapter 3, the living context of cells is their active management of
information. Cells assess information internally and, dependent on that self-
generated appraisal, communicate to other cells, deploying their limited assets to
sustain cellular balance and protect crucial self-identity. Cellular information
assessment is dependent on the complex linkages that comprise the cellular
senomic apparatus, beginning with the cell’s plasma membrane in immediate
contact with the external environment and extending across its entire internal
milieu (Baluška & Miller, 2018; Miller et al., 2020a; Baluška et al., 2021b).
Crucially, that internal assessment of information constitutes a measurement. Its
meaning is an at-the-moment evaluation of the impact of that external
environmental stimulus vis-à-vis the cell’s self-referential state of preference that
references to its robust retrievable and deployable memory. In simplest terms,
any informational inputs (temperature, light, bioactive molecules) can be
considered a deflection from the mean, which the cell measures to determine its
contingent deployment of resources to meet this variable. As has been
emphasized, cells measure information since all cellular information is
imprecise. Perfect information does not require the expenditure of scant energy
for its assessment.
Evolutionary biologists have traditionally overlooked that cells measure
information; indeed, the study of evolution has not traditionally centred on cells.
Instead, it began as a discipline devoted to rigorous observation and, in the latter
half of the 20th century, devolved into a focus on population genetics.
Consequently, the ramifications of the critical issue of the ability of intelligent
cells to measure information was unappreciated until the last few years (Miller,
2016a, 2018; Miller et al., 2019, 2020a, 2020b). However, the scope of cellular
measurement of information is vital to all biological and evolutionary
development.
In this chapter, the direct connections between measurement, communication,
and natural cellular engineering will be investigated. Through that exploration, it
will be explained why the prior concepts of genes as the centre of biological
activity must be thoroughly reconsidered in a modern context. In 20th-century
neo-Darwinism, genes were presumed to control cells and determine cell fates.
In the 21st century, genes are acknowledged as tools of intelligent, measuring
cells. Instead of the prior conception of our central genome as a nearly inviolable
genetic repository, it has been conclusively demonstrated that genes and the
entire genetic panoply of cells are flexible and malleable participants in cellular
problem-solving.

Our Contemporary View of Genes

Any re-examination of the concept of the role of the gene in biological and
evolutionary development has a corresponding derivative. The acclaimed
concept of Crick’s central dogma must be freely reappraised. Crick’s central
dogma of molecular biology states that the information stream in cells follows a
strict directional path from DNA to RNA to proteins. That interpretation of
biological molecular flow strongly encouraged a belief system asserting the
primacy of genes. Recently, major deficiencies in that dictum have become
apparent. For example, the reverse transcription of DNA from RNA was once
believed to be rare. Recent research now suggests otherwise. A theta polymerase
repairs DNA converting RNA code into DNA in cells as efficiently as HIV
reverse transcriptase (Chandramouly et al., 2021). Moreover, the
unidirectionality of the flow of cellular information from DNA to RNA to
proteins is also contravened by two specific factors whose impact is now being
more fully explored. First, the extent and heritability of epigenetic changes had
been vastly underestimated in the past. Epigenetic changes are now known to
significantly affect the course of evolution as a source of genomic plasticity and
modulation (Torday & Miller, 2020; Ashe et al., 2021). Second, organisms
continuously adjust their genomes through read–write genomic editing (Shapiro,
1992, 2019; Witzany, 2011).
The originating conceptual frame underlying modern epigenetics is generally
accredited to Jean Baptiste Lamarck in his 1809 Philosophie Zoologique.
Lamarck conceived of an evolutionary system where individuals developed new
traits by reacting to their environment, thereby acquiring heritable
characteristics. A frequent example of a Lamarckian type of inheritance would
be the theory that giraffes acquired their long necks by constantly reaching for
leaves in trees. Although initially rather popular, it became identified with
vitalistic thinking and was ultimately discredited since no specific biological
mechanism could be identified in earlier decades.
However, in a series of inventive experiments with Drosophila melanogaster,
Waddington (1961) seemed to confirm the possibility of external forces altering
gene expression through a process of ‘genetic assimilation’. Environmental
stresses could trigger biomolecular processes that regulate genetic expression
independently of the specific DNA sequences. Waddington termed this process
epigenetics. Such epigenetic changes have been confirmed as a source of
heritable variations through processes such as methylation that modify DNA
structure while leaving the underlying code unchanged. Other epigenetic
changes can result from horizontal gene transfers, which include transposable
elements (TEs), interspecific hybridization, viral incursions, or shifting
relationships with a contributory microbiome from symbiosis or parasitism
(Jablonka & Lamb, 2008; Torday & Miller, 2020).
A variety of epigenetic influences affect the nuclear genome. Accordingly,
heredity is now understood to be a much more pluralistic process than was
originally thought. In the 21st century, the genome is now considered a
reciprocating organ within an organism as an organized whole. Since phenotype
is expressed through the proteome, even though the proteome may not directly
alter DNA, its information content distinctly reverberates back to the genome to
affect its regulation and expression (Burley & Kamada, 2002; Stadhouders et al.,
2019).
Contrary to long-held presumptions, the current view of the genome regards it
as a highly flexible, adaptive, read–write informational system that directly and
responsively contributes to evolutionary innovation (Shapiro, 2013). The
genomic read–write system permits cells to actively write their information
content into their genomes through natural genetic engineering, epigenetic
formatting, structural adjustments, symbiogenetic cell mergers, horizontal
transfers, and interspecific hybridizations (Shapiro, 2013, 2017). The exact
details of these complex processes need not be our specific concern in this
chapter. However, it is important to mention these as they indicate the wide
range of processes that can flexibly alter genomic content. Further, another type
of genetic input, termed mobile genetic elements, disperse across genomes,
representing pertinent information that functions akin to ‘plug-in’ cassettes.
These small snippets of genetic code can modify cellular networks by impacting
nucleoprotein structures and, through domain shuffling, ultimately affecting
phenotype (Shapiro, 2016). Reciprocally, phenotype affects the genome, forming
flexible, adaptive pathways to meet contemporary environmental stresses. The
extent of these interchanges is profound. It is currently estimated that mobile
elements comprise the majority of eukaryotic genomes (Arkhipova &
Yushenova, 2019), and further, these insertions are not random (Miller et al.,
2021). Indeed, there is growing evidence that a substantial proportion of gene
editing is non-random (Zamai, 2020).
Accordingly, TEs, additional types of genetic particles called integrative and
conjugative elements, and the great varieties of small RNAs all constitute an
environmentally responsive organism-wide, multi-domain genetic mobilome.
These genetic players represent an ‘on-call’ information repository for the
flexible, adaptive responses of cells to environmental challenges (Miller, 2016a;
Miller et al., 2021). Necessarily then, evolution must extend beyond its prior
genomic focus to accommodate the entire panoply of sources of information that
can affect cells, their genomes, and other genetic constituents. All of this active
genetic mobilome participates in finely tuned coordinated processes, incurring
viruses, and competent RNAs (Witzany, 2009, 2014). And further, all of these
genetic constituents are elements of the read–write informational system of cells
that interact with its essential internal organelles and plasma membrane.
The proteome, too, is undergoing its own reconceptualization. Indeed, the
proteome is now understood to be more complex than either the genome or
transcriptome (Carbonara et al., 2021). Rather than representing canonical
proteins, the proteome is being re-imagined as a myriad of ‘proteoforms’
emerging as isoforms, splice variants, and separate modifications before, during,
or after transcription and translation (Carbonara et al., 2021). There is a growing
appreciation that proteomics reflects the actual status of the cell compared to
genomics or transcriptomics. This accumulating knowledge directly influences
our understanding of cell dynamics, especially in immunology and cancer
research (Urbiola-Salvador et al., 2022).
Over the last several decades, research has revealed the substantial epigenetic
evolutionary impact of TEs (Warren et al., 2015). TEs were originally
considered little more than genetic parasites capable of transmitting some
genetic information (Hua-Van et al., 2011). However, their contribution to
biological and evolutionary development and an extensive range of activities has
been clarified (Federoff, 2012; Hedges & Belancio, 2011). TEs as ‘jumping
genes’ are small segments of ‘restless’ DNA that can shift position in genomes,
affecting its size or range of expression. Some of these remain within an
ancestral genome, while others can be transmitted across species boundaries
where they can be either active or dormant (Hedges & Belancio, 2011). That
interspecies transmission relates to the fact that several TEs have been found in
viruses that specifically target eukaryotes. These can act as vectors of horizontal
transmission to eukaryotes as a form of infectious spread. Since TEs can affect
gene regulatory networks and either enhance or silence adjacent genes, it is not
surprising that scrupulous intracellular mechanisms exist to regulate TE
expression as part of the information management system of cells.
At one time, it was assumed that gene duplications were responsible for the
size of genomes. Consequently, it was surprising to discover that up to two-
thirds of the human genome consists of TEs. These TEs not only expand
genomic size but stimulate further genetic rearrangements, ultimately affecting
genetic expression in both animals and plants (Hirsch & Springer, 2017;
Drongitis et al., 2019). Some TEs, such as LINE1, repeat 500,000 times in the
human genome. For years, this component of our genome was thought to be
‘junk’ DNA. However, research has uncovered that LINE1 is an important co-
factor in embryonic development and affects RNA networks (Fadloun et al.,
2013). Further, TEs convey many transcription factors that influence molecular
linkages in the genome but also extend beyond it to modulate immunity and
cellular responses to environmental stresses (Wagner & Lynch, 2010).
Accordingly, the modern picture of TEs emphasizes their substantial role in gene
regulation and expression. Altogether, these various genetic factors contribute to
our modern understanding of the central genome as a flexible and even
malleable genetic repository that contributes to biological variation and
evolutionary diversification.
Among the most evolutionarily significant TEs are infectious retroviruses,
another form of retroelement (Boeke & Stoye, 1997). Retroviruses have helped
shape evolutionary outcomes, contributing adaptive value (Shapiro, 2016). For
example, retroviral insertions account for the origin of syncytiotrophoblastic
tissues of the mammalian placenta (Black et al., 2010). Indeed, the substantial
array of retroelements in species’ genomes can be seen as residues of previous
infection interchanges across evolutionary development, with many of them
contributing phenotypic and metabolic variation and serving as a source of
biological novelty (Witzany, 2011; Bennetzen & Wang, 2014; Soucy et al.,
2015).
The discovery of all the preceding means of adding or adjusting the genetic
complement of cells and organisms commissions an enlarged framework of the
true nature of our genetic complement. Genes are tools of flexible cells
functioning as retrievable and deployable memory. Genes serve sentient,
competent cells, enabling accurate self-similar reproduction and permitting
biological variations as flexible problem-solving to meet environmental stresses.

An Engineering Cycle Derives From the Information Cycle

Because cells measure information, they communicate. If information were
perfect and measurement was not required, communication would not be needed.
The point of communication is to convey the meaning of the self-produced
internal assessment of information to other cells. Communication is the sharing
of information, and as previously indicated, this translates into improved validity
in the internally measured assessment of ambiguous environmental variables
through collective appraisal. This aggregate information assessment is termed
effective information (EI*) since it represents the summation of multiple
separate cellular information measurements, which propels multicellularity
(Miller, 2018). Further, as introduced in Chapter 7, any internal assessment
information is an expenditure of work. That work issues an obligatory work
signature, leading to a reiterating information cycle (see Figure 7.2 in Chapter
7).
Any reiterating cycle in biology that is energy expensive has a purpose.
Undoubtedly, any sharing of information is an expression of cellular cooperation
and an evident distribution of resources. Necessarily, this collaborative impulse
is an active expression of cellular consciousness. Although the cellular
information cycle involves some obligatory cell–cell communication, the sharing
of the internal appraisal of information as measurement is predominately
contingent on cognitive assessment. Pertinently, however, it is not just that
cellular consciousness permits the cooperative sharing of information. All life
depends on this living feature. Even unicellular organisms such as bacteria freely
and abundantly associate via highly integrated and complex, collaborative
biofilms as a vast consortium of different unicellular genotypes and phenotypes
(Wojciech et al., 2018). Consequently, it is not just that cooperation can be
attributed to cellular consciousness. Cellular consciousness is explicitly
dependent on cooperation to continue to exist. The perpetuation of the cellular
form, which equates with the perpetuation of self-identity, is dependent on
cooperation, which explains the dominance of multicellularity on the planet.
Correspondingly, all cellular processes are purposed for the continuous
protection of cellular self-identity, which is its state of consciousness self-
awareness (Miller et al., 2019). Consequently, cellular collaboration is not an
epiphenomenon of consciousness but is an embedded living attribute,
inseparable from its entirety.
How does this obligatory interrelationship express further in biological terms?
Because cells can measure and communicate, they can engineer. Cells cooperate
to engineer collective solutions to cellular stresses, a process that has been
described as natural cellular engineering (Miller et al., 2020a, 2020b; Torday &
Miller, 2020). What are cells engineering? They are engineering conducive
habitats as niche constructions. For example, the localized tissue ecologies that
are part of your body, like your intestines and gut microbiome, are examples of
natural cellular engineering as niche constructions. You are their product, and so
is every other visible creature on the planet (Miller et al., 2019, 2020a). All
organisms are part of a reiterative cellular information cycle (Figure 8.1).
Figure 8.1 The cellular engineering cycle.

The external cellular environment offers biological information as cues,

triggering the cellular information cycle. The dynamics of the cellular
information cycle stimulate a reiterating work channel based on the collective
appraisal of information (EI*), deployed among cells as collaborative natural
cellular engineering, which can include a co-partnering viral contribution. This
coordinated cellular process produces unicellular collective biofilms and the
united tissue ecologies that constitute all multicellular eukaryotes. Biological
variations result from differing natural cellular engineering outputs as
differential cellular expressions of cell-based problem-solving. Those cellular
solutions that are ‘fit enough to survive’ continue the reproductive cycle.
How do we humans engineer? We appraise information, communicate,
cooperate, serve co-dependent functions, and compete. What are we
engineering? Solutions to human problems and concerns, such as houses, cars,
jet engines, books, scotch tape, or air conditioning. All are solutions to problems
or, alternatively, attempts to achieve a state of preference, which is just another
form of problem-solving. Quite directly, the reason that humans can engineer is
that their cells do. We are their engineering product. If they couldn’t engineer,
we would not be able to do so, because we would not be here. How do we
engineer? We use tools, like hammers or saws. Cells use their tools. All aspects
of the cell are its tools. Indeed, it has been pointed out that the cell itself should
be regarded as the first example of niche construction (Torday, 2016). This niche
construction activity that created the crowded, active environment of the cell is a
masterpiece of internal engineering.
Humans use tools of all kinds and depend on retrievable and deployable
memory to conduct successful engineering operations. All the vital components
of the cell are its tools, including its genes. Accordingly, the senome, genome,
and epigenome are all tools of the intelligent, measuring cell. Even the genes in
our obligatory constituent microbiomes serve our cells. Genes are a crucial
component of the retrievable and deployable memory system of cells. This
perspective is quite the opposite of what had been previously believed. In 20th
century biology, genes were the masters and controllers of cells. Cells exist to
serve genes and their perpetuation. Despite this confusion, which was most
effectively fostered by Richard Dawkin’s celebrated The Selfish Gene (1976) and
came to be regarded as the most influential science book of the 20th century, the
conclusion that genes are tools of cells is intuitively obvious. Genes outside of
cells are inert.
Exactly how are genes serving? Genes aid consciousness as part of cellular
problem-solving. In particular, genes serve by being critical tools in natural
cellular engineering. There is one other obvious requirement for any engineering
project. Cells, as engineering participants, require a plan or some type of
template. Although it is in vogue to insist that this plan simply emerges de novo
from the conjoining action of cells, self-produced electrical gradients, and
bioactive communications (Hao et al., 2021), an actual informational template is
required (Miller et al., 2020b). Although genes are tools of that templating
process, the actual plan lies in an overlying information matrix, which will be
discussed in the next chapter. When genes are properly placed into their context
as flexible tools of cells that use them to solve problems, five further
implications derive, some of which are not obvious.

1. First, cells are engaged in collaborative engineering. Consequently, this collaborative engineering
produces the complex cellular ecologies that constitute the bodies of all multicellular eukaryotes
(including you). All phenotypes are the result of concordant natural cellular engineering (Miller et
al., 2020a). Notably, phenotype not only includes observable features like height, weight, hair colour
or texture, or limbs but all metabolic processes. If you look up the definition of phenotype, the
internet will commonly define phenotype as genetic expression. However, there is a vital difference
that should be fully accounted for in modern biology. That genetic expression is a reciprocating
effect of the cellular assessment of environmental cues and collaborative cellular decisions about
how to productively adjust to new stresses. Consequently, phenotypic variations are the result of
concordant differential natural cellular engineering and niche constructions in reciprocation with a
flexible read–write cellular genetic complement.
2. When coordinated biological expression as phenotype is accredited as being due to natural cellular
engineering, it is unquestionably driven by largely non-random processes. That coordinated
engineering is a direct manifestation of cellular problem-solving in response to environmental and
epigenetic impacts (Miller et al., 2021).
3. Since all multicellular eukaryotes are holobionts with active participants from each of the four
domains (Prokaryota, Archaea, Eukaryota, Virome), any holobionic multicellular variation as co-
engineering must be a product of co-engineering among representatives of all four domains (Miller
et al., 2020a). Consequently, the nature of the relationship of the virome to cells requires re-
evaluation. Although viruses are typically described in terms of host–pathogen interactions, that
represents a small minority of the complex interplay between viruses and cells. In the main, viruses
are co-partners with cells in natural viral–cellular engineering, working along with cells in
maintaining suitable niche constructions.
4. Natural cellular engineering and its coupled process of natural genetic engineering are expressions of
cellular problem-solving. However, the explicit purpose of cellular problem-solving is precisely
directed to the protection of the self-integrity of all cellular constituents (Miller et al., 2019). Cells
collaborate volitionally, and cells have learned that their individual interests are best served within a
collaborative form. Indeed, this individual cellular impulse to protect both individual self-identity
and the self-integrity of others is so ingrained that it has been characterized as form of altruism. As
noted in Chapter 2, Gürol Süel and colleagues at the University of California, San Diego found that
distinctly separate colonies of Bacillus subtilis will communicate distress to one another, stimulating
volitional reciprocating adjustments in nutrient uptake of the non-stressed colony in response to
nutrient depletion in a common environment (Prindle et al., 2015). Cells in one colony will sacrifice
to aid the other.
5. When genes are acknowledged as tools of cells subordinate to and reciprocating within a replete
cognitive cell-based informational interactome, the general narrative of evolutionary development
requires a complete reappraisal. In sum, and as will be discussed next, cellular consciousness
changes all previous theories of biological and evolutionary development. Almost everything that
comprises the core of the modern synthesis requires revision since the narrative changes from
genetic mutations and gene frequencies to our contemporary understanding of intelligent, measuring
cells as organized wholes.
Biological and Evolutionary Consequences of Genes as Tools
Darwin’s 1859 On the Origin of Species continues to be acknowledged as the
seminal text in evolutionary biology. However, it is often overlooked that his
inspiration was a theory of forms (Bowler, 2003). With the advent of genetics in
the mid-20th century, evolutionary biology was transformed into a theory of
genes, becoming instilled within the prevailing, canonical neo-Darwinian
modern synthesis. In Darwin’s time, two central questions dominated the debate.
How can life’s diversity and history be explained, and how do form and function
match (Pigliucci, 2007). Lamarck offered an answer through continuous
environmentally induced adaptation, and his conjectures were well regarded in
the 19th century (Gould, 2002). Indeed, it is often overlooked that Darwin was
partial to Lamarckian precepts, offering his own version, termed ‘pangenesis’ in
his 1868 Variation in Plants and Animals under Domestication, attempting to
justify the transfer of traits of somatic cells to offspring under environmental
pressure. Despite summary rejection during the 20th century, Lamarck’s
perceptions are now reinvigorated within the burgeoning science of epigenetics.
Similarly, other previously sacrosanct areas of evolutionary biology are being
substantially re-evaluated. Noble (2021) insists that the modern synthesis, first
formulated in 1942 with the birth of genetic studies, remains steeped within four
governing illusions: the absolute primacy of natural selection, the inviolable
separation between somatic and germ cells, Crick’s central dogma of a
unidirectional flow of genetic information, and a rejection of Darwin’s
gemmules which presumed active cross-connections between somatic cells and
the germ line. All have been contradicted by modern studies, but stubborn
beliefs have impeded the development of a fully coherent alternative to the
modern synthesis.
Of these outdated concepts, perhaps the most nettlesome has been the
commanding influence of Crick’s central dogma asserting primacy of genes.
Nonetheless, the accuracy of that dictum has been increasingly questioned
(Shapiro, 2009, 2021; Camacho, 2019). An embedded belief still exists that the
central dogma remains true according to Crick’s original pronouncement that
‘once sequential information has passed into protein it cannot get out again’,
known informally as the ‘sequence hypothesis’. Recent CRISPR analysis has
begun to call even that into question (Ille et al., 2022). Nonetheless, any narrow
vision of genetic adjustments misses the essential dynamic of a whole-cell flow
of information that is certainly not unidirectional. That entire flow of
information enables a cell to uphold itself, expressed as its self-referential self-
integrity, sustaining its crucial homeorhetic balance and granting it adaptive
flexibility (Miller et al., 2020a). Consequently, the genome and the rest of the
cell-based genetic complement are considered facets of a whole-cell read–write
informational architecture as a crucial component of the cell-wide critical feature
of its information management system.
An alternative conceptual model is now offered that better explains the elusive
nature of living organisms and the complexities of cellular dynamics.
Specifically, the central dogma is replaced by a cell-wide read–write information
system embodied within the cellular form that is compatible with framing
biological and evolutionary development through the flow of information.
Consequently, the cell must be regarded as an organized whole in which the
proteome has a vital reciprocating impact on the genetic resources of the cell,
contravening Crick’s central dogma. Consequently, genes and genetic material
are tools within the information management system of competent, sentient cells,
enabling the requisite harnessing of stochastic and non-stochastic informational
inputs to yield productive outputs. Through this differing frame, evolutionary
biology is returned to its Darwinian roots as a theory of forms and not genes.
Crucially, those forms are shaped by the congruent action of the entire suite of
capacities of intelligent cells as organized wholes rather than genes as ‘selfish’
quasi-autonomous agents, as previously presumed.
Fortunately, contemporary research has spurred a substantial reappraisal of
genomes and how the entire suite of genetic components in cells operate. That
research has displaced the previous conception of genomes as a blueprint (Ball,
2016; Miller, 2018; Miller et al., 2020b; Torday & Miller, 2020). Previously, a
common metaphor for the genome was that it represented ‘the book of life’.
However, it is now understood that the genome is not a book in any traditional
sense. Instead, genes are a type of ‘translational dictionary between two different
worlds (languages), i.e. the world of nucleic acids and the world of proteins’
(Cartwright et al., 2016). The now-refuted metaphor failed to account for the
dynamic, read–write capabilities of the genome by which it flexibly serves
continuous cellular adaptation. Further, the vital role of the large fraction of the
central genome that is non-coding can now be honoured. Research has
demonstrated that this extensive peripheral non-coding DNA protects the
eukaryotic genome through a complex set of interactions. Hence, rather than a
book, a genome is better analogized to an insect colony, which functions as an
extended social habitat exhibiting common defence mechanisms (Qiu et al.,
2017).
Consequently, 21st-century biology views the genome as speaking a common
language deployed across the living planet (Torday & Miller, 2020). The genome
and the entire array of genetic participants in cells play a crucial role in
evolutionary development as one of the primary mechanisms of information
transfer as community-wide cell–cell communication. Far from the common
conception of viruses painted in neo-Darwinism within a traditional host–
pathogen model, the virome is a critical co-partner in information transfer as
cell–cell communication and as a co-engineering participant with cells in cellular
problem-solving.
Therefore, viruses, retroviruses, subviral particles, and retroelements assist
cells in their continuous adaptation to a shifting environment. Goldenfeld and
Woese (2007) insisted that the neo-Darwinian conception of the virome as mere
pathogens was a fundamental misapprehension. Instead, the virome should be
viewed as a collective memory repository of community-wide genetic
information, thereby contributing to evolutionary dynamics. Notably, viral
incursions do not necessarily trigger immediate results as potential cellular co-
partners. Both non-pathogenic and pathogenic viruses can display latency and sit
quietly within the cellular milieu. In this sense, the virome can be considered ‘on
call’ for future deployment in times of environmental stress, with resulting
bioactive expression. Similarly, TEs, alongside retroviral inclusions, are now
known to be appreciable participants in evolutionary development, partly
accounting for continuous cellular adaptation but also intermittently triggering
bursts of rapid speciation and evolutionary transitions that account for brisk
adaptive variation (Oliver & Greene, 2011).
Cells can produce new phenotypes through collaborative natural cellular
engineering. This process is the biological expression of multicellular
assessment and measurement of informational cues of imposed environmental
stresses. Through their collective action, congruent phenotypic variations as
cellular niche constructions emerge. Necessarily, both random inputs and non-
random cell-generated responses impact that coordinated cellular engineering
(Miller et al., 2020a, 2020b, 2021). As part of this interleaved process, a logical
processor decides if any generated new state is a preferable environmental
response or should be discarded. That logic processor is cellular
cognition/sentience.
At one time, it was presumed that the central genome subsumed this role as
the controlling agency of cell fates. Modern studies indicate that the genome is
crucial, but as a participant in a cell-wide read–write memory system rather than
a developmental agency. Instead, the information management system of the cell
permits the productive separation of conflicting environmental stimuli,
distinguishing between random noise and significant cellular information, and
melding them into integrated, purposeful outputs. Consequently, random inputs
are channelled into practical biological expression as the ‘harnessing of
stochasticity’ (Noble & Noble, 2018). In this manner, random events can be put
to productive purposes. However, for that to be the case, there must be a
biological logic processor coordinating this cell-wide information management
system (Miller, 2018). Unquestionably, genes do not suffice. Instead, they serve
the logic processor, which is, the cellular consciousness assumed in the CBC
theory.
The old-fashioned model of evolution ensconced in the neo-Darwinian
modern synthesis regarded random replication errors as the actual drivers of
evolution (Bowler, 2003). Nonetheless, replication errors are subject to highly
controlled error correction mechanisms in which the ability to correct errors via
DNA polymerases can vary substantially depending on genome location and
type of error (Kunkel, 2009). Epigenetic marks are also subject to revision,
suppression, or deletion during two life-cycle stages. The cellular judgement of
their biological suitability is largely determined during the obligatory
recapitulation through the unicellular zygotic state and then further during early
embryogenesis (Torday & Miller, 2016a). During this critical transition period,
cells make decisions for their immediate and long-term benefits. Many of those
epigenetic imprints are random occurrences. Nonetheless, some are differentially
preserved and heritable. That differential has a significant impact on
evolutionary development as a harnessing of stochasticity to sustain cellular
balance or offer novel, beneficial results.
This same narrative determines any viral contribution to adaptive cellular
responses. Viral genetic memory, either DNA or RNA, can be modified by
several variational mechanisms, such as recombination, random point mutations,
post-replicative repair, regulation of lysis, or relaxing polymerase proofreading
(Sanjuan & Domingo-Calap, 2016). Each of these is further influenced by
environmental factors (Zamai, 2020). This mechanism resembles a type of
genetic algorithm through which the generation of new phenotypes intimately
links to genome-wide protein–protein interactions that reciprocally interact with
viral replication/transcription (Pan et al., 2008). Clearly, there are sets of protein-
based biochemical mechanisms that can write on viral and cellular memory by
‘intentionally’ modifying DNA/RNA, contravening Crick’s central dogma.
Perhaps the most consequential reason that the prior presumption of the
primacy of genes must be reconsidered is the rapidly increasing understanding of
the critical impact of our trillions of co-partnering microbial partners on our
biological and evolutionary development (Gilbert et al., 2010; Miller, 2013,
2016b, 2018; Chiu & Gilbert, 2015; Miller et al., 2020a; Torday & Miller, 2020).
It is currently estimated that the human microbiome has between 10 and 100
trillion constituents (Thursby & Juge, 2017). Some estimates of the human gut
microbiome suggest that there are ten times as many bacterial cells as our
personal eukaryotic cells, and their total genetic complement might be 100 times
greater than our intrinsic human one. Others dispute that number and insist that
the ratio is closer to one to one (Sender & Fuchs, 2016).
However, it bears emphasis that these estimates are for bacterial cells as the
most accessible type of microbial constituency for evaluation. None of these
estimates include the virome, and nearly every bacterial cell has its constituency
of phages (viruses in bacterial cells) that contribute to its metabolic outputs.
Furthermore, each of our body sites has its personalized constituent microbiome.
For example, human testes have a dedicated microbiome that contributes to
testicular function (Altmäe et al., 2019). None of these should be considered
passive since microbes function as gene-swapping collectives (Goldenfeld &
Woese, 2007).
Our obligate microbiome is a crucial participant in all of our metabolic
processes and serves a critical reciprocating role in our adaptive resiliency
(Miller, 2016a, 2020b, 2018; Miller et al., 2020a; Torday & Miller, 2020). Over
the last several decades, research has confirmed that the microbiome of
holobionts has a substantial role in biological development based on extensive
mutual dependencies (Kelly et al., 2017). Our constituent microbiome has a
considerable impact on our phenotypes. Through that partnering contribution,
microbiomes significantly contribute to holobionic phenotypes (Lynch & Hsiao,
2019). Most readers are likely to be familiar with the broad impact our gut
microbiome has on our metabolism, partially governing satiety, obesity, and
bowel function. However, our microbiome also crucially influences our brain
and nervous system. For example, our microbiome is essential for the proper
operation of our human gut (Cho & Blaser, 2012), brain, and central nervous
system, even affecting our moods and behaviours (Cryan & Dinan, 2012).
Further, the microbiome has a critical influence on the entire suite of functions of
our immune system, serving as a critical interface between health and disease
(Postler & Ghosh, 2017). Research reveals that every aspect of our metabolism
and physiology has a co-dependent relationship with our microbiome and
adaptive immune responses across our lifespan (Hooper et al., 2012).
Accordingly, it is insufficient to consider evolutionary development through
the restrictive lens of a central genome absent the contribution of this essential,
obligatory contribution factor comprising a genetic complement of millions of
genes that vastly outweighs our paltry 23,000 or so genes. That peripheral,
correspondent genome may not be primary, but neither is it inconsequential.
What role does this obligate microbial genome serve? It is the ready response
system to immediate environmental stresses (Miller et al., 2019). Our relatively
insulated central genome reacts more slowly. Together, they comprise our
exceptionally competent biological system.
Nor is it realistic to singularly concentrate on DNA. Our vast repertoire of
cellular RNA agents represent critical aspects of cell–cell communication,
coordination, and regulation (Villarreal & Witzany, 2019). Most viruses, as
mostly RNA agents, also participate in this intercellular communication grid. All
of these have a complex working relationship with cells, along with TEs, circular
DNAs, and RNA stem loops that contribute to every aspect of cellular life, exert
regulatory controls, alter adaptive immunity, and participate in evolutionary
transitions (Witzany, 2020).

That Was Then, This Is Now: The Demise of the Selfish Gene
The thorough revision of our previous concept of the nature of the genome
heralds a complete reappraisal of biological and evolutionary development. In
the 20th century, evolutionary thought was dominated by the theory of the
‘selfish’ gene (Dawkins, 1976). Evolution was the product of natural selection. It
was not about species or communities but a narrative of preserving individuals
as vessels for their selfish genes. In that era, genes and gene frequencies were
thought to rule. Biology in the 21st century is transformative and explicitly
cognition based. In 21st-century biology, cellular consciousness is biology’s
driving force. The central enacting expression of that cellular consciousness is
the cell’s requisite measurement of the informational cues that the environment
contributes. Cells measure because living information is imprecise.
Consequently, the cell’s sentient capacity to sense that its information is
uncertain represents the distinct root of cellular self-awareness, supported by its
vast panoply of bioactive molecules, energetic fields, and the full array of its
senomic physical apparatus. From that living base, all life spills forward.
To measure better, cells collaborate. This requisite impulse energizes natural
cellular engineering and, correspondingly, since cells intimately partner with the
virome, natural viral–cellular engineering. The purpose of that engineering is
clear-cut. Cellular engineering and, indeed, all cellular communication and the
cellular deployment of resources are tasked to solve problems. In cellular terms,
problem-solving equates with the maintenance of self-referential homeorhetic
balance. Thus, the role of the cell’s entire genetic complement, including its
central genome and abundant supporting cytoplasmic genetic constituency such
as plasmids and circulating small RNAs, clarifies. All the cell’s genetic material
is part of a flexible read–write informational architecture supporting cellular
self-identity as reciprocating, retrievable, and deployable memory purposed for
cellular problem-solving. Reproduction must now be viewed differently.
Reproduction is another form of problem-solving for cells to sustain the three
cellular forms over billions of years. Responsive genomes participate in that
process through the self-editing processes of natural genetic engineering and
continuous modifications by epigenetic impacts.
If the genome and other intracytoplasmic genetic participants function as
memory, what exactly are they remembering? Genomic memory is the repository
of the continuous narrative of cellular solutions to environmental stresses. All
multicellular organisms are an expression of that narrative in biological form.
Through this continuous reciprocating process, cells maintain themselves
through constant assimilation of the external environment. To accomplish that,
cells form holobionic tissue ecologies that further aggregate to become us, as
holobionts. Consequently, evolution can be reappraised beyond a 20th-century
narrative of genes to an entirely different, fluid dynamic of intelligent, measuring
cells upholding their fates through collaborative information assessment and
fluid communication (Miller et al., 2021). Strikingly, biology cannot be a
primarily random process. All cellular actions are based on self-generated
internal measurements and their further communication to stimulate communal
actions. Such deliberative actions represent cellular predictions that are the
opposite of random (Miller et al., 2020a, 2020b).
Over 40 years ago, and long before the contemporary research that underpins
this chapter, the brilliant physicist Walter Elsasser intuited what still represents
the most illuminating concept of the gene (Elsasser, 1981). Working within a
framework of quantum physics, he believed that all biological forms
fundamentally represent expressions of the superposition of states. The concept
of superposition is difficult and non-intuitive but has been confirmed
innumerable times. In physical systems, many configurations are possible at any
time. Superposition indicates that the most probable state is not any specific
fixed one but instead represents a combination of all possibilities that
superimpose on each other. Organisms achieve their form by ‘settling’ into one
or another superposition among the many into discrete biological expressions.
Elsasser insisted that this type of living system could never be controlled by any
simple mathematical rules. Instead, the ‘selection’ from among this large
reservoir of possibilities represents an act of creativity for that organism.
Consequently, heredity reproduction is a process of ‘creativity with constraints’.
Necessarily, these must conform with quantum mechanics, and those constraints
are why ‘progeny tends to resemble progenitors’. This viewpoint significantly
changes the prevailing view that evolution is a mechanistic process that is an
endless stream of minor errors, as the modern synthesis stubbornly maintains.
Instead, a new biology emerges in which a gene is an ‘operative symbol which
functions as the releaser of a creative process’ (Elsasser, 1981, p. 131).
There is a critical entailment from this edifying insight. Any released cellular
creativity derives from the self-referential measuring assessment of information.
Although not obvious, any information or cell–cell communication purposed
towards creativity as biological expression is necessarily a prediction by both
specific cells and collaborating cells as co-engineering. Yet, this coordinated
process is precisely how biological variation emerges. Environmental inputs
stimulate cells to co-engineer in alternative directions. Hence, biological
variations are not random events. Instead, biology variations are purposeful and
creative expressions sourced through cellular predictions (Miller et al., 2020a,
2020b).
Additional research is needed to establish the entire role of the genome and its
constraints. However, it is now clear that far from being a passive participant, as
once believed, the genome is a direct and flexible participant through consistent
and responsive self-editing as natural genetic engineering and epigenetic
modifications (Witzany, 2011; Shapiro, 2016, 2019). The genetic mobilome,
including large numbers of TEs, is crucial for cellular adaptation in cooperation
with its flexible genome (Shapiro, 2017). Accordingly, non-selfish genes assist
essential symbiotic partnerships among cells and their companion viruses to
attain and sustain compatible habitats as niche constructions. Within this
narrative, genes are tools. What is the glue that binds these complex processes?
Cellular sentience forms that critical bond.
All cells are self-referential cognitive, sentient agents. Computers are logical
but share none of these defining attributes. Computers have no ambiguities.
They share no doubts, preferences, or experiences, nor can they harness random
occurrences, like human engineers often do, in any manner like the living frame.
Neither do our genes. As we noted in the Prologue, AI devices have already
passed a version of the Turing test and seduced a perceptive human into
believing it is fully conscious. Yet, it is still a computer, offering a passing
simulation of a breathing human but only remaining an engineering deception.
9
The N-Space Episenome
Life as Information Management

Life Requires Information

The specific point of this volume is an attempt to place the elusive character of
consciousness into a robust biomolecular basis. Nonetheless, some attributes of
cellular consciousness stand apart from any known biomolecules or membranes.
Unquestionably, the elusive sense of consciousness includes some types of non-
physical representations that participate in composing our apprehension of
reality and thereby govern our lives. As will be explained, this non-physical
attribute of the living state is its connection with information space. This chapter
will discuss how our relationship with information underpins our existence, how
organisms obtain information for internal self-analysis, and how they share
information among themselves.
Consciousness/cognition/sentience began some 3.7 billion or more years ago
and is coincident with life. We can confidently make this statement since our
proof of life is specifically dependent on its embedded collaborative
characteristics as a hallmark of cognitive action evinced as microbial mats and
stromatolites (Nutman et al., 2019). As single cells do not fossilize, only life in
its colonial form leaves evidence of its prior existence. In Chapter 7, we
emphasized that this type of colonial life was crucially dependent on the cellular
sharing of information. Information must be disseminated and combined among
cells since all the information that any cell has is ambiguous, as has been
previously detailed (Torday & Miller, 2017). For this specific reason, intelligent
cells measure information as an internal self-referential process necessary to
assess the its validity (Miller et al., 2020a). Indeed, that sensing of uncertainty
and its obligate measurement can be considered the defining characteristic of
cellular cognition as central to all cellular problem-solving that is imperative for
survival (Miller, 2018).
Further, as previously noted, cells share measurements through abundant
communication to improve the validity of their assessment of environmental
cues. This drive is elemental and underscores the cellular information cycle
introduced in Chapter 7. Importantly, cognitive awareness of information
uncertainty as life’s condition propels its collaborative assessment.
The foregoing has a remarkable entailment that has received scant attention
but is nonetheless absolutely crucial. The cellular process of measuring the
validity of environmental information is entirely internal to the cell (Cárdenas-
García, 2020; Miller et al., 2020a). Any information that any cell might analyse
must traverse an external membrane and then be transmitted multiple times
within the internal architecture of any cell across its pertinent senomic apparatus.
Consequently, the intracellular analysis (measurement) of information is
conditioned within that flux which necessarily imposes substantial noise,
distancing any intracellular assessment of information away from its presenting
value by imposing potential sources of error (Miller, 2018; Miller et al., 2019,
2020a, 2020b). Accordingly, anything that a cell knows about its environment is
based on its exclusive self-referential analysis of that sensory information—and
any information that cell has is entirely self-produced. Although the same
principle of information insecurity holds true for shared information, collective
assessment narrows the range of possibilities beyond the appraisal of any
individual cell. All sensed information for cells, even in combination, always has
some level of uncertainty and inherent noise due to a loss of integrity through its
active transmission from outside the cell to its interior.
Even when cells are self-similar, each is a self-referential agent making its
individual measurements. However, the collaborative networking of cells often
requires cells of different types to communicate and cooperate. For example,
biofilms frequently have constituencies of dissimilar microbial species. All
multicellular eukaryotes are complex, seamlessly integrated assemblages of
highly differentiated cells and a coexisting and obligatory microbial cohort that
at least equals the number of native eukaryotic cells (Miller, 2016b). All must
precisely integrate for an organism’s survival. Therefore, because multicellular
collaboration is one of life’s essential requirements, a natural question arises.
How might each cell’s individual, self-generated cellular measurements be
shared within the multicellular whole to yield useful predictions if they are
unalike due to differentiation or by being a frankly different species? How might
all these disparate separate cellular ‘selves’ effectively communicate their
idiosyncratic measurements of ambiguous environmental inputs to one another
to compare them and produce effective biological outcomes?
By default, it must be assumed that collective cellular measurement obliges
some common frame of reference to yield consonant and productive biological
outputs (Miller et al., 2020b). Cells must have a collective referential measuring
platform to collaboratively engineer effective biological products. Consequently,
we need to explore the unfamiliar terrain of information space and how cells
organize to measure together successfully.
To begin, we need to deal with what ought to seem straightforward but is
decidedly not. Exactly what is information? The concept is quite clear to us in
our normal, casual conversations. We exchange information all the time.
However, among scientists, there has to be a formal definition of information
that can be deemed scientifically testable and refutable, and that is precisely
where the problems start. Surprisingly, there is no formal definition of
information that garners universal acceptance. As a result, how we might define
information is equivocal. Some even argue that the term information has no
specific meaning at all (Roederer, 2004).
We could write an ocean of words about this topic, and many academics do.
However, it is possible to be rigorous and still keep it simple. Information is the
sum of the interactions between matter and energy that an observer can
appreciate. For most people, an observer is a cognitive agent. Of course, many
scientists would argue that information exists even when there is no perceiving
cognitive agent. However, for our purposes, information to a living cell is the
aggregate of those interactions between matter and energy that represent
environmental cues. What matters to living agents are differences in the
environment that might upset their dynamic state of balance. Therefore, the
cellular meaning of information is a perceptible self-referential difference.
Fortunately, one of the most widely accepted formal definitions of information is
MacKay’s 1969 formulation in which information is deemed ‘a distinction that
makes a difference’, which Bateson (1973) changed to the often quoted, ‘the
elementary unit of information—is a difference which makes a difference’
(Floridi, 2003). Accordingly, in the self-referential living frame, information
forms when there is a ‘difference that makes a difference’ to that self-referential
organism, thereby becoming a subject of internal measurement and potential
cell–cell communication and bioactive deployment (Miller, 2020a).
Why does a difference matter? Because the interactions of matter and energy,
those that constitute external reality, can only be sensed based on a difference
sufficient to impact cellular sentience. Only matter–energy differences will
stimulate the cell’s senomic apparatus to become a subject of internal
measurement. The only thing a cell knows is what it can sense.

What Is Information Space-Time?

With that background, let’s tackle the unfamiliar concept of information space-
time. At first, this type of conceptual frame might seem quite abstract. However,
there is good news. All of the complex mathematics that makes physicists giddy
is not required. The fundamental concept of space-time is that there is a four-
dimensional ‘fabric’ in which physical objects are embedded and energetic
actions occur. Naturally, this concept has been formally expressed in
mathematical terms to explain gravity as a curvature of space-time. However, for
our purposes, it is easier and more productive to simply accept that there is an
observable universe of objects and energy available to interrogation by a self-
referential observer as their universal interactions. All of the universe is space-
time, and all of that universe is potential information to the appropriate observer.
Accordingly, for any self-referential conscious entity, there is an external
universe of potential information that might impact it. For any observer, or any
cell for that matter, there is an outward external environment that stimulates its
senses. Naturally, that external environment is composed of matter and energy.
However, as odd as it might seem, we do not directly sense matter or energy.
They only exist through their interaction with one another as it travels across the
interstices between cells and crosses the external cellular membrane. What is
sensed is the product of biomolecular processing of events and stimuli. For
example, on the most simple level, if light does not strike an object to make it
classically observable, it is unknown to us if we are limited to experiencing it
just through vision. Similarly, every one of our senses requires an interaction
between matter and energy, which potentially constitutes information to us.
Naturally, it depends on where we are with respect to the stimulus and many
other factors. We experience light with an energy spectrum in the 700 nm range
as red. But, of course, there is no ‘redness’ in the light; the self-referential
experience emerges from the interaction with particular cellular functions. If you
can imagine all of these overlapping cues as a field of potential sources of
information, then you would approximate the concept of what information
space-time means to any organism. Consequently, all living creatures assess their
physical environment through an individual self-referential interpretation of
information space-time. Cells experience the environment in exactly the same
manner.
Each cell assesses its potential sources of information from a theoretically
unlimited field of possibilities from an individual self-referential information
space-time matrix which is termed its Pervasive Information Field (PIF) (Miller,
2016a). Consider this PIF to be the effective boundary of the extent of all
possible sources of information available to any specific cell, representing the
summary envelope of all the matter–energy interactions that could become a
‘difference that makes a difference’. This information field concept was initially
conceived by Lloyd (2002) as a means of defining a universal, scale-free, self-
organizing system and had been initially applied to concepts of information
storage and for describing and modelling social systems (Plikynas et al., 2012).
Subsequently, it has been directly applied to biological systems to help explain
cellular dynamics (Miller, 2016a, 2018).
This field concept is particularly useful in the context of cells because the
transmission of cell–cell signals is more like a broadcast than a targeted
communication. Unlike a directed communication network, a field of
information directly implies an extensive range of possibilities and inputs
without any requirement for exclusivity. Moreover, the concept of fields in
biology further implies a potential for overlap, which is easily understood as the
intersection of conjoining fields. Within this overlapping matrix, information can
be shared and be mutually accessible to a variety of observer-participants and an
information field is roughly analogous other familiar fields, such as
electromagnetic fields. Just as with these well-understood energy fields, whose
effects trail off at a distance, in an information field, information quality from
remote sources would be less than those informational cues derived from more
proximate sources. In biology, particularly with mediums and membranes,
distance from a relevant source is an impactful source of ambiguity, thus helping
to understand a cellular context where information is conditioned within
uncertainties and noisy distortions (Miller, 2016a, 2018; Torday & Miller, 2017).
Harken back to our discussion of communication within and between cellular
collectives in Chapter 2 for an example of how this kind of biomechanism
operates in prokaryotes.
The PIF concept specifically comports with the self-referential frame as it is
an individualized connection to information space defining the limits of ‘self’.
As the summary field of all the potential informational inputs to any cell, it helps
explain the living condition that all the information that any cell has is internally
produced. Any stimulus from a cell’s information field can only be interpreted
after it has passed through the interposed plasma membrane which serves as an
integral feature of its self-referential status. Necessarily, that passage imposes
conditional uncertainties. Therefore, internally received information must be
measured to assess its validity and its meaning vis-a-vis cellular balance.
Accordingly, the cellular plasma membrane co-aligns, and indeed, co-evolved
with the cell representing the competent interface between the cellular interior
and its exterior, governing its sensory inputs (Baluška et al., 2021b).
Consequently, all the information that a cell possesses is a function of the
senomic apparatus of the cell.
 As previously outlined in Chapter 7, the senome is conceived as cell-wide,
information architecture, initiating at the plasma membrane as the outer
bioactive interface between the external environment of the cell and its complex
internal working. Thus, the senome represents a type of sensory organ for
assessing environmental cues (Baluška & Miller, 2018). In this way, cellular
informational impacts are conveyed across the cell in a highly coordinated
fashion, enabling the contingent deployment of cellular resources that ultimately
become cellular predictions. The senome represents a pivotal gateway between
the internal milieu of a cell and its external environment in its reception of
information which, in turn, has its impact on the epigenome and genome,
thereby facilitating the continuous assimilation of the environment to maintain
crucial self-referential homeorhetic preferences and balance (Baluška & Miller,
2018). From the entire constellation of universal information that a cell might
sense, there must be a reliable compact representation that will ultimately permit
accurate cellular predictions from its internally self-generated measurements. In
this manner, the cellular PIF is an integral part of the cellular senomic apparatus.

The N-Space Episenome Guides Multicellularity

Since each cell has its individual PIF and senome architecture and must
necessarily experience the environment individually, how might each of these
‘selfish’ entities collaborate, cooperate, trade resources, or artfully compete if
they are entirely distinct separate and competent selves? In answer, there must be
a platform that permits the sharing of information through concordant
measurement. Consequently, an N-space Episenome has been proposed that
represents just such a space-time platform for the conjoint assessment of
information, conceived as an aggregation of all of the individualized cellular
PIFs of participants in a multicellular network (Miller et al., 2020b). This
collective space-time matrix can be considered a multicellular organism-wide
summary informational architecture as a common platform for systematic self-
referencing for co-aligned measurements among individual cells. Thus, many
types of very different cells can productively collaborate in confrontation with
ambiguous environmental cues. These cues derive from external N-space and
necessarily impact every individual cell whose cross-communication with other
ecological partners permits multicellular cooperation. Just as a PIF represents the
field of potential direct and indirect sensory inputs to an individual cell, the N-
space Episenome is its multicellular counterpart (Figure 9.1).
Figure 9.1 The partitioning of N-space. Each cell has a pervasive information field (PIF), which represents
the summary field of all potential information inputs that can be received by its senome, genome, and
epigenome. In holobionts, these individual cellular PIFs aggregate into a reiterative information field
projection as an N-space Episenome. The N-space Episenome information field permits concordant cellular
measurement of environmental cues and also serves as a heritable and transferable information architectural
matrix templating organismal morphogenesis and development.

The N-space Episenome represents a whole-cell informational field

projection. It is not itself directly material, but it achieves functional physicality
by its correspondence with biological expression. Information can be deemed
physical in cognitive systems since it directly relates to physical degrees of
freedom (Walker et al., 2016). Furthermore, there is a direct link between the
external environment with its uncertain informational cues and the cellular
senomic apparatus. In turn, that cell-wide interface triggers the cell’s internal
measurement of the incurring information to assess its meaning, which leads to
its bioactive deployment as a physical action. Therefore, the N-space Episenome
acts as an informational matrix that connects and coordinates the cellular
senome, as the summation of the cellular sensory mechanisms, with the genome
and epigenome of each individual cell to achieve comporting multicellularity
(Baluška & Miller, 2018; Miller et al., 2020b). Consequently, the N-space
Episenome acts as a reciprocating read–write informational matrix that is the
guidepost of multicellular life.
Through this process, individual cells combine their individual measurements
of environmental cues based on their individual cellular senomic apparatus and
self-appraised internal measurement of that informational meaning. In the
aggregate, as a ‘wisdom of crowds’ writ at the cellular scale, cells improve the
quality of their EI* to mitigate environmental ambiguities (Miller, 2018).
It should not be considered controversial to assert that there must be a
common referencing platform to permit the productive multicellular work as co-
engineering and niche construction that characterizes multicellular life. Although
humans and cells do not share the same cognitive frame, both are competent
problem-solvers at scale. For us to work together at our scale, we must find and
deploy a common means of communication and use common referencing
measurement tools for a specific project, such as a ‘kilometre’, ‘metre’, or
‘dollar’. For cells to work in concert, they must do the same. Certainly, cells
share signalling mechanisms to communicate as, for example, in quorum
sensing. Since each cell measures separately, by living definition, they must
share their senomic measurements of environmental stresses so that they might
co-engineer to yield productive biological expressions.
Consequently, an N-space Episenome is a requisite attribute of multicellular
life. The appraisal of that necessity is plain enough if we consider our human
engineering endeavours. As humans, we readily find a shared means of
communication and measurement for any enterprise. Certainly, their absence
would render any co-engineering project a chaotic mess. Notably though, we all
have a nearly identical species-specific genome and react to stresses using the
same human toolbox as our framework. In contrast, eukaryotic multicellular life
is radically different. As holobionts, we are vast assemblages of cohabitating
differentiated cells and an intimately partnering microbiome. Moreover, it is
certain that our constituent microbiome with its trillions of constituents are
essential participants in our metabolism, physiological mechanisms, and
adaptive capacities (Miller, 2016b). However, there is no doubt that that each of
these microbial players is an individual ‘self’ (Ford, 2009, 2017; Trewavas &
Baluška, 2011; Miller et al., 2019; Reber & Baluška, 2022; Reber et al., 2022,
Baluška et al., in press). Moreover, each of these microbial partners has a
completely different genetic complement compared to eukaryotic cells and uses
a diverse toolbox to problem-solve. Yet, all comport with one another to produce
harmonious holobionic metabolism, physiology, phenotypes, and cognitive
responses to environmental stimuli. Accordingly, an N-space Episenome is a
necessity to permit comprehensive, successful, and consistent coordinated
responses to both sudden and long-term environmental stresses (Miller et al.,
2020b).
How this summary information field is specifically constructed has been
directly addressed in detail elsewhere (Miller et al., 2020b; Baluska et al.,
2021b). In basic terms, this type of informational architectural field can be
productively analogized by its relationship to the non-physical k-space used in
magnetic resonance imaging. K-space is a mathematically generated compact
topological space that contains other compact sub-spaces within it. These
partitions in k-space can be used to generate an anatomical magnetic resonance
image as a read–write field projection. Each compact subdivision in k-space is
its own compartment with its distinguishable data, but also contains a
representation of the entire data matrix that has been generated. In this manner,
the data make the image, but the image can be used to reverse reconstruct that
sub-partitioned data. The inherent reciprocality within k-space is similar to how
cells share information space as a conjoined N-space Episenome comprised of
sub-compartment individual PIFs. Although further details are outside of the
scope of this chapter, interested readers are directed to the references.
As a field projection, the N-space Episenome can be regarded as a replete
informational landscape and a summary field of all of the conjoined cellular
information spaces (PIFs), thus functioning as a shared field of measurement and
a developmental canvas with its own dimensions, limitations, and boundaries
(Miller et al., 2020b). Accordingly, it is a guiding field of potential shared
informational inputs that is in constant reciprocation with biological materiality,
impacting its genome, epigenome, and the full range of cytoplasmic constituents,
especially its endomembranes. Crucially, all of these are aspects of its senomic
architecture enabling real-time cellular responsiveness to environmental cues.
Consequently, the N-space Episenome, just as the case for its senome, is intrinsic
to cellular consciousness.
Furthermore, it is not sufficient that this shared information platform merely
serves as a centrepiece of real-time responses to environmental cues. Research
has revealed that every stage of holobionic life has its necessary microbial
contribution at all successive stages, including the fetal experience (Miller,
2016b). There is a constituent exposure to microbial influences throughout fetal
development, both from maternal microbially supplied metabolites that have
transplacental circulation and a small exposure to microbial life in utero (Miller,
2016b). Even if these transplacental microbes are few in number in fetuses
compared to what is experienced by a newborn, the assault of ‘foreign’ cells and
viruses would be overwhelming if there was not a suitable platform for
coordinate responses. Further, embryogenesis requires flawless coordination
among a great variety of fully differentiated eukaryotic cells proceeding
uninterruptedly and with absolute precision if development is going to be
successful. The tiniest migratory errors at early stages would be immensely
damaging. Thus, holobionic life mandates a functioning information architecture
that must pre-exist birthing. No emergent phenomena could account for this
intricately coordinated process (Miller et al., 2020b).
Successive generations of scientists have attempted to identify a templating
mechanism for morphogenesis. Although a variety of bioenergetic fields have
been proposed that might account for coordinated embryogenesis and further
developmental morphogenesis, none of these have been validated (Miller et al.,
2020b). All other potential candidates for such a controlling developmental
mechanism suffer from a similar deficiency. Each would have to be a product of
emergence from cellular multicellularity. Just as with our prior discussion of the
‘emergentist’s dilemma’ for the origin of cognition, the same requirement applies
to developmental templating and morphogenesis. Furthermore, cells are not
automatons. Each self-generates its individual interpretation of environmental
cues. Nonetheless, they must intricately coordinate.
Consequently, the N-space Episenome must be heritable and transferable,
functioning as an information-templating architecture and essential information
nexus, facilitating the sharing of relevant information from the zygote forward to
guide multicellular embryogenesis and holobionic morphogenesis (Miller et al.,
2020b; Baluška et al., 2022a). The critical migration of neural crest cells is a
good example of that necessity. Neural crest cells represent a transient
embryonic cell population that migrates collectively to various locations
throughout early embryogenesis, contributing various cell types to several
different organs (Szabó & Mayor, 2018). Research has documented that this is
an exquisitely coordinated process that proceeds along exact embryonic
pathways. Furthermore, neural crest cells exhibit a variety of differential
migratory behaviours. At some points along this pathway, these cells co-align in
mass-like sheets, edging towards the fetal brain, whereas elsewhere, they
migrate in chains towards the fetal trunk. Deploying a range of concordant
signals, they manage to collectively move. Yet, research has demonstrated that
this migration pattern is not under genetic control (Szabó & Mayor, 2018).
Instead, the N-space Episenome acts as a heritable spatiotemporal templating
informational matrix, governing cell–cell coordination across multicellular
holobionic lifespans.
The further advantage of the N-space Episenome concept is that it offers a
framework resolving how epigenetic processes yield coherent organismal
responses. Although traditionally overlooked, it is necessarily true that any
epigenetic markers are initially expressed at the level of individual cells before
they can become organism-wide expressions of phenotypic variation (Miller et
al., 2019). How might trillions of individual cells sort epigenetic impacts as valid
environmental cues if they must, perforce, be self-interpreted?
It is not only cells that participate in information space. Viruses must have
their own form of senomic capacity since they very capably utilize cellular
resources and, pertinently, have their own type of nucleocapsid boundary. The
senome model is appropriate for viruses since they use a complex arbitrium
system to communicate that links to viral memory (Brady et al., 2021). Through
this means, viruses link to cellular information space and presumably, then, to
their target cellular N-space Episenome, thereby energizing the virocellular
symbioses that are the cornerstone of biology. Conversely, cells must
reciprocally link to viral information space since they engage in co-engineering
for a broad range of problem-solving, and cells must gauge what level of
resources can be devoted to any interactions that are volitional (Miller et al.,
2021, 2023).
A great deal of environmental information is noise which must be reliably
distinguished from more meaningful inputs. Noise is a constant feature in
biological systems. Nonetheless, cells do not merely deal with it but can deploy
certain forms of noise productively, channelling some either stochastic
informational inputs or random events into productive outputs. Noble (2017)
termed this biological process the ‘harnessing of stochasticity’. However, in
order to accomplish this, as Noble and Noble (2018) asserted, ‘[organisms] must
employ a comparator to find the solution that fits the challenge’ and to do so, it
must have agency and make choices. The N-space Episenome functions in the
role of that multicellular comparator as a common reference platform and a form
of institutionalized organismal memory that complements retrievable and
deployable genetic memory. Thus, the N-space Episenome permits sufficient
plasticity to meet current environmental stresses but adheres to a constraining
long-term memory repository that represents a counterbalancing constraint
against adaptive oversteering (Miller et al., 2020b).

The Relationship of the N-Space Episenome to Consciousness

Although it is common to regard information merely as an abstraction, it is far
from that. Indeed, it represents biology’s actual propulsive force as it is
fundamental to biological expression. Consequently, the flow of information is
biology’s currency. Since biology begins with conscious self-awareness, that
flow must be central to the sentience that defines the living state. Consequently,
any understanding of consciousness must be predicated on issues of information
management.
To better appreciate that relationship, it is clear that the basic principle we
began this chapter with is a critical feature in understanding cognition even in
the simplest, unicellular organisms. Information can be viewed as being
physical, just like matter or energy, since it represents the interaction between
these two elemental universal components, and it is these intersections that
actually yield biological outputs. Consequently, the structures in nature can be
deemed information (Dodig-Crnkovic, 2022). Accordingly, N-space represents
the entirety of the continuous interactions between matter and energy throughout
the universe as a universal information matrix. Of course, it is only information
if there is an observer to perceive and interpret it. However, all cells are
conscious agents, and therefore, all are observers (Torday & Miller, 2016b).
Certainly, many physicists argue that the inanimate is capable of
measurement, serving as observers of universal quantum phenomena (Fields et
al., 2021). However, we can leave that rather abstruse consideration aside and
concentrate on the more readily understandable realm of the living. In that
instance, it becomes easier to conceptualize the dynamics of an individual
cellular PIF. It can be thought of as the functional boundary of universal
information space that is accessible to the cell, even in the most indirect sense.
Accordingly, a PIF is a circumscribed compartment of information space that is
the complete realm of informational cues that a cell might detect through its
senomic apparatus. For convenience, it can be thought of as its ‘field of view’
concerning otherwise limitless universal informational possibilities. Importantly,
this narrowing of a limitless panoply of information is a requisite of conscious
self-reference since this circumscription of universal N-space is vital to
successful information management in the living state. The reasoning behind this
is straightforward. Life is problem-solving and organizing the flow of
information to support that is absolutely critical to successful adaptive solutions.
The flow of information is a defining parameter of self-referential consciousness
since adaptive ability equates with intelligence. Necessarily then, intelligent
sorting of any set of a potentially limitless range of informational inputs is
essential for information management. Accordingly, biology requires
partitioning of any universal information set so that information can be
coherently managed. Conscious cells manage information through their
constitutive senomic apparatus as their receptive information gateway and initial
interpreter of environmental informational cues. Crucially though, the cell
derives all of its knowable information that can impact its senome from its PIF,
which is its relevant partitioning of universal information space (Miller, 2016a;
Baluška & Miller, 2018).
With this background, the correct biological order clarifies. The senome, with
its intelligent plasma membrane, is central to life, and genes are tools of the
intelligent cell as vital forms of retrievable and deployable memory as discussed
in Chapter 8. It is the cellular senome that actually confronts the environment,
receiving bioactive information that stimulates its electrically charged plasma
membrane, initiating a cascade of cell-wide responses. Received and initially
analysed information is conveyed across the cell to interact with myriad other
intracellular participants (cytoskeleton, organelles, intracellular vesicles). In turn,
each of these has their individual micro-senomic architectures to ultimately
deliver productive intracellular measurements (Baluška et al., 2021b). It is only
in this manner that cells can determine whether or not it is worth expending
further scant cellular resources through either volitional energy-intensive cell–
cell communication or the bioactive deployment of cellular/molecular resources.
All of these activities support cellular consciousness. Thus, cellular
consciousness must be regarded as a cell-wide organized whole.
As noted above, cellular PIFs combine into a multicellular correspondent
mutualizing platform as their relevant N-space Episenome, representing a further
unifying compaction of universal information space. That N-space Episenome
serves as the critical element of the information management system of the
holobiont. Accordingly, just as the cellular PIF is central to cellular conscious
self-reference, the multicellular further ordering of information space into a
multicellular N-space Episenomic space-time partition must be crucial to its
form of aggregate consciousness. Consequently, our human consciousness is a
manifestation of multicellular information management that corresponds to a
conjoining N-space Episenome. Therefore, just as it has been asserted that our
N-space Episenome underlies morphogenetic templating by recapitulating pari
passu with the critical cellular plasma membrane, so does our capacity for
conscious self-reference. Thus, it is no longer surprising that our form of
consciousness is species specific even though our genetic makeup compared to
chimpanzees is 98.5% identical (Mittleman et al., 2021). Our N-space
Episenome is idiosyncratically our own, linked to our species-specific senomic
apparatus and distinct attributes of our plasma membrane translating intact from
generation to generation, preserving its correspondent connection to information
space-time. All are foundational aspects of our consciousness (Miller, 2023).
While some might feel that this link between the senomic information
processing of individual cells and that of humans is a bit of a stretch, it really is
not. As noted in several earlier chapters, evolutionary mechanisms function by
building on earlier successful forms and functions. The N-space Episenome was
first arrived at by unicellular prokaryotes and has served as an essential platform
for those of all species that evolved from them. Put simply: if it works, keep it.
The partitioning of universal N-space into functional partitions that match
biological forms is highly explanatory for conscious self-awareness.
Unquestionably, consciousness exists. Further, as this book unequivocally
asserts, it has existed from the first fully competent cell forward. Still, how
conscious self-reference operates remains elusive, just as its origins remain
enigmatic. However, that does not mean that no progress has been made. Two
indispensable determinants can be readily identified through the information
space framework. Conscious self-reference is demonstrably dependent on both
boundary conditions and retrievable and deployable memory. In the absence of
either, no intelligent life would exist on this planet.
On this planet, biology demands reciprocating liberties and constraints. That
exact intersection resides within the still little-explored interstices of our
intelligent membranes and the manner in which their integrated functions convey
across a living cell with all of its complex, interrelated cellular tools. The result
is a summation as a Gestalt, an organized whole. What are those cellular
characteristics that are fundamental to conscious self-reference? Sentience
requires knowing ambiguity which impels the measurement of uncertain
informational cues and the productive management of that information. Thus,
the sentient process of information management requires a partitioning of
universal information space-time linked to fully competent memory.
These specific requirements for conscious self-reference on our planet carry a
significant further implication. The possibility of universal consciousness almost
certainly rests upon these same particulars. On Earth, our plasma membrane-
based senomic boundary system is exquisitely sensitive to an enormous range of
environmental cues. This boundary is lipid dependent and deploys a number of
novel mechanisms to sustain the cellular interior, including a variety of gap
junctions that discriminatively permit only some environmental molecules across
the cellular interface. Further, cells are equipped with an array of retrievable and
deployable memory tools permitting coherent adaptation, including a genome
that can be faithfully inherited due to robust error correction mechanisms.
For a living organism, information is a difference that makes a difference. We
live within the borderline where those differences occur. Every living organism
attaches to information space-time and uses bioactive molecules and
bioenergetic fields to interpret information. That interpretation is the centrality of
our consciousness as the foundation of decision-making. Consequently,
understanding our own consciousness requires the rigorous examination of how
individual cells, multicellular organisms, and collections of them critically
access, interpret, and deploy information within requisite boundaries.
Thus, life on this planet is the product of two definable linked forces:
boundaries and retrievable and deployable memory. Might there be any other
intelligent life in the universe? Is there any possibility of pan-consciousness?
Those enticing possibilities remain elusive unknowns. However, the
requirements of information management that decidedly represent the ground
state of intelligence on this planet impose remarkable hurdles. Moreover, since
physicists assure that all local processes in the universe are indeed ‘universal’,
then other-worldly intelligence would have to exhibit corresponding attributes of
boundaries and memory. Most particularly, a functional partitioning of universal
N-space would then be a universal requirement for consciousness. Although still
unknown, it is possible that these requisites are very specific to this planet with
its exact privileges and limitations. Whatever the case, there is no doubt that
earthly cellular consciousness requires a very particular type of boundary system
and a broad palette of adjunctive tools that permit a very particular ordered state.
As of this moment, there is no indication of any sort of interstellar equivalency.
Conscious intelligence requires a means of ordering information/sensory
inputs. Consequently, the conscious cell is competent precisely because it has an
informational boundary that represents its limit. Similarly, multicellular
companionate life requires its N-space partition as its obligate N-space
Episenome. The context of cellular problem-solving mandates this cellular
attachment to information space. It is only through its conjoining offices that
trillions of eukaryotic body cells and a multitude of co-dependent microbes can
produce consonant results generation after generation (Miller, 2016b; Miller et
al., 2020a). Necessarily, self-referential consciousness links to effective memory
and an intelligent, discriminating membrane. On this planet, without that crucial
combination, there would not be any consciousness that we could interrogate.
10
Anaesthetics and Their Cellular Targets

Introduction
The reader might wonder, what is the point of a chapter on anaesthetics in a book
devoted to the examination of the foundations of sentience, in particular one
based on the principle that life and consciousness are coterminous The point is
rather straightforward—as we will see, all species are sensitive to anaesthetics
and the question essentially asks itself. Why? Why would even the most
primitive unicellular organisms be sensitive to and respond to anaesthetics if
they did not feel pain, and did not suffer under stress? As we will see, the
biological mechanisms involved in the manner in which cells respond to
anaesthetics are not simple and, while still not completely understood, it is clear
that considerable biomolecular resources are involved. A core principle of
evolutionary biology is that processes that require the expenditure of
biomolecular resources are ones that are essential for life. In short, all sentient
species respond to anaesthetics simply because they are sentient, have valenced
experiences, and feel pain.

Discovery of Anaesthesia via Euphoria and Party Life

Humans used diverse plants and their products for relieving pain and altering
consciousness. Many years ago, opium poppy was cultivated by Sumerians
beginning as early as 5000 BC (Krikorian, 1975). In a long search for chemicals
to relieve pain in humans, a momentous breakthrough was achieved in 1846. On
16 October of this year, surgeon John Warren, in a public demonstration,
removed a tumour from patient with help of ether anaesthesia with dentist
William T. G. Morton acting as the first anaesthetist. A few months prior,
Morton had reported that ether made tooth extraction painless (Bigelow, 1846;
Rinaldi, 2014). However, the true pioneer of anaesthesia was a young surgeon,
Crawford Williamson Long, who organized social gatherings in 1841 using a
novel substance known as ‘party gas’ where people inhaled ether in order to
attain euphoria. He noted that some confused participants had not recognized
either blows or falls and acted as if they had not perceived any pain. Noting this
correlation, Long had used ether to remove a small tumour from the neck of a
patient, James M. Venable, on 30 March 1842. Unfortunately for Long, there
was no official record of this event. There was a serious controversy about the
discovery of anaesthesia and even the US Congress was involved in the case
known as the ‘ether controversy’ in 1847 (Boland, 1923; Anaya-Prado &
Schadegg-Peña, 2015). Notably, there was even earlier precedence for this type
of discovery. Similar parties known as ‘laughing gas parties’ began in 1799
based on inhaled nitrous oxide, organized by a young chemist Humphry Davy
who later became the president of the Royal Society in London. He organized
these gas parties in Bristol and noted the pain-killing effects of nitrous oxide
inhalation (Hardman, 2017). Unfortunately, these ‘laughing gas parties’ were not
followed by any medical usage of this pain-relieving gas.

Claude Bernard—Sensitivity to Anaesthetics Is Fundamental

to Life
The effects of ether on plants was tested and reported almost immediately after
its initial surgical use (Clemens, 1848). Claude Bernard (1878) considered
susceptibility to anaesthetics a basic feature of life and documented that not only
humans but also animals and plants respond similarly to anaesthetics by losing
environmental responsiveness and awareness. His famous statement ‘all life can
be anaesthetized, the rest is dead’ dominated the field of anaesthesia in the 19th
century (Perouansky, 2012; Grémiaux et al., 2014). His unitary view of life was
based on his personal experiments documenting very similar sensitivities and
responses to anaesthetics in humans, animals, and plants (Bernard, 1878).
The mystery of anaesthesia includes three fundamental features. First, all life
can be rapidly and reversibly anaesthetized; second, specific concentrations of
anaesthetics are needed to achieve the anaesthesia; and third, also the recovery
from anaesthesia is fast after the removal of the anaesthetic agent. All of these
anaesthetic principles were well recognized in Claude Bernard’s time but our
understanding of these issues remains rudimentary and fragmented (Baluška et
al., 2016; Kelz & Mashour, 2019). As we will discuss in the next sections,
sensitivity to anaesthetics is an ancient feature which originated and evolved
when life was still procellular-unicellular. Obviously, there were specific
functions for anaesthesia induced by stress-mediated endogenous anaesthetics
relevant for adaptation and evolution of these ancient proto-organisms. As all
organisms produce their own endogenous anaesthetics when they are under
challenging stressful conditions, it can be proposed that these short-term
analgesia and anaesthesia states are important for organismal adaptation and
survival (Baluška et al., 2016).

Sensitivity to Anaesthetics Evolved in Unicellular Organisms

Although the research and ideas of Claude Bernard were well known, the myth
that anaesthetics act specifically on neurons became a persistent one which
ended only after Charles Ernest Overton showed that muscle cells are also
sensitive to diverse anaesthetics (Overton, 1901). Moreover, ether and
chloroform were shown to suppress fermentation of sugar to alcohol by
Saccharomyces cerevisiae. This action was considered to be further evidence
that living organisms are involved in fermentation even at a time when the
doctrine of spontaneous generation still dominated life sciences. Similar to
Bernard, also Overton confirmed the sensitivity of plants to anaesthetics
(Overton, 1901). We will discuss plant anaesthesia in the next section and
Chapter 11. However, the effect of anaesthetics on unicellular organisms is a
necessary prelude. Anaesthetics affect diverse unicellular organisms, from
minute cyanobacteria up to relatively large protozoa and algae (Baluška et al.,
2016; Kelz & Mashour, 2019). In 2008, James M. Sonner proposed that the
general capacity to respond to anaesthetics allowed unicellular organisms to
cope with diverse stressful situations causing perturbations of their plasma
membrane and ion channel activities (Sonner, 2008). Of crucial importance, the
first 2 billion of years of life on the planet Earth was unicellular and the
evolutionary origins of sentience and cognition are based on prokaryotic and
eukaryotic unicellular organisms evolving in the very difficult climatic
conditions of the relatively young Earth.

Cellular Targets and the Molecular Nature of Anaesthetic

Actions
The mystery of anaesthesia has persisted for almost two centuries despite an
immense amount of research devoted to this vital phenomenon. As discussed
above, prokaryotic bacteria are sensitive to anaesthetics and, therefore, it is not
surprising that mitochondria which evolved from symbiotic bacteria are also
sensitive to anaesthetics. As early as the 19th century, Claude Bernard had
reported that both cellular respiration and photosynthesis are affected by
anaesthetics. After more than 100 years of lipid and protein research, the
contemporary science of anaesthesia is still mired in diverse theories which fail
to fully explain why and how molecules that vary so widely in their
physicochemical properties and sizes can equally cause the same end effect of
anaesthesia in all living organisms (Baluška et al., 2016; Kelz & Mashour,
2019). Necessarily, there must be a common denominator that underlies that
widespread effectiveness. The only biological substrate sensitive to anaesthetics
and linking all these diverse organisms is the excitable plasma membrane which
is densely populated with ion channels, transporters, sensors, and receptors,
serving as an intelligent bioelectric border between the cellular interior and
extracellular exterior.
Charles Ernest Overton and Hans Horst Meyer independently discovered that
the potency of anaesthetics is related to their lipid solubility. This correlation
between anaesthetic potency and lipid solubility is known as the Meyer–Overton
rule of anaesthesia (Perouansky, 2012, 2015). It still holds true but its previously
unassailable credibility has been diminished by a mainstream focus that has
moved towards proteins as potent hypothetical receptors of general anaesthetics.
Although anaesthetics show very different chemical and biophysical properties,
the Meyer–Overton rule is valid for most of them and there is no other available
theory that comes any closer to explaining anaesthesia better as this largely
dismissed one (Sandberg & Miller, 2003). Recently, attempts have been made to
reinvigorate the Meyer–Overton rule, updating it through a model focusing
anaesthetic action on a bioactive lipid bilayer densely populated by numerous
transmembrane and membrane-associated proteins (Sandberg & Miller, 2003;
Eger et al., 2008). Even if critical membrane-based proteins should turn out to be
the ultimate targets of anaesthetics, lipid-bilayer changes induced by inserting
anaesthetics are relevant due to structural changes in the membrane which then
alter the conformation of all transmembrane proteins. These reciprocating effects
cannot be separated. Indeed, most proteins that are affected by anaesthetics are
transmembrane or membrane-associated proteins that populate ion channels as
well as diverse receptors and sensors (Urban, 2008; Campagna et al., 2003).
Moreover, the hydrophobic pockets of critical proteins, lipid–protein interfaces,
and interfacial water are particularly relevant for anaesthetic action (Kundacina
et al., 2016; Riveros-Pereza & Riveros, 2018). Among the numerous
anaesthetics, ethylene and xenon are particularly interesting examples as they
illuminate the whole mystery of anaesthetics and anaesthesia. Ethylene is an
almost forgotten general anaesthetic which is chemically close to ether (Urban &
Bleckwenn, 2002; Campagna et al., 2003) and had been commonly used in
surgery for over 100 years (Luckhardt & Carter, 1923; Dillard, 1930). Ethylene
was a very promising and gentle general anaesthetic with almost no side effects;
however, accidents, due to careless handling, led to its being supplanted by other
anaesthetics in modern surgery (MacDonald, 1994). Intriguingly, ethylene is
known as a plant stress hormone produced in large amounts in ripening fruits
(Baluška et al., 2016). In the next sections, we will discuss these important
aspects in detail.
Plants are sensitive to both local and general anaesthetics. This fact has been
known since 1846 when Clemens reported ether-induced plant anaesthesia using
Mmimosa leaves and Berberis stamens just 1 year after the discovery of ether
anaesthesia by William Morton (Clemens, 1848; Bonns, 1918; Eger et al.,
2014b). Bonns provided a detailed overview of numerous papers published on
the effects of anaesthetics on plants between 1847 and 1918 (Bonns, 1918).
Although most of these papers have been forgotten, a fresh initiative is reviving
this important field of plant physiology (Pavlovič et al., 2020; Baluška &
Yokawa, 2021) despite rather fierce resistance (Draghun et al., 2021; Nick,
2021). Nevertheless, there are convincing reports on using volatile anaesthetics
in the immobilization of Mimosa leaves at concentrations very close to those
used in human surgeries (Okazawa et al., 1993). As we will discuss in more
detail in the next section and in Chapter 11, plants represent an important
centrepiece within the never-ending debate on cellular targets of the anaesthetics.
In cellular anaesthesia, their organelles, such as mitochondria and
chloroplasts, are individual targets of anaesthetics (Sonner & Cantor, 2013;
Woods et al., 2021). This is not surprising as both mitochondria and chloroplasts
were originally independent organisms which entered into symbiosis with their
host cells some 1–2 billion years ago, retaining individual endomembranes. With
respect to chloroplasts, the timing of their symbiotic origin is more or less clear
(Keeling, 2010; McFadden, 2014), whereas the timing and identity of
mitochondrial prokaryotic symbiotic organisms is still debated. One of the
consequences of mitochondrial sensitivity to anaesthetics is lowering of ATP
levels which have direct impacts on several energy-demanding processes
including exocytosis, endocytosis, and cytoplasmic streaming (Ewart, 1903;
Jung et al., 2022).
Furthermore, several studies suggest that the cytoskeleton represents a
sensitive target of anaesthetics. Both actin filaments and microtubules are
reported to be affected by anaesthetics, inhibiting cytoplasmic motility and
streaming, as well as the functioning of dendritic spines of neurons (Kaech et al.,
1999; Platholi et al., 2014). Not only the cytoskeletal polymers themselves but
also their motor complexes, including kinesins and myosins, are reported to be
inhibited by anaesthetics (Miyamoto et al., 2000; Yoon et al., 2011).

Pressure Reversal of Anaesthesia Hints at the Physical Basis

of Consciousness
One of the most fascinating but seldom discussed issues in contemporary
physiology literature is the so-called pressure reversal of anaesthesia, well
documented in newts and mice decades ago (Lever et al., 1971). Since then, this
fascinating phenomenon has been confirmed in all tested organisms (Vadakkan,
2015; Weinrich & Worcester, 2018), strongly suggesting that there are some
fundamental biophysical features underlying anaesthesia. A similar response to
pressure has been validated in plants, where pressure reverses promotion of seed
germination via anaesthetics (Hendricks & Taylorson, 1979, 1980). All this
suggests that spatial distances among some critical bio-molecules are relevant
for both the onset of and recovery from anaesthesia in all organisms. This spatial
aspect of anaesthetics and their impacts on cells and their ordered biomolecules
can be explained by either binding to critical hydrophobic pockets of relevant
proteins or by their insertion into biological membranes, altering their
biophysical properties and excitability. As we will discuss below, this lipid
ordering and membrane structure have been reported as relevant features of
anaesthetic action, further supporting lipid-based theories of anaesthesia.
Unfortunately, some reports failed to confirm this phenomenon and it remains a
relatively obscure observation. Additionally though, pressure alone can
immobilize animals and then, surprisingly, anaesthetics induce recovery of their
pressure-induced immobility, known as an ‘awakening effect’ of anaesthetics
(George & Pandit, 2021).

Ordered Lipids and Lipid Rafts as Subcellular Targets of

Anaesthetics
Ever since Meyer and Overton independently discovered a strong correlation
between anaesthetic potency and solubility in oil and codified it as the Meyer–
Overton rule, the lipid theory of anaesthesia has become generally accepted.
From 1900 through the 1980s, lipid theory was the dominant one, but it lost its
primacy after the discovery that ion channels and several ligand-gated sensors at
the plasma membrane also represent targets of anaesthetics (Campagna et al.,
2003; Urban, 2008). Currently, the dominant view is that there are multiple
target sites in cells for the anaesthetics, and this seems to be one of the reasons
that our understanding is progressing rather slowly.
One of the recent discoveries strongly supporting a lipid-based theory of
anaesthesia are so-called lipid nanodomains (rafts) representing highly ordered
domains of structural lipids (Lingwood & Simons, 2010; Simons & Sampaio,
2011). These lipid rafts represent a silent revolution in our understanding of
biological membranes basing a new perspective based on lipid homogeneities in
concurrence with a well-validated fluid mosaic model (Singer & Nicholson,
1972). The fluid mosaic model conceptualizes the plasma membrane as a mosaic
of a large palette of bioactive molecules including phospholipids, cholesterol,
proteins, and carbohydrates, giving the membrane a fluid character. Initially, the
concept of lipid rafts met strong opposition (Edidin, 2003; Munro, 2003) but
they are now accepted and Nicolson updated the fluid mosaic model to include
lipid rafts in 2013 (Nicolson, 2014; Nicolson & Ferreira de Mattos, 2022).
Importantly, lipid rafts are organized via evolutionarily ancient proteins
containing prohibitin-likedomains (PHB) including the Reggie/Flotillin family.
These proteins are present in membranes including in bacteria, protozoa,
plants, and animals (Morrow & Parton, 2003; Rivera-Milla et al., 2006). They
organize lipid nano-domains (rafts) which then provide platforms for diverse
signalling proteins involved in assembly of endosomal pathways (Langhorst et
al., 2006; Ma et al., 2022) serving as entry points for viruses including the
SARS-CoV2 virus (Sorice et al., 2021; Bakillah et al., 2022). Lipid rafts based
on sterol-derived, ordered structural lipids provide a unique micro-environment
for specific sensors and other signalling biomolecules representing targets for
anaesthetics (Weinrich & Worcester, 2013; Booker & Sum, 2013). Interestingly,
the pressure which reverses anaesthetics also promotes lipid ordering and
formation of domains in model lipid raft membranes (Worcester & Weinrich,
2015).

Anaesthetics and Electrons: Hydrophobic Pockets of Proteins

Sensitive to Anaesthetics
Proteins with hydrophobic pockets are also relevant to the pressure reversal of
anaesthesia (Eckenhoff, 2008; Urban, 2008) in which weak van der Waals–
London forces are involved in electron donor/acceptor events, mediating the
sensitivity of these proteins to anaesthetics (Vos et al., 1993; Hameroff, 2006). In
particular, general anaesthetics inhibit electron mobility within these
hydrophobic pockets of sensitive proteins which act as targets of general
anaesthetics (Johansson et al., 2003; Hameroff, 2006). Importantly, mobile
electrons participate in anaesthetic actions. For example, the respiratory
mitochondrial complex I based on mobile electrons is inhibited by anaesthetics
in single-cell organisms, plants, and animals including humans (Kelz &
Mashour, 2019; Jung et al., 2022).
A new twist in understanding anaesthesia was provided by Luca Turin and co-
authors reporting that there is a connection between electron currents in cells and
general anaesthesia (Turin et al., 2014; Turin & Skoulakis, 2018). Recently,
Smith et al. (2021) reported that radical pairs of electrons are similarly important
in this respect. Intriguingly, xenon behaves like all other anaesthetics in this
respect, even when it is chemically inert and physically shapeless (Turin et al.,
2014). Electron mobility might also be behind the so-called electro-anaesthesia
phenomena, when pulsed electrical currents have been reported to induce
anaesthesia-like states with reversible loss of consciousness (Papir-Kricheli &
Magnes, 1982; Francis & Dingley, 2015).
Importantly, the proteins sensitive to anaesthetics are so-called electronic
proteins and are equipped with hydrophobic pockets that use mobile electrons to
accomplish dynamic changes in three-dimensional conformations. Anaesthetics
bind and fill resulting hydrophobic pockets, causing inactivity of these proteins
and freezing their conformation (LaBella et al., 1999). This protein effect may
represent one of major impacts of anaesthetics on cells and their life-supporting
activities beyond their effects on the bio-membranes. As many of these proteins
are localized within membranes and transmembrane sensors, receptors, and ion
channels, they are relevant for the dynamic assembly and maintenance of
senomic fields (and were discussed in Chapters 6 and 9). Consequently, it is
highly probable that the senome and its cellular and supracellular fields are also
affected by anaesthetics.

Ancient Origins of Action Potentials Sensitive to Anaesthetics

in Plants and Animals
In all multicellular organisms, just as in unicellular ones, the most obvious
impact of anaesthetics is sudden cessation of mobility (Kelz & Mashour, 2019).
In both animals and plants, electric action potentials animate movements and
these stop with immediate exposure to anaesthetics with impacts on both critical
transmembrane proteins and the lipid-bilayer of membranes. With action
potentials, there is rapid and brief reversal of membrane voltage polarity
(Andersen et al., 2009) directly impacting vesicle behaviour at the plasma
membrane (Baluška & Wan, 2012). Moreover, sensitivity of the actin-based
cytoskeleton is also relevant insofar as tissue and organ movements in plants and
animals are based on actin-myosin interactions. Importantly, these action
potentials apparently evolved from very ancient plasma membrane repair
processes, most probably originating in unicellular organisms (Goldsworthy,
1983; Brunet & Arendt, 2016). Pertinently, this plasma membrane repair system
resembles the neuronal synaptic transmission apparatus (Steinhardt et al., 1994).
And notably, the cellular events associated with long-distance action potentials
link to, and originate from, ancient cellular stress responses corresponding to the
close linkages of anaesthetics with cellular stress responses at the bioelectric cell
periphery (Baluška & Wan, 2012; Baluška & Mancuso, 2019). All this is
important for our understanding of why anaesthesia is central to our
understanding of the life. The Claude Bernard unitary hypothesis of anaesthesia
is getting strong support.

Endogenous Anaesthetics for Coping With Stress

Dual physiological and evolutionary roles for anaesthesia would be logical from
the perspective of the unitary hypothesis of anaesthesia, asserting this
phenomenon as the most obvious definition of life. As Bernard maintained in
1878, it is ubiquitously necessary for coping with severe stress at cellular and
higher levels of biological organization (Selye, 1975). Numerous studies have
reported that heavy stress induces the endogenous production of substances
having anaesthetic and analgesic effects on humans and diverse organisms
including prokaryotic bacteria, unicellular protists, fungi, plants, and animals
(Baluška et al., 2016). Hans Selye postulated a unified theory of stress as part of
a mysterious adaptation energy which allows effective repair and adaptation
processes (Selye, 1975; Coleman, 2012). In humans, anticipation of pain induces
the endogenous biosynthesis of opiates and cannabinoids both of which lower
pain perception (Vaughan, 2006; Corcoran et al., 2015). This adaptive
phenomenon is well known as stress-induced analgesia (Ferdousi & Finn, 2018;
al’Absi et al., 2021). It allows humans and animals to survive extremely stressful
insults, including devastating wounds and presumably evolved very early. Plants
are also known to produce numerous endogenous substances which have
anaesthetic and analgesic effects (Baluška et al., 2016). These painkillers of
plant origin were discovered by humans very early in our history with the first
documented examples of their use going back more than 5000 years. Another
example of the mind-altering psychoactive substances in plants are indole
alkaloids (Omar et al., 2021; Wibowo et al., 2021); including the N,N-
dimethyltryptamine (DMT) which is found to be produced not only in plants, but
also in animals including humans (Barker, 2018; Cameron & Olson, 2018).
As James Sonner and Robert Cantor (2013) concluded, consciousness and
endogenous anaesthetics obviously evolved together long before the evolution of
nervous systems, beginning with the advent of cellular life several billion years
ago. They highlighted ethanol as the best evidence for the importance of
endogenous anaesthetics and anaesthesia in biological evolution. As ethanol is
toxic to all organisms, one would expect that a long evolutionary period of
spontaneous mutations would eliminate responses to ethanol. However, as that is
not the case, it can be surmised that the mutations that would be required to
block the toxic impact of ethanol on organisms would be more harmful to the
organism than the ethanol production itself. Correspondingly, some beneficial
effects of ethanol might also be present in smaller amounts. Plants produce
endogenous ethanol under stress along with other useful anaesthetics (Baluška et
al., 2016; Tsuchiya, 2017). Furthermore, impacts of ethanol on plant root apices
(Kagenishi et al., 2022) resemble the effects of other anaesthetics on root apex
cells (Yokawa et al., 2019).

Syncope, Thanatosis, and Interoceptive Paralysis of Cells

Sudden loss of consciousness is behind the phenomenon known as thanatosis or
feigning of death (Rogers & Simpson, 2014; Humphreys & Ruxton, 2018) and
appears to be connected to an overload of interoceptive sensory systems due to
an extreme danger. It has also proved to be a successful strategy to survive under
diverse life-threatening situations (Skelhorn, 2018; Asakura et al., 2021).
Closely related to thanatosis is syncope which is the sudden loss of
consciousness associated with loss of postural tone (Alboni & Alboni, 2014; da
Silva, 2014). Thanatosis is highly conserved and an ancient anti-predatory
survival strategy in animals. There are some common issues connecting the
thanatosis with near-death experiences recorded in humans (Kondziella, 2020;
Peinkhofer et al., 2021). Importantly, unicellular organisms, such as budding
yeast, respond to environmental stress with a sudden loss of metabolism and
intracellular shutdown. In addition, the simple perturbation of the plasma
membrane with local anaesthetics is enough to induce this paralysis in
unicellular organisms (Uesono, 2009; Uesono et al., 2008, 2016). These findings
suggest that endogenous anaesthetics could also be behind life-protecting
phenomena such as syncope, thanatosis, and other death-feigning phenomena.

Summary
This exegesis on the biomolecular manner of action of anaesthetics clearly
supports our CBC model. As noted, one of the keys to our approach is that
functions, mechanisms, and processes that were adaptive, with significant
Darwinian fitness, are not lost. They are maintained and become the foundation
for evolutionary change over time. Showing that all species, all organisms are
sensitive to anaesthetics and that all share underlying biomolecular modes of
operation reinforces the proposition that all species, all organisms, feel,
experience pain, and react to stress—including the simplest prokaryotes,
bacteria, and archaea. In short, all organisms have valenced experiences—they
are sentient. In Chapter 11, we will take a similarly deep look at sentience in
plants where the biomechanisms differ but the underlying proposition that all
living organisms are sentient holds.
11
Plant Sentience
Linking Cellular Consciousness to the Cognitive and Behavioural
Features of Plant Life

Ancient Origins of Plants in Algal Protists: Similarities With

Photosynthetic Animals
Plants diverged from animals at the unicellular level by the endosymbiotic
capture of ancient cyanobacteria which evolved into their chloroplasts some 1.5–
2 billion years ago. Hence, plants and animals share approximately two-thirds of
their 1.5 billion years of evolution and, of course, have common biological roots
(Bouteau et al., 2021; Gilroy & Trewavas, 2022). The reason why plants do not
have brains or any devoted sensory organs directly links to their sessile nature.
Being unable to escape from herbivores to become the basis of the land food
chain would not have been possible if they had not evolved rooted bodies
(Trewavas, 2014; Gilroy & Trewavas, 2022). A reasonable speculation is that the
ultimate reason for the sessile nature of plants was the acquisition of
photosynthetic bacteria and switching to autotrophic nutrition using these
symbiotic organelles. Nevertheless, it is clear that when animals obtained
functional photosynthetic chloroplasts and switched to autotrophy, they also
acquired a sessile lifestyle as also exhibited by species such as corals (Baluška &
Mancuso, 2009a, 2009b). Additional support for this perspective is provided by
sacoglossan sea slugs. These slugs use ‘stolen’ chloroplasts for their nutrition
(Rumpho et al., 2000). This incorporation and maintenance of algal chloroplasts
in animal cells is termed kleptoplasty and these chloroplasts are capable of being
maintained within cells of the animal digestive system for extended periods of
time (Händeler et al., 2009; Pierce & Curtis, 2012). Kleptoplasty allows sea
slugs to survive for as long as a year without any organic food from their
environment (Laetz et al., 2017; Cartaxana et al., 2021).
The case of corals is interesting in that their long-term symbiosis with
photosynthetic algae is possible only because they are sessile organisms.
Although corals are animals, they harbour single-celled photosynthetic
dinoflagellates and are characterized by a sessile lifestyle allowing the assembly
of ecologically complex coral reefs (Wood, 2003; Blackall et al., 2015). Corals
also show several other plant-like features, including modular metameric bodies
and a high capacity for regeneration (Davy et al., 2012; Rosset et al., 2021). The
symbiotic integration in corals, however, is less stable than in plants. Algal
symbionts leave coral host cells under stress, a phenomenon that accounts for
coral bleaching. Currently, coral reefs are facing a global crisis due to warming
of the oceans and other less well-understood climatic shifts (Bhagooli & Hidaka,
2004; Weis, 2019). However, corals and their reefs are known to recover their
symbiotic partners, enabling reef rejuvenation after mass extinction events (van
Oppen & Medina, 2020) since coral-based symbiotic networks are robust,
demonstrating high recovery potentials (Boilard et al., 2020; Williams &
Patterson, 2020).
Interestingly, besides corals, there are several other examples of animals
capturing chloroplasts and using them for their autotrophic nutrition including
hydra, sea anemones, sponges, and ciliates such as Paramecium (Venn et al.,
2008; Miyokawa et al., 2022). The common theme in all of these animals is that
many of the supporting features resemble plants. In other words, these animals
evolved several plant-specific attributes due to their symbiotic chloroplasts and
photosynthesis. This is relevant as it reveals that plants are not as different from
animals as is generally believed (Baluška & Mancuso, 2009a; Bouteau et al.,
2021). Accordingly, there is a tight co-evolutionary path among pollinators,
frugivores, and seed disperser partners—including us humans.

From Chlamydomonas to Cognitive Stress-Induced

Multicellularity
One of the best understood unicellular green algae is Chlamydomonas
reinhardtii which has served as a cytological model for decades. Its full genome
was acquired and published in 2007 (Merchant et al., 2007; Blaby et al., 2014).
Chlamydomonas represents an excellent model system to study the evolution of
multicellularity. Under stressful situations, it switches to multicellular assemblies
(Ratsliff et al., 2013; de Carpentier et al., 2022). One of the strategic advances of
multicellularity is that a larger body size is an advantage against predators since
it no longer fits within the primary predator’s prey scale. Indeed, Herron and
colleagues reported that when C. reinhardtii is exposed to its ciliate predator
Paramecium tetraurelia, they evolve to multicellularity, proving an effective
defence against predation (Boyd et al., 2018; Herron et al., 2019). Another
natural predator, Peranema trichophorum also induces transient aggregation of
Chlamydomonas which reverts back to its unicellular state when these predators
are removed (Sathe & Durand, 2016). It can be expected that the evolution of
multicellular colonies that formed ancient unicellular algae (Herron et al., 2009;
Herron, 2016) was also accomplished under pressure from their predators.
Joining of forces, the coordination of cellular activities (Kirk, 2005; Umen &
Herron, 2021), and associated sociality (de Carpentier et al., 2019, 2022) are
cognitive achievements, guided by cellular cognition, sentience, and
communication. Similar examples of stress-induced multicellularity are known
among bacteria (Claessen et al., 2014; La Fortezza & Velicer, 2021) and social
amoebae (Bonner, 2009; Schaap, 2021). It is possible that individual
cells/organisms make cognitive decisions to join forces after evaluating their
environmental landscape as dangerous for their survival (La Fortezza & Velicer,
2021; Schaap, 2021). In this new evolutionary perspective, the origin of
multicellularity is a cognitive phenomenon based on cellular sentience.

Dinoflagellate Algae as Hunters Enjoying Protist Vision

At the cellular level, organisms harbouring photosynthetic chloroplast in their
cells—including corals, algae, and plants—are more complex than fungi and
animals. For example, Paramecium bursaria harbour lower mitochondrial
numbers after hosting endosymbiotically green algae Chlorella variabilis
(Kodama & Fujishima, 2022). Importantly, endocellular symbiotic organelles
have been found to organize camera-like sensory ocelloids allowing a type of
vision in protists (Hayakawa et al., 2015; Gavelis et al., 2015). In this newly
discovered protist eye, symbiotic mitochondria act as cornea-like structures and
modified chloroplasts perform retina-like functions (Gavelis et al., 2015;
Yamashita & Baluška, 2023). Interestingly, chloroplast thylakoids also act as
retina-like organs in the eyespots of Chlamydomonas algae (Kreimer, 2009; Ueki
et al., 2016). Vision used by algal hunters is strong evidence for a kind of
strategic information management and problem-solving cognitive abilities based
on cellular sentience. In the next section, we will discuss similar cognitive
phenomena in sex cells (gametes) during sexual reproduction in algae, plants,
and animals.

Cognition of Protist-Like Sex Cells (Gametes)—The Special

Case of Flowering Plants
In recent conceptual papers, we have discussed sentience and cognition in
unicellular protists and asserted an analogical framework in protist-like sex cells
(gametes) of multicellular organisms (Baluška et al., 2022a, 2022b, in press).
Whereas oocytes (in plants termed egg cells) resemble rather slow, actin
cytoskeleton-based amoeba-like cells, sperm cells very closely resemble
flagellated protists propelled via cytoskeleton-based microtubules. Intriguingly,
this is not a new observation. Nearly 150 years ago, Ernst Haeckel noted that
oocytes of Olynthus sponges have amoeba-like features (Haeckel, 1878) and
some Porifera oocytes even feed on bacteria in a fashion similar to
contemporary amoebae (Sciscioli et al., 1994; Lanna & Klautau, 2010). On the
other hand, sperm cells move rapidly using their eukaryotic flagella propelled
via a microtubular cytoskeleton, thereby closely resembling flagellated protists
(Avidor-Reiss et al., 2019, 2022). The central part of the sperm flagella
regulatory complex is a centrosome-centriole apparatus (Schatten et al., 2011;
Khanal et al., 2021). Although flowering plant sperm cells lack flagella, this is a
secondary loss as most non-flowering plants have flagellated, motile sperm cells
(Renzaglia & Garbary, 2001; Norstog et al., 2004). Despite their rather large
evolutionary distance, there are further common issues connecting sperm cell
biology and behaviour in plants and animals, especially their nuclear migrations
and fusions (Kawashima et al., 2014; Fatema et al., 2019).
In all organisms, sperm cells are highly motile and all their activities are
focused on their prime task of finding receptive oocytes/egg cells for cell–cell
fusion. In less complex animals such as sponges, in some instances sperm cells
are released into water by one sponge and taken up by another for sexual
reproduction. In this case, once sperm cells are acquired, they are first
internalized into special cells known as choanocytes which transport them
through internal tissues up to the oocytes. Other sponges release both sperm cells
and oocytes into the water and the sperm cells search for freely floating oocytes
for potential fusion. The first mode is closer to the situation in animals and
plants when sperm cells are introduced into female bodies and then actively
search for oocytes. As this is a difficult task, it is not surprising that sperm cells
rely on cellular cognition based on senomic sentience to fulfil their task.
Consequently, it is also not surprising that animal and human sperm cells show
many neuronal features and express various neuronal proteins (Zitranski et al.,
2010; Matos et al., 2021). There is extensive communication between the cells
of the female human reproductive tract and navigating sperm cells which is
essential for the success of the sexual reproduction (Yeste et al., 2017; Zaferani
et al., 2021). From some 100 million sperm cells deposited in the female tract in
humans, only a small fraction will reach the oviduct (Lefièvre et al., 2009;
Reynaud et al., 2015) in which the oocyte is waiting for competent sperm cells.
Undoubtedly, this is a complex, difficult task for sperm cells. Hence, both
cognitive sex cells and large numbers of them are required to ensure successful
fertilization.
Nitric oxide released by cells of the female reproductive tract assists sperm
cells in their navigation (Machado-Oliveira et al., 2008; Lefièvre et al., 2009).
Intriguingly, pollen tubes of flowering plants that carry plant sperm cells also use
nitric oxide as a signalling molecule for cellular navigation through their style
(stalk of a pistil) tissues to reach plant oocytes (Prado et al., 2011). In addition,
navigating the pollen tube towards plant egg cells also relies on GABA gradients
and glutamate as signalling molecules, activating plant-specific glutamate
receptors (Palanivelu et al., 2003; Michard et al., 2011). Non-flowering plants
have freely swimming flagellate sperm cells with the exceptions of cycads and
gingko trees that keep flagellated sperm cells entrapped within pollen tubes
(Klink & Wolniak, 2001; Vaughn & Renzaglia, 2006). Intriguingly, pollen tubes
are tip-growing cells, resembling neuronal axons (Lev-Yadun, 2001; Palanivelu
& Preuss, 2001), which navigate towards egg cells via cognitive pathfinding as
these are deeply buried within stigma (a specially adapted portion of the pistil
modified for the reception of pollen) tissues (Kessler & Grossniklaus, 2011;
Palanivelu & Tsukamoto, 2011). This close similarity between the intrusive and
polar growth of neuronal axons and pollen tubes, guided via similar neuronal
principles, are excellent illustrations of the cognitive aspects of plant sexual
reproduction and the higher levels of complexity of flowering plants. Although
pollen tubes lack flagellate, motile sperm cells, their specialized cells are rich
cognitive players in complex plant sexual reproduction.

Plant Cognition and Behaviour—From Root Foraging, via

Manipulation of Pollinators and Bodyguards, up to Plant
Mimicry
Plants live a sessile life which requires exquisite sensory systems to experience
and properly evaluate a challenging environment and adapt effectively. Invasive
root systems are essential for plant nutrition and anchoring in soil. These
complex systems use root-specific sentience to search the soil for water and
those mineral elements that are essential for plant nutrition. Root apices are
endowed with plant-specific intelligence and cognitive capacity to achieve this
difficult mission in a dark, challenging underground environment (Baluška &
Mancuso, 2021; Baluška et al., 2021b). Intriguingly, a similar strategy is used by
parasitic plants. These plants will extend a haustorium, a slender projection,
from their roots, enabling the parasite to penetrate its target plant tissues and
absorb nutrients from it (Yoshida et al., 2016). The only difference is that the
parasitic plants do not bother to search for water and minerals in a dangerous
underground soil environment. Instead, they tap directly into the relevant
nutritional streams in host plants. Intriguingly, they often use sophisticated
sensory systems to find the most promising host plants. For example, dodder
(Cuscuta) uses plant-specific versions of sniffing (Runyon et al., 2006; Mescher
et al., 2006), perhaps comparable to a form of vision (Parise et al., 2021), to
identify the most suitable host plants. Additionally, there are recent reports on
plant-specific hearing where sound waves strong enough to activate relevant
plasma membrane receptors inform plants about important proximal
environmental cues, including streaming water in the case of roots or buzzing
pollinator insects in the case of flowers (Rodrigo-Moreno et al., 2017; Veits et
al., 2019).
In leaves and stems, trichomes (fine outgrowths or appendages) act as
sensitive plant hearing devices (Liu et al., 2017; Peng et al., 2022). Even further,
there are other more exotic and surprising sensory faculties of plants. For
example, some plants are capable of sensing electric fields generated by buzzing
insect pollinators such as bumblebees (Clarke et al., 2017; Vallejo-Marín, 2019).
Gagliano et al. (2012) suggested that some plants deploy root apex sonar-like
root navigation and the growing maize root apex is known to generate regular
clicking sounds which could inform the growing root apex about nearby physical
properties, especially the presence or absence of water in the soil ahead of its
projected growth trajectory (Baluška et al., 2021b). Relevantly, maize root apices
generate abundant electric spikes (Masi et al., 2009) which might be critical for
their cognitive faculties.
Foraging plant roots assess diverse signals of both abiotic and biotic origin to
localize and find water enriched with critical mineral nutrients. Roots of the
same plant team-up together, showing signs of swarm intelligence to fight, deter,
and kill roots of competing neighbour plants (Novoplansky, 2009; Shemesh et
al., 2010). Roots use specific exudates to define their identities and monitor their
neighbour plants (Gruntman & Novoplansky, 2004; Biedrzycki et al., 2010). The
relevance of these root processes permitting kin and self/non-self recognition
have been investigated and are being practically utilized in plant agriculture
(Yang et al., 2018; Anten & Chen, 2021). However, until recently, the cellular
background of these intelligent plant behaviours had remained obscure until the
CBC model of cellular sentience provided a novel, theoretical platform for
understanding the relevant scientific questions and helping to guide experimental
studies.
Although much is being learned about the cognitive abilities of flowering
plants, there is still much that remains unknown. For example, the factors that
enable recognition of host plants by parasitical climbing vines have not yet been
completely clarified. Nor is it fully understood how this action can sometimes be
associated with mimicking of these host plants nor the parasitical plants’ abilities
for recognizing, attracting, and manipulating their host’s potential pollinators.
As plants are sessile, they need some assistance to spread their male sex cells
which can be enclosed within pollen grains. The most readily available
mechanism for that dispersion is relying on the wind for pollination. However,
some flowering plants have entered into tight co-evolution with their pollinators
which act as assistants in their sexual life. In order to attract these pollinators
which are typically insects, they lure them with attractive colours, odours, and
shapes and also provide them with sugar-rich liquid nectar. Nectar secretions
increase in those flowers that are often visited by their pollinators. Besides
sugars, nectars are enriched by other often addictive substances, including
caffeine (Nepi et al., 2018; Wink, 2018; Mustard, 2020). These biomechanisms
allow plants to control the behaviour of their pollinators and select which of
them are most welcome to provide this service to them (Kessler et al., 2010).
Intriguingly, GABA and diverse other neuroactive substances increase the
cognitive abilities of bees and other pollinators (Nepi, 2014; Carlesso et al.,
2021). Besides the flower nectar, plants also produce extra-flower nectar to
manipulate insects to provide further services for them. An estimated 8,000
plants use extrafloral nectaries to manipulate insects (Grasso et al., 2015). For
example, acacia trees use extra-floral nectaries to attract and manipulate ants,
increasing their aggressivity, thereby providing plants some protection from
diverse herbivores (Grasso et al., 2015). Ants associated with acacia trees show
extremely aggressive behaviour. They will attack animals, even elephants and
antelopes, and certainly deserve their insect bodyguard status (Bentley, 1977;
Grasso et al., 2015).
A further conspicuous example of the dominant role of plants over their insect
‘servants’ is provided by orchids which attract their insect pollinator only by
providing abstractive clues such as shapes, colours, and forms mimicking female
partners (Schiestl, 2005; Jersáková et al., 2006). This mimicry is convincing
enough that the fooled males will try to repeatedly copulate with their female-
mimicking flowers (Gaskett et al., 2008). A further baffling example of plant
mimicry is provided by the Amazonian rainforest woody vine Boquila
trifoliolata which is able to mimic several host plants with differing leaf shapes
(Gianoli & Carrasco-Urra, 2014; Gianoli et al., 2021). This plant mimics
different aspects of their host plant leaves, including shapes, sizes, textures, and
colours. It remains a mystery how Boqguila is capable of this level of complex
mimicry (Baluška & Mancuso, 2016; Gianoli, 2017).
Surprisingly, a recent experiment with plastic artificial host plants suggests
that some kind of plant vision might be involved (White & Yamashita, 2022;
Yamashita & Baluška, 2023). This effect, if replicated, would explain why
Boqguila can mimic such diverse physical features as shape, size, and colours of
host plant leaves. Although generally ignored but especially surprising, plant
mimicry is demonstrated by weeds grown with domesticated crop plants, a
phenomenon known as ‘Vavilovian mimicry’, named after Nikolai Vavilov who
dubbed them ‘secondary crops’ (McElroy, 2014). This effect has particular
agricultural significance since it is thought that oat and rye plants evolved from
weeds into important crop plants.
Almost all current literature on plants delves into evolutionary theories based
on genetics and gene population frequencies (Huang et al., 2018; Ye et al.,
2019). However, and of vital importance, plant sensory systems and cognition
are largely ignored. Undoubtedly, however, it would be important to devote
substantial attention to plant sensory systems, cognition, and sentience (Baluška
& Mancuso, 2021; Yamashita & Baluška, 2023) to gain any valid understanding
of evolutionary mechanisms.

Root–—Fungal Networks: Supracellular Sentience Is

Relevant for the Gaia Concept
About 700 million years ago, ancient, small, and simple plants moved from
water to land together with ancient fungi. This first colonization of the terrestrial
habitat represents the decisive event in evolution of complex life on our planet
(Becker, 2013; Žárský et al., 2022) beyond the crucial endosymbiotic fusion of
Prokaryota to yield Eukaryota. With respect to the water-to-land transition, the
favoured hypothesis is that the first land plants somehow evolved from
streptophyte algae. However, ancient algae alone could not have launched this
transition since they have no physiological features that would permit them to
transform the barren stone land into a life-supporting habitat with lasting niche
constructions. In contrast to these algae, ancient fungi were able to assist that
transition through the weathering of rocks, thus enabling the tight symbioses
between plants and their symbiotic fungi. One can imagine that this interaction
might have begun first as a loose association, just as can be observed with
modern lichens, and only later energized the algae and fungi mergers that
generated the first land plants (Jorgensen, 1993). In fact, most data strongly
suggest that the first land plants needed very tight interactions with their
symbiotic fungi (Remy et al., 1994; Wang & Huang, 2021). In addition to their
role in rock weathering, fungi also assisted the early land plants in coping with
high levels of light stress and dramatic temperature shifts, as well as with their
problems finding water and mineral nutrients on dry land (Pirozynski &
Malloch, 1975; Selosse & Le Tacon, 1998). Although fungal hyphae networks
are well studied with respect to uptake and transport of water and mineral
nutrients, published data reveal that they transmit diverse signals and
information-loaded molecules (Simard, 2018; Fukasawa et al., 2020). These
networks are also active in bioelectric communication supported by linked action
potentials (Volkov & Shtessel, 2020; Thomas & Cooper, 2022). All these new
discoveries about reciprocating interactions are consistent with the Gaia concept
(Markoš, 1995; Lenton & Latour, 2018) in which integrated organisms,
especially bacteria, protists, fungi, and plants shape the whole biosphere through
direct and indirect influences on the atmosphere, pedosphere, and even the
geosphere. Indeed, the fungal hyphae and plant/tree root network act in a similar
fashion to the internet which was only invented by our technological civilization
a few years ago. The important difference is that the natural ‘wood-wide web’
(Sen, 2001; Giovannetti et al., 2006) was invented by living cells some 500
million years ago, representing a living and evolving system composed of
sentient cells.

Anaesthetics and Plants: From Cytoplasmic Streaming Up to

Traps of Carnivorous Plants
Plants have served as valid objects of study for investigations of anaesthetics
ever since their anaesthetic pain-relieving properties in humans were discovered
in 1846 (as was discussed in more detail in Chapter 10). Here we focus on two
aspects, their effects on cytoplasmic streaming in plant cells and their impacts on
carnivorous plants hunting insects. Some large plant cells provide an excellent
experimental system for studying cytoplasmic streaming and contractility.
Eduard Strasburger used this topic as his signatory one in his rectorial speech at
the University of Bonn in 1891 (Strasburger, 1891; Volkmann, 2013). Alfred
Ewart published an extensive review on this topic in 1903 (Ewart, 1903). He
credited Willy Kühne as the first to report that ether and chloroform arrest
cytoplasmic streaming in the large stamen cells of Tradescantia virginica in a
manner similar to that when they are exposed to electric fields (Kühne, 1864;
Ewart, 1903). Interestingly, Kühne was a student of Emil du Boys-Reimond who
discovered action potentials and initiated the field of experimental
electrophysiology. Others confirmed that anaesthetics not only block the
movements of supracellular organs, as discussed below, but also arrest
subcellular movements in cytoplasm (Osterhout, 1952; García-Sierra & Frixione,
1993).
Since their discovery, anaesthetics have intrigued researchers for their ability
to not only block the sensory awareness of organisms, including pain, but have
similar effects on the movements of their organs, causing general immobility
(Seyfarth, 2006; De Palma & Pareti, 2011). Importantly, action potentials are
linked to cytoplasmic streaming as there is a sudden cessation whenever an
action potential is fired (Ewart, 1903; Baluška & Mancuso, 2019). It has been
proposed that the subcellular actions of anaesthetics on excitable membranes are
critical in these supracellular effects on plants and animals, including humans. In
all organisms, anaesthetics cause immobility via impacts on the excitable plasma
membrane, blocking action potentials and organ movements. In plants, the best
studied organs are the leaves of Mimosa pudica and leaf traps of carnivorous
plants (Yokawa et al., 2018; Scherzer et al., 2022). Obviously, long-distance
bioelectric signalling has the same biological features in plants and animals. It is
essential for the movement of organs, proceeding via the same membranous
anaesthetic targets as those that block subcellular cytoplasmic streaming.

The N-Space Episenome of Plant Bodies: A Central

Commander and Centre of Plant Self-Identity
As we have discussed in Chapter 6, bioelectric activities of the excitable plasma
membrane generate bioelectric fields around themselves which extend across the
inside of the cell and radiate outward. In his recent book The Song of The Cell,
Siddhartha Mukherjee (2022) reminds us of the five basic tenets of life. To
complement them, the CBC theory adds a sixth and seventh, thus providing us
with the Cell Theory of Life:
1. All living organisms are composed of one or more cells.
2. The cell is the basic unit of structure and organization in all organisms.
3. All cells come from other cells.
4. Normal physiology is a function of cellular physiology.
5. Macro-organic disease, as a breakdown of physiology, is the result of disrupted cellular physiology.
6. In addition to the genome and epigenome, every cell is endowed with a senome that underlies cell
sentience.
7. Sentience and consciousness of all multicellular organisms derives from senome-based cellular
 sentience.

Tenets 1 and 2 were proposed by Theodor Schwann and Matthias Schleiden;

tenets 3, 4, and 5 come from Rudolf Virchow. We are adding tenets 6 and 7 to
complement these and, in so doing, complete the definitions of imperatives of
cellular life. As all organisms are based on one or more cells endowed with
cellular sentience, it is only logical that all multicellular organisms are endowed
with an existential consciousness that permits their navigation through life and
survival. These seven tenets, then, are the essential precondition for biological
evolution as it has been sustained for more than 4 billion years. Notably, tenets 6
and 7 suggest that the senome of the cell is the basic unit of mental life. Plant
cells are more complex than animal and human cells due to their chloroplasts,
representing a second endosymbiotic organelle. This status means that the
metabolic and senomic integration of plant cells is more complex than animal
cells insofar as they ultimately require more integrated components.
As discussed in Chapter 9, we have proposed that senomes (Baluška & Miller,
2018) merge together and assemble N-space Episenomic fields (Miller et al.,
2020a, 2020b) which guide organismal life and evolution. The evolution of such
integration was very slow which explains the long timeline in the evolution of
the eukaryotic cell as a combination of several pre-existing prokaryotic cellular
life forms, thereby permitting their further evolution as true multicellular
organisms within the new domain, Eukaryota. Plants do not possess a centralized
neuronal system like the central nervous systems in animals. However, their
requisite cell-based N-space Episenome could explain how they can generate
self-agency, sociality, and cognition even without a central neuronal organ
(Baluška & Mancuso, 2009a, 2009b, 2020, 2021).
From this perspective, the N-space Episenome of plant root–fungal hyphae
networks of the wood-wide-web is the largest and oldest episenomic field on the
planet Earth. It started on its evolutionary path with the first water-based plants
and fungi moving to land some 400 million years ago. As it is of central
importance for the Earth’s climate (Baluška & Mancuso, 2020), these same roots
are also essential for the future of our civilization.
12
Issues of Ethics and Morality
Entailments of the CBC

Introductory Remarks
One of the central themes of this book is that our CBC model and its associated
research strategy differs in fundamental ways from what we have been calling
the ‘standard approach’. We begin the exploration of sentience and
consciousness with the simplest life forms and follow the evolution of cognition
as it developed in more complex species. As noted in several places, the more
common framework is the one that begins with the mental life of Homo sapiens
and looks backward through the evolutionary tree for behavioural
commonalities, biomechanical analogues, and homologues of sentience.
Working within the standard framework, the approach to issues of ethics, animal
welfare, imposition of suffering, the guidelines and regulations of medical
research, commerce, and food processing is relatively straightforward. The
efforts turn on identifying the species that are determined to be sentient, feel
pain, and experience suffering and establish guidelines for their welfare. As we
will see, problems have emerged within this framework primarily because
different researchers and advocates for welfare identify different species and
clades as ones that do, in fact, suffer, do feel pain, and should be given
consideration in all aspects of relevant commercial and research enterprises.
The CBC, on the very other hand, invites, or better, insists that a variety of
additional issues be put under the microscope. We will try to cover all that seem
relevant, noting that in most cases we have no definitive conclusions, only a
motivated framework within which to operate. Our hope here is to engage in and
encourage discussion, debate, and bring in an alternative point of view. We have
a conceptual platform, it tends to be inclusive, but pragmatic and emphasizes the
dignity of all life forms, the interconnectedness of individual organisms and the
planet, builds on efforts to preserve the ecology of complex biospheres, and
outlines a general framework for how to function ethically, behave morally, do
as little damage, cause as little pain as possible, and work to mitigate that which
results from actions taken and decisions made.
These are issues that have not, so far as we have been able to discern, been
broached in the literature but, in our view, need to be. As we have noted in
several places (Baluška et al., in press; Reber et al., in press), the Homo sapiens-
focused strategy is non-optimal and is the reverse of that taken in the physical
and chemical sciences. There, the standard approach has been to begin with the
simple and work towards more complex circumstances as insight and
understanding develop. A critical feature of our CBC model is that it emulates
the natural sciences—begin with the simplest species. In this final chapter, we
will examine the manner in which these two research strategies deal with matters
of morality, ethics, and species welfare.
Let us begin this exploration with a simple fact about the carbon-based life on
this planet—one that some might find uncomfortable:
Except for unicellular prokaryotes and photosynthetic organisms, who are content to consume sugars
and minerals, every organism on the planet lives by ingesting other organisms. Ingesting, of course, is
made possible by engaging in acts that damage or kill other organisms—with a few species that wait
for others to do the deed and then come in for feeding.

In the following discussion we will raise issues that have been part of a variety
of ongoing conversations in fields as diverse as moral philosophy, evolutionary
biology, medical research, food science and commerce, species welfare, and the
role of governmental regulation. In addition, there are issues that have
significant personal features in lifestyles and still others that make contact with
larger social and cultural deliberations. Our goal here is to focus on the
implications of extending these issues to other biological domains examined in a
framework based on evolutionary biology and the deep message of the CBC
model.

The Standard Model Versus the CBC Model

Those who work within the standard model have had ongoing discussions on a
variety of ethical issues but the efforts have led to a crazy-quilt array of varying
opinions on pain, animal suffering, and animal welfare. One can see this pattern
in a recent overview of the issue by UK psychologist Matan Mazor and
colleagues (Mazor et al., 2022) who examined the link between consciousness
and ethics. They noted that for centuries the central point has turned on whether
one believes that the species under consideration has a mind, and perforce, must
be thought of as conscious. Perspectives have run the gamut from Aristotle who
argued that only fully rational humans had an existential consciousness and that
concerns about other species were not an issue, through Kant’s position that only
‘autonomous’ organisms were so mentally endowed, and Bentham’s focus on
whether they could suffer and experience pain. Mazor et al. reviewed the many
conclusions drawn by philosophers, psychologists, anatomists, entomologists,
primatologists, and neuroscientists. Not surprisingly, all have taken the
‘standard’ approach and the search is for behaviours and/or neural structures that
are sufficiently similar to those observed in humans that the species can be
considered to have a palpable consciousness and thereby have valenced
experiences and, critically, can suffer.
We maintain that all these varied approaches and the mutually contradictory
conclusions they have come to are simply missing the point: life and sentience
are coterminous so, yes, all species including the simplest unicellular
prokaryotes, suffer when experiences with negative valence are present. As
noted in the review of prokaryote behaviours in Chapter 2, unicellular species
learn to avoid places where aversive chemicals are present, locomote away from
temperatures that are dangerously low or high, block entry of molecules that
they detect might cause cellular damage, and communicate distress at lowered
nutrient levels—all of which support the conclusion that they are sentient, have
valenced experiences, and are capable of suffering. At the cellular level,
suffering need not equate with our specific human context. As has been
explained, cells have a well-defined state of preferential balance. When
perturbed, cells rapidly mobilize their limited resources to correct that loss of
essential equipoise to restore their preferential state. We humans do the same at
our scale. Further, as we discussed in Chapter 11 on the sentient life of plants,
flora also display a host of behaviours and biomolecular functions that are
compelling evidence that they too are conscious beings and aware of aversive
states. So, unlike those who have clung to the ‘standard model’, we have to
confront the ethical issues that these data raise from a very different footing.

Utilitarianism
The philosophical model that lies behind many of the discussions about welfare
of species is utilitarianism or its earlier instantiation, consequentialism. There
have been a variety of different forms of utilitarianism put forward over many
centuries, but in all, the guiding standard is to try to ascertain the ultimate
consequences of actions, to determine to what extent decisions and operations
based on them increase overall utility—where utility is treated as a general goal
and applied across all the ‘individuals’ impacted by the decisions and actions. In
short, choose actions that have the least negative impact on the species under
consideration and, of course, those that maximize satisfaction and happiness.
There are a number of variations on utilitarianism but each holds onto this
foundation principle. Actions and decisions should be judged on the basis of
which choices maximize happiness, satisfaction, and wellness for the most
‘individuals’. In the standard interpretations, the ‘individuals’ in the analysis are
people.1 In more recent approaches, the coverage extends to ‘sentient beings’
and, again we find the usual struggles to identify which species to include and
which choices and decisions should be made to provide for maximum welfare
for them. We are comfortable with this broad and non-technical utilitarianism—
with the understanding that it does not resolve many of the problems that emerge
when decisions need to be made. Its advantage is that it provides a pragmatic
framework within which to operate.
British moral philosopher Phillipa Foot, a critic of utilitarianism, introduced a
thought experiment some years back known as the trolley problem in which a
runaway trolley is barrelling down the tracks and heading towards five people
who, in the original version, have been tied to the tracks by a mad philosopher.
However, there is a switch you can pull which will divert the train to a siding.
On the siding, however, is a single person, also tied down. Do you pull the
switch? Do you act in a manner that brings about the death of an individual but
saves the lives of five others? The dilemma has been so thoroughly studied and
so many variations on the theme developed, that there is a sub-field in moral
philosophy known as ‘trolleyology’. It is easy to see how the situation can be
made more complex and other factors play a role. For example, in one variation
the single individual is a large, obese person on a bridge over the trolley tracks.
The only way to save the five persons is to push the obese person over the edge
of the bridge—an act very different from simply pulling a switch. In another, the
five are all convicted child rapists and the single individual a respected jurist.
Now, how do you deal with the situation? Put your father or your child on the
single-person track. Et cetera.
In the more familiar terrain of the CBC, we can have a variation on the
problem where the entities are sentient unicellular organisms and the setting is a
Petri dish where a stream of antibiotics is heading towards five prokaryotes but
can be diverted to the other side where there is a single cell. If the five are all
Mycobacterium tuberculosis, which are deadly, and the single cell is
Lactobacillus acidophilus, which promotes health, the choice is easy. Flip the
species and the decision changes. Note that the taking of life of equally sentient
organisms ceases to be the critical feature. While the emotional impact of deaths
of the organisms in the Petri dish version is far less than when human beings are
involved, there is little doubt that we would prefer to kill as many deadly
bacteria as we can and protect the lives of beneficial ones.
But in the final analysis, the deep problem with utilitarianism turns on the
difficulty, if not impossibility, of ascertaining what the ultimate consequences of
actions will be. The trolley problem is a nice example of what philosopher Dan
Dennett calls an ‘intuition pump’ in that it stimulates critical thinking in an area
or on an issue but it does not lead to any satisfying conclusions. There are, in
most complex situations where the principle is raised, just too many unknowns
and efforts to make decisions about actions and choices based on what are often
simply educated guesses about the future impact of decisions. In short, we have
adopted a pragmatic utilitarianism. We appreciate the importance of analyses of
the ultimate outcomes of choices and actions but appreciate the criticism that in
most circumstances the final decisions will be lacking in ultimate utility.

The Precautionary Principle

The precautionary principle is a broad ethical standard that is tucked into
utilitarian thinking and calls for decision-makers to take into account the
possible harm that might ensue if a particular course of action is chosen. It gets
invoked in a host of circumstances, such as considerations about whether novel
medicines or treatments should be provided to the public, decisions about which
species can be used in medical and biological research, and whether new
inventions or engineering techniques that might have an adverse impact on the
environment should be adopted. In the context of the topics we are considering
here, the relevant concern is whether it should be a factor when decisions are
made about the welfare of various species and how we should treat them.
British philosopher Jonathan Birch, whose approach to animal sentience was
discussed in Chapter 1, argues for establishing a conceptual bar for when to
apply the principle and it is, not surprisingly, based on the determination of
sentience and the experience of pain. When, Birch maintains, there is compelling
evidence that a species or family is sentient and feels pain, then caution should
be taken when dealing with its members and regulations should be put in place
that protect them from unnecessary harm or suffering (Birch, 2017). Species that
are determined to be insentient, or ones where there is insufficient evidence that
they are, do not need to have any precautionary guidelines in place. Australian
economist Yew-Kwang Ng (2017), a supporter of the precautionary principle,
hedges when the discussions turn on species he regards as non-sentient. When,
he maintains, there is no reason to conclude an organism is sentient then the
issue of welfare is not relevant because those species simply have ‘no welfare’.
 Several of those who wrote commentaries on Birch’s paper pointed out that
there are other considerations that should play a role in the decisions. As in the
discussion above on the trolley problem, should we distinguish between species
that are detrimental to our lives and those that are beneficial? Mosquitoes are the
only species that kill more humans than humans. Do they deserve to be granted
precautionary treatment? How do we feel about the five species of bacteria that
collectively are the second largest killer of humans causing fully one in eight
deaths (Ikuta et al., 2022)?
It is not hard to see the problem that the CBC stance has to deal with. One of
us (Reber, 2017) wrote a comment on Birch’s paper arguing that, since all
species including unicellular prokaryotes are sentient, all species should be
subjected to the kinds of concerns that the precautionary principle insists on. But
there are complicating factors in play. We will quote a section from Reber’s
commentary as it lays out the issues that are opened by our theory:
Then there are those sentient bacteria. Some probiotic species, like Lactobacillus acidophilus, promote
health; others like Mycobacterium tuberculosis are deadly; and still others like Escherichia coli have
strains, some beneficial, others decidedly not. Should only some come under animal protection
legislation when presumably all share equivalent mental states? We routinely tolerate the imposition of
pain when a goal deemed worthwhile is involved.

As noted above, the debate has been going on literally for centuries with most—
scientific researchers, philosophers, and government regulatory bodies—
concluding that there should be some forms of oversight to prevent or mitigate
suffering when a species is considered to have an existential consciousness. A
classic example of the kinds of issues raised can be seen in the ongoing
discussion involving fish pain. The opening salvo was a paper published in the
online journal Animal Sentience by Brian Key (2016) titled ‘Why fish do not feel
pain’. The paper has received over 40 (as of late 2022) published commentaries
and Key has responded in three separate essays.
Key’s primary claim is that fish do not feel pain because they lack the cortical
structures that are known to be implicated in human experiences of pain. Some,
such as biologist Georg Striedter (2016), argued that the lack of a neocortex does
not imply a lack of painful experiences and maintains that there is not sufficient
evidence to come to any conclusive answer. Others, such as Stuart Derbyshire
(2016), sided with Key. One of us (Baluška, 2016) commented that there is
compelling evidence that plants react to events that cause cell damage by
producing chemicals that have painkilling properties and, importantly, as
discussed in Chapter 10, are sensitive to anaesthetics. If plants feel pain without
anything resembling a mammalian cortex, it is almost certainly the case that
such neural structures are not essential and that fish do, in fact, feel pain.
Stuart Derbyshire (2016) began his commentary with a sentence that makes
clear where the problem is and why there is even a discussion about whether or
not fish feel pain: ‘Debate about the possibility of fish pain focuses largely on
the fish’s lack of the cortex considered necessary for generating pain.’ Again, we
see how the ‘standard model’ of starting the explorations with human
experiences and human neuroanatomy throws the issue into totally unnecessary
confusion. The mental states of Homo sapiens who are suffering are embedded
with human mental representations precisely because of the ways in which our
nervous systems are wired and how the various cortical and subcortical centres
and pathways deal with the environmental inputs. But the conclusion that fish do
not feel pain is absurd. Do they feel pain differently than we do? Does the lack
of a neocortex have an impact on the kinds of pain they experience? Doubtlessly.
They also respirate differently, locomote differently, process the visual spectrum
differently, and detect odours differently. Piscean species and mammals evolved
on distinct branches of the evolutionary tree. But it is misleading in the extreme
to conclude that, because their brains are wired differently from ours, that they
lack certain cortical centres and pathways, that they do not actually feel pain,
and do not suffer when their bio-physiological beings are under stress. The fish
flopping about helplessly in the bottom of a boat with a fishing hook piercing its
mouth is drowning and is doubtlessly in considerable pain.
Similar arguments have been put forward by bio-ethics philosophers
Mikhalevich and Powell (2020) who point to the cognitive functions of
invertebrates and argue that they should have the same kinds of standards of
treatment as vertebrates. As they put it, excluding invertebrates is ‘motivated by
cognitive-affective biases that covertly influence moral judgment’. In a similar
vein Robert Jones (2013) presented an overview of the various ethical
considerations that arise when animals are used in industrial food production and
preparation as well as in scientific research. Not surprisingly, both efforts focus,
as we have seen consistently, on multicellular, larger species and use evidence of
sentience as the criterion for recommending concerns about well-being and the
imposition of government regulations. Once again, we appreciate their efforts
but view them as limited. The issues are larger and pertain across the
evolutionary tree. As we outlined in detail in Chapter 10, there is virtually no
doubt that all living organisms suffer and feel pain as negatively valenced
experiences in some form and note that all respond to anaesthetics in
biomolecularly similar fashions—all of which function to mitigate the
unpleasant experiences. What is the point, evolutionarily speaking, of a species
being sensitive to and responding in appropriate ways to anaesthetics if it did not
experience something akin to what we call ‘pain?’ It would be a waste of
biomolecular resources for no gain—which is not an adaptive evolutionary
strategy.

Welfare—The Need to Diminish Suffering and the Planetary

Partnership
Recognizing that all living organisms can feel pain, can suffer, makes it clear
that we oppose the stance that Key and Derbyshire cavalierly take and support
making species welfare a central concern. Our position is that all species should
be treated with dignity with the understanding that the rights and needs of other
species are held in the balance. From our framework, since all living organisms
share fundamental biomolecular functions, we are all in a planetary partnership,
one that calls for a reciprocal relationship between parties. Maintaining a broad,
interlocking affiliation with others involves acknowledging the dignity (self-
identity) of each other. Planetary biology is the narrative of the maintenance of
conscious self-reference. The CBC model emphasizes planetary stewardship and
obliges fully embracing all other creatures including plants as partners in the
fullest sense of the word. When we dispose of living planetary resources, our
duty should be to try our best to maintain or strengthen the planetary
connectedness of a living partnership.
But, there is no question that our CBC stance opens a can of worms and all of
its ramifications have to be addressed. Pertinently, there are only two things we
securely know: (a) all cells are conscious, hence all multicellular organisms are
as well; and (b) all of evolution is a consequence of that reality as co-evolution
and co-development across all species. However, admittedly, many of the
particulars of intelligent life remain opaque. Pain among different organisms is a
good example, which is one reason why it has become the focus of much debate.
The fact remains that we do not know which organisms feel pain in the sense we
understand it since pain, just like the wavelengths of perceived light, is
differently sensed among organisms. But, of course, if a plant does not feel pain,
our kind of pain, it is certainly stressed by events that threaten its existence or
well-being—as was discussed in Chapter 11. This experience contradicts its state
of preference, can be categorized as unpleasant or negatively valenced, and,
because of this subjective state, requires the mobilization of resources to mitigate
it. However, we need to keep in mind that things in the world of flora are not
simple. Many plants thrive by adroit pruning, by the removal of branches and
limbs. For example, the hardy oleander, a plant commonly used as a living fence,
flowers much more lushly when pruned annually and, interestingly, actions that
limit its growth produce a healthier plant that is more disease and pest resistant.
Unpruned oleander looks distressed with many dead vines and areas of diseased
segments. Other species, such as the prickly pear cactus, also grow more
vigorously through self-pruning. Such traits suggest that these mechanisms and
others we described in the previous chapter emerged over time simply because
they had evolutionary advantages.
We are, as yet, unprepared to make too many judgements of ‘better’ good for
many types of living organisms. Cutting grasses might be a negative for the
grasses but sends more sunlight to the level of the earth, which brings up worms,
which attracts birds, that fertilize the soil. No decision about what to do with
plants is only about plants. It is encased in an entire local ecological frame, with
complex further ramifications. This issue, of course, is not new. Mad Magazine,
one of the longest running publications of cartoon humour (1971–2018), once
featured a parody of the Flash Gordon character who was the hero in a limited
series of comic books published by DC Comics and the protagonist in a widely
trashed film of the same name. The characters in the story had landed on a planet
which, to their astonishment, had mud people. If they stepped on mud, they
realized that they were hurting the mud people. The joke was that they realized
they were trapped because it turned out that there were also air people, rock
people, and so on. Everywhere they went, something said ‘ouch’. In the end,
they decided that if you are going to hurt something no matter how or where you
move, just get moving.
We do not know the answers and cannot offer any specific conclusions. Again,
our role in this chapter is to initiate debate—with the understanding that it takes
place within the CBC framework. All organisms are conscious but we have been
gifted special planetary privileges due to our unique human conscious frame of
reference that links to unparalleled engineering and problem-solving (and
creating) capacities—although we eschew the panpsychism that the Flash
Gordon parody reflects. In our theory, only biologically based organisms are
sentient and can feel pain. Such privileges carry countervailing responsibilities.
Our planetary dominance obliges thoughtful planetary stewardship.

Stress and Negative Experience in Plants

The CBC framework opens up other related concerns and, as we hinted above,
understanding the role of flora is one. Because all cells are conscious, all
multicellular organisms are as well. And, as noted in several places, evolutionary
mechanisms rarely operate by jettisoning functional and adaptive traits and
sentience is about as adaptive a characteristic as there is. In short, it would be
extremely unlikely if the millions of species in the plant world were to have
evolved without the capacity to experience stress as negative and not to have
biomolecular functions to mitigate it. Having said that, we recognize that many
of the particulars of intelligent life in plants remain opaque but need to bring up
a few of those ‘intuition pumps’.
1. Let us return to the one we touched on earlier. Does grass hurt when you mow it? Interestingly, this
is an oft-asked question on social media where the answer is almost invariably ‘no’ but without any
reason why. Like a lot of other plant species, grass, being a member of a clade of monocots, likely
evolved to cope well with being eaten, or in modern times, mowed. The situation is similar to that in
fruits, nuts, berries, and a host of other plant species that serve as another organism’s food. In all
cases, it is an effective way for sessile species to distribute their genes to other locales which,
depending on the symbiotic relationship between the species, can be very far away. Many bird
species, especially migratory ones, fly immense distances. Similarly, many species of ungulates
travel in herds over great areas in their search for sustenance. Hence, these granular species likely
evolved so that there is no suffering when some of their organs, tissues, and cells are cut or eaten.
2. Here is another touched on briefly above. Are plants stressed when pruned? As noted, it is likely that
there are many that are not. In many species of bushes, shrubs, and trees, pruning promotes healthy
growth. It is also best done at the collar of the offshoot branch. Trees and other plants that invite
pruning evolved antibiotic substances that are concentrated at the collar and operate to prevent or
reduce the likelihood of an infection. The implication is that a mechanism evolved that functions to
increase the chances of a plant’s survival, even if it appears on the surface to be one that would, in
others species, produce tissue damage and suffering. It is also apparently the case that the point
where the off-branch emerges is structurally weaker, making this the point most likely to be break off
under naturally occurring conditions. Again, this would have evolutionary advantages and would
have emerged well before pruning scissors were invented.
3. Generally speaking, is there a need to address the larger question of welfare in flora? Since the CBC
theory argues that the functions that emerged in prokaryotes were/are carried across all subsequent
species, the capacity to experience stress as negatively valenced, to suffer, goes along for the full
evolutionary ride. The reason this gets complex is because the current approach to animal welfare, as
noted above, turns on whether the species under consideration are sentient.

Recently, writer Matthew Rozsa ventured into the field in a non-technical essay
in the popular magazine Salon (Rozsa, 2022). While doing due diligence as a
reporter and writer, he focused on our work and the CBC model noting that
‘plants seem to possess a different set of evolutionary tools that suggest they
may experience consciousness, albeit in a radically different way from us’. He
also interviewed one of us (Baluška) and a colleague, Spanish philosopher of
science Paco Calvo, and reported that:
‘We should acknowledge that plants are complex living systems which deserve dignity, as it is stated in
the Swiss Constitution through amendment from 2008 (see Harmon, 2009)’, Baluška argued. ‘As
animals, humans and plants are in close co-evolution and have the same biological origins, we should
treat them as living organisms deserving dignity.’
Calvo noted that, even if humans only acknowledge that plants have a very
primitive form of consciousness, that should still make us feel ‘uneasy’ at the
realization that ‘plants are agents, and not mere objects or resources to be
exploited more or less wisely’.
In short, plants should be dealt with in the same manner that most ethicists
have argued other sentient species should be. Use the precautionary principle to
prevent unnecessary stress and recognize that they are part of the fully balanced
environment within which we all live. Apply a pragmatic utilitarian position in
an effort to recognize what the implications of our actions are and try to mitigate
what suffering we do cause. We began this chapter with the observation that all
species, other than prokaryotes and photosynthetic eukaryotes, can survive only
by damaging or killing and consuming other organisms. It is simply not possible
to survive without causing stress and pain but it can be handled with grace and
sensitivity and an acknowledgement that we are all encased in a complex,
interlocking biosphere in which all are worthy of being treated with dignity—
and, yes, in a complex ecologically structured world, this includes those who are,
shall we say, not our best friends when it comes to our own well-being. Of
course, in households with the pragmatic utilitarianism values we are promoting,
insects like ants, bees, and spiders who venture indoors are gracefully shown the
door and told to handle life as best they can. Mosquitoes and cockroaches are
swatted with no regrets.

Vegetarianism and Veganism

So far we have worked around a topic that sits up front when the issue of plant
sentience is raised: what are the implications of the CBC model for vegetarians
and vegans? There are many reasons for adopting a vegetarian or vegan diet;
these include promoting health, the previously raised issues of animal welfare,
concerns about the treatment of sentient species in industrialized food processing
and science, worries about the excessive use of environmental resources,
religious convictions,2 dislike of the ‘mouth feel’ of meats, and, of course,
ethical considerations that arise from the stress and pain that the animals that
provide sustenance undergo. For vegans, all these considerations play out as well
with the additional feature that no animal-derived foods are eaten so that eggs,
dairy products, and gelatin are not consumed.
But these concerns are, once again, applied to what are thought to be sentient
species and as we have seen repeatedly, plants are not regarded as sentient and,
as a result, generally not accorded considerations of species welfare. The CBC,
as we have noted countless times, changes the way this issue must be viewed.
All cellular life is conscious, senses external events, experiences and evaluates
internal conditions, thinks, makes decisions, and has negatively valenced
sensations and perceptions. Is there a way for vegetarians and vegans to adapt to
this compelling reality—particularly those who have adopted their lifestyle for
ethical reasons? There is, and it is obvious. Restrict your diet to those plants that
want to be eaten, those whose evolutionary history is marked by the
development of biomolecular mechanisms that render them tasty and nutritious
to other species and did so for fundamental evolutionary reasons. Being edible
was an excellent strategy for sessile species to evolve as it supports the
distribution of their DNA to areas other than their immediate location. These
include virtually all the floral forms that we have touched on: grains, rices,
berries, fruits, nuts, legumes, beans, root vegetables, leafy greens, herbs, and
many spices.
It is also worth keeping in mind that plants and other species co-evolved and
have, over time, developed modes of communication networks with plants that
we and other species eat that are part of our epigenetic adjustments to
environmental cues. For example, exosome-like nanoparticles that are ingested
from ginger, carrots, or grapes can be absorbed by macrophages and affect
mammalian gene expression. We share a tightly linked co-evolutionary
connection with all participants in our relevant ecosystem, since we are
contributing back our cellular DNA and microbial partners to plants.

Altruism and Its Place in Evolution

As discussed in Chapter 2, prokaryotes display a form of altruism. When cells in
the middle of a colony become nutritionally stressed, they communicate their
metabolic condition to others in the biomass who adjust nutrient uptake and cell
division until the nutritional deficits are mitigated. We have called these
demonstrations ‘altruism’ because they have the criterial features that have been
used when referring to similar behaviours in other species. The cells on the
periphery, the ones that reduce cell division and nutrient uptake, are putting
themselves at risk to benefit their colony-mates. Being on the periphery of a
biofilm means being in contact with predators, viruses, shifts in the chemistry,
and physical properties of the environment. Reducing cell division and nutrients
is risky. Being in the centre is protection from these dangers but, of course, there
is a limited food supply. See Humphries et al. (2017) and Prindle et al. (2015) for
details on these mechanisms and how they operate and note that Humphries and
colleagues observed these effects when they took place between different species
and different colonies—an example of cross-kin altruism.
These effects, which molecular biologist Gürol Süel dubbed ‘time sharing’,
are examples of the kinds of ecological integrity that is characteristic of all life.
When displayed by relatively simple unicellular species, the full expression of
the interactive N-space Episenome is, of course, going to be relatively simple
but, in keeping with our overall theme, these fundamental biomechanisms
emerged with the first life forms and became the organic platforms for all of
evolution. We are not saying that these ur-forms of altruism that unicellular
prokaryotes display are accompanied by self-expressed feelings of having done
something noble or a sense of thankfulness for the efforts of their conspecifics.
But we are saying that they are experienced as valenced states of awareness.
Sustaining selfhood of each ecological environment should be considered an
explicitly positive ethical goal. The larger question of ethical conduct remains an
individual one but, once the sentience of all organisms is recognized, we are all
jointly tasked to limit our ‘taking’ from any ecology and to take care to remain
within the limits of sustaining ecological partnership relations. Putting oneself at
risk for the potential benefit of others is deeply embedded in our evolutionary
history. It is part of the partnership, the ecological, social links that bind all
members of whatever community they live in, be it a sophisticated functioning
society or a Petri dish. Every organism is a discrete self with its own character.
Every ecological setting also has its distinct pattern of combinatorial self-hood.
This way of framing the issues reflects the principles discussed earlier in
Chapters 3 and 9 where we identified the importance of a cellular pervasive
information field and N-space Episenome. Self-hood is, at its core, a reiterating
phenomenon at differing scales. Holobionts and unicellular organisms combine
in ecological systems that support the lives of all participants.
It is worth noting that phrasing the larger issue of moral functioning in this
manner is a form of consequentialism in that it points to a philosophical stance
that emphasizes actions that, in ideal settings, bring about the optimal end-states
for those settings. See moral philosopher Douglas Portmore’s book
Commonsense Consequentialism (Portmore, 2011) for a detailed analysis of this
perspective. Recently The Guardian had an article reflecting on the Law
Society’s argument that legal rights should be extended to animals, plants, and
even rivers on grounds similar to what we and Portmore are proposing
(Siddique, 2022). Such regulatory shifts would promote biodiversity, mitigate
the impacts of climate change, and have generally beneficial effects on the
planet. Several countries, including Ecuador and Bolivia, where climate change
has had a significant impact on the ecology, have embraced the principle by
making ‘ecocide’ a prosecutable offense.
The Final Word
Well, there really is no ‘final word’—not when adherents of the CBC model
such as us confront the full extent of its entailments. We have raised these issues
here primarily to promote discussion and to tune thinking towards the notion of a
participatory dignity that we believe all should embrace. Make decisions within
the scope of a pragmatic utilitarianism, use the precautionary principle when
doubt is encountered, do as little damage to others (all others) as you can, and
cause as little stress as possible as you live your lives. It is what we try to do.

1 Wikipedia has a useful entry that touches on the various utilitarian approaches that have been put
forward and the various critiques on them (https://en.wikipedia.org/wiki/Utilitarianism).
2 We note that many of the points we are making here are very similar to the foundation principles of
Jainism where the path to enlightenment calls for non-violence and harm reduction to all life forms,
including plants.
 APPENDIX I

An Exercise in Lexicography: Defining(?) Consciousness

As noted in the Preface and sprinkled throughout the book, there were reasons
for taking the non-definitional route when dealing with our core term,
consciousness.1 One of them was what we found while doing our due diligence,
searching for a useful definition of our central concept. A reasonable place to
start the exercise, we figured, was to look for ‘official’ definitions of the term in
the peer-reviewed reference literature. The most ‘official’ place we know that fits
this description is the Penguin Books Dictionary of Psychology and, since one of
us, Arthur Reber, wrote it, we felt comfortable in starting there. In the first
edition, which was published in the middle 1980s, back when cognitive
psychology was emerging from the hinterlands and rapidly becoming the
dominant approach in psychology, consciousness was given there as:
1. Generally, a state of awareness; a state of being conscious. This is the most general usage of the
term and is intended in phrases like ‘he lost consciousness’. 2. A domain of mind that contains the
sensations, perceptions and memories of which one is momentarily aware; that is, those aspects of
present mental life that one is attending to (see attention). 3. That component of mind available for
introspection. This meaning is found in the older writings of structuralists and other introspectionists.
4. In psychoanalysis, the conscious.

The term has a distinctly checkered history. It has been represented at times as the central focus of
psychology (e.g., structuralism) and at others has been banned from the psychologist’s lexicon as
representing nothing more than the epiphenomenal flotsam of bodily activity (e.g., behaviorism). The
ongoing fascination with it, however, stems from the compelling sense that consciousness is one of the
defining features of our species: that to be human is to possess not only self-awareness but the even
more remarkable capacity to scan and review mentally which we are aware of. [Note: the bolding here
is not for emphasis. It simply signals that the term is defined elsewhere in the dictionary.]

The entry went on to discuss other connotative issues but this gives us a pretty
good feel for how the term had been used in psychology. It did the job and
touched most of the issues, but it didn’t do justice to the range of issues currently
under discussion. The entry was also entirely species-centric. It dealt only with
human consciousness and treated the term as though it denoted functions and
processes only found in Homo sapiens. What was being reflected, of course, was
the bias of the field. Twenty years, three editions, and two new co-authors later,
the fourth edition (now with Emily Reber and Rhianon Allen) still displays these
same themes. There is more up-to-date material but the definition still reflects a
species-centric stance. If there ever is a fifth edition, this narrowness of vision
will be changed.2
How about our chief competitor, the Macmillan Dictionary of Psychology?
The entry on consciousness was written by lexicographer Stuart Sutherland.
Here, there is equally little assistance. Sutherland wrote:
The having of perceptions, thoughts, and feelings; awareness. The term is impossible to define except
in terms that are unintelligible without a grasp of what consciousness means. Many fall into the trap of
confusing consciousness with self-consciousness—to be conscious it is only necessary to be aware of
the external world. Consciousness is a fascinating but elusive phenomenon; it is impossible to specify
what it is, what it does, or why it evolved. Nothing worth reading has been written about it.

Sutherland’s approach rather made it seem that consciousness was like a cold.
You cannot really understand what it is like or how you feel unless you have had
one. Clever but not terribly illuminating—although Sutherland’s tilt toward the
subjective, experiential aspect was typical of the way most used the term. That
last line was, for those who knew him, classic Sutherland. It also made his easily
the most frequently quoted definition.
These two efforts came from psychologists with a cognitive orientation. It is
possible that psychologists’ efforts might prove wanting as we tend to have our
own views on things mental. So let us turn to the authoritative, eight-volume The
Encyclopedia of Philosophy compiled and edited by another long-gone old
friend of one of us (Reber), philosopher Paul Edwards. Paul reached out to
philosopher Charles Landesman to handle the entry on consciousness and
Landesman promptly provided more heat than light:
The term ‘consciousness’ occurs in philosophy, psychology, and common speech with a variety of
different meanings. In this article those meanings will be discussed which are relevant to the
formulation of several recurrent philosophical problems.

Unfortunately those ‘meanings’ turned out to be categories of reference which

allowed Landesman to duck all definitional demands. He started out treating
consciousness as though it could (should?) be thought of as self-knowledge and
then provided a historically sensitive overview of this issue with attendant
discussions about introspection, mental states, and whether or not these states of
consciousness are made up of separate, non-material ‘stuff’ (i.e. the ‘Hard
Problem’ back before it was so named). It wasn’t that Landesman’s entry wasn’t
scholarly. It was. But stripped bare of the many segues, what was left was not
much more than the folk psychology connotations common in the field and it
certainly did not give us a definition.
 The next place checked was the entry in Simon Blackburn’s respected Oxford
Dictionary of Philosophy. Alas, it was a lot like Landesman’s. When thrown a
hard slider up and in, Blackburn also ducked, bailed right out of the batter’s box.
His definition wasn’t a definition at all. The entry started out:
Possibly the most challenging and pervasive source of problems in the whole of philosophy.

And then he described and outlined those problems without making any attempt
to define the term itself.
But lexicographic cowardliness of this kind is nothing compared with the
Penguin Dictionary of Philosophy edited by Thomas Mautner. You might think
you or someone had made some kind of alphabetic sorting error but search as
you may you will not find an entry for consciousness! And nothing for
unconscious, or experience, or awareness. Fascinating how a term regarded as
‘the most challenging and pervasive source of problems in the whole of
philosophy’ by Blackburn can be utterly neglected by Mautner.
Beginning in 1995, Stanford University began publishing, editing, and
regularly updating the freely accessible Stanford Encyclopedia of Philosophy. It
has become one of the most respected online sources for general information on
concepts and terms in the field. The entry on consciousness begins in a manner
that by now those of you still with us here should be ready for:
Perhaps no aspect of mind is more familiar or more puzzling than consciousness and our conscious
experience of self and world. The problem of consciousness is arguably the central issue in current
theorizing about the mind. Despite the lack of any agreed upon theory of consciousness, there is a
widespread, if less than universal, consensus that an adequate account of mind requires a clear
understanding of it and its place in nature. We need to understand both what consciousness is and how
it relates to other, nonconscious, aspects of reality.

What comes next follows the same familiar path only, being the Stanford
Encyclopedia of Philosophy, it is far more extensive than most sources. In fact,
the remainder of the entry is over nineteen thousand words long and explores
scores of specific issues, theories, disputes, and occasional resolutions in the
field without, of course, any suggestion of an effort at a definition.
Wikipedia’s page tells a similar story though it does have a telling sentence in
its rather extensive entry:
Despite the difficulty in definition, many philosophers believe that there is a broadly shared underlying
intuition about what consciousness is. [Emphasis added.]

We share this sentiment.

 Searches through the writings of individual scholars who study consciousness
yielded pretty much the same looseness of meaning. Neither Owen Flanagan’s
respected Consciousness Reconsidered nor David Chalmers’ controversial The
Conscious Mind seriously attempt a definition. In The Nature of Consciousness:
Philosophical Debates, edited by Ned Block, Flanagan, and Güven Güzeldere,
none of the many authors is particularly helpful; ditto with those who
contributed to Jonathan Cohen and Jonathan Schooler’s edited, interdisciplinary
volume Scientific Approaches to Consciousness.
It really was becoming amusing. No matter how far afield we went we could
find no genuine lexicographic help anywhere. It was not as if authors were all
consciously(!) avoiding the issue—though it was pretty clear that more than a
few were. And it was not that that the sorts of definitions that were being
provided just did not satisfy. In the few cases where someone actually made an
attempt to come to grips with the meaning of the term, they usually produced (a)
variations of the ‘definitions’ given by Sutherland and Blackburn, that is, lists of
issues that have arisen when contemplating consciousness; or (b) complaints
about how no one really has a coherent sense of what consciousness is other than
that personal sense that each of us has of whatever the heck it is that each of us
certainly has.
John Searle, not surprisingly, has also tackled the definitional problem and,
not surprisingly, he feels that he has a way to deal with it. From his book, The
Mystery of Consciousness:
One often hears it said that ‘consciousness’ is frightfully hard to define. But if we are talking about a
definition in common sense terms, sufficient to identify the target of the investigation, as opposed to a
precise scientific definition of the sort that typically comes at the end of a scientific investigation, then
the word does not seem to me hard to define. Here is the definition: Consciousness consists of inner,
qualitative, subjective states and processes of sentience or awareness. Consciousness, so defined,
begins when we wake in the morning from a dreamless sleep—and continues until we fall asleep
again, die, go into a coma or otherwise become ‘unconscious’. It includes all of the enormous variety
of the awareness that we think of as characteristic of our waking life. It includes everything from
feeling a pain, to perceiving objects visually, to states of anxiety and depression, to working out cross
word puzzles, playing chess, trying to remember your aunt’s phone number, arguing about politics, or
to just wishing you were somewhere else. Dreams on this definition are a form of consciousness,
though of course they are in many respects quite different from waking consciousness.

This is not bad, not at all. It is vintage Searle with its focus on the empirically
demonstrable but when you unpack this paragraph it really turns out to be a
compendium of those mental events, states, and experiences that he feels should
be tucked under the umbrella term itself—which is pretty much the same place
where we arrived when embracing the folk-psychology meaning. Searle, of
course, acknowledges this when he tosses in this line: ‘[W]e are talking about a
definition in common sense terms, sufficient to identify the target of the
investigation.’
Of course, none of this denotative turmoil is new. George Miller, one of the
first to mount a serious research programme in cognitive psychology, fretted
about how this favourite topic of his had been abused. He manifested his
unhappiness in his usual, elegant way. For him, consciousness had become:
A word worn smooth by a million tongues. Depending upon the figure of speech chosen it is a state of
being, a substance, a process, a place, an epiphenomenon, an emergent aspect of matter, or the only
true reality. … Perhaps we become confused because whenever we are thinking about consciousness,
we are surrounded by it, and can only imagine what consciousness is not.

It is worth noting that George Miller wrote this back when psychology was just
beginning to emerge from decades of dominance by behaviourism—and,
amusingly, penned while he and the unrepentant B. F. Skinner, who regarded
such topics as unfit for the attention of serious scientists, were colleagues in the
same department at Harvard.
This contorted denotative and connotative mess gains us, we hope, a little
sympathy for our bailing out on any serious efforts to ‘damn it, define your
terms’ or to track down the meanings of the many others like mind, subjective,
phenomenal, sentience, awareness, or self and self-aware—all of which have, for
centuries now, been worked over by many.
Looking back over this material you can see that strong tendency to tie the
various meanings to the human experience, to our kinds of subjectivity, our
kinds of minds. Essentially all took on the task of defining consciousness
beginning with the presumption that it was a mental state primarily experienced
by members of our species. While it is true that there were a few efforts such as
Donald Griffin’s (1992) that did touch upon the possibility of animal minds, or
for that matter, plant or protozoan minds, it was rare to find an effort at a
definition that was free from species narcissism. And even when the possibility
of consciousness in another species was considered plausible, the subjective
state was still viewed within the context of, or by comparison with, human
experience. Because the focus of the CBC model is on the initial emergence of
sentience, when all was said and done, it just seemed wisest to fall back on the
folk psychology senses of the many terms used as loose synonyms for
consciousness. This, of course, is precisely what virtually all of those working in
the many overlapping and interlocking fields of consciousness science have
done.
 1 Some of the material in this appendix appeared in Reber (2017). It is reproduced here with permission
from both Reber and the publisher, Oxford University Press.
2 Penguin has let us know it is extremely unlikely that there will be any future editions. The reason? The

obvious, the Internet.

 APPENDIX II

Glossary of Technical Terms in the Biological Sciences

As noted in the Preface, in order to understand the many complex functions of

cells that are responsible for cellular sentience, we needed to examine the
underlying biomolecular mechanisms responsible. To smooth the way for
readers lacking a background in cell biology, we have compiled this glossary.
The definitions are straightforward and as non-technical as possible. Note that
when a term in a definition is in boldface, it means that it has its own entry.

action potentials: The rapid rise and subsequent fall of voltage across
biomembranes.
adenosine diphosphate (ADP): ATP molecule lacking one phosphate
group.
adenosine triphosphate (ATP): An energy-carrying molecule found
in all living cells.
ADP: See adenosine diphosphate.
algae: Photosynthetic unicellular protists.
anaesthetics: Compounds that act on specific, sensitive, cellular
targets, especially biomembranes. They induce diminished
sensitivity (analgesia) and loss of consciousness (anaesthesia)
depending on biochemical properties and dosage.
archaea: Prokaryotic, unicellular organisms lacking a nucleus.
However, they have numerous eukaryotic features and are
considered possibly the most ancient form of life. See eukaryote
and prokaryote.
ATP: See adenosine triphosphate.
ATPases: A class of enzymes that catalyse transformation of ATP
 into adenosine diphosphate (ADT) for cellular energy
deployment.
axons: Projections of neurons that conduct action potentials away
from the neuronal cell body.
basal bodies: Protein complexes that function in the assembly of
eukaryotic flagella and cilia.
bioelectric code: Information encoded through bioelectric states of
cellular molecules, structures, and processes that are essential for
guiding growth, development, morphogenesis, and behaviour of
organisms.
bioelectric field: An electric field generated by fluxes of charged ions
across biomembranes.
biogenesis: Life from life. Generation of living organisms from pre-
existing life, particularly of the same type.
biological Maxwell’s demons: Cellular systems with information
processing capabilities contributing to intracellular structural order.
They operate by controlling what is allowed to enter and leave a
cell through its membrane. The name comes from the thought
experiment proposed by James Clerk Maxwell in 1867 to test the
second law of thermodynamics.
biological order: The totality of the ordered cellular structures and
processes essential for the living status of cells.
bioluminescence: Internally generated light emission by organisms in
which light energy is released by biochemical reactions based on a
light-emitting pigment luciferin interacting with the oxidative
enzyme luciferase.
biomembrane: The selectively permeable sheet-like barrier
separating the inside contents of cells from the external
environment.
biophotons: Photons of light in the ultraviolet and ultra-weak ranges
 produced by electronically excited biomolecules, especially those
associated with the production of reactive molecular species.
bioplasma: Networks of electromagnetic fields generated within
cells.
biopoiesis: Life from non-life. The concept that life develops from
non-living matter and the basis for a widely accepted theory of the
origin of life on Earth.
biosemiotics: The integration of biology and semiotics treating all
organisms as sign-generating and information-interpreting living
systems.
biosphere: The sum of all ecosystems on Earth as they evolved
through the functions of biopoiesis and biogenesis.
calcium waves: Wave-like, localized increases of cytoplasmic
calcium.
carnivorous plants: Plants that have evolved leaf-traps to hunt,
capture, and consume insects and small animals.
cell sentience: Cellular awareness of the external environment and
itself.
cellular circadian clocks: Biochemical oscillators within cells that
are synchronized with solar time.
cellular communication: Communication within and between cells.
cellular organelles: Membrane-bound compartments within
eukaryotic cells. See organelles.
cellular respiration: The set of metabolic reactions within cells that
allows conversion of chemical energy of organic macromolecules
into ATP molecules. In eukaryotic cells, cellular respiration is
accomplished within their symbiotic (see symbiosis)
mitochondria.
central dogma: The concept that the flow of genetic information is
 unidirectional from DNA to RNA and proteins. This outdated
dogma asserted that once information had gone from DNA into
proteins, it could not go back into the genetic code. This
unidirectional process is now known to be incorrect.
centrioles: Cylindrical structures composed of tubulin proteins
organized as nine sets of short microtubule triplets. They play a
role in organizing the microtubules that serve as the cell’s skeletal
system.
centrosomes: Organelles that serve as the main structures allowing
seeding and polymerization of microtubules in eukaryotic cells.
Typically, they consist of two centrioles surrounded by
pericentriolar material.
chemiosmotic theory: A theory based on ATP synthesis through
proton electrochemical coupling. In this process the electron-
transport chain is arranged so that an energy-rich proton gradient is
generated across the inner membrane of a mitochondrion, driving
ATP synthesis.
cilia: Microscopic, hair-like protrusions on the surfaces of many
eukaryotes. They are organized by the cell’s basal bodies and
composed of microtubules and microtubular motor proteins. In
some organisms they vibrate and cause changes in the surrounding
fluids, in others they enable cellular locomotion.
ciliary rootlet: Intracellular extension of ciliary basal bodies (see
basal body) providing structural support to a cilium.
ciliates: Protists that are covered by numerous cilia.
coacervate: Aqueous phase rich in biological macromolecules formed
as large colloidal particles that precipitate out in aqueous medium.
Coacervates are considered the first pre-cells which gradually
transformed into living cells.
coevolution: The process where one species evolves in response to
 the evolutionary changes in another species. The changes
themselves typically cause reciprocal adaptation.
cyanobacteria: Ancient photosynthetic bacteria that still thrive in all
planetary environments.
cytokinesis: The process of cell division where a ‘mother’ cell
separates into two ‘daughter’ cells. See mitosis.
cytomatrix: The complex cooperative macromolecular relationship
between cellular interior and the complex set of interior and
exterior water networks.
cytoplasm: All the internal cellular content of a cell, except for the
nucleus and vacuoles.
cytoplasmic calcium: Calcium ions freely localized within the
cytoplasm.
cytoplasmic streaming: Flow of the cytoplasm within the cellular
interior.
cytoskeleton: The network of protein polymers forming filaments
and tubules in the cytoplasm of many living cells, giving them
shape and coherence.
dendrites: Branched tubular extensions of neurons which pick up
impulses from neighbouring neurons.
dendritic spines: Protrusions on the dendrites of neurons which
receive impulses from axons of adjacent neurons.
dimerize: The process in which two molecules combine and create a
single polymer called a ‘dimer’.
electrome: The totality of ionic currents and signals within an
individual cell.
electron transport chain: The transfer of electrons from electron
donors to electron acceptors enabling their transmembrane
transport. The process functions by driving the creation of ATP
 used by the cell as energy for metabolic processes and cellular
functions.
electrophysiology: The physiology of organisms with a focus on
bioelectric phenomena.
electrostatics: A subdiscipline of biophysics studying electrical
charges of ions and membranes.
embryogenesis: The development of an embryo from a fertilized
oocyte (egg cell).
endocytosis: A process of the internalization of a part of the
extracellular space into the cell by membrane invagination.
endogenous anaesthetics: Anaesthetic compounds synthesized
internally in organisms under stress. Many plant species produce
their own anaesthetics.
endosomes: Intracellular, membranous compartments generated by
the process of endocytosis.
endosymbiosis: A form of symbiosis where the symbiont lives within
the body of a host organism. It is almost certainly the process
whereby the first eukaryotes evolved.
engram: A unit of cognitive information imprinted in cellular
structures.
entropy: Disorder, randomness, and uncertainty. The second law of
thermodynamics states that in all closed systems, entropy always
increases. Organisms, in their goal for survival, appear to act
against entropy to create states of greater order.
enzymes: Proteins that act as catalysts accelerating biological
reactions.
epigenesis: Formation of organisms from an original seed, spore, or
fertilized egg. Epigenesis replaced the now discredited theory of
preformationism.
epigenome: The sum of all non-coding DNA/RNA-based hereditary
information of an organism. Besides the machinery regulating the
packaging of DNA into chromatin and chromosomes, the
epigenome includes all cellular structures acting as templates for
their own replication. It is one means by which organisms adapt to
the environment without requiring a change in the genetic code.
ether: An anaesthetic agent that induces loss of pain sensing
(analgesia) and loss of consciousness (anaesthesia).
ethylene: A plant stress hormone that also acts as a general
anaesthetic agent.
eukaryotes: Complex cells with a nucleus containing the cell’s
genome and a large number of intracellular organelles. The first
eukaryotes are believed to have been formed through
endosymbiosis where a small prokaryote was incorporated by a
larger one.
excitability: The capacity of cells to be excited by stimuli. It’s a
fundamental function for survival of all cellular life and based on
processes generated by biomolecular operations on the cell’s
excitable plasma membrane.
exosome: A extracellular vesicle released from eukaryotic cells.
exteroception: Sensing of events and stimuli in the external
environment. It is an essential feature of the sensory/perceptual
processes of all cells and more complex organisms (compare with
interoception).
flagella: The membranous protrusions from cells used both for
motility and as a sensing apparatus.
flagellate: 1. A hair-like protrusion on a cell’s membrane that can be
rotated or used in a whip-like fashion for propulsion. 2. A group of
cells, mostly protists and male sex cells, that use microtubule-
based flagella for movements.
frugivores: Animals that feed primarily on fruits and other plant
organs.
gamete: See sex cells.
gene: The basic unit of genetic information. The term gene was
introduced by Danish plant physiologist and geneticist Wilhelm
Johannsen in 1909. The concept of a gene is still evolving and has
several different meanings.
gene expression: The transfer of information encoded in sequences of
nucleotides used in the synthesis of proteins, transfer RNAs, small
nuclear RNAs, and non-coding RNAs enabling biological actions.
genome: The sum of all protein-coding DNA/RNA-based hereditary
information of an organism.
holobiont: A multicellular, eukaryotic organism comprised of both its
own eukaryotic cells and its partnering microbiome, forming a
cohesive, adaptive unit through symbiosis.
homeorhesis: The tendency of organisms to return back to their
original trajectories. A ‘trajectory’ can be either movement based or
an internal, sentient process. Compare with homeostasis in which
organism returns to states of stability.
homeostasis: The tendency of organisms to return to their original
biological, physiological state. Compare with homeorhesis where
the tendency is for an organism to return to an original trajectory.
hydrophobic pockets: Protein domains proposed to act as the
primary targets of anaesthetics.
hyphae: Long fungal filaments that can branch, fuse, or join together
to form mycelia cords (see cilia).
info-autopoiesis: The process of the internal self-production of
information. All the information that any cell has about events or
stimuli in the environment must cross the plasma membrane and is
ultimately self-interpreted inside the cell.
interfacial water: A unique state of water with high viscosity and
ordered structure having separate thermodynamic features.
interoception: The sensory/perceptual processing of internal
operations and status of all cells and more complex organisms.
Compare with exteroception.
invagination: Process of biomembrane folding to form a cavity
which can be pinched off as a vesicle.
ions: Molecules with electrical charges.
ionic wave: The flow of ions along cellular structures.
lichens: Composite organisms based on fungi, algae, or
cyanobacteria.
lipid bilayer: The double-layer of phospholipids that forms the main
structure of a biomembrane.
lipid rafts: Domains of biomembranes enriched with ordered
sterols.
luciferase: An oxidative enzyme producing bioluminescence from
luciferin.
luciferin: A biomolecule that emits light in its excited state through
enzymatic activity of luciferase.
macromolecular crowding: A condition that emerges when
biological macromolecules form collectives at very high
concentrations.
membrane: See biomembrane.
membrane potential: The difference in the electric potential between
the inside and outside of the biomembrane. The interior is
typically negative with respect to the exterior, a feature that
generates energy across the membrane, allowing the transmission of
molecular signals between the cellular interior and the external
environment.
membrane repair: Generally, any of several processes that maintain
the structural and functional integrity of biomembranes.
microbiome: A community of microorganisms living together with
their host organism.
microtubules: Polymers of tubulin representing part of the
cytoskeleton of eukaryotic cells. Typically, 13 protofilaments join
together to form a microtubule.
mimicry: The ability of organisms to imitate features of other
organisms for their own advantage and protection.
mitochondria: Symbiotic organelles of most eukaryotic cells
responsible for the cellular aerobic respiration that produces
adenosine triphosphate (ATP). Believed to have originally been a
free-living bacterium that became incorporated in a host cell. See
symbiosis.
mitosis: A process where a single cell divides into two ‘daughter’
cells with identical genomic complements and provides each with
an equal division of the plasma membrane. Mitosis is the typical
process of tissue growth and development.
molecular motors: Protein complexes that use ATP to fuel their
movements.
morphogenesis: The processes that coordinate the origin and
development of physical characteristics.
multi-vesicular bodies: A special class of late endosomes which
internalize vesicles.
mycorrhiza fungi: Symbiotic fungi that colonize plant roots. These
ancient fungi, which first evolved some 460 million years ago,
allowed early plants to live on land.
nano-intentionality: Intentional faculties of biological
macromolecules allowing intrinsic goal-directedness of all cells.
 Nano-intentionality is specific for living cells, and helps explain the
difference between computer architecture, AI, and living systems.
nanotube: A microscopic tubular, membranous connection between
cells forming tubular nanotubes which play a role in
communication and the transfer of cellular resources.
N-space: A term derived from mathematics and used to describe the
four-dimensional fabric that represents the totality of universal
information potentially available to appropriate observers.
N-space Episenome: A multicellular partitioning of N-space that
structures multicellular morphogenesis and the coordinated
embryogenesis. The N-space Episenome is a heritable, adaptive,
information blueprint that guides growth and development from
conception forward and is essential for reproduction and
development.
nucleotides: Organic molecules consisting of a nucleoside and a
phosphate and serving as monomeric units of the nucleic acid
polymers—deoxyribonucleic acid (DNA) and ribonucleic acid
(RNA). Nucleotides are the basic structural unit of DNA and RNA.
ontogenesis: Development of organisms from oocytes (eggs)
fertilized by sperm cells.
organelles: Localized structured compartments of eukaryotic cells
each of which performs specific cellular functions.
oxidative phosphorylation: A cell process that harnesses the
reduction of oxygen, generating high-energy phosphate bonds to
form adenosine triphosphate (ATP) which is necessary for
metabolism in all organisms.
peripersonal space: The space surrounding an organismal body that
is in reach of, or can be reached by, adjacent organisms as an
essential component of bodily self-consciousness.
pervasive information field (PIF): A specific sub-domain
 compartment of universal N-space representing the totality of all
potential information available to a cell at any moment. This subset
of bio-information is required by cells for effective information
management.
phospholipids: A class of lipids which self-assemble the lipid
bilayers of biomembranes.
photosynthesis: The process of converting the light energy of
photons into the chemical energy of biological molecules.
piezoelectricity: The accumulation of electric charge in some
biomolecules in response to mechanical stress. In cells, the
bioelectricity induced by pressure.
PIF: see pervasive information field.
plant sexuality: The sexual reproduction of plants through the
fertilization of female sex cells (egg cells) by male sex cells (sperm
cells).
pollen tubes: Tip-growing tubular plant cells that act as carriers of
male sex cells.
pollinators: Insects or other organisms that transport plant pollen
grains from flower to flower, serving plants in their sexual
reproduction.
polymerization: The process of polymer assembly from associating
monomers.
polymers: Biological macromolecules composed of numerous
repeating subunits (monomers).
preformationism: The once-popular theory that organisms developed
from their own miniature versions. For example, a human sperm
cell was thought to have a tiny person inside and often depicted as
such. The term, however, is still used in some contexts to refer to
functions that are epigenetic (see epigenesis.)
prokaryotes: Single-celled organisms, including bacteria and
archaea, that, unlike eukaryotes, lack a nucleus. Their DNA is
distributed loosely throughout the organism’s interior.
proprioception: The sense of body location, position, and movement.
proteome: The sum of all cellular proteins.
protists: Single-celled eukaryotes such as protozoa and simple
algae.
proto-cells: Non-living, self-organized nano- and micro-sized
biochemical structures that formed in the prebiotic ‘soup’ and are
considered the likely progenitors of fully competent cells.
proton-motive force: The biological processes whereby proton
gradients operate across membranes driving ATP synthesis.
protoplast: A term proposed by Johannes von Hanstein for the entire
cell interior, excluding the cell wall and extracellular matrix.
protozoa: A class of single-celled eukaryotic organisms including
amoeba and paramecia, among others.
radical pairs of electrons: Correlated electron spins involved in the
magneto-perception of birds and a critical element in seasonal
migration. Interestingly, they are also an element in xenon-induced
general anaesthesia.
reactive molecular species: Reactive and charged biomolecules
produced through cellular metabolism and signalling pathways.
Note that ‘species’ here, and in the following entry, refers to a group
of radicals, not a genetically related group of organisms.
reactive oxygen species (ROS): An unstable molecule that contains
oxygen that easily reacts with others in a cell. Excessive build up is
associated with cellular damage, especially to DNA and RNA.
receptors: Biological macromolecules in sense organs. The term has
wide, general reference and also denotes structures that are
 distributed across a cell’s biomembranes or an organism’s body that
are capable of receiving and transmitting signals.
redox: A type of chemical reaction in which the oxidation states of
biomolecules change. When electrons are lost, oxidation occurs or
is increased; a gain of electrons produces a decrease in oxidation.
redox code: A set of principles governing and maintaining redox
homeostasis. A redox reaction is a type of chemical interaction that
involves a transfer of electrons between two entities.
redox potential: Oxidation/reduction potential measured as the
tendency of a chemical species to acquire or lose electrons. Each
molecular species has its own intrinsic redox potential. See reactive
molecular species.
regeneration: The process in which an organism is able to reassemble
and reform missing parts or organs.
rhizoplasts: Contractile structures connecting the basal bodies of
eukaryotic flagella and cilia with the surface of the nucleus.
root–fungal networks: Huge networks organized by plant roots and
hyphae of symbiotic fungi which serve in the transport of water
and nutrients and as a means of information exchange across whole
ecosystems.
ROS: See reactive oxygen species.
ROS waves: The flow of reactive oxygen species propagating over
considerable distances in response to cellular stimulation.
self-organization: In biology, the ability of life processes and
biomolecular functions to generate and maintain biological order.
senome: The totality of all bioelectric and sensory activities of
biomembranes and their associated organelles and biomolecules
based on the fluxes of all ionic and other cellular charged particles.
senomic field: A bio-electromagnetic field generated by
 biomembranes and forming a crucial part of the cell’s sensory
apparatus.
sensors: In biology, sensors are macromolecules, typically protein
complexes, which detect some abiotic or biotic parameters and
convey sensory information into the cell.
sex cells: Reproductive haploid cells, also known as gametes. In
multicellular organisms, male sperm cells are smaller and motile,
whereas female oocytes are large and non-motile.
spontaneous generation: A theory believed for centuries that
organisms regularly arise from non-living matter.
sterols: Organic compounds vital for functions of biomembranes.
symbiosis: A long-term interaction between organisms benefiting all
partners involved. Examples include your partnering microbiome or
the beneficial relationship between ants and acacia trees. The ants
provide the tree with protection against predators and the tree
supplies nutrients to the ants. See also, endosymbiosis.
synaptic domains: Cell–cell adhesion domains consisting of cell-
surface molecules and special types of intercellular bonds critical
for cellular communication.
syncope: Loss of consciousness and muscle strength characterized by
fast onset, short duration, and spontaneous recovery.
thanatosis: Death-feigning marked by tonic immobility. It is a
defensive anti-predatory strategy used by several animal prey
species.
tubulin: Globular proteins which dimerize and form cytoskeletal
polymers known as microtubules.
tunnelling nanotube: A microscopic cytoplasmic bridge between
cells used for cellular communications and exchange of cellular
resources. See nanotube.
valenced experiences: Context-dependent (subjective) awareness of
environmental signals, events, or stimuli. ‘Valenced’ here simply
means that the experiences are marked by either positive or
negative feelings.
vesicles: Biomembrane-derived small, intracellular or extracellular
compartments enclosed by lipid bilayers used to move substances
within or outside cells.
viruses: Semi-living infectious agents that reproduce only inside
living cells. Viruses infect life forms and provoke immune
responses in cells and organisms, but are also crucial partners in
cellular adaptation.
vitalism: The view that living organisms are fundamentally different
from non-living entities by having some type of special essence, an
élan vital.
voltage: The difference in electric potential and charges between two
points.
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Index

For the benefit of digital users, indexed terms that span two pages (e.g., 52–53) may, on occasion, appear
on only one of those pages.

aboutness 17
Ackermann, M. 29
actin cytoskeleton 63–64, 70–73, 86
action potentials 68–69, 72, 146–47
Adamo, G. 14
adaptation 25
adjacents 95
algae 151–52, 153
altruism 32–33, 113–14, 175–76
anaesthetics 63–64, 71, 139–49
action potential sensitivity 146–47
cellular targets 141–44
discovery of 139–40
electro-anaesthesia 146
endogenous anaesthetics 147–48
lipid theory 142–43, 144–45
Meyer–Overton rule 142–43
molecular actions 141–44
plant sensitivity 140, 141, 143, 159–60
pressure reversal 144
proteins with hydrophobic pockets 145–46
sensitivity to 140–41
unicellular organisms 141
anticipation 95
antipodal information 94–95
archaea 62–63, 65–66
assumptions 1–2
ATP 85
ATP synthases 84
attractive field 48
auditory sensing, plants 155–56
avian consciousness 12
avoidance learning 25–26

Bacillus subtilis 32–33, 113–14

Barron, A. B. 14, 21
Bateson, G. 91
bee consciousness 15
Berg, H. C. 23
Bernal, J. D. 38–39
Bernard, C. 140–41
binding problem 5–6, 63–64
bio-clocks 33–34, 60, 68
bioelectricity 56–60, 67–69, 72–73, 81–82, 86–87, 158–59
bio-electromagnetic fields 81–82
bioenergetics 56–57, 67–68, 73
biofilms 31–32, 81–82
biological attraction 48
biological continuity 47–48
biological learning 47–48
biological memory 47–48
biological ordering 47–48
Birch, J. 13, 16, 21, 167–68
bird consciousness 12
Boquila trifoliolata 157–58
Bray, D. 6
Brentano, F. 17
Broom, D. 15–16, 20
Brown, D. A. 23
Bruni 23

calcium waves 74–75

cancer 80, 81, 108
Cantor, R. 148
Casadesus, J. 30
Caulobacter crescentus 29
cells
bioelectric aspects 56–60
biological expressions of information architecture 101–4
emergence of first cells 55–56
evolution 60–61, 64–66
information cycle 96–98
multicellular and archaeal nature of eukaryotic cells 62–63
reality creation 99–101
slow emergence of eukaryotic cells 63–64
symbiotic evolution of eukaryotic cells 60–61
tools of 112–19
Cellular Basis of Conscious (CBC) theory 1–2, 58–59, 164–65
cellular electrome 86–87
cellular metallome 86
centrin 61
centrosomes 73–74
cephalopod consciousness 15–16
Chalmers, D. 5
chilly start hypothesis 40
Chinese Room thought experiment xvi–xvii
chirality 39
Chittka, L. 15
Chlamydomonas reinhardtii 152–53
chloroplasts 143, 151–52, 153
choanocytes 154–55
circadian clocks 33–34, 60, 68
coacervates 56
collaboration 46, 110, 120
Collins, H. xx
communication 31–33, 46–47, 103–4, 110, 119
community clay theory 40
complementarity 47
computationalism xvi–xx
consciousness, criteria for 13, 15–16, 20–22
consequentialism 176
constraints 48–49
continuum of consciousness 10–11
cooperation 46, 110, 120
corals 151–52
corvid consciousness 12
Crick, F. 38, 106, 115
criteria for consciousness 13, 15–16, 20–22
crustacean consciousness 16
Cuscuta 155–56
cuttlefish consciousness 15–16
cyanobacteria 24, 34, 60
cytoplasmic crowding 83
cytoplasmic matrix 69–70
cytoskeleton
membrane-cytoskeleton adhesions 70–71
senomic micro-fields 82–83
sensitivity to anaesthetics 143

Damasio, A. 6–7
D’Ari, R. 30
Darwin, C. 43, 114–15
Davies, P. 38
Davy, H. 139–40
Dawkins, R. 112, 119–20
decision-making 30–31
deep-hot biosphere model 40
demons 70–71, 79
Derbyshire, S. 169
Dexter, J. P. 26
DishBrain system 27–28
DNA 59, 77–78
dodder 155–56
Dodig-Crnkovic, G. xx
Driesch, H. 44
Dussutour, A. 26, 27

Edwards, J. 5–6
effective information (EI*) 97, 110
electro-anaesthesia 146
electromagnetic ripples 82–83
electrome 86–87
electronic proteins 146
electron transport 56–59
electrostatic interactions 86
Elsasser, W. 48–49, 53, 121
embryogenesis 131–32
emergentist’s dilemma 4
endocytosis 72–73, 79
endoplasmic reticulum 74
endosomal sorting complexes required for transport (ESCRT) complex 65–66
endosymbiosis 20, 61
engineering cycle 110–14
entropy 40–41
epigenetics 106–7, 117–18, 132–33
Epstein, R. xvii–xviii
Escherichia coli 23, 27, 30
ethanol 148
ethics and morality 163–77
altruism 175–76
pain sensitivity 168–69, 170–71
precautionary principle 167–70
standard model versus the CBC model 164–65
utilitarianism 165–67
vegetarianism and veganism 174–75
welfare issues 170–72
ethylene 142–43
Euglena 69–70
evolution
ancient bioelectric and redox codes 59
genes as tools 114–19
key driver of life 51–52
multicellularity 60–61, 62–63
stability 10–11
symbiotic evolution of eukaryotic cells 60–61
viruses as key players 64–66
exclusion zone water 71
exteroception 78–79
extracellular vesicles 81, 83

fatigue 34
fetal development 131–32
first eukaryotic common ancestor (FECA) 65–66
first universal cellular ancestor (FUCA) 55–56
fish pain 168–69
fluid mosaic model 145
Fodor, J. xvi
Foot, P. 166
forms, theory of 114–16
Foster, K. R. 33
free radicals 57–58
free will xix
functionalism xvii
fungi 158–59

GABA 74–75, 155, 157

Gaia concept 158–59
genes
beginning of life 41
contemporary view 106–9
gene expression 30, 31–32, 34
as tools of cells 112–19
genome
as blue-print 116
book of life 116
epigenetics 107
memory 120–21
mobilome 107–8, 121–22
non-coding 116
read–write system 106, 107–8, 115–16, 117
transposable elements (TEs) 107, 108–9, 116–17
Ginsberg, S. 15
Glasgow, R. 9
glutamate 155
Godfrey-Smith, P. 15–16
Golden, S. 34
graded autocatalysis replication domain (GARD) model 41–42
grass cutting 171, 172

habituation 26
Haeckel, E. 153–54
HAP2/GCS1 65–66
Hard Problem of consciousness 5
harnessing of stochasticity 99–100, 117
hearing, plants 155–56
Heisenberg uncertainty principle 94
Hoffman, P. 85–86
homeorhesis 46, 57–58
homochirality 39
Howard, S. R. 15
Hunter, P. 13
hydrothermal vents 41

immunity 80, 83, 108

immunological memory 29–30
information 89–104, 105–6
antipodal information 94–95
biological information versus computer data 92–96
 cells as biological expressions of information architecture 101–4
cellular information cycle 96–98
collective shared assessment 96–97
definition 90–91, 125
effective information (EI*) 97, 110
engineering cycle 110–14
flow of information 102
info-autopoiesis 99
information space-time 126–28
integrated information theory 100
necessity for life 123–25
noise 99–100
pervasive information fields 126–28, 134–35
reality creation 99–101
self-referential information 47, 94–95, 97–98, 99, 101–2, 103, 121, 123–24, 125, 134–35, 136
Shannon information 90–91
stochasticity of information 99–100, 117
structures in nature as information 134
third state information 95
insect consciousness 13–14, 15
integrated information theory 100
intentionality 17
interfacial water 85–86
interoception 78–79
interoceptive paralysis 148
interstitial water 70–71
iron-sulphur world–metabolism-first model 41

Jablonka, E. 15
James, W. 5–6
Jennings, H. S. 25–26
Jones, R. 169–70

Kagan, B. 27–28
Kauffman, S. 39, 45
Key, B. 14, 168
Klein, A. 14, 21
kleptoplasty 151
Kondev, J. 30
Koshland, D. 28
k-space 131

Lamarck, J. B. 106–7, 114–15

language, consciousness and 17
Language Models for Dialog Applications (LaMDA) xiii–xiv
last eukaryotic common ancestor (LECA) 62–63, 65–66
last universal common ancestor (LUCA) 19–20
laughing gas parties 139–40
learning 24–28, 47–48
Lemoine, B. xiii
Levin, M. xiv–xv, 9
life
coterminous with consciousness 45
definition 37–38
evolution as a key driver of life 51–52
materialistic holism (organicism) 52–53
minimal life 49–50
necessity of information 123–25
origin of life 38–42, 55–56
process-led definition 51
rules of life 45–49
as a verb 45
vitalism–mechanistic debate 43–45
LINE1 109
lipid theory of anaesthesia 142–43, 144–45
lipid world model 41–42
Loew ben Bezalel, J. xv–xvi
Long, C. W. 139–40
Lyon, P. 8, 21–22

MacKay, D. 91
Macnab, R. 28
Macphail, E. 17
Margulis, L. 7, 61
Masi, M. 51
materialistic holism 52–53
Mathis, R. 29
Maxwell’s demons 70–71, 79
Mazor, M. 164–65
mechanistic–vitalism debate 43–45
melatonin 74–75
memory 28–30, 47–48, 77–78, 120–21
metallome 86
Meyer, H. H. 142–43
Meyer–Overton rule 142–43
microbial mats 31
microbiome 118–19
microtubules 63–64, 71, 86
Mikhalevich, I. 169–70
Miller, W. B., Jr. 23
mimicry, plants 157–58
Mimivirus 42
minimal life 49–50
minimal selfhood 9
Mitchell, A. 27
Mitchell, P. 73
mitochondria, anaesthesia 143
mobilome 107–8, 121–22
Monod, J. 30
morality, see ethics and morality
morphogenesis 132
Morton, W. T. G. 139–40
mTOR 49–50
Müller, J. J. A. 12
multicellularity 6, 46, 47, 48, 49
cellular information cycle 97–98
cognitive stress-induced multicellularity 152–53
evolution 60–61, 62–63
N-space Episenome 128–33, 135–36
self-referential framework 97–98, 101–2
senomic micro-fields 83
multiple genesis hypothesis 42
multivesicular bodies 81

Nagel, T. 16–17
nanobrain 50
nano-intentionality 70
nano-protoplasts 70
navigational learning 26–27
neovitalism 44
nervous system, prerequisite for consciousness 2–5
neural crest cells 132
neurons
information validity 103
pattern learning 27–28
pollen tubes resembling 155
Ng, Y.-K. 167–68
niche construction 112
Nieder, A. 12
nitric oxide signalling 155
Noble, D. 115, 133
Noble, R. 133
noise 99–100
non-equilibrium principle 48
Norris, V. 7–8
Nowak, M. 51–52
N-space Episenome 81–82
consciousness 133–37
functional partitioning 135–36
multicellularity 128–33, 135–36
plants 160–61
self-identity 160–61
Nurse, P. 51–52

observer/participant effect 94–95

octopus consciousness 15–16
oocytes 153–54
Oparin, A. 38–39
optimality 49
orchids 157–58
organicism 52–53
Overgaard, M. 13–14
Overton, C. E. 141, 142–43
oxidation fields 82

pain sensitivity 168–69, 170–71

Pandoravirus 42
panspermia 43
Paracelsus xv–xvi
paralysis induction 148
Paramecium bursaria 153
party gas 139–40
Pasteur, L. 43
pattern learning 27–28
perceptual systems, unicellular species 22–24
Pereira, C. 7
peripersonal space 82
peroxiredoxins 68
Persat, A. 23
pervasive information fields 126–28, 134–35
phenotype 113, 117
photosynthesis 33–34, 57–58, 151–52
Physarum polycephalum 26, 27
planetary thermocycling 40
plants
action potentials 68–69
anaesthetic sensitivity 140, 141, 143, 159–60
ancient origin in algal protists 151–52
bioelectricity 158–59
bodyguards 157
carnivorous plants 159–60
cognition and behaviour 155–58
cognitive stress-induced multicellularity 152–53
electric field sensing 156
endogenous anaesthetic production 147–48
flowering plants 153–55
grass cutting 171, 172
hearing 155–56
mimicry 157–58
N-space Episenome 160–61
parasitic plants 155–56
photosynthesis 151–52
pollen tubes 155
pollinators 157–58
protist-like sex cells 153–55
pruning 170–71, 172–73
root–fungal networks 158–59
root systems 155–56
self-identity 160–61
self-pruning 170–71
 sentience 10, 151–61
sessile nature 151
stress as a negative experience 172–74
transgenerational memory 77–78
vision 153, 155–56, 158
plasma membrane 56, 58–59, 67–68, 71, 72–73, 78–81, 82–83, 136
pollen tubes 155
Ponte, G. 15–16
Portmore, D. 176
Powell, R. 169–70
precautionary principle 167–70
prediction 95
pressure reversal of anaesthesia 144
problem-solving 46–47, 113–14, 120
prohibitin homology domains 145
Pross, A. 2
proteins, anaesthesia 145–46
proteome 108
proto-cells 55–56
proto-consciousness 58–59
proton transport 56–59
protoplasm crowding 69–70
Pseudomonas aeruginosa 23
Putnam, H. xvi
pyramidal model consciousness 10–11

qualia 7–8, 100

quantum consciousness 7
quorum sensing (signalling) 31, 93

radioactive beach hypothesis 40

rapamycin 49–50
reactive clouds 82
reactive oxygen species 74–75
read–write genomic system 106, 107–8, 115–16, 117
reality creation 99–101
Reber, A. S. 168
reciprocation 47
recursion 47
Reddy, J. S. K. 7
redox code 57–58, 59–60, 68, 74–75
respiration 57–58
retroviruses 109
rhizoplast 61
ribosomes 69
RNA 59, 119
RNA world hypothesis 41, 42
rotary ATPases 84
Rozsa, M. 173
Saccharomyces cerevisiae 25, 27
Sagan, C. 51–52
Schrödinger, E. 37
Searle, J. xvi–xvii
sea slugs 151
self-identity 28, 62, 110, 113–14, 120, 160–61
self-integrity 113–14
selfish gene 112, 119–20
self-organization 69–70
self-preservation 48
self-referential information 47, 94–95, 97–98, 99, 101–2, 103, 121, 123–24, 125, 134–35, 136
self-repair 48
self-similarity 102
Selye, H. 147–48
senome 59, 72–73, 80–83, 128, 135
sensory systems 22–24, 70–71
sentience, law of 47–48
Shannon information 90–91
Shapiro, J. A. 9
Sharp, C. 33
sleep 34
socialization xx
Sonner, J. M. 141, 148
sperm cells 153–55
sponges 153–55
spontaneous generation of life 43
stable non-equilibrium principle 48
Standard Model of Consciousness 2–5, 164–65
Stentor roeselii 25–26
stochasticity of information 99–100, 117
stress
as a negative experience in plants 172–74
stress-induced analgesia 147–48
stress-induced multicellularity 152–53
submarine hydrothermal vents 41
Süel, G. 32–33, 113–14
superposition 121
survival, law of 48
synaptic vesicles 79
syncope 148
Synechococcus elongatus 34
Szent-György, A. 100–1
Szilard macromolecule engine 71

Tagkopoulos, I. 27
Tavazoie, S. 25
temporal awareness 33–34, 60, 68
thanatosis 148
third state information 95
Thomas, L. 38
thought experiments xvi–xvii, 166
time sharing 32–33
Tomasik, B. 8–9
tools, cellular 112–19
transposable elements (TEs) 107, 108–9, 116–17
trolley problem thought experiment 166
tubulin-based cytoskeleton 73–74
Turin, L. 146

uncertainty relation 97
unicellular organisms
communication 31–33
decision-making 30–31
fatigue 34
learning 24–28
memory 28–30
sensitivity to anaesthetics 141
sensory and perceptual systems 22–24
temporal awareness 33–34
thanatosis 148
utilitarianism 165–67

V-ATPases 84
Vavilovian mimicry 158
vegetarianism and veganism 174–75
vesicles 55–56, 78–81, 83
viruses
cellular engineering 113, 116–17
form of life 50
genetic memory modification 118
key players in cellular evolution 64–66
retroviruses 109
transposable elements (TEs) 108–9
virus world hypothesis 42
vision, plants 153, 155–56, 158
vitalism–mechanistic debate 43–45

Waddington, C. H. 107
Warren, J. 139–40
Wilson, C. 15
wisdom of cells 96–97

xenon 146

Yang, J. 25

zinc world hypothesis 41