Siddhartha Mukherjee

The Gene

1-Page Summary

Scientists have known for centuries that biological traits get passed
from one generation to the next, but it was only recently—with a
great deal of trial and error, and several technological
advancements—that they learned exactly how that happens. The
Gene explores key moments in the ongoing study of genetics, with a
particular focus on the people behind those moments.

Every part of our bodies, from toenails to hair and everything in

between, is built based on the instructions coded into our genes.
Therefore, understanding what genes are and how they work is
crucial to understanding our bodies, our health, and even our
identities (after all, our brains are also built from those genetic
instructions). Siddhartha Mukherjee wrote The Gene to give the
average reader a basic grounding in the history and the science of
genetics, to better understand what we know about ourselves and
how we know it.

Mukherjee is an immunologist and geneticist known for his work in

the field of cancer research, a field closely linked to genetics. The
Gene: An Intimate History is Mukherjee’s second book, published
after The Emperor of All Maladies, an in-depth study of the history of
cancer research. The Emperor of All Maladies was published in late
2010 and won the 2011 Pulitzer Prize for General Non-Fiction.

Our commentary will provide background information and

explanations to help readers understand the science behind The
Gene. We’ll also examine advancements in genetics since The
Gene’s publication in 2016.

Part 1: Discovering the Gene

Danish botanist Wilhelm Johannsen coined the word “gene” in 1909,
but Mukherjee starts The Gene by talking about three scientists
who made crucial strides in the field of genetics before that term
even existed: Charles Darwin, Gregor Mendel, and Hugo de Vries.

We’ll begin this guide by discussing the groundwork of genetics

those three men laid. Then we’ll discuss what genes are, how they
work, and how scientists have learned to understand and
manipulate genetic information. We’ll also talk briefly about how
our genes impact our personal identities. Finally, we’ll end with
Mukherjee’s ideas about the future of genetics, as well as the legal
and ethical challenges the field currently faces.

Darwin’s Theory of Evolution

Mukherjee begins the story of genetics in 1859, when Charles

Darwin published his theory of evolution, titled On the Origin of
Species by Means of Natural Selection (commonly shortened to The
Origin of Species). Darwin developed his theory by studying finches
in the Galapagos Islands, where he found that birds on different
islands had distinctly different beak shapes—for example, one beak
type was well suited for cracking open nuts, while another was
effective at digging insects out of tree bark.
Darwin concluded that each type of finch had evolved to thrive in
its particular environment. This happened because traits that help
organisms survive and reproduce tend to get passed on to the next
generation, while less suitable traits tend to get outcompeted and
die out. In this case, because the conditions on each island were
slightly different, over time those traits diverged and created
noticeably different types of finches.

Pre-Darwinian Theories of Species

Before Darwin published The Origin of Species, other

prominent biologists put forward their own theories
about how and why different species appeared. A couple
of notable theories were:

Creationism—The belief that God designed the Earth and

everything that would ever live on it. Creationists believe
that God created the Earth around 6,000 years ago, along
with complex organisms to inhabit it. This theory also
states that all species (including humans) were created in
their current forms and will keep those forms for as long
as the species exists.

Catastrophism—Catastrophism states that large-scale

natural disasters must have occurred periodically
throughout history, suddenly wiping out some species
and allowing new species to take their places. However,
while that has happened—for instance, the meteor that
killed the dinosaurs—we now know that it’s not the main
reason why some species go extinct and new species
 emerge.

However, Mukherjee tells us that while Darwin accurately explained

the results of evolution, he wasn’t able to figure out how it worked.
Darwin (incorrectly) proposed small “particles” of inheritance
produced by cells and carried in the blood, which he called
gemmules.

Darwin theorized that streams of these particles from each parent

would mingle in their offspring, thereby blending the parents’ traits.
He called this theory pangenesis (meaning “originating from
everything”) to illustrate that any given gemmule could come from
anywhere in the body.

He also believed that, because any cell could produce gemmules,

those gemmules would carry information about changes that cell
had undergone—for instance, injuries, or muscles made stronger
through a lifetime of exercise. In other words, pangenesis theory
relied in part on the inheritance of acquired characteristics, rather
than purely genetic ones.

(Shortform note: Some modern scientists think pangenesis theory

may be more accurate than previously thought. Some studies have
shown that certain experiences—especially traumatic ones—leave
genetic markers that can be passed on to offspring. For example, an
animal might instinctively be afraid of the scent of a predator, even if
it’s never smelled that predator before and therefore shouldn’t know
what it is. Furthermore, some scientists report finding free-floating
genetic material in the blood, which would be a perfect match for
Darwin’s gemmules. However, this theory is still controversial and
unpopular in the scientific community.)

Mendel’s “Unit of Heredity”

In 1864, not long after Darwin published The Origin of Species,

biologist and Augustinian friar Gregor Mendel made another major
breakthrough in genetics (although that word didn’t exist yet). By
breeding and studying pea plants with obviously different traits—
such as different heights, different colored flowers, and so on—he
discovered clear patterns of inheritance across generations.

Most importantly, according to Mukherjee, Mendel discovered that

traits would be passed on completely; for example, if he cross-
pollinated a purple-flowered plant with a white-flowered plant, the
offspring would have purple flowers. This ran counter to the popular
theory of Mendel’s time that traits would “blend” during inheritance,
in which case that plant would end up with pale purple flowers, or
some purple and some white.

If traits get passed on completely intact, Mendel reasoned, then

there must be a “unit” of heredity: self-contained packets of genetic
information representing a single trait—which Mendel called factors
—rather than a stream of particles mixing with other streams like
Darwin proposed.

Mendel’s Laws of Inheritance

Aside from his concept of a unit of heredity, Mendel is

credited with creating two “laws” that describe patterns of
 inheritance:

The Law of Segregation. Organisms have two

copies of each gene—one from each of their
parents—which may be different from one another.
When an organism reproduces, it randomly passes
on one gene from each pair.

The Law of Independent Assortment. Genes are

passed on to offspring independently of each
other. In other words, offspring inheriting one trait
doesn’t guarantee they’ll inherit a different trait—
blond hair doesn’t always go with blue eyes, for
example.

De Vries Fills in the Gaps

Mukherjee recounts that in the 1890s, Dutch botanist Hugo de Vries

made the next major step toward modern genetics by recognizing
that a self-contained unit of heredity perfectly explained Darwin’s
observations of how species evolve. In other words, Mendel and
Darwin’s discoveries were both parts of a single, cohesive theory of
evolution.

De Vries added one point of his own to this theory: There must be a
chance, however small, that genetic information could
spontaneously change during reproduction. In other words, de Vries
introduced the concept of mutations.

Mutations are a critical part of evolutionary theory because

evolution requires diversity—natural selection can’t “select” genes
that don’t exist—and without mutations, there would be no way for
new traits to appear. For example, Darwin’s finches couldn’t have
developed different types of beaks unless there were already slight
beak differences coded into their genes.

Sources of Genetic Diversity

As de Vries noted, evolution needs diversity—there must

be a large pool of genes and gene combinations for
natural selection to “select” from.

Broadly speaking, there are two sources of genetic

diversity:

Mutations. Sudden changes to the DNA in a sperm

or egg cell. You could think of these as genetic
errors that happen during reproduction. Some
mutations are harmless, while others (as with
genetic diseases) are devastating. Rarely, by pure
chance, a mutation could also be beneficial—for
example, a slight change in eye structure might
help someone see far away more easily.

Sexual reproduction. Combining genes from two

different organisms results in offspring with unique
combinations of traits. For example, if one parent
has blond hair and blue eyes, while the other has
brown hair and brown eyes, their child might have
blond hair and brown eyes. Part of the reason for
 these unique combinations is a process called
crossing over, which we’ll discuss in the next
section.

Part 2: Chromosomes and DNA

With the foundation of genetics established, Mukherjee moves on
to explain how we learned about the biological mechanisms behind
inheritance. Namely, he discusses the structures inside of cells that
carry genes—called chromosomes—and the actual genetic code
found in DNA.

In the early 1910s, geneticist Thomas Morgan bred thousands of fruit

flies to study inheritance patterns. He looked for visible traits such
as eye color and wing shape, then traced them through numerous
generations of fruit flies. Through his observations, Morgan made
two crucial discoveries about genes.

The first was what he termed linkage: Morgan noticed that, contrary
to Mendel’s Law of Independent Assortment, certain traits were
almost always inherited together. He correctly concluded that the
genes controlling those traits were somehow physically linked
together.

(Shortform note: Specifically, genes are considered linked when

they consistently appear together over three or more generations.
The odds of the same genes appearing together by chance in
almost every individual across three generations is nearly zero, so
that benchmark allows geneticists to say that genes are linked with
a high degree of certainty.)

One of Morgan’s student assistants, Alfred Sturtevant, later

elaborated on that discovery, noting that how frequently genes are
inherited together directly correlates with how close together they
are on the chromosome. In other words, two genes that are very
close to each other will almost always be inherited together, while
genes that are far apart have no more than a 50/50 chance of
appearing together.

Sturtevant began plotting fruit fly chromosomes based on this

discovery, which was the beginning of the field we now call gene
mapping.

(Shortform note: Today, a sturt—named in honor of Alfred

Sturtevant’s work with gene mapping—is a unit of distance used for
chromosomes. One sturt is the distance that results in a 1%
difference in the chance that two genes will be inherited together.)

Morgan also discovered a phenomenon that he called crossing over:

Once in a while, closely linked traits will not be inherited together,
suggesting that genes can somehow change position or swap
places. He determined that it happened because pairs of
chromosomes—one copy of a chromosome from the mother and
one from the father—can exchange genes with each other to create
new combinations of traits. This process is very unlikely to separate
closely linked genes, but it can happen.

(Shortform note: Crossing over (which, as we mentioned earlier,

occurs during sexual reproduction) is a key source of genetic
diversity. That genetic diversity, which leads to a greater number of
trait combinations in the next generation—and therefore more
chances for natural selection to work—is one of the reasons why
nature generally favors sexual reproduction in complex species like
humans.)

Genes Are Made of DNA

Scientists were beginning to understand where genes can be found,

how they’re arranged, and why that matters. However, geneticists
still had no idea how genes actually work, or even what they’re
made of.

Mukherjee tells us that, ironically, scientists discovered nucleic acids

(DNA and RNA) in the 1920s, but they decided that nucleic acids
were much too simple to carry genetic information. Therefore, they
dismissed those molecules in favor of studying proteins, which were
more complex, and (in Mukherjee’s words) more interesting.

Thanks to their relatively simple structures, nucleic acids would

remain largely unappreciated until the 1940s, when molecular
biologists Oswald Avery, Colin MacLeod, and Maclin McCarty
demonstrated that DNA, not proteins, carries genetic information.
Oswald published their findings in 1944.

After scientists learned what DNA is, Mukherjee says that the next
question was, naturally, what it does. In other words, what does it
actually mean that DNA “carries genetic information?”

Biologists George Beadle and Edward Tatum discovered the answer

in 1945: DNA contains instructions for building the proteins that
make up just about everything in our bodies. So, in a very real sense,
our genes contain the blueprints for our bodies.
 What Do Proteins Do?

The proteins produced from our genetic instructions do

an enormous range of tasks. While scientists aren’t sure
exactly how many are at work in the human body, some
estimates say we have over 100,000 different proteins
carrying out various functions.

Some of the largest categories of proteins include:

Antibodies. Antibodies are crucial to the immune

system; they bind to pathogens and mark, trap, or
destroy them.

Enzymes. Enzymes help the body carry out

biochemical processes like digestion.

Structural proteins. Proteins help shape and

support every part of the body, from bones to
muscles to skin.

DNA’s Four Nucleotides

DNA itself is made of four base chemicals called nucleotides:

adenine (A), cytosine (C), guanine (G), and thymine (T). Mukherjee
tells us that all genes, regardless of species, consist of those four
nucleotides in various combinations. Nucleotides have two key
binding sites that make them perfect for creating chains of DNA:
One site at the “bottom” of the molecule where the next nucleotide
attaches itself, and one that binds to the other DNA chain of the
double helix.

(Shortform note: Some virus genomes are made of RNA, not DNA, a
fact that Mukherjee himself puts in a footnote much later in The
Gene. However, DNA is a more stable molecule than RNA, and it’s
easier to repair in case of damage. That’s why nearly all life on Earth
has evolved with DNA. In theory, there could be complex
multicellular organisms with RNA genomes, but so far, no such
species has been discovered.)

In 1953, molecular biologists James Watson and Francis Crick—

using data from another scientist named Rosalind Franklin, who
went uncredited in their paper—developed the first accurate model
of DNA, the now-famous “double helix” model.

While creating that model, Watson also discovered that the four
nucleotide bases are actually two pairs: T is always linked to A, and
C is always linked to G. That happens because those nucleotide
pairs chemically bond to one another and thereby hold the DNA
molecule together.

Form Fits Function

“Form fits function” is an old maxim of biology. It means

that because all the parts of our bodies work together like
a complex organic machine, you can deduce what each
part of that machine does from how it’s built—for
example, we can tell that red blood cells carry oxygen
because they have binding sites for oxygen molecules.
 Scientists were using “form fits function” logic when they
dismissed nucleic acids in favor of proteins. They were
looking for a type of molecule that could encode very
complicated data (the blueprints for an entire human
body), and proteins can have extremely complex
structures, so they seemed like more likely candidates
than the relatively simple nucleic acids.

A nucleotide is like a single letter—each one has little

meaning on its own, so scientists dismissed them as
useless. Watson, Crick, and Franklin’s work showed how
DNA strings many “letters” (nucleotides) together to form
coherent “sentences” (genes)—they discovered how
DNA’s form fits its function. The structure of DNA is
perfect for encoding complex genetic information: It’s a
stable molecule thanks to the bonded nucleotide pairs,
it’s easy for enzymes to interact with, and it can encode
any amount of data using different combinations of
nucleotides.

Genes Switch On and Off

After researchers discovered how DNA encodes the information

that determines how an organism will develop, it wasn’t long before
they identified exactly how these genes function in real time.

Every cell in an organism’s body contains a set of that organism’s

genes; in fact, each of its cells has identical DNA. This is logical, since
every organism starts out as a single cell (a fertilized egg) which then
replicates itself countless times. However, that seems to imply that
all of its cells should be the same, which clearly isn’t the case. One
cell becoming skin while another becomes bone or brain tissue is a
matter of activating and deactivating certain genes at certain times.

To illustrate the point, Ed Lewis—a geneticist working with fruit flies

in the 1950s—discovered that some rare mutations would lead to
flies having wildly different body structures, such as a leg growing
out of the head. He concluded that there must be genes regulating
when and how other genes are expressed, which he called effectors.
Errors in those effectors led to the mutations he was observing: For
example, one such mistake might activate the “grow antenna” genes
in cells on the fly’s thorax.

Genes Function Like Computers

Gene regulators—Lewis's "effectors"—come in two types:

Activators begin or increase protein production by

binding to sites called enhancers.

Repressors slow or stop protein production by

binding to sites called silencers.

Furthermore, any given gene can have multiple

enhancers and silencers that work under different
conditions. This actually allows cells to carry out basic if-
then programming, like microscopic computers.

For example, E. coli has a relatively simple operon

(collection of related genes) that helps it break down
lactose for energy. However, there are two regulators
 controlling when that operon activates:

The lac repressor normally blocks this operon, but

turns off in the presence of lactose.

The catabolite activator protein activates this

operon when levels of glucose (E. coli’s preferred
food) are low.

So, this operon’s if-then statement would be: If lactose is

present, and glucose is not present, then produce
lactose-digesting enzymes.

How Genes Create Proteins

The process in which DNA creates functional proteins is intricate

and involves many different enzymes (proteins that aid chemical
reactions). However, Mukherjee describes the process in two broad
steps:

1. Transcription. Enzymes read the DNA “blueprint” and create a

matching RNA molecule of the genes to be translated into proteins.

(Shortform note: This step is crucial because only a small part of

your genome gets transcribed into RNA at a time. If your cells read
your DNA directly and made proteins based on that, they could end
up trying to create an entire genome’s worth of proteins at once.)

2. Translation. Other enzymes read instructions encoded in the RNA

molecule, retrieve the needed amino acids (simple organic
compounds that make up proteins) from the blood, and assemble
them into proteins.

(Shortform note: There are a total of 20 amino acids that, when put
together in various combinations and shapes, create countless
proteins. Of those 20, nine are considered essential amino acids
because our bodies can’t produce them. In other words, they’re
essential parts of our diet, because the only way we can get those
amino acids is by breaking down proteins from other organisms that
produce them. Perhaps the best-known essential amino acid is
tryptophan, which is found in turkey (among other sources), and is
supposedly responsible for the post-Thanksgiving drowsiness many
people experience.)

Parts 3 and 4: Writing and Reading Genes

Scientists had discovered that the language of biology is encoded in
DNA, and it consists of only four letters. The next step for geneticists
was to figure out how to read and write in that language.

Editing Genomes

Mukherjee tells us that, in 1970, Stanford biochemists Paul Berg and

David Jackson successfully created recombinant DNA—DNA
containing genes from multiple different sources—by inserting the
genome of a virus called SV40 into the DNA of a bacteriophage (a
type of virus that infects bacteria).

Combining the genomes of two species was an exceptional feat in

itself, but it also hinted at a way to quickly and efficiently create
drugs such as insulin and certain antibiotics—substances that are
normally produced inside of living organisms. For example,
inserting an insulin-creating gene into a virus’s genome and allowing
that virus to replicate would naturally mean that the insulin gene
gets replicated as well. In other words, by editing viruses’ genomes,
scientists could turn them into microscopic medicine factories.

(Shortform note: Today, recombinant DNA technology has many

uses even outside of medicine, particularly in agriculture. Most
notably, by altering plant genomes, scientists can create crops that
resist diseases, require less water or less fertilizer, and have greater
yields than their unaltered counterparts.)

Reading Genes With Gene Sequencing

As we’ve said, it isn’t nucleotides themselves that encode genetic

information—four chemicals aren’t nearly enough to account for the
enormous array of proteins that our bodies produce—but rather the
order in which those nucleotides are arranged. Therefore,
Mukherjee tells us that in order to decode genetic instructions,
scientists first had to learn how to sequence genes—in other words,
to determine exactly which nucleotides are present and in what
order.

In 1977, Cambridge biochemist Frederick Sanger fully sequenced a

genome for the first time. Using specially tagged nucleotides, he
was able to follow along as the virus replicated itself, painstakingly
copying down the approximately 5,400 base pairs of a virus called
Phi X174. By doing so, he was able to match genes with the proteins
they created—in essence, he learned how to read the virus’s genetic
code.
 Innovations in DNA Sequencing

“Sanger Sequencing'' is still the method of choice for

small-scale sequencing projects, such as finding a
mutation in a single gene. Geneticists favor Sanger
Sequencing partly due to its low cost and high accuracy,
and partly because it’s a well-established procedure that
most geneticists will already be familiar with.

However, Sanger’s method isn’t efficient or cost-effective

for large projects like whole genome sequencing. That’s
because Sanger Sequencing can only sequence one
fragment of DNA at a time, and those fragments are
relatively short—anywhere from 300 to 1,000 nucleotide
pairs. An improved method called next-generation
sequencing (NGS) can sequence millions of those
fragments simultaneously, making it much more suitable
for large-scale projects.

Intergenic DNA and Introns: Genetic “Filler”

Mukherjee adds that, as scientists continued sequencing genomes

of different species, they found something very odd: Animal
genomes contain long stretches of DNA that don’t actually code for
proteins. These noncoding zones can be found both between genes
(where they’re called intergenic DNA) and within genes (called
introns).

In fact, in humans, a full 98% of our genome doesn’t code for

anything. Mukherjee says that even geneticists aren’t sure why that
is, and he explains the three competing theories:

1. The noncoding DNA regulates genes—the extra space helps

control when they’re activated and deactivated.

2. The noncoding DNA serves some other purpose that we haven’t

yet discovered.

3. The noncoding DNA is genetic junk left over from millions of

years of evolution, and it serves no purpose at all.

(Shortform note: Contrary to what Mukherjee writes here, scientists

do know at least one purpose of introns: Noncoding sections of
DNA get removed from the transcribed genetic instructions,
effectively breaking up genetic “sentences'' into individual “words.”
This is significant because it allows for alternative splicing—
essentially, rearranging the remaining pieces into different
combinations. This process allows a single gene to code for multiple
different proteins.)

Gene Sequencing in Medicine

Mukherjee says that nowadays, improved gene sequencing

technology allows doctors and researchers to find and diagnose
genetic diseases.

A doctor of internal medicine named Victor McKusick led the

charge to bring genetics to medicine. He first became interested in
genes in 1947, when he found that a certain disease (now called
Peutz-Jeghers syndrome) ran in families and concluded that it must
be the result of a defective gene.

By 1998, McKusick had discovered some 12,000 disease-causing

gene variants. He’d also found that some disorders are the result of a
single mutation—such as sickle-cell anemia—while others are much
more complex. For example, Down’s syndrome is the result of
someone inheriting an entire extra chromosome, while conditions
like cancer and heart disease can be influenced (though not directly
caused) by numerous different genes.

In many cases, gene sequencing techniques even allow doctors to

diagnose diseases and disorders in utero, allowing the mother to
make informed decisions about whether to proceed with the
pregnancy. The first such case occurred in 1968, when a woman
known only as J.G. decided to terminate her pregnancy rather than
give birth to a child who was likely to live a very short and painful
life.

Types of Mutation

There are so many disease-causing variants of genes

because DNA codes for complex and highly specific
proteins, and mutations often result in those proteins
being made incorrectly (or not being made at all). Since
proteins carry out thousands of different tasks within the
body, those mutations can interfere with bodily functions
in countless ways.

Broadly speaking, there are three types of mutation:

A silent mutation has no effect; despite the

mutation, the gene ends up coding for the same
protein. It’s like replacing one word in a sentence
with another word that means the same thing. For
example, ”I’m driving to the store” becomes “I’m
going to the store.”

A missense mutation causes the gene to produce a

different protein than usual. Proteins with missense
mutations are often less effective or efficient in
carrying out their tasks, if they can perform them at
all. For example, in sickle-cell anemia, a change in
the protein hemoglobin causes red blood cells to
become deformed and rigid, making it more
difficult for those cells to carry oxygen throughout
the body. Again, imagine replacing one word in a
sentence, but this time you replace it with
something that changes the meaning—“I’m driving
to the store” becomes “I’m dancing to the store.”

A nonsense mutation makes it so the gene’s

instructions are cut off early, usually making the
protein stunted and nonfunctional. For example, in
cystic fibrosis, a missing or nonfunctional cell
membrane protein prevents moisture from
passing through and entering the lungs. As a result,
mucus that would normally get cleared out of the
lungs becomes too thick and sticky to expel. A
nonsense mutation is like replacing a word with a
period, so “I’m driving to the store” becomes just
“I’m.”
The Human Genome Project

In 1989, a group of biologists began the massive undertaking of

sequencing the entire human genome. A council of 12 advisers,
chaired by American geneticist Norton Zinder, led the effort.

Mukherjee tells us that the human genome contains over three

billion base pairs—for a sense of scale, remember that the first fully
sequenced genome was a virus consisting of about 5,400 base
pairs. Completing the project would take an estimated 50,000
person-years and cost three billion dollars—about a dollar per base
pair.

However, in spite of its massive scope, the Human Genome Project

(HGP) released a first draft of the complete human genome just
over a decade later, in 2000. Then, in 2003, the HGP’s chair officially
declared it complete: Every human gene had been accurately
sequenced and mapped. The Project uploaded its final results to
the internet, where the genome map is still publicly available today.

However, Mukherjee says that even with all of this understanding of

human genetics—where every gene is, what it codes for, and how—
we still understand very little about how all these different genes
coordinate and cooperate to build and maintain our bodies. In other
words, Mukherjee believes that the next step for scientists should
be a deeper study of human genomics: in other words, how the
genome as a whole works.

Side Benefits of the Human Genome Project

 The Human Genome Project had benefits far beyond
simply improving our understanding of human genetics.

Medical benefits: The data from the HGP helps

doctors identify and treat genetic diseases, and
find genetic markers that may put someone at risk
for conditions ranging from cancer to heart
disease.

Scientific benefits: Over the course of the HGP,

scientists developed improved gene sequencing
technology and techniques that continue to be
used today.

Economic benefits: Every dollar the US

government invested in the HGP returned an
estimated $141 to the US economy, largely through
creating new jobs that only exist because of a
mapped human genome.

However, there are also legal and ethical concerns about

how the information in the HGP could be misused. In
particular, there’s the chance that genetic data could be
used to discriminate against people who carry certain
genes or come from certain backgrounds.

Part 5: Genetics and Identity

We’ve now had a brief overview of the history of the gene up to the
present day. The remainder of this guide will focus on the current
state of genetics, how genes impact us personally, and what the
future might hold for both the field of genetics and the human race.

As we’ve said, our genes contain the blueprints for our bodies.
Therefore, in a very real sense, our genes determine who we are.
According to Mukherjee, each of us has crucial elements of who
we’ll become—our ability to learn, to use language, and even our
physical appearance—encoded in our DNA.

Our Genetic Identities Are Very Similar

Mukherjee says that genetically speaking, humans are all much

more similar than we are different. People who believe in significant
differences between “races”—for instance, that people of Asian
descent are naturally good at math, or that those of African descent
are more athletic—are mistaken; there simply isn’t enough genetic
variation to account for such differences.

Mukherjee adds that every human alive today can trace his or her
lineage down the maternal line to one woman who lived in Africa
about 200,000 years ago. The fact that we have a common
ancestor, especially such a recent one (by evolutionary standards),
also suggests that we’re much more alike than people think.

Furthermore, scientists now believe that the first humans left Africa
less than 100,000 years ago. Mukherjee tells us that it would take
several times that long, at least, for any significant genetic
differences to arise—in other words, for us to split into different
“races.”

(Shortform note: If we all came from a common ancestor, and are

still almost genetically identical as Mukherjee states, how do we
explain the differences that do exist between ethnicities? The most
obvious difference between “races'' is skin color, which has changed
more quickly than other traits because of natural selection.
Populations that live near the Earth’s equator tend to have darker
skin because it protects them from the intense sun and UV rays.
Conversely, people who live far from the Earth’s equator—especially
people in the northern hemisphere—tend to have pale skin so they
can more efficiently absorb energy from the limited amount of
sunlight they get.)

Genetic Differences Between Individuals

While Mukherjee is correct that there’s not much genetic variation

between races (so to speak), there can be a great deal of genetic
variation between individuals.

The most obvious example of genetic differences between

individuals is biological sex (male versus female). This is most
commonly explained as a difference of a chromosome—females
have matching XX chromosomes, while males have one X and one
smaller Y chromosome—but Mukherjee says the difference is even
smaller than that.

Mukherjee says that in 1989, a geneticist named Peter Goodfellow

narrowed “maleness” to a single gene on the Y chromosome,
simply called SRY. To test his theory, Goodfellow genetically altered
female mice to carry a copy of the SRY gene. Some of the offspring,
though chromosomally female (XX chromosomes) seemed male in
both anatomy and behavior. In other words, by altering a single
gene, Goodfellow completely changed the identities of those mice.
This is just one example of how our genetics play a role in who we
are.

(Shortform note: While a single gene may explain both sex and
behavior in mice, humans are quite a bit more complex. Scientists
have, to date, identified 19 separate genes that help determine the
masculinity or femininity of the human brain—in other words,
whether that person will “feel like” and identify as a man, a woman,
or neither. When a person’s brain and biological sex don’t match, it
can result in a condition called gender dysphoria, where the person
feels trapped in the wrong body.)

Environment Plays a Large Role in Identity

Very few traits are purely genetic because most of them are also
influenced by the environment. For example, identical twins (who,
by definition, have all the same genes) could look and act very
differently if one becomes a professional athlete while the other
becomes an office worker.

Also, Mukherjee says that genes often create tendencies or

predispositions toward certain kinds of behavior, but those
behaviors still won’t appear unless the environment draws them
out. For example, someone who’s genetically predisposed to
alcoholism could go his or her entire life without ever drinking, and
therefore without becoming addicted to alcohol.

Different Types of Environment

A major part of a person’s identity is how he or she acts,

but, as Mukherjee says, our traits and behaviors are
heavily influenced by our environment. In fact, in Behave,
Robert Sapolsky—a professor of biology and neurology—
explains that there are actually three different types of
environment that interact with our genetics to determine
how we act in any given moment:

Physical environment. Our surroundings influence

how we act in numerous ways. For instance, if the
area is clean and well-maintained, we’re more
likely to be polite and follow the rules because it
seems like the sort of place where that’s expected.

Moral environment. How close we are to a

situation, both physically and emotionally,
determines how we’ll respond to it. For example, if
we see a child in danger, we’re likely to jump into
action; if we read a story about a child in danger,
we’re more likely to do nothing. Similarly, if the
child is someone we know personally, we’re much
more likely to try to help than if the person is a
stranger.

Social environment. We’ll often factor who’s nearby

into our decisions about how to act. For instance,
men tend to be more decisive and aggressive
when women are nearby. Also, people tend to be
more likely to put themselves in danger if others
are around—perhaps because there’s the chance
that they’ll help, or maybe simply for the chance to
be seen as a hero.
The Environment Permanently Changes Our Genes

We’ve said before that genes switch on and off as you grow from a
single cell into an infant, and that’s why you have so many different
types of cells even though they all have the same DNA. However,
genes also switch on and off throughout our lives in response to
environmental factors. For example, when you’re exercising, your
body will activate genes that burn extra nutrients in order to boost
your energy.

Even more interestingly, Mukherjee says that those repeated

activations and deactivations leave permanent marks. Molecules
called methyl tags attach themselves to genes during this process,
and enough methyl tags on a gene can affect how it works. For
example, researchers believe that some cases of cancer are due to
these methyl tags blocking the “off switch” for cell division, causing
potentially deadly tumors to form.

(Shortform note: Environmental effects on genes may be even more

widespread and impactful than Mukherjee suggests. In Lifespan,
geneticist David Sinclair explains his theory that these long-term
changes in gene function are the reason why we age. Even more
astoundingly, Sinclair believes that it’s possible to undo these
changes with genetic engineering—to remove the methyl tags and
return cells to their original functions. In short, Sinclair believes that
someday it will be possible to reverse the aging process, and that it
might even happen in our lifetimes.)

Eugenics: The Misuse of Genetics

In 1883, biologist Francis Galton published a book called Inquiries
into Human Faculty and Its Development. Galton, inspired by his
cousin Darwin’s work, theorized that selective breeding programs
could improve the human race much more quickly than natural
selection would: Those with desirable traits like high intelligence,
health, and physical strength would be encouraged (or forced) to
breed, while those with undesirable traits like chronic illness would
be prevented from breeding. Mukherjee points out that Galton’s
ideas were deeply immoral from the start, and implementing them
would severely infringe on people’s reproductive freedoms.

Galton’s ideas reached their terrifying conclusion decades later. In

1933, Adolf Hitler became chancellor of Germany. Hitler dreamed of
using eugenics to create a “perfect” human race, and so his
followers began massacring undesirables—a label that included
Jews, Roma, and disabled people, among others. By 1934, they were
forcibly sterilizing some 5,000 people every month, and by the time
of Hitler’s death in 1945, the Nazis had killed an estimated 11 million
people in pursuit of Hitler’s ideal human race. The subject of
eugenics has been largely off-limits in the scientific community ever
since.

Mukherjee says that, if any good can be said to have come from the
Holocaust, it came from making eugenics taboo.

Iatrogenics: Hurting by Trying to Help

Eugenics and the Holocaust are some of the most

extreme and horrifying examples of iatrogenics—harm
caused by an attempt to make things better. Statistician
Nassim Nicholas Taleb discusses iatrogenics in Antifragile,
saying that people almost invariably make matters worse
when they try to improve on what nature has created.

The term iatrogenics comes from medicine. Until

relatively recently, when doctors discovered the existence
of germs and started using proper antiseptic techniques,
people commonly got sick and died from the very offices
and hospitals where they sought treatment. Doctors
trying to help ended up causing more harm. Similarly,
Taleb believes that events ranging from wars to climate
change are the result of people forcing their will upon the
world when it isn’t needed or wanted.

According to Taleb, this damage happens because people

put their trust in science and mathematics—predictions,
models, and the like—when those processes are
inevitably flawed. The natural world is the result of
millions of years of competition and evolution, while
human ideas and interventions are based on extremely
limited studies and tests.

Therefore, Taleb believes that we need to fundamentally

change how we think about taking action. Currently, the
burden of proof rests on the naysayers: People who are
against an idea have to prove that it’s dangerous or
harmful. Instead, Taleb believes that people in favor of an
idea should have to prove that it’s not harmful, or at least
that the benefits will be worth whatever harm it could
cause. So, for example, if scientists want to move forward
with genetic engineering projects, Taleb would first want
them to prove that their work can’t reasonably be used to
 harm people or damage the environment.

Part 6: Genetic Engineering—the Future of

Genetics?
Mukherjee believes we now understand genetics well enough that
our next step forward is to start manipulating genes. In this section,
we’ll discuss how scientists have already begun to explore the
possibilities of gene manipulation with new technologies like stem
cell research. However, progress is slow due to ethical and legal
concerns, especially when it comes to modifying human genes.

Gene Therapy Could Be the Future of Medicine

Mukherjee says that gene therapy—using genetic engineering to fix

damaged or disease-causing genes—offers promising treatments
for diseases ranging from hemophilia and cystic fibrosis to cancer.

(Shortform note: Safe and effective gene therapy is still a work in

progress. In the US, it’s currently only available to patients who agree
to participate in clinical trials.)

One major area of study is in pluripotent stem cells: immature cells

that can be genetically manipulated to grow into any type of adult
cell. While there are obvious ethical issues with harvesting
immature cells from human embryos, doctors now believe it’s
possible to manipulate the genomes of adult cells so that they
revert to stem cells. From there, the cells can grow into whatever’s
needed. In other words, doctors may be able to treat patients using
stem cells harvested from their own bodies.

Theoretically, doctors could use these stem cells to regenerate

damaged nerves and organs, helping people to heal from injuries
and diseases that are otherwise untreatable.

(Shortform note: Aside from exciting new treatment possibilities,

stem cells are also useful to model how diseases progress and to
test new drugs. For example, a researcher could take a cell sample
from a patient, grow that sample into new tissue, and observe how
the disease affects it. The researcher could also use that sample to
test experimental treatments without putting the patient’s health at
risk.)

Mukherjee also discusses CRISPRs: “Clustered Regularly

Interspaced Short Palindromic Repeats”—in simple terms, repetitive
and easily identifiable sequences of nucleotides.

A gene editing technique called CRISPR-Cas9 targets those

sequences using an enzyme called the Cas9 nuclease, allowing
scientists to make precise cuts to DNA. That, in turn, allows specific
sequences of DNA to be removed and other sequences to be
inserted. In short, scientists can use this technique to make precise,
controlled edits to a cell’s DNA, thereby changing the genetic
instructions encoded in it. Editing genes this way could potentially
cure a wide range of genetic diseases, correct harmful mutations,
and possibly even treat cancer.

Problems With CRISPR

 While CRISPR-Cas9 is a powerful gene editing technique,
it has several serious limitations that scientists are still
working to overcome:

Hard to scale. It’s difficult to edit DNA in large

numbers of cells at once, which severely limits
CRISPR’s usefulness as a treatment for widespread
or systemic issues throughout the body.

Not 100% effective. Even genes that are targeted by

CRISPR may not show edited genomes as
intended.

Not 100% precise. Though rare, CRISPR can affect

genes other than the intended targets. These
unintended edits could, in theory, cause the sorts
of harmful mutations that CRISPR-Cas9 is
intended to correct—for example, an uncontrolled
mutation could cause cancer.

Germline Editing: Inheritable Changes

Mukherjee says that gene therapy currently only affects the person
it's performed on and doesn’t get passed to that person’s children.
However, it’s theoretically possible to create a human embryo using
genetically modified stem cells, if those stem cells can be
converted into gametes (sperm and eggs). While that should be
possible—stem cells should be able to turn into any type of cell—
the technique is still unproven.
But if scientists could create genetically modified embryos in this
way, it would mean all of that person’s cells, including his or her
gametes, would carry the modifications. Therefore, those changes
would be passed down to any children the person had. At that
point, Mukherjee says, we would have gone from editing a person’s
genes to editing a person’s genome; in doing so, we’d have created
an entirely new type of organism, and potentially changed the gene
pool forever.

(Shortform note: The first, and so far the only, known instance of
germline editing happened in 2018: Biologist He Jiankui used gene-
editing techniques on human embryos with the goal of creating
people who were immune to HIV. Three gene-edited babies were
born from He’s work. While those three people are apparently
healthy children today, many scientists agree that He crossed an
ethical line by performing the procedure on people who couldn’t
consent to it—meaning both the embryos and any children they
might have in the future. Those scientists also argue that the
children could suffer unintended side effects, such as harmful
mutations or cancer. He served a three-year prison sentence for
violating medical regulations, which ended in April of 2022.)

Germline Editing: Legal, Practical, and Ethical Concerns

Currently, germline modifications—changes that will be passed on

to future generations—are illegal, and Mukherjee says that’s a wise
policy for several reasons. On a practical level, scientists’
understanding of genomics is still limited; we simply don’t know
enough about how genes interact with each other and with
environmental factors. That means that even a seemingly beneficial
change to a gene could have unforeseen and devastating
consequences.

Furthermore, on an ethical level, genetically modifying the human

race raises uncomfortable echoes of eugenics and the Holocaust,
and poses many difficult questions. For example, should we
engineer away undesirable traits if we can do it without killing living
people, or would that be giving medical treatment without consent?
Should parents be able to choose what traits their children will have,
thereby creating “designer babies?” If we’re able to “improve” the
human genome, would that change what it means to be human—in
other words, would people who don’t have those changes be
considered somehow less than human?

These are deep moral questions without easy answers; but they’re
questions that Mukherjee believes we’ll have to face before we
push genetics too much farther.

Counterpoint: In Support of Germline Editing

Dr. John Harris—one of the world’s leading authorities on

bioethics—believes that scientists have not only the right,
but the moral responsibility to use germline editing to
prevent genetic diseases and thereby reduce human
suffering.

Harris argues that there’s no evidence backing up

concerns about side effects, and that those who talk
about human rights, dignity, and personal identity can’t
adequately explain how germline engineering will infringe
on any of those things.
 Furthermore, Harris points out that many people argued
strongly against in-vitro fertilization (IVF) using many of
the same points: that it’s unnatural, that there could be
side effects, or that people born from IVF would be
inherently different somehow; not quite human.
However, today, IVF is a widely used and accepted
treatment for infertility—the children born from IVF are
perfectly healthy, and there’s no sense of exclusion or
“otherness” because of how they were born. Harris
believes that someday the arguments against germline
editing will prove to be just as unfounded as those
against IVF were.

Exercise: Review What You’ve Learned From The

Gene

The Gene contains a lot of information about both the history and
science of genetics. Take a moment now to think about what you’ve
read, and consider what you know now that you didn’t know before.

What’s something you’ve learned about the history of genetics? This

could be an important scientist whose name you didn’t know, or a
surprising discovery you weren’t aware of.
What’s something you’ve learned about the science of genetics?
This might be something about how genes are made, what they do,
or how scientists can manipulate them,

What’s something in your own genetics that influences how you see
yourself? Some examples might be your gender, your skin color, or
an exceptional trait like being very tall.

If scientists could safely change something about your genetics,

would you want them to? Why or why not? What would you change
about yourself, if anything?