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Searching for a Mechanism
A History of Cell Bioenergetics
John N. Prebble
3
1
Oxford University Press is a department of the University of Oxford. It furthers
the University’s objective of excellence in research, scholarship, and education
by publishing worldwide. Oxford is a registered trade mark of Oxford University
Press in the UK and certain other countries.
Published in the United States of America by Oxford University Press

198 Madison Avenue, New York, NY 10016, United States of America.
© Oxford University Press 2019
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a retrieval system, or transmitted, in any form or by any means, without the
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rights organization. Inquiries concerning reproduction outside the scope of the
above should be sent to the Rights Department, Oxford University Press, at the
address above.
You must not circulate this work in any other form

and you must impose this same condition on any acquirer.
Library of Congress Cataloging-in-Publication Data

Names: Prebble, J. N. (John N.), author.
Title: Searching for a mechanism : a history of cell bioenergetics / by John N. Prebble.
Description: New York, NY : Oxford University Press, 2019. |
Includes bibliographical references and index.
Identifiers: LCCN 2018023975 | ISBN 9780190866143
Subjects: LCSH: Bioenergetics—History.
Classification: LCC QH510.P74 2018 | DDC 572/.43—dc23
LC record available at https://lccn.loc.gov/2018023975
1 3 5 7 9 8 6 4 2
Printed by Sheridan Books, Inc., United States of America

In memory of Peter Mitchell (1920–1992), whose genius laid the foundation for the
revolution in our understanding of cell bioenergetics.
To Pat
Contents
Preface xi
Acknowledgments xv
List of Abbreviations xvii
1. Introduction: Respiration, phosphorylation, and mechanism 1

1.1 Respiration, photosynthesis, and bioenergetics 2
1.2 Vitalism 3
1.3 Historical questions 5
1.4 Phosphorylation 13
1.5 Mechanisms 14
1.6 The relevance of cell bioenergetics to the question of mechanism 15
2. From physiology to biochemistry: Respiration and oxidation from 1600 to 1900 17

2.1 Initiation of the experimental study of respiration 18
2.2 John Mayow’s Tractatus Quinque 20
2.3 Stephen Hales’s Vegetable Staticks 22
2.4 Respiration and combustion 23
2.5 The location of respiration 26
2.6 Thermodynamic questions 28
2.7 Bernard’s criticism of slow combustion 31
2.8 Hofmeister’s integration of cell biology 32
2.9 O2 and oxidation 33
2.10 Spectroscopy, hemoglobin, and animal pigments 35
2.11 Cell-free systems 38
3. Relating phosphorylation, respiration, and oxidation: 1900–1945 41

3.1 Resolving nineteenth-century questions 41
3.2 Achievements of the first half of the twentieth century 42
3.3 Yeast and animal juices: The importance of phosphate 43
3.4 Thunberg, Wieland, and the nature of biological oxidation 47
3.5 Warburg’s Atmungsferment 51
3.6 Keilin’s cytochrome 54
3.7 DPN (NAD) and its oxidation 59
3.8 Muscle, lactic acid, and energy 61
3.9 Adenosine triphosphate and muscle phosphates 62
3.10 Aerobic ATP synthesis: Engelhardt and Kalckar 65
vii
3.11 Phosphorylation linked to respiration: Belitzer and Ochoa 68
3.12 Lipmann: The significance of phosphorylation 69
4. Emergence of the field of cell bioenergetics: 1945–1960 73

4.1 Emergence of a new field 73
4.2 The mitochondrion as the location of respiratory activity 74
4.3 Further elucidation of the respiratory chain 76
4.4 Phosphorylation 82
4.5 Sites for phosphorylation 85
4.6 Seeking to understand the mechanism of phosphorylation 87
4.7 The phosphorylating enzyme 91
4.8 Fragmenting mitochondria 91
4.9 Physiological aspects of mitochondria 94
5. Defining the mechanism: 1960–1977 97

5.1 What mechanism? 97
5.2 The first proton theory: Robert J. P. Williams 99
5.3 The chemiosmotic hypothesis of Peter Mitchell 100
5.4 Revising the respiratory chain 104
5.5 Exploring the ATP synthase 108
5.6 Reconstituting oxidative phosphorylation 111
5.7 Bacteriorhodopsin 112
5.8 Conformational theories 113
5.9 Mitochondrial membranes 117
5.10 Ion movements across the mitochondrial membrane 119
5.11 Resolving the mechanism 122
6. Discovering photosynthesis 128

6.1 The development of ideas on photosynthesis 128
6.2 Initial studies of photosynthesis 129
6.3 The importance of water and CO2 131
6.4 Energy 132
6.5 Discovering chlorophyll and chloroplasts 133
6.6 Understanding the nature of photosynthesis 137
6.7 Photosynthetic bacteria and an oxidation–reduction mechanism 139
6.8 Light and dark reactions 141
6.9 O2 evolution and the Hill reaction 143
6.10 CO2 assimilation 146
6.11 Discovering photophosphorylation 149
7. Elucidating the photosynthetic light reaction 154

7.1 The fourth period of photosynthetic history 154
7.2 Seeking a coherent model of photosynthesis 155
7.3 The photosynthetic unit 158
viii Contents
7.4 Two light reactions and a reaction center 161
7.5 The Z-scheme and two photosystems 162
7.6 The contribution from bacterial photosynthesis 167
7.7 The chloroplast electron-transport chain 171
7.8 Chloroplast photophosphorylation 175
8. The impact of protein technology: 1977–1997 181

8.1 The fifth period of investigation 181
8.2 The chemiosmotic mechanism for oxidative and photosynthetic
phosphorylation 182
8.3 The Q cycle 183
8.4 Stoichiometric problems in mitochondria 186
8.5 Uncoupling and uncoupling proteins in mitochondria 188
8.6 Bacteriorhodopsin, a bioenergetic protein 190
8.7 Understanding the respiratory chain 194
8.8 Elucidating the mechanism of respiratory chain complexes 195
8.9 Photosynthetic complexes 200
8.10 Adenine nucleotide transport 205
8.11 The ATP synthase 207
9. The search for mechanism 214

9.1 Photosynthetic and oxidative biochemistry—the relationship 214
9.2 The course of bioenergetics history 216
9.3 Does methodology drive bioenergetics? 218
9.4 The significance of the membrane 223
9.5 Membrane proteins 224
9.6 The concept of mechanism 225
9.7 Revolution, hypothesis, and crisis 229
9.8 Resolving the crisis: Accepting the chemiosmotic theory 233
References 237
Index 267
Contents ix
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Preface
The twentieth century saw the elucidation of many of the fundamental problems of the
biological sciences. A major achievement was the development of metabolic biochem-
istry. However, within this general field, one of the most significant challenges was the
endeavor to understand the mechanisms of bioenergetics. The complexity of this field be-
came apparent when the links between the mechanisms of various processes in oxidative
phosphorylation, photosynthesis, and cellular transport across membranes began to be
appreciated. These areas had previously been studied independently, but in the middle of
the century their relationships were increasingly understood and the term bioenergetics
was often used to cover the emerging field.
Biologists have been concerned with mechanisms for several centuries, but with the
development of modern methods, the significance of the term mechanism has been
recognized. Philosophers, in a rather different way, have long had an interest in mech-
anism but this has been revitalized in recent times with the application of this concept
to the philosophy of the biological sciences. So the idea of searching for a mechanism
seems to be particularly appropriate to the consideration of the history of scientific
studies about respiration. These developed through basic issues of metabolism to the
crunch question of how cells acquire their energy from the oxidation of foodstuffs such
as carbohydrates. Here I trace the history of the search for mechanisms in a group of key
biological fields that progressively merged toward the end of the twentieth century. This
study is not intended to add to the philosophical ideas on mechanism, but rather to see
the way in which mechanisms in one specific area were elucidated over time, from the
early seventeenth to the end of the twentieth century.
Few problems have taxed biologists as much as the fundamental mechanisms of bio-
energetics. This book is designed partly to explore the often-heated debates particularly
in the 1960s and 1970s, when theories and experimental interpretations in bioenergetics
were fought over so passionately that the period was known by some as the Ox phos wars.
It is also intended to place this important period in biological research in its historical
setting. Thus the story of what is now known as bioenergetics is traced from the first ex-
perimental studies of respiration and photosynthesis in the enlightenment of the seven-
teenth and eighteenth centuries to the modern period. The climax of the account comes
in the brilliant resolution of the mechanism of adenosine triphosphate (ATP) synthesis
in animals, plants, and microorganisms by the proton-translocating ATP synthase at the
end of the twentieth century. Such a history reflects the history of biology as a whole as it
moved from a primarily observational study to the highly technical investigations of the
second half of the twentieth century.
xi
Like most history, writing a science history raises questions about defining the
margins of the discussion both in time and in subject matter. A major issue has been
where to start. In his history of respiration, David Keilin went back to the second-century
Greek physician and philosopher Galen. I have chosen to start with a brief discussion
of seventeenth-century ideas, when a truly experimental approach to the study of res-
piration was initiated. The photosynthesis story is best begun at the beginning of the
eighteenth century with the work of Stephen Hales, whose ideas also contributed to the
respiration story. I have concluded the story at the end of the twentieth century with a
discussion of the enzyme-synthesizing ATP because of its innate interest and because it
demonstrated an important result of the search for mechanism. The scope of the book
has been slightly narrow, being confined to the discussion of respiration, oxidative, and
related aspects of phosphorylation, photosynthesis, and cognate areas, such as facets of
membrane transport and specific issues in microbial biochemistry. Fields such as mus-
cular contraction, which might arguably have been included in a discussion of bioener-
getics history, have been mostly omitted and similarly some areas of microbial energetics.
Of course, restrictions of space have entailed selecting issues to which particular at-
tention should be given in order to maintain a comprehensible narrative, and this has
necessitated some rather difficult choices. Thus judgments have had to be made about
which particular scientific contributions should be included, which contributions should
be seen as central to the history of bioenergetics, and which might be set aside in order
to focus on the major lines of development. This is particularly so in the later part of
the twentieth century in which there is a vast amount of material and a wide range of
approaches to the subject. Inevitably many rather personal choices have been made.
I apologize to those who feel that important aspects of the subject have been omitted or
that the work of particular scientists who made valuable contributions has been ignored
or should have been given more weight. Another issue that has emerged arises from the
nature of the field of bioenergetics that has been noted for its lack of consensus. Although
I have covered most of the most obvious disagreements in my discussion I have been
advised that in some more recent research, I may not have been sufficiently sensitive to
the varying viewpoints. I apologize to those who feel I have misrepresented particular
aspects of their interests.
The history has been divided into several phases, each initiated by a major advance
often outside the field of bioenergetics and affecting biochemistry more generally. These
phases do not have broad applicability as the phases I have recognized for respiration and
phosphorylation are not identical with those identified for photosynthesis. After having
much in common at the beginning, the two areas of study have tended to proceed sep-
arately, partly because the events associated with the light reaction had no counterpart
in animal cell respiration. However, in the second half of the twentieth century, the two
fields have been more or less merged in the field of bioenergetics. Indeed it is not possible
to consider the one without the other as each has made major contributions to the other.
In telling this story I have felt it right to make points through appropriate quotations
of the leading workers in the field. This allows the historical figures to be heard. However,
in the later period this becomes more difficult; frequently a wide variety of workers
are jointly developing the field, and a somewhat random choice has been made. I have
also attempted to minimize the technical aspects as much as possible, although it is not
xii Preface
possible to describe the development of ideas in a subject such as biochemistry without
recourse to a certain amount of chemistry. Further, in the later stages, the use of highly
complex techniques has been discussed without much explanation of what is actually
involved.
What is the justification for a book on the history of cell bioenergetics? The history
of science is a discipline in which it is important that both historians and scientists par-
ticipate. This story is told by a scientist in the hope that his approach will provide some
illumination on an area generally enlightened by contributions of historians and also
philosophers. What I have sought to do here is to give a coherent though brief account
of the history of those events associated with the energetics of cell respiration and pho-
tosynthesis over more than three centuries. There is already a widely acclaimed book by
Joseph Fruton on the history of biochemistry as well as the extensive account by Marcel
Florkin; both of these present aspects of bioenergetics within a broad discussion of bio-
chemistry but do not give it the detailed attention it deserves. There have been a number
of essays on specific events and short periods of biochemical history but there is clearly
a need to put all of these within a broad historical perspective. That perspective also
illustrates some of the effects of the major developments in the chemical aspects of bio-
logical science, the preparation of cell-free systems at the turn of the twentieth century,
the ability to describe metabolic pathways, the development of techniques for handling
membrane proteins, and so on. However, the justification for the book is in my view the
need for a history of bioenergetics comparable to that of Michel Morange’s A History of
Molecular Biology. I hope I have come some way in achieving that goal.
But why single out bioenergetics? Metabolic biochemistry developed only slowly in
the earlier part of the twentieth century, but its achievements were substantial—the gly-
colytic pathway, the citric acid cycle, and so on. The same period began to identify aer-
obic phosphorylation as a major source of ATP but the mechanism was not apparent. By
the 1950s it was clear that there was a challenging problem to solve. The difficulties in
finding a solution, the choice between different hypotheses, and the problem of success-
fully working with membranes provide interesting historical developments not as ap-
parent in other areas of metabolic biochemistry. Such problems were solved by bringing
together quite diverse researches, many drawn from cell biology. Thus the roots of this
endeavor are to be found in several almost independent lines of research that come to-
gether to create the field in the 1950s. Such a story surely needs to be told.
I came into the study of bioenergetics in the 1960s, a most exciting period in the
history of this field. I am grateful to those who encouraged me in this early period,
particularly Dudley Cheesman, who taught me the value of the historical approach to
biochemistry, to my colleagues Peter Zagalsky and particularly John Lagnado, who
encouraged me to take up the teaching of bioenergetics in the single Honours bio-
chemistry course at Bedford College, University of London. An abiding inspiration
from that period was the occasional lectures of Peter Mitchell that sparked my enthu-
siasm for the subject. I should also record my appreciation of brief but sound advice
on writing science history from my friend of student days, Bob Olby. I am grateful
to colleagues who kindly read part or most of the manuscript and provided valuable
comment, Bruce Weber and Peter Rich and also Ann Marshall. I also wish to rec
ord my appreciation of the detailed and constructive comments of two anonymous
Preface xiii
reviewers and the staff of the Oxford University Press. Finally, I wish to record my
immense debt to my wife, Pat, who has encouraged me over the years and who has had
the patience to read and reread my manuscript.
John N. Prebble
School of Biological Sciences
Royal Holloway, University of London
November 2017
xiv Preface
Acknowledgments
I wish to express my appreciation to Professor Mikuláš Teich for permission to reproduce

several textual extracts from his A Documentary History of Biochemistry 1770–1940.
I wish to record my thanks to those who gave me photographs for my earlier book on
the subject and that I have reused here, Professor Stanley Bullivant (Fig. 4.1), Professor
Humberto Fernández-Morán (Fig. 5.4), Professor Lester Packer (Fig. 5.6), and Dr. Jean
Whatley (Fig. 7.1).
I acknowledge the permission to reproduce figures by the American Chemical Society
(Fig. 8.5), Elsevier (Figs. 5.6, 6.6, 7.2, and 8.3), Glynn Research Ltd. (Fig. 8.1), Nature
Publishing Ltd. (Figs. 7.4, 8.4, and 8.6), Oxford University Press (Figs. 3.9 and 3.10),
Pearson Educational Ltd. (Figs. 4.1b and 7.1), Rockefeller University Press (Figs. 5.4 and
5.5), Springer (Figs. 6.1, 6.4, and 8.7), and Wiley (Fig. 3.15).
xv
Abbreviations
Δψ membrane potential
Δp proton motive force
ADP adenosine diphosphate
ATP adenosine triphosphate
ATPase adenosine triphosphatase, ATP synthase
BChl bacteriochlorophyll
Bph bacteriopheophytin
Chl chlorophyll
CoA coenzyme A
Cu copper
Cyt cytochrome
DCPIP dichlorophenol indophenol
DCMU dichlorophenyldimethylurea
DNA deoxyribonucleic acid
DNP dinitrophenol
DPN, DPNH diphosphopyridine nucleotide, oxidized and reduced, respectively
(also known as NAD, NADH)
Em midpoint potential
EPR electron paramagnetic resonance
ETP electron-transport particle
Fo, F1 the two major components of the ATP synthase (ATPase)
FAD flavin adenine dinucleotide
Fd ferredoxin
Fe-S iron-sulfur center or protein
FMN flavin adenine mononucleotide
Fp flavoprotein
GDP guanosine diphosphate
GTP guanosine triphosphate
[H]‌ reducing equivalent
Mn manganese
NAD, NADH nicotinamide adenine dinucleotide, oxidized and reduced, respec-
tively (also known as DPN, DPNH, or coenzyme I)
NADP, NADPH nicotinamide adenine dinucleotide phosphate, oxidized and
reduced, respectively (also known as TPN, TPNH, or coenzyme II)
P680, P700, P870 reaction center pigments
PC plastocyanin
xvii
PETP phosphorylating ETP
Pi inorganic phosphate
PMF proton motive force
PQ plastoquinone
PSI, PSII photosystems I and II, respectively
Q quinone (as in Q-cycle), used for ubiquinone also to denote electron
acceptor for PSII
SDS sodium dodecyl sulfate
TPN, TPNH triphosphopyridine nucleotide, oxidized and reduced, respectively
(also known as NADP and NADPH)
UCP uncoupling protein
X electron acceptor for PSI
Z electron donor for PSII
xviii Abbreviations
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1
Introduction
Respiration, Phosphorylation, and Mechanism
Toward the end of the Second World War, just before the development of much modern
biology began, the Austrian physicist Erwin Schrödinger (1887–1961) considered, in a
small influential book, what were the essential features of life?1 His prime concern was
what might be described as the genetic aspect, but his other major concern was with
energy. The former aspect, which has been well documented, became the molecular bi-
ological revolution and has been a major subject of interest for historians of biology.
Because it developed simultaneously, the bioenergetics revolution was overshadowed by
the development of molecular biology. So, it has been largely overlooked although re-
cently the Belgian cell biologist and Nobel Laureate2 Christian De Duve (1917–2013)
drew attention to what he referred to as “the other revolution in the life sciences,” that
concerning cell bioenergetics.3 Indeed De Duve felt that the energetic aspect is arguably
as fundamental as the information element and in fact preconditions it.4 This history is
an attempt to rebalance the view of biology so that those cellular processes that provide
the energy for life are brought into sharper focus.
The story of cell bioenergetics is primarily concerned with the synthesis of adenosine
triphosphate (ATP), sometimes referred to as the energy currency of the cell.
Its central theme is the processes of oxidative phosphorylation and photo
phosphorylation, whose mechanisms remained obscure for many years. Indeed, un-
derstanding oxidative phosphorylation and photophosphorylation proved to require an
appreciation of the energetics of other aspects of cellular processes, particularly those
1
Schrödinger 1944. Schrödinger shared the Nobel Prize in physics in 1933 “for the discovery of
new productive forms of atomic theory”
2
The Nobel Prize in Physiology or Medicine for 1974 was awarded jointly to Albert Claude,
Christian De Duve, and George E. Palade “for their discoveries concerning the structural and
functional organisation of the cell”
3
De Duve 2013.
4
An unusual approach to this relationship between molecular biology and photosynthesis has
been provided by Doris Zallen (1993a) who, when considering the bioenergetics of photosyn-
thesis, felt that this field of study should logically be included within molecular biology. This view
was based on a rather general set of criteria for defining “molecular biology” that were then seen
to cover the molecular side of photosynthesis research since about 1920. This does not sit com-
fortably with the history of photosynthesis and is not pursued further here.
1
associated with membranes and membrane transport so that the field can readily be re-
ferred to as cell bioenergetics. In fact, the term bioenergetics was probably not introduced
into the field until Albert Szent-Györgyi published a small book under that title in 1957;
it was also similarly used by Albert Lehninger in 1963 and came into more general use at
about that time, although some thought it was “too flashy”!5 Nevertheless, after the field
had become well established in the 1950s, specialist journals began to appear. A dedi-
cated set of volumes within the journal Biochimica et Biophysica Acta was published from
1968 onward, known simply as BBA Bioenergetics. In 1973 BBA Reviews in Bioenergetics
began publication. A totally independent journal, The Journal of Bioenergetics6 was
produced from 1970 onward. These journals dealt with problems of photosynthesis
as well as oxidative phosphorylation, although specialist photosynthetic journals also
emerged around the same time.7
1.1 RESPIRATION, PHOTOSYNTHESIS,

AND BIOENERGETICS
This history commences with the work of those in the seventeenth century who sought
to understand the process of breathing and passes through metabolic biochemistry,
concluding with the elucidation of the molecular mechanisms of key enzymes in bioen-
ergetics. Although the story of metabolic biochemistry (which is often taken to include
bioenergetics) essentially belongs to the twentieth century, progress in this area cannot
be understood without recourse to previous centuries. Thus from the seventeenth cen-
tury onward it is possible to trace a path of early thinking that eventually laid the ground-
work for the dramatic success of twentieth-century studies.
In the seventeenth century, the development of a fruitful experimental approach to
science opened new possibilities. A new generation of those perhaps best described as
experimental natural philosophers began to pursue physiological issues including the
mechanism of respiration. Such activities also expressed themselves in the founding of
the Royal Society in 1660 in England and in France the Académie Royale des Sciences in
1666. These early physiologists initially investigated questions concerned with breathing,
but this quickly led to others about the role of air and its influence on the properties of
blood. It was particularly the chemical revolution at the end of the eighteenth century
that combined with these early studies on respiration to provide a serious field of respi-
ration for the nineteenth and early twentieth centuries. However, prior to the twentieth
century principally physiologists and chemists led the field. Thus I start the discussion in
the seventeenth century, although others such as David Keilin and Marcel Florkin have
traced the influence of the classical world, especially Aristotle and Galen, on this period.
The story of photosynthesis can similarly be traced back to the beginning of the eight-
eenth century when it shares some of the same origins as studies on respiration. However,
5
See Edsall 1973; Lehninger 1965.
6
This later became the Journal of Bioenergetics and Biomembranes.
7
Photosynthetica began publication in 1967 and Photosynthesis Research in 1980. Earlier work
on photosynthesis had tended to be published in journals of plant physiology.
2 Searching for a Mechanism

the development of the field in the nineteenth century is much dominated by questions
about the role of light and chlorophyll, thus following a path independent of respira-
tion. The second half of the twentieth century brought the realization that many of the
problems faced by those working on photosynthesis are similar to those in oxidative
phosphorylation, and this resulted in the two streams coming together, so justifying the
treatment of both histories as one.
The history of respiration has been explored by others, including the Cambridge bi-
ochemist David Keilin (1887–1963), who first formulated the respiratory chain, and the
Belgian biochemist Marcel Florkin (1900–1979); they have probed earlier issues in more
detail than I have.8 However, in general they have not pursued questions relating to bio-
energetics, although there is a good introduction in Florkin.
1.2 VITALISM
This history is concerned with those who sought to establish the mechanisms that un-
derlie the process of respiration and later the conservation of metabolic energy as ATP
together with those operative in photosynthesis. In all this, there is an underlying as-
sumption that the processes being discussed can be understood in terms of the chemical
and physical sciences. The quest for mechanism has been primarily an attempt to ex-
plain the relevant cellular processes more or less exclusively in terms of normal labora-
tory investigation. Thus there is no need to resort to the concept of a vital principle or a
vital force in order to explain the operation of living things. Such ideas hold that some
processes that are part of living things but are not evident in the nonliving lie beyond
the realm of laboratory science. Particularly in the nineteenth century, many scientists
invoked the idea of vital forces in order to explain the mysterious properties of living
things; such vital forces did not appear to be open to normal scientific investigation. The
idea seemed necessary when nineteenth-century advances in the physics and chemistry
of the inanimate world did not seem to be capable of application to living things.
The idea that living things possess a quality that cannot be explained in material
terms can be traced back to Aristotle. It was suggested that there was something spe-
cial about living things that distinguished them from the inorganic world, a view pre-
sent through most of scientific history. In essence it was the question as to whether
living organisms could be explained in terms of chemistry and physics without re-
course to vitalistic ideas.
During the eighteenth century, the idea of a vital force developed in order to explain
the inability to replicate living processes in the laboratory. As physicist and physiologist
Hermann von Helmholtz (1821–1894) put it in 1861,
The majority of the physiologists in the last century [eighteenth century], and
in the beginning of this century, were of opinion that the processes in living
8
The discussion here is only brief. Readers are referred to the coverage of nineteenth-century
respiration and related issues in Florkin (1972, 1975a), Fruton (1999), Keilin (1966), Needham
(1971), and Teich (1992).
Introduction 3
bodies were determined by one principal agent, which they chose to call the vital
principle.9
The precise meaning attached to the terms vital force or vital principle varied from au-
thor to author, but it became an integral part of biological and chemical thinking. One
of the leading German chemists of the mid-century, Justus von Liebig (1803–1873), pro-
fessor of chemistry at Giessen, Germany, wrote in his Animal Chemistry,
Viewed as an object of scientific research, animal life exhibits itself in a series

of phenomena, the connection and recurrence of which are determined by the
changes which the food and the oxygen absorbed from the atmosphere undergo
in the organism under the influence of the vital force.10
Here vitalistic ideas are used to explain those aspects of the living that cannot be explained
by the use of chemistry and physics.
But toward the end of the nineteenth century, the belief that materials were produced
in the organs under the influence of the vital force was being challenged. By 1878, Claude
Bernard (1813–1878) was strongly opposing vitalism and questioned Liebig’s previous
statement and asked what is this vital force?
The chemistry of the laboratory and the chemistry of the living body are sub-
ject to the same laws; there are not two chemistries; this Lavoisier said. Only the
chemistry of the laboratory is carried out by means of agents and apparatus that
the chemist has created while the chemistry of the living being is carried out by
agents and apparatus that the organism has created.11
Many developments at the end of the nineteenth century and at the beginning of the
twentieth century challenged the vitalist’s approach, such as the demonstration that the
process of yeast fermentation could be shown outside the living cell, the isolation of
enzymes, and so on.
Thus, by the beginning of the twentieth century, there was a prevailing view that the
functioning of biological systems could be explained in terms of chemistry and physics
and that biological systems were fully open to scientific investigation. True, vitalism was
not quite dead, but it was certainly in terminal decline.
So even in 1912, Sir Frederick Gowland Hopkins (1861–1947), one of the founders of
modern biochemistry, could talk about the “spectre of vitalism” in his classic paper to the
British Association.12 Indeed it was at the end of this paper that Hopkins expressed his
9
Helmholtz 1861, p.120.
10
Liebig 1842, p.9.
11
Bernard 1878, p.161. Although Bernard’s anti-vitalist view is strongly expressed here in this
late lecture, earlier notes suggest that his view on vitalism was much more ambivalent in his
earlier years. (See Holmes 1974, p.407.)
12
Hopkins 1913, p.159.
4 Searching for a Mechanism

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of comparison is necessary to constitute it does not touch the
question of its possibility. However we come to have it, however
reducible to impressions the objects may be, it is not only other than
the idea of either object taken singly; it is not, as an idea of
resemblance might be supposed to be, constituted by the joint
presence or immediate sequence upon each other of the objects.
Here, then, is an idea which is not taken either from an impression
or from a compound of impressions (if such composition be
possible), and this idea is ‘the source of all our reasonings
concerning matters of fact.’
The comparison is between present and past experience of

succession of objects.
299. The modern followers of Hume may perhaps seek refuge in

the consideration that though the relation of cause and effect
between objects is not one in the way of resemblance or one of
which the idea is given by comparison of the objects, it yet results
from comparisons, which may be supposed to act like chemical
substances whose combination produces a substance with properties
quite different from those of the combined substances, whether
taken separately or together. Some anticipation of such a solution, it
may be said, we find in Hume himself, who is aware that from the
repetition of impressions of sense and their ideas new,
heterogeneous, impressions—those of ‘reflection’—are formed. Of
this more will be said when we come to Hume’s treatment of cause
and effect as a ‘natural relation.’ For the present we have to enquire
what exactly is implied in the comparisons from which this
heterogeneous idea of relation is derived. If we look closely we shall
find that they presuppose a consciousness of relations as little
reducible to resemblance, i.e. as little the result of comparison, as
that of cause and effect itself. It has been already noticed how
Hume treats the judgment of proportion between figures as a mere
affair of sense, because such relation depends entirely on the ideas
compared, without reflecting that the existence of the figures
presupposes those relations of space to which, because (as he
admits) they do not depend on the comparison of ideas, the only
excuse for reckoning any relation sensible does not apply. In the
same way he contents himself with the fact that the judgment of
cause and effect implies a comparison of present with past
experience, and may thus be brought under his definition of
‘philosophical relation,’ without observing that the experiences
compared are themselves by no means reducible to comparison. We
judge that an object, which we now find to be precedent and
contiguous to another, is its cause when, comparing present
experience with past, we find that it always has been so. That in
effect is Hume’s account of the relation, ‘considered as a
philosophical one:’ and it implies that the constitution of the several
experiences compared involves two sorts of relation which Hume
admits not to be derived from comparison, (a) relation in time and
place, (b) relation in the way of identity.
Observation of succession already goes beyond sense.
300. As to relations in time and space, we have already traced out

the inconsistencies which attend Hume’s attempt to represent them
as compound ideas. The statement at the beginning of Part III., that
they are relations not dependent on the nature of compared ideas, is
itself a confession that such representation is erroneous. If the
difficulty about the synthesis of successive feelings in a
consciousness that consists merely of the succession could be
overcome, we might admit that the putting together of ideas might
constitute such an idea of relation as depends on the nature of the
combined ideas. But no combination of ideas can yield a relation
which remains the same while the ideas change, and changes while
they remain the same. Thus, when Hume tells us that ‘in none of the
observations we may make concerning relations of time and place
can the mind go beyond what is immediately present to the senses,
to discover the relations of objects’ [1] the statement contradicts
itself. Either we can make no observation concerning relation in time
and place at all, or in making it we already ‘go beyond what is
immediately present to the senses,’ since we observe what is neither
a feeling nor several feelings put together. If then Hume had
succeeded in his reduction of reasoning from cause or effect to
observation of this kind, as modified in a certain way by habit, the
purpose for which the reduction is attempted would not have been
attained. The separation between perception and inference, between
‘intuition’ and ‘discourse,’ would have been got rid of, but inference
and discourse would not therefore have been brought nearer to the
mere succession of feelings, for the separation between feeling and
perception would remain complete; and that being so, the question
would inevitably recur—If the ‘observation’ of objects as related in
space and time already involves a transition from the felt to the
unfelt, what greater difficulty is there about the interpretation of a
feeling as a change to be accounted for (which is what is meant by
inference to a cause), that we should do violence to the sciences by
reducing it to repeated observation lest it should seem that in it we
‘go beyond’ present feeling?
[1] P. 376. [Book I, part III., sec. II.]
As also does the ‘observation concerning identity,’ which the

comparison involves.
301. Relation in the way of identity is treated by Hume in the third
part of the Treatise [1] pretty much as he treats contiguity and
distance. He admits that it does not depend on the nature of any
ideas so related—in other words, that it is not constituted by feelings
as they would be for a merely feeling consciousness—yet he denies
that the mind ‘in any observations we may make concerning it’ can
go beyond what is immediately present to the senses. Directly
afterwards, however, we find that there is a judgment of identity
which involves a ‘conclusion beyond the impressions of our senses’—
the judgment, namely, that an object of which the perception is
interrupted continues individually the same notwithstanding the
interruption. Such a judgment, we are told, is a supposition founded
only on the connection of cause and effect. How any ‘observation
concerning identity’ can be made without it is not there explained,
and, pending such explanation, observations concerning identity are
freely taken for granted as elements given by sense in the
experience from which the judgment of cause and effect is derived.
In the second chapter of Part IV., however, where ‘belief in an
external world’ first comes to be explicitly discussed by Hume, we
find that ‘propensities to feign’ are as necessary to account for the
judgment of identity as for that of necessary connection. If that
chapter had preceded, instead of following, the theory of cause and
effect as given in Part III., the latter would have seemed much less
plain sailing than to most readers it has done. It is probably because
nothing corresponding to it appears in that later redaction of his
theory by which Hume sought popular acceptance, that the true
suggestiveness of his speculation was ignored, and the scepticism,
which awakened Kant, reduced to the commonplaces of inductive
logic. To examine its purport is the next step to be taken in the
process of testing the possibility of a ‘natural history’ of knowledge.
Its bearing on the doctrine of cause will appear as we proceed.
Identity of objects an unavoidable crux for Hume. His account of

it.
302. The problem of identity necessarily arises from the fusion of

reality and feeling. We must once again recall the propositions in
which Hume represents this fusion—that ‘everything which enters
the mind is both in reality and appearance as the perception;’ that
‘so far as the senses are judges, all perceptions are the same in the
manner of their existence;’ that ‘perceptions’ are either impressions,
or ideas which are ‘fainter impressions;’ and ‘impressions are internal
and perishing existences, and appear as such.’ If these propositions
are true—and the ‘new way of ideas’ inevitably leads to them—how
is it that we believe in ‘a continued existence of objects even when
they are not present to the senses,’ and an existence ‘distinct from
the mind and perception’? They are the same questions from which
Berkeley derived his demonstration of an eternal mind—a
demonstration premature because, till the doctrine of ‘ideas,’ and of
mind as their subject, had been definitely altered in a way that
Berkeley did not attempt, it was explaining a belief difficult to
account for by one wholly unaccountable. Before Theism could be
exhibited with the necessity which Locke claimed for it, it was
requisite to try what could be done with association of ideas and
‘propensities to feign’ in the way of accounting for the world of
knowledge, in order that upon their failure another point of
departure than Locke’s might be found necessary. The experiment
was made by Hume. He has the merit, to begin with, of stating the
nature of identity with a precision which we found wanting in Locke.
‘In that proposition, an object is the same with itself, if the idea
expressed by the word object were no ways distinguished from that
meant by itself, we really should mean nothing.’ ‘On the other hand,
a multiplicity of objects can never convey the idea of identity,
however resembling they may be supposed. … Since then both
number and unity are incompatible with the relation of identity, it
must lie in something that is neither of them. But at first sight this
seems impossible.’ The explanation is that when ‘we say that an
object is the same with itself, we mean that the object existent at
one time is the same with itself existent at another. By this means
we make a difference betwixt the idea meant by the word object and
that meant by itself without going the length of number, and at the
same time without restraining ourselves to a strict and absolute
unity.’ In other words, identity means the unity of a thing through a
multiplicity of times; or, as Hume puts it, ‘the invariableness and
uninterruptedness of any object through a supposed variation of
time’. [1]
[1] Pp. 489, 490. [Book I, part IV., sec. II.]
Properly with him it is a fiction, in the sense that we have no such

idea. Yet he implies that we have such idea, in saying that we
mistake something else for it.
303. Now that ‘an object exists’ can with Hume mean no more
than that an ‘impression’ is felt, and without succession of feelings
according to him there is no time. [1] It follows that unity in the
existence of the object, being incompatible with succession of
feelings, is incompatible also with existence in time. Either then the
unity of the object or its existence at manifold times—both being
involved in the conception of identity—must be a fiction; and since
‘all impressions are perishing existences,’ perishing with a turn of the
head or the eyes, it cannot be doubted which it is that is the fiction.
That the existence of an object, which we call the same with itself, is
broken by as many intervals of time as there are successive and
different, however resembling, ‘perceptions,’ must be the fact; that it
should yet be one throughout the intervals is a fiction to be
accounted for, Hume accounts for it by supposing that when the
separate ‘perceptions’ have a strong ‘natural relation’ to each other
in the way of resemblance, the transition from one to the other is so
‘smooth and easy’ that we are apt to take it for the ‘same disposition
of mind with which we consider one constant and uninterrupted
perception;’ and that, as a consequence of this mistake, we make
the further one of taking the successive resembling perceptions for
an identical, i.e. uninterrupted as well as invariable object. [2] But
we cannot mistake one object for another unless we have an idea of
that other object. If then we ‘mistake the succession of our
interrupted perceptions for an identical object,’ it follows that we
have an idea of such an object—of a thing one with itself throughout
the succession of impressions—an idea which can be a copy neither
of any one of the impressions nor, even if successive impressions
could put themselves together, of all so put together. Such an idea
being according to Hume’s principles impossible, the appearance of
our having it was the fiction he had to account for; and he accounts
for it, as we find, by a ‘habit of mind’ which already presupposes it.
His procedure here is just the same as in dealing with the idea of
vacuum. In that case, as we saw, having to account for the
appearance of there being the impossible idea of pure space, he
does so by showing, that having ‘an idea of distance not filled with
any coloured or tangible object,’ we mistake this for an idea of
extension, and hence suppose that the latter may be invisible and
intangible. He thus admits an idea, virtually the same with the one
excluded, as the source of the ‘tendency to suppose’ which is to
replace the excluded idea. So in his account of identity. Either the
habit, in virtue of which we convert resembling perceptions into an
identical object, is what Hume admits to be a contradiction, ‘a habit
acquired by what was never present to the mind’; [3] or the idea of
identity must be present to the mind in order to render the habit
possible.
[1] ‘Wherever we have no successive perceptions, we have no

notion of time.’ (p. 342) [Book I, part II., sec. III.].
[2] P. 492. [Book I, part IV., sec. II.]
Succession of like feelings mistaken for an identical object: but the

feelings, as described, are already such objects.
304. The device by which this petitio principii is covered is one

already familiar to us in Hume. In this case it is so palpable that it is
difficult to believe he was unconscious of it. As he has ‘to account for
the belief of the vulgar with regard to the existence of body,’ he will
‘entirely conform himself to their manner of thinking and expressing
themselves;’ in other words, he will assume the fiction in question as
the beginning of a process by which its formation is to be accounted
for. The vulgar make no distinction between thing and appearance.
‘Those very sensations which enter by the eye or ear are with them
the true objects, nor can they readily conceive that this pen or this
paper, which is immediately perceived, represents another which is
different from, but resembling it. In order therefore to accommodate
myself to their notions, I shall at first suppose that there is only a
single existence, which I shall call indifferently object and
perception, according as it shall seem best to suit my purpose,
understanding by both of them what any common man may mean
by a hat, or shoe, or stone, or any other impression conveyed to him
by his senses’. [1] Now it is of course true that the vulgar are
innocent of the doctrine of representative ideas. They do not
suppose that this pen or this paper, which is immediately perceived,
represents another which is different from, but resembling, it; but
neither do they suppose that this pen or this paper is a sensation. It
is the intellectual transition from this, that, and the other successive
sensations to this pen or this paper, as the identical object to which
the sensations are referred as qualities, that is unaccountable if,
according to Hume’s doctrine, the succession of feelings constitutes
our consciousness. In the passage quoted he quietly ignores it,
covering his own reduction of felt thing to feeling under the popular
identification of the real thing with the perceived. With ‘the vulgar’
that which is ‘immediately perceived’ is the real thing, just because it
is not the mere feeling which with Hume it is. But under pretence of
provisionally adopting the vulgar view, he entitles himself to treat
the mere feeling, because according to him it is that which is
immediately perceived, as if it were the permanent identical thing,
which according to the vulgar is what is immediately perceived.
Fiction of identity thus implied as source of the propensity which is

to account for it.
305. Thus without professedly admitting into consciousness

anything but the succession of feelings he gets such individual
objects as Locke would have called objects of ‘actual present
sensation.’ When ‘I survey the furniture of my chamber,’ according to
him, I see sundry ‘identical objects’—this chair, this table, this
inkstand, &c. [1] So far there is no fiction to be accounted for. It is
only when, having left my chamber for an interval and returned to it,
I suppose the objects which I see to be identical with those I saw
before, that the ‘propensity to feign’ comes into play, which has to
be explained as above. But in fact the original ‘survey’ during which,
seeing the objects, I suppose them to continue the same with
themselves, involves precisely the same fiction. In that case, says
Hume, I ‘suppose the change’ (which is necessary to constitute the
idea of identity) ‘to lie only in the time.’ But without ‘succession of
perceptions,’ different however resembling, there could according to
him be no change of time. The continuous survey of this table, or
this chair, then, involves the notion of its remaining the same with
itself throughout a succession of different perceptions—i.e. the full-
grown fiction of identity—just as much as does the supposition that
the table I see now is identical with the one I saw before. The
‘reality,’ confusion with which of ‘a smooth passage along resembling
ideas’ is supposed to constitute the ‘fiction,’ is already itself the
fiction—the fiction of an object which must be other than our
feelings, since it is permanent while they are successive, yet so
related to them that in virtue of reference to it, instead of being
merely different from each other, they become changes of a thing.
With Hume continued existence of perceptions a fiction different

from their identity. Can perceptions exist when not perceived?
306. Having thus in effect imported all three ‘fictions of
imagination’—identity, continued existence, and existence distinct
from perception—into the original ‘perception,’ Hume, we may think,
might have saved himself the trouble of treating them as separate
and successive formations. Unless he had so treated them, however,
his ‘natural history’ of consciousness would have been far less
imposing than it is. The device, by which he represents the ‘vulgar’
belief in the reality of the felt thing as a belief that the mere feeling
is the real object, enables him also to represent the identity, which a
smooth transition along closely resembling sensations leads us to
suppose, as still merely identity of a perception. ‘The very image
which is present to the senses is with us the real body; and ’tis to
these interrupted images we ascribe a perfect identity’. [1] The
identity lying thus in the images or appearances, not in anything to
which they are referred, a further fiction seems to be required by
which we may overcome the contradiction between the interruption
of the appearances and their identity—the fiction of ‘a continued
being which may fill the intervals’ between the appearances. [2]
That a ‘propension’ towards such a fiction would naturally arise from
the uneasiness caused by such a contradiction, we may readily
admit. The question is how the propension can be satisfied by a
supposition which is merely another expression for one of the
contradictory beliefs. What difference is there between the
appearance of a perception and its existence, that interruption of the
perception, though incompatible with uninterruptedness in its
appearance, should not be so with uninterruptedness in its
existence? It may be answered that there is just the difference
between relation to a feeling subject and relation to a thinking one—
between relation to a consciousness which is in time, or successive,
and relation to a thinking subject which, not being itself in time, is
the source of that determination by permanent conditions, which is
what is meant by the real existence of a perceived thing. But to
Hume, who expressly excludes such a subject—with whom ‘it exists’
= ‘it is felt’—such an answer is inadmissible. He can, in fact, only
meet the difficulty by supposing the existence of unfelt feelings, of
unperceived perceptions. The appearance of a perception is its
presence to ‘what we call a mind,’ which ‘is nothing but a heap or
collection of different perceptions, united together by certain
relations, and supposed, though falsely, to be endowed with a
perfect simplicity and identity’. [3] To consider a perception, then, as
existing though not appearing is merely to consider it as detached
from this ‘heap’ of other perceptions, which, on Hume’s principle that
whatever is distinguishable is separable, is no more impossible than
to distinguish one perception from all others. [4] In fact, however, it
is obvious that the supposed detachment is the very opposite of
such distinction. A perception distinguished from all others is
determined by that distinction in the fullest possible measure. A
perception detached from all others, left out of the ‘heap which we
call a mind,’ being out of all relation, has no qualities—is simply
nothing. We can no more ‘consider’ it than we can see vacancy. Yet
it is by the consideration of such nonentity, by supposing a world of
unperceived perceptions, of ‘existences’ without relation or quality,
that the mind, according to Hume—itself only ‘a heap of
perceptions’—arrives at that fiction of a continued being which, as
involved in the supposition of identity, is the condition of our
believing in a world of real things at all.
[2] Pp. 494, 495. [Book I, part IV., sec. II.]

[4] Ibid.
Existence of objects, distinct from perceptions, a further fiction

still.
307. It is implied, then, in the process by which, according to

Hume, the fiction of a continued being is arrived at, that this being is
supposed to be not only continued but ‘distinct from the mind’ and
‘independent’ of it. With Hume, however, the supposition of a
distinct and ‘independent’ existence of the perception is quite
different from that of a distinct and independent object other than
the perception. The former is the ‘vulgar hypothesis,’ and though a
fiction, it is also a universal belief: the latter is the ‘philosophical
hypothesis,’ which, if it has a tendency to obtain belief at all, at any
rate derives that tendency, in other words ‘acquires all its influence
over the imagination,’ from the vulgar one. [1] Just as the belief in
the independent and continued existence of perceptions results from
an instinctive effort to escape the uneasiness, caused by the
contradiction between the interruption of resembling perceptions
and their imagined identity, so the contradiction between this belief
and the evident dependence of all perceptions ‘on our organs and
the disposition of our nerves and animal spirits’ leads to the doctrine
of representative ideas or ‘the double existence of perceptions and
objects.’ ‘This philosophical system, therefore, is the monstrous
offspring of two principles which are contrary to each other, which
are both at once embraced by the mind and which are unable
mutually to destroy each other. The imagination tells us that our
resembling perceptions have a continued and uninterrupted
existence, and are not annihilated by their absence. Reflection tells
us that even our resembling perceptions are interrupted in their
existence and different from each other. The contradiction betwixt
these opinions we elude by a new fiction which is conformable to the
hypotheses both of reflection and fancy, by ascribing these contrary
qualities to different existences; the interruption to perceptions, and
the continuance to objects’. [2]
Are these several ‘fictions’ really different from each other?
308. Here, again, we find that the contradictory announcements,

which it is the object of this new fiction to elude, are virtually the
same as those implied in that judgment of identity which is
necessary to the ‘perception’ of this pen or this paper. That
‘interruption of our resembling perceptions,’ of which ‘reflection’ (in
the immediate context ‘Reason’) is here said to ‘tell us,’ is merely
that difference in time, or succession, which Hume everywhere else
treats as a datum of sense, and which, as he points out, is as
necessary a factor in the idea of identity, as is the imagination of an
existence continued throughout the succession. Thus the
contradiction, which suggests this philosophical fiction of double
existence, has been already present and overcome in every
perception of a qualified object. Nor does the fiction itself, by which
the contradiction is eluded, differ except verbally from that
suggested by the contradiction between the interruption and the
identity of perceptions. What power is there in the word ‘object’ that
the supposition of an unperceived existence of perceptions,
continued while their appearance is broken, should be an
unavoidable fiction of the imagination, while that of ‘the double
existence of perceptions and objects’ is a gratuitous fiction of
philosophers, of which ‘vulgar’ thinking is entirely innocent?
Are they not all involved in the simplest perception?
309. That it is gratuitous we may readily admit, but only because

a recognition of the function of the Ego in the primary constitution of
the qualified individual object—this pen or this paper—renders it
superfluous. To the philosophy, however, in which Hume was bred,
the perception of a qualified object was simply a feeling. No
intellectual synthesis of successive feelings was recognized as
involved in it. It was only so far as the dependence of the feeling on
our organs, in the absence of any clear distinction between feeling
and felt thing, seemed to imply a dependent and broken existence of
the thing, that any difficulty arose—a difficulty met by the
supposition that the felt thing, whose existence was thus broken and
dependent, represented an unfelt and permanent thing of which it is
a copy or effect. To the Berkeleian objections, already fatal to this
supposition, Hume has his own to add, viz. that we can have no idea
of relation in the way of cause and effect except as between objects
which we have observed, and therefore can have no idea of it as
existing between a perception and an object of which we can only
say that it is not a perception. Is all existence then ‘broken and
dependent’? That is the ‘sceptical’ conclusion which Hume professes
to adopt—subject, however, to the condition of accounting for the
contrary supposition (without which, as he has to admit, we could
not think or speak, and which alone gives a meaning to his own
phraseology about impressions and ideas) as a fiction of the
imagination. He does this, as we have seen, by tracing a series of
contradictions, with corresponding hypotheses invented, either
instinctively or upon reflection, in order to escape the uneasiness
which they cause, all ultimately due to our mistaking similar
successive feelings for an identical object. Of such an object, then,
we must have an idea to begin with, and it is an object permanent
throughout a variation of time, which means a succession of
feelings; in other words, it is a felt thing, as distinct from feelings but
to which feelings are referred as its qualities. Thus the most primary
perception—that in default of which Hume would have no reality to
oppose to fiction, nor any point of departure for the supposed
construction of fictions—already implies that transformation of
feelings into changing relations of a thing which, preventing any
incompatibility between the perpetual brokenness of the feeling and
the permanence of the thing, ‘eludes’ by anticipation all the
contradictions which, according to Hume, we only ‘elude’ by
speaking as if we had ideas that we have not.
Yet they are not possible ideas, because copied from no

impressions.
310. ‘Ideas that we have not;’ for no one of the fictions by which
we elude the contradictions, nor indeed any one of the contradictory
judgments themselves, can be taken to represent an ‘idea’ according
to Hume’s account of ideas. He allows himself indeed to speak of our
having ideas of identical objects, such as this table while I see or
touch it—though in this case, as has been shown, either the object
is not identical or the idea of it cannot be copied from an impression
—and of our transferring this idea to resembling but interrupted
perceptions. But the supposition to which the contradiction involved
in this transference gives rise—the supposition that the perception
continues to exist when it is not perceived—is shown by the very
statement of it to be no possible copy of an impression. Yet
according to Hume it is a ‘belief,’ and a belief is ‘a lively idea
associated with a present impression.’ What then is the impression
and what the associated idea? ‘As the propensity to feign the
continued existence of sensible objects arises from some lively
impressions of the memory, it bestows a vivacity on that fiction; or,
in other words, makes us believe the continued existence of body’.
[1] Well and good: but this only answers the first part of our
question. It tells us what are the impressions in the supposed case
of belief, but not what is the associated idea to which their liveliness
is communicated. To say that it arises from a propensity to feign,
strong in proportion to the liveliness of the supposed impressions of
memory, does not tell us of what impression it is a copy. Such a
propensity indeed would be an ‘impression of reflection,’ but the
fiction itself is neither the propensity nor a copy of it. The only
possible supposition left for Hume would be that it is a ‘compound
idea;’ but what combination of ‘perceptions’ can amount to the
existence of perceptions when they are not perceived?
Comparison of present experience with past, which yields relation

of cause and effect, pre-supposes judgment of identity;
311. From this long excursion into Hume’s doctrine of relation in

the way of identity—having found him admitting explicitly that it is
only by a ‘fiction of the imagination’ that we identify this table as
now seen with this table as seen an hour ago, and implicitly that the
same fiction is involved in the perception of this table as an identical
object even when hand or eye is kept upon it, while yet he says not
a word to vindicate the possibility of such a fiction for a faculty
which can merely reproduce and combine ‘perishing impressions’—
we return to consider its bearing upon his doctrine of relation in the
way of cause and effect. According to him, as we saw, [1] that
relation, ‘considered as a philosophical’ one, is founded on a
comparison of present experience with past, in the sense that we
regard an object, precedent and contiguous to another, as its cause
when all like objects have been found similarly related. The question
then arises whether the experiences compared—the present and the
past alike—do not involve the fiction of identity along with the whole
family of other fictions which Hume affiliates to it? Does the relation
of precedence and sequence, which, if constant, amounts to that of
cause and effect, merely mean precedence and sequence of two
feelings, indefinitely like an indefinite number of other feelings that
have thus the one preceded and the other followed; or is it a relation
between one qualified thing or definite fact always the same with
itself, and another such thing or fact always the same with itself?
The question carries its own answer. If in the definition quoted
Hume used the phrase ‘all like objects’ instead of the ‘same object,’
in order to avoid the appearance of introducing the ‘fiction’ of
identity into the definition of cause, the device does not avail him
much. The effect of the ‘like’ is neutralized by the ‘all.’ A uniform
relation is impossible except between objects of which each has a
definite identity.
[1] Above, pars. 298 and 299.
… without which there could be no recognition of an object as one

observed before.
312. When Hume has to describe the experience which gives the
idea of cause and effect, he virtually admits this. ‘The nature of
experience,’ he tells us, ‘is this. We remember to have had frequent
instances of the existence of one species of objects, and also
remember that the individuals of another species of objects have
always attended them, and have existed in a regular order of
contiguity and succession with regard to them. Thus we remember
to have seen that species of object we call flame, and to have felt
that species of sensation we call heat. We likewise call to mind their
constant conjunction in all past instances. Without any farther
ceremony we call the one cause, and the other effect, and infer the
existence of the one from the other’. [1] It appears, then, that upon
experiencing certain sensations of sight and touch, we recognize
each as ‘one of a species of objects’ which we remember to have
observed in certain constant relations before. In virtue of the
recognition the sensations become severally this flame and this heat;
and in virtue of the remembrance the objects thus recognized are
held to be related in the way of cause and effect. Now it is clear that
though the recognition takes place upon occasion of a feeling, the
object recognized—this flame or this heat—is by no means the
feeling as a ‘perishing existence.’ Unless the feeling were taken to
represent a thing, conceived as permanently existing under certain
relations and attributes—in other words, unless it were identified by
thought—it would be no definite object, not this flame or this heat,
at all. The moment it is named, it has ceased to be a feeling and
become a felt thing, or, in Hume’s language, an ‘individual of a
species of objects.’ And just as the present ‘perception’ is the
recognition of such an individual, so the remembrance which
determines the recognition is one wholly different from the return
with lessened liveliness of a feeling more strongly felt before.
According to Hume’s own statement, it consists in recalling ‘frequent
instances of the existence of a species of objects.’ It is remembrance
of an experience in which every feeling, that has been attended to,
has been interpreted as a fresh appearance of some qualified object
that ‘exists’ throughout its appearances—an experience which for
that reason forms a connected whole. If it were not so, there could
be no such comparison of the relations in which two objects are now
presented with those in which they have always been presented, as
that which according to Hume determines us to regard them as
cause and effect. The condition of our so regarding them is that we
suppose the objects now presented to be the same with those of
which we have had previous experience. It is only on supposition
that a certain sensation of sight is not merely like a multitude of
others, but represents the same object as that which I have
previously known as flame, that I infer the sequence of heat and,
when it does follow, regard it as an effect. If I thought that the
sensation of sight, however like those previously referred to flame,
did not represent the same object, I should not infer heat as effect;
and conversely, if, having identified the sensation of sight as
representative of flame, I found that the inferred heat was not
actually felt, I should judge that I was mistaken in the identification.
It follows that it is only an experience of identical, and by
consequence related and qualified, objects, of which the memory
can so determine a sequence of feelings as to constitute it an
experience of cause and effect. Thus the perception and
remembrance upon which, according to Hume, we judge one object
to be the cause of another, alike rest on the ‘fictions of identity and
continued existence.’ Without these no present experience would, in
his language, be an instance of an individual of a certain species
existing in a certain relation, nor would there be a past experience of
individuals of the same species, by comparison with which the
constancy of the relation might be ascertained.
[1] P. 388. [Book I, part III., sec. VI.]

Hume makes conceptions of identity and cause each come before
the other. Their true correlativity.
313. Against this derivation of the conception of cause and effect,

as implying that of identity, may be urged the fact that when we
would ascertain the truth of any identification we do so by reference
to causes and effects. As Hume himself puts it at the outset of his
discussion of causation, an inference of identity ‘beyond the
impressions of our senses can be founded only on the connexion of
cause and effect.’ … ‘Whenever we discover a perfect resemblance
between a new object and one which was formerly present to the
senses, we consider whether it be common in that species of
objects; whether possibly or probably any cause could operate in
producing the change and resemblance; and according as we
determine concerning these causes and effects, we form our
judgment concerning the identity of the object’. [1] This admission,
it may be said, though it tells against Hume’s own subsequent
explanation of identity as a fiction of the imagination, is equally
inconsistent with any doctrine that would treat identity as the
presupposition of inference to cause or effect. Now undoubtedly if
the identity of interrupted perceptions is one fiction of the
imagination and the relation of cause and effect another, each
resulting from ‘custom,’ to say with Hume, that we must have the
idea of cause in order to arrive at the supposition of identity, is
logically to exclude any derivation of that idea from an experience
which involves the supposition of identity. The ‘custom’ which
generates the idea of cause must have done its work before that
which generates the supposition of identity can begin. Hume
therefore, after the admission just quoted, was not entitled to treat
the inference to cause or effect as a habit derived from experience
of identical things. But it is otherwise if the conceptions of causation
and identity are correlative—not results of experience of which one
must be formed before the other, but co-ordinate expressions of one
and the same synthetic principle, which renders experience possible.
And this is the real state of the case. It is true, as Hume points out,
that when we want to know whether a certain sensation, precisely
resembling one that we have previously experienced, represents the
same object, we do so by asking how otherwise it can be accounted
for. If no difference appears in its antecedents or sequents, we
identify it—refer it to the same thing—as that previously
experienced; for its relations (which, since it is an event in time, take
the form of antecedence and sequence) are the thing. The
conceptions of identity and of relation in the way of cause and effect
are thus as strictly correlative and inseparable as those of the thing
and of its relations. Without the conception of identity experience
would want a centre, without that of cause and effect it would want
a circumference. Without the supposition of objects which ‘existing
at one time are the same with themselves as existing at other
times’—a supposition which at last, when through acquaintance with
the endlessness of orderly change we have learnt that there is but
one object for which such identity can be claimed without
qualification, becomes the conception of nature as a uniform whole
—there could be no such comparison of the relations in which an
object is now presented with those in which it has been before
presented, as determines us to reckon it the cause or effect of
another; but it is equally true that it is only by such comparison of
relations that the identity of any particular object can be ascertained.
Hume quite right in saying that we do not go more beyond sense

in reasoning than in perception.
314. Thus, though we may concede to Hume that neither in the
inference to the relation of cause and effect nor in the conclusions
we draw from it do we go ‘beyond experience,’ [1] this will merely
be, if his account of it as a ‘philosophical relation’ be true, because in
experience we already go beyond sense. ‘There is nothing,’ says
Hume, ‘in any object considered in itself that can afford us a reason
for drawing a conclusion beyond it’ [2]—a statement which to him
means that, if the mind really passes from it to another, this is only
because as a matter of fact another feeling follows on the first. But,
in truth, if each feeling were merely ‘considered in itself,’ the fact
that one follows on another would be no fact for the subject of the
feelings, no starting-point of intelligent experience at all; for the fact
is the relation between the feelings—a relation which only exists for
a subject that considers neither feeling ‘in itself,’ as a ‘separate and
perishing existence,’ but finds a reality in the determination of each
by the other which, as it is not either or both of them, so survives,
while they pass, as a permanent factor of experience. Thus in order
that any definite ‘object’ of experience may exist for us, our feelings
must have ceased to be what according to Hume they are in
themselves. They cease to be so in virtue of the presence to them of
the Ego, in common relation to which they become related to each
other as mutually qualified members of a permanent system—a
system which at first for the individual consciousness exists only as a
forecast or in outline, and is gradually realized and filled up with the
accession of experience. It is quite true that nothing more than the
reference to such a system, already necessary to constitute the
simplest object of experience, is involved in that interpretation of
every event as a changed appearance of an unchanging order, and
therefore to be accounted for, which we call inference to a cause or
the inference of necessary connection; or, again, in the identification
of the event, the determination of its particular nature by the
discovery of its particular cause.
[1] Above, pars. 285 & 286.
[2] P. 436 and elsewhere. [Book I, part III., sec. XII.]
How his doctrine might have been developed. Its actual outcome.
315. The supposed difference then between immediate and

mediate cognition is no absolute difference. It is not a difference
between experience and a process that goes beyond experience, or
between an experience unregulated by a conception of a permanent
system and one that is so regulated. It lies merely in the degree of
fullness and articulation which that conception has attained. If this
had been what Hume meant to convey in his assimilation of
inference to perception, he would have gone far to anticipate the
result of the enquiry which Kant started. And this is what he might
have come to mean if, instead of playing fast and loose with
‘impression’ and ‘object,’ using each as plausibility required on the
principle of accommodation to the ‘vulgar,’ he had faced the
consequence of his own implicit admission, that every perception of
an object as identical is a ‘fiction’ in which we go beyond present
feeling. As it is, his ‘scepticism with regard to the senses’ goes far
enough to empty their ‘reports’ of the content which the ‘vulgar’
ascribe to them, and thus to put a breach between sense and the
processes of knowledge, but not far enough to replace the ‘sensible
thing’ by a function of reason. In default of such replacement, there
was no way of filling the breach but to bring back the vulgar theory
under the cover of habits and ‘tendencies to feign,’ which all suppose
a ready-made knowledge of the sensible thing as their starting-point.
Hence the constant contradiction, which it is our thankless task to
trace, between his solution of the real world into a succession of
feelings and the devices by which he sought to make room in his
system for the actual procedure of the physical sciences.
Conspicuous among these is his allowance of that view of relation in
the way of cause and effect as an objective reality, which is
represented by his definition of it as a ‘philosophical relation.’ It is in
the sense represented by that definition that his doctrine has been
understood and retained by subsequent formulators of inductive
logic; but on examining it in the light of his own statements we have
found that the relation, as thus defined, is not that which his theory
required, and as which to represent it is the whole motive of his
disquisition on the subject. It is not a sequence of impression upon
impression, distinguished merely by its constancy; nor a sequence of
idea upon impression, distinguished merely by that transfer of
liveliness to the idea which arises from the constancy of its sequence
upon the impression. It is a relation between ‘objects’ of which each
is what it is only as ‘an instance of a species’ that exists
continuously, and therefore in distinction from our ‘perishing
impressions,’ according to a regular order of ‘contiguity and
succession.’ As such existence and order are by Hume’s own showing
no possible impressions, and by consequence no possible ideas, so
neither are the ‘objects’ which derive their whole character from
them.
No philosophical relation admissible with Hume that is not derived

from a natural one.
316. It may be said, however, that wherever Hume admits a

definition purporting to be of a ‘philosophical relation,’ he does so
only as an accommodation, and under warning that every such
relation is ‘fictitious’ except so far as it is equivalent to a natural one;
that according to his express statement ‘it is only so far as causation
is a natural relation, and produces an union among our ideas, that
we are able to reason upon it or draw any inference from it’; [1] and
that therefore it is only by his definition of it as a ‘natural relation’
that he is to be judged. Such a vindication of Hume would be more
true than effective. That with him the ‘philosophical’ relation of
cause and effect is ‘fictitious,’ with all the fictitiousness of a
‘continued existence distinct from perceptions,’ is what it has been
the object of the preceding paragraphs to show. But the
fictitiousness of a relation can with him mean nothing else than that,
instead of having an idea of it, we have only a ‘tendency to suppose’
that we have such an idea. Thus the designation of the philosophical
relation of cause and effect carries with it two conditions, one
negative, the other positive, on the observance of which the logical
value of the designation depends. The ‘tendency to suppose’ must
not after all be itself translated into the idea which it is to replace;
and it must be accounted for as derived from a ‘natural relation’
which is not fictitious. That the negative condition is violated by
Hume, we have sufficiently seen. He treats the ‘philosophical
relation’ of cause and effect, in spite of the ‘fictions’ which it
involves, not as a name for a tendency to suppose that we have an
idea which we have not, but as itself a definite idea on which he
founds various ‘rules for judging what objects are really so related
and what are not’. [2] That the positive condition is violated also—
that the ‘natural relation’ of cause and effect, according to the sense
in which his definition of it is meant to be understood, already itself
involves ‘fictions,’ and only for that reason is a possible source of the
‘philosophical’—is what we have next to show.
[1] P. 394. [Book I, part III., sec. VII.]

[2] Part III. § 15.
Examination of his account of cause and effect as ‘natural relation’.
317. That definition, it will be remembered, runs as follows: ‘A

cause is an object precedent and contiguous to another, and so
united with it in the imagination that the idea of the one determines
the mind to form the idea of the other, and the impression of the
one to form a more lively idea of the other.’ Now, as has been
sufficiently shown, the object of an idea with Hume can properly
mean nothing but the impression from which the idea is derived,
which again is only the livelier idea, even as the idea is the fainter
impression. The idea and the object of it, then, only differ as
different stages in the vivacity of a feeling. [1] It must be
remembered, further, in regard to the ‘determination of the mind’
spoken of in the definition, that the ‘mind’ according to Hume is
merely a succession of impressions and ideas, and that its
‘determination’ means no more than a certain habitualness in this
succession. Deprived of the benefit of ambiguous phraseology, then,
the definition would run thus: ‘A cause is a lively feeling immediately
precedent to another, [2] and so united with it that when either of
the two more faintly recurs, the other follows with like faintness, and
when either occurs with the maximum of liveliness the other follows
with less, but still great, liveliness.’ Thus stated, the definition would
correspond well enough to the process by which Hume arrives at it,
of which the whole drift, as we have seen, is to merge the so-called
objective relation of cause and effect, with the so-called inference
from it, in the mere habitual transition from one feeling to another.
But it is only because not thus stated, and because the actual
statement is understood to carry a meaning of which Hume’s
doctrine does not consistently admit, that it has a chance of finding
acceptance. Its plausibility depends on ‘object’ and ‘mind’ and
‘determination’ being understood precisely in the sense in which,
according to Hume, they ought not to be understood, so that it shall
express not a sequence of feeling upon feeling, as this might be for
a merely feeling subject, but that permanent relation or law of
nature which to a subject that thinks upon its feelings, and only to
such a subject, their sequence constitutes or on which it depends.
[1] See above, paragraphs 195 and 208. Cf. also, among other
passages, one in the chapter now under consideration (p. 451)
[Book I, part III., sec. XIV.]—‘Ideas always represent their objects or
impressions.’
[2] The phrase ‘immediately precedent’ would seem to convey

Hume’s meaning better than his own phrase ‘precedent and
contiguous.’ Contiguity in space (which is what we naturally
understand by ‘contiguity,’ when used absolutely) he could not have
deliberately taken to be necessary to constitute the relation of cause
and effect, since the impressions so related, as he elsewhere shows,
may often not be in space at all.
Double meaning of natural relation. How Hume turns it to account.
318. It is this essential distinction between the sequence of feeling

upon feeling for a sentient subject and the relation which to a
thinking subject this sequence constitutes—a distinction not less
essential than that between the conditions, through which a man
passes in sleep, as they are for the sleeping subject himself, and as
they are for another thinking upon them—which it is the
characteristic of Hume’s doctrine of natural relation in all its forms to
disguise. Only in virtue of the presence to feelings of a subject,
which distinguishes itself from them, do they become related
objects. Thus, with Hume’s exclusion of such a subject, with his
reduction of mind and world alike to the succession of feelings,
relations and ideas of relation logically disappear. But by help of the
phrase ‘natural relation,’ covering, as it does, two wholly different
things—the involuntary sequence of one feeling upon another, and
that determination of each by the other which can only take place
for a synthetic self-consciousness—he is able on the one hand to
deny that the relations which form the framework of knowledge are
more than sequences of feeling, and on the other to clothe them
with so much of the real character of relations as qualifies them for
‘principles of union among ideas.’ Thus the mere occurrence of
similar feelings is with him already that relation in the way of
resemblance, which in truth only exists for a subject that can
contemplate them as permanent objects. In like manner the
succession of feelings, which can only constitute time for a subject
that contrasts the succession with its own unity, and which, if ideas
were feelings, would exclude the possibility of an idea of time, is yet
with him indifferently time and the idea of time, though ideas are
feelings and there is no ‘mind’ but their succession.
If an effect is merely a constantly observed sequence, how can an

event be an effect the first time it is observed? Hume evades this
question;
319. The fallacy of Hume’s doctrine of causation is merely an

aggravated form of that which has generally passed muster in his
doctrine of time. If time, because a relation between feelings, can be
supposed to survive the exclusion of a thinking self and the
reduction of the world and mind to a succession of feelings, the
relation of cause and effect has only to be assimilated to that of time
in order that its incompatibility with the desired reduction may
disappear, The great obstacle to such assimilation lies in that
opposition to the mere sequence of feelings which causation as
‘matter of fact’—as that in discovering which we ‘discover the real
existence and relations of objects’—purports to carry with it. Why do
we set aside our usual experience as delusive in contrast with the
exceptional experience of the laboratory—why do we decide that an
event which has seemed to happen cannot really have happened,
because under the given conditions no adequate cause of it could
have been operative—if the relation of cause and effect is itself
merely a succession of seemings, repeated so often as to leave
behind it a lively expectation of its recurrence? This question, once
fairly put, cannot be answered: it can only be evaded. It is Hume’s
method of evasion that we have now more particularly to notice.
Still, he is a long way off the Inductive Logic, which supposes an

objective sequence.
320. In its detailed statement it is very different from the method

adopted in those modern treatises of Logic which, beginning with
the doctrine that facts are merely feelings in the constitution of
which thought has no share, still contrive to make free use in their
logical canon of the antithesis between the real and apparent. The
key to this modern method is to be found in its ambiguous use of
the term ‘phenomenon,’ alike for the feeling as it is felt, ‘perishing’
when it ceases to be felt, and for the feeling as it is for a thinking
subject—a qualifying and qualified element in a permanent world.
Only if facts were ‘phenomena’ in the former sense would the
antithesis between facts and conceptions be valid; only if
‘phenomena’ are understood in the latter sense can causation be
said to be a law of phenomena. So strong, however, is the charm
which this ambiguous term has exercised, that to the ordinary

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Printed by Sheridan Books, Inc., United States of America

1. Introduction: Respiration, phosphorylation, and mechanism 1

2. From physiology to biochemistry: Respiration and oxidation from 1600 to 1900 17

3. Relating phosphorylation, respiration, and oxidation: 1900–​1945 41

4. Emergence of the field of cell bioenergetics: 1945–​1960 73

5. Defining the mechanism: 1960–​1977 97

6. Discovering photosynthesis 128

7. Elucidating the photosynthetic light reaction 154

8. The impact of protein technology: 1977–​1997 181

9. The search for mechanism 214

I wish to express my appreciation to Professor Mikuláš Teich for permission to reproduce

1.1 RESPIRATION, PHOTOSYNTHESIS,

2 Searching for a Mechanism

Viewed as an object of scientific research, animal life exhibits itself in a series

4 Searching for a Mechanism

The comparison is between present and past experience of

299. The modern followers of Hume may perhaps seek refuge in

Observation of succession already goes beyond sense.

300. As to relations in time and space, we have already traced out

[1] P. 376. [Book I, part III., sec. II.]

As also does the ‘observation concerning identity,’ which the

[1] P. 376. [Book I, part III., sec. II.]

Identity of objects an unavoidable crux for Hume. His account of

302. The problem of identity necessarily arises from the fusion of

[1] Pp. 489, 490. [Book I, part IV., sec. II.]

Properly with him it is a fiction, in the sense that we have no such

[1] ‘Wherever we have no successive perceptions, we have no

[2] P. 492. [Book I, part IV., sec. II.]

[3] P. 487. [Book I, part IV., sec. II.]

Succession of like feelings mistaken for an identical object: but the

304. The device by which this petitio principii is covered is one

[1] P. 491. [Book I, part IV., sec. II.]

Fiction of identity thus implied as source of the propensity which is

305. Thus without professedly admitting into consciousness

[1] P. 493. [Book I, part IV., sec. II.]

With Hume continued existence of perceptions a fiction different

[1] P. 493. [Book I, part IV., sec. II.]

[2] Pp. 494, 495. [Book I, part IV., sec. II.]

Existence of objects, distinct from perceptions, a further fiction

307. It is implied, then, in the process by which, according to

[1] P. 500. [Book I, part IV., sec. II.]

[2] P. 502. [Book I, part IV., sec. II.]

Are these several ‘fictions’ really different from each other?

Library of Congress Cataloging-in-Publication Data

3. Relating phosphorylation, respiration, and oxidation: 1900–1945 41

4. Emergence of the field of cell bioenergetics: 1945–1960 73

5. Defining the mechanism: 1960–1977 97

8. The impact of protein technology: 1977–1997 181