All Genetics Is Epigenetics
This is a preliminary draft of one chapter of a book-in-progress
tentatively entitled, “Evolution As It Was Meant To Be — And the Living Narratives That Tell Its Story”.
You will find
a fairly lengthy article serving as a kind of extended abstract of major
parts of the book. This material is part of the
Biology Worthy of Life
Project. Copyright 2017-2021
The Nature Institute.
All rights reserved. Original publication: May 7, 2019.
Last revision: May 7, 2019.
You and I harbor trillions of “sub-creatures” in our bodies. I am not
referring to the microorganisms in our guts, but rather the cells we
consider our own — the constituents of our muscles and brains, our livers
and bones, our lenses and retinas. Each of these cells, embedded in its
supportive environment, sustains a dauntingly complex and unique way of
life. If we had first discovered such cells floating singly in a pool of
water and had observed them through a microscope, we would have judged
them to be distantly related organisms. Phenotypically (that is, in
visible form and function) one cell type can differ from another as much
as an amoeba differs from a paramecium.
All the cells in the human body have descended from a single cell (zygote)
with a single
And just as hundreds of different cell types have arisen from that one
zygote, so, too, have the multicellular, intricately organized entities we
know as lung, heart, eye, kidney, and pancreas, along with all our other
organs. Supremely interdependent as these are, each is nevertheless a
functioning organic world of altogether distinctive character.
For the past century these facts of development have been thought to
present a (largely ignored) problem for the gene-centered view of life.
The developmental biologist Frank Lillie, who had directed the prestigious
Marine Biological Laboratory at Woods Hole, Massachusetts, and would go on
to become president of the National Academy of Sciences, remarked in 1927
on the contrast between “genes which remain the same throughout the life
history” of an organism, and a developmental process that “never stands
still from germ to old age”. In his view, “those who desire to make
genetics the basis of physiology of development will have to explain how
an unchanging complex can direct the course of an ordered developmental
(Lillie 1927, pp. 367-8).
This ordered developmental stream, of course, includes generation of the
hundreds of different cell types in our bodies. It is hard to understand
how a single genomic “blueprint” — or any other way of construing a fixed
genetic sequence — could by itself provide the definitive causal basis for
these hundreds of radically distinct ways of living. If the blueprint is
compatible with all of them, do we have compelling grounds for thinking
that it fundamentally determines any one type of cell, or organ,
let alone all of them together? One might reasonably expect that other
factors direct the developmental process toward particular outcomes of
such different sorts.
A more balanced understanding arises when we watch how every cell displays
its character through its life as a whole. That character, in all its
qualitative richness, somehow seems decisive. DNA is caught up in
a seamless and integral way of being. When we grasp this integral nature,
we quickly realize that the idea of DNA as the crucial causal determinant
of the whole is an impossible one. As a specific kind of liver cell
passes through its developmental lineage, it must sustain its entire
organization in a coherent and well-directed manner from one cell
generation to the next — including, for example, the cytoskeletal and cell
membrane organization described in
It must also bring about and orchestrate the elaborate performances of its
chromosomes we saw in
— performances that are unique to this type of cell and that chromosomes
themselves have no way to set in motion.
(We will look at this “ordered developmental stream” from a slightly
difficult angle — and in an evolutionary context — in
“Evolution Writ Small”.)
Every individual part, including DNA, is shaped by, and gives expression
to, the character of a larger whole. As functional participants in
diverse physiological processes, our genes do not in fact “remain the same
throughout life”. They, like all parts of a cell or organism, gain their
identity and meaning only within the context of innumerable,
interpenetrating, living narratives
An old problem
Coming to our own day, we find a peculiarly late-arriving acknowledgment
of old problems. Here is where we encounter that rather mysterious and
too often abused keyword of contemporary molecular biology:
epigenetics (along with its companion, epigenome). The
discipline of epigenetics drives today’s effort to answer Lillie’s
long-ignored question: What is the relation between our genes and the
“ordered developmental stream” that puts those genes to such diverse uses?
But today the question has gained additional dimensions. The Human Genome
Project and its successors surprised many by revealing an unexpectedly low
number of human genes relative to many other organisms — roughly the same
number, for example, as in the simple, one-millimeter-long, transparent
roundworm, Caenorhabditis elegans. Many began to ask: If genes
really do account for the organism in all its complexity, how can it be
that a primitive worm boasts as many genes as we do? "As far as
protein-coding genes are concerned", wrote Ulrich Technau, a developmental
biologist from the University of Vienna, "the repertoire of a sea anemone
… is almost as complex as that of a human"
(Technau 2008, p. 1184).
A further revelation only compounded the difficulty: our own genome was
found to have a great deal in common with that of many animals. In
particular, we were said to share about 98.5% of our genome with
chimpanzees. A good deal of verbal hand-wringing and chest-beating
ensued. How could we hold our heads up with high-browed, post-simian
dignity when, as the New Scientist reported in 2003, “chimps are
human”? If the DNA of the two species is more or less the same, and if, as
nearly everyone seemed to believe, DNA is destiny, what remained to make
us special? Such was the fretting on the human side, anyway. To be
truthful, the chimps didn’t seem much interested.
All this news conspired to bring epigenetics to the fore. In 2010 the
editors of the journal Nature wrote:
By 2004, large-scale genome projects were already indicating that genome
sequences, within and across species, were too similar to be able to
explain the diversity of life. It was instead clear that epigenetics
… could explain much about how these similar genetic codes are
expressed uniquely in different cells, in different environmental
conditions and at different times.
(Nature editors 2010)
And in 2015 a contributor to the same journal described a huge,
epigenome-centered project, sponsored by the US National Institutes of
Health, which was “likely to provide a leap forward in pinning down one of
the central mysteries of biology: how do cells with the same genetic
instructions take on wildly different identities?”
Lillie’s old question had finally come center stage. But had the meaning
of the question really been recognized? And what, after all, is
this mysterious thing called epigenetics?
Epigenetics — a useful term?
Etymologically, the word epigenetics suggests something like “on
top of genetics” or “added to genetics”. In common technical use, the
word refers today to “heritable changes in gene function that are not due
to changes in DNA sequence” — where the DNA sequence is a
succession of nucleotide bases constituting the “letters” of the so-called
genetic code, and heritable applies not only to what can pass from
parent organisms to their progeny, but also what passes from any given
cell to its daughter cells. In other words, epigenetic refers to
that which is not rock-bottom genetics, not genetics proper, while yet
somehow touching on genetics.
This usage, however, remains deceptively gene-centered. This is shown by
the prevailing notion that epigenetics has to do only with secondary
“annotations” of the primary “genetic program”. For example, researchers,
having discovered certain chemical transformations of both DNA and the
overall substance of chromosomes, typically refer to these transformations
as innocent-sounding and transient “marks” on an otherwise fundamental and
essentially unchanging reality.
But if we are wondering just how fundamental and unchanging the meaningful
genetic sequence is, then this way of speaking smacks of circular
reasoning. We can refer to the chemical transformations as mere marks
only because we have already concluded that whatever cells do with their
genome cannot be considered genuinely transformative and creative — cannot
redefine what the genome is. In other words, we prefer to keep the genome
a kind of static, “eternal” essence that, unlike all the other parts of an
organism, need not continually become what it is or else cease to
Rather than think of epigenetics as the application of incidental marks,
we could conceive it more realistically as encompassing all the ways DNA
is caught up in the activity of its larger context and brought into
service of the whole. I say “more realistically” because there is, in
fact — as two molecular biologists recently put it in the journal
Nature — “an avalanche of biochemical evidence revealing a complex
and versatile array of molecular mechanisms that regulate gene expression
without changing DNA
(Cervantes and Sassone-Corsi 2019).
In other words, what genes mean to the organism is not merely a matter of
the DNA sequence or a “genetic code”. It is more a question of the many
different ways an organism can employ its genes.
So the word epigenetics may usefully remind us that what is “on top
of” DNA is nothing less than the functioning organism as a whole. But a
word that threatens to encompass just about everything begins to lose its
value as a special term. And this in turn suggests that we could just as
well retire the word and get on with describing how organisms carry out
their organically integrated lives — express their own character — and how
they constrain their genes to serve that character.
In the mammalian genome, chromosomes normally come in pairs, one inherited
from the mother and the other from the father. Any given gene occurs
twice, with separate versions (alleles) located on the two
chromosomes. These two alleles may or may not be identical. For example,
there are mice that, in their natural (wildtype) state are
dark-colored — a color that is partly dependent on a gene known as
Kit. The mice normally have two identical copies of this gene.
When, however, one of the Kit alleles is mutated a certain way, the
mouse shows white feet and a white tail tip.
That result was perfectly natural (if you call such artificial gene
manipulations "natural"). But it is also where the story becomes
interesting. Scientists at the University of Nice-Sophia Antipolis in
France took some of the mutant, white-spotted mice and bred them together
(Rassoulzadegan et al. 2006).
In the normal course of things, some of the offspring were again wildtype
animals — neither of their Kit alleles was mutant.
However, to the researchers' surprise, these "normal", wildtype offspring
maintained, to a variable extent, the same white spots characteristic of
the mutants. It was an apparent violation of Mendel’s laws of
inheritance: while the genes themselves were passed between generations
properly, their effects did not follow the “rules”. A trait was displayed
despite the absence of the gene previously corresponding to it.
Apparently something in addition to the genes themselves — something
“epigenetic” — figured in the inheritance of the mice offspring, producing
the distinctive coloration.
Another group of researchers, led by Michael Skinner at the University of
Washington, looked at the effects of the fungicide vinclozolin on
Banned in Scandinavia and Europe but allowed on some crops in the U.S.,
vinclozolin is an endocrine-disrupting chemical. If pregnant female rats
are exposed to it while their embryos are undergoing sexual organ
differentiation, the male offspring develop serious problems as adults —
death of sperm-generating cells, lowered sperm count and motility and,
later, immune abnormalities and various diseases including cancer. The
remarkable thing is that the effects were found to be transmitted over
four generations without weakening. That is, acquired characteristics —
deficiencies in embryos brought on by fungicide exposure — were inherited
by offspring who were not subject to the same exposure.
Inheritance aside, puzzling results such as these put the question, “Are
genes equivalent to destiny?” in a new light. In 2007 a team of
researchers at Duke University reported that exposure of pregnant mice to
bisphenol A (a chemical that was then used in many common plastics such as
baby bottles and dental composites) “is associated [in the offspring],
with higher body weight, increased breast and prostate cancer, and altered
reproductive function“. The exposure also shifted the coat color of the
mice toward yellow — a change again found to be transmitted across
generations despite its not being linked to a gene mutation. Moreover,
the changes brought on by the chemical were negated when the researchers
supplemented the maternal diet with folic acid, a B vitamin
(Dolinoy et al. 2007).
And so an epigenome that responds to the environment can respond to
healthy as well as unhealthy influences. As another illustration of this:
researchers at McGill University in Montreal looked at the consequences of
two kinds of maternal behavior in rats. Some mother rats patiently lick
and groom their newborns, while others generally neglect their pups. The
difference turns out to be reflected in the lives of the offspring: those
who are licked grow up (by the usual measures) to be relatively confident
and content, whereas the neglected ones show depression-like symptoms and
tend to be fearful when placed in new situations.
This difference is correlated with different levels of activity in
particular genes in the hippocampus of the rats’ brains. Not that the
gene sequences are themselves mutated in the usual sense. Rather, the
researchers found that various epigenetic modifications in the hippocampus
alter the way the genes work
(Weaver et al. 2004).
Other investigations have pointed toward similar changes in the brains of
human suicide victims who were abused as children
(Poulter et al. 2009).
What has perhaps excited the general public most is this application of
epigenetic studies to human beings. Take, for example, the frequently
cited Dutch Hunger Winter during the winter and spring of 1944–1945. The
much-studied effects of this famine were found to extend, not only to the
children of women who were pregnant during the months of hunger, but also
to their grandchildren.
Such findings seemed to make clear that our environments and our responses
to those environments can play a major, shaping role in our lives. This
seems to have encouraged in many the hopeful thought, “Maybe we are not
really just gene-driven machines” — which surely is true enough, but also
rather strange. I will try to explain.
Is the appeal to epigenetics an
attempt to recover ourselves?
Do we really need evidences such as those cited above to convince
ourselves that we are not gene-driven automatons — that the things
we do and the responses we offer to environmental challenges
really matter? I imagine we all know better. Do we not all know that our
own choices about the way we treat our children, our spouses, our friends
and neighbors, our colleagues at work, and the material world around us
matter a great deal, and that the effects of such behaviors can play down
through subsequent generations?
Do we not know that everything we do, whether it is running a marathon in
hot weather or sitting and shivering in cold weather, comprehensively
affects our physiology, including specific genetic responses that are
owing precisely to our choice of activity? And do we not know that
the surgeon’s delicate disentangling of blood vessels and nerves, or the
pianist’s evocation of a special mood while performing an all-too-familiar
piece, are likewise produced in part by bringing genes into the service of
extraordinarily refined and expressive muscular activity — an activity
that neither genes nor anything else could compel from anyone?
If we have lost those awarenesses, then I doubt that new discoveries
emerging from the world’s molecular biological laboratories will make much
difference. On the other hand — and to be fair — I understand that the
narrative of mindless, implacable law and blind chance that we are given
by contemporary science can become an oppressive reality for the human
spirit. So it is hardly surprising that we should immediately grasp at
whatever scraps of more encouraging news should dribble out of those
But the fact remains that there is little hope for the human spirit unless
the entire story about mindless, implacable law and blind chance is
unmasked as the pitiful fantasy it really is. Anyone who doubts this need
only look at what began happening quickly after the discovery of
“epigenetic” effects. No sooner had certain gene-regulatory “marks” been
found on key elements of the chromosome than some began to suggest that
they constituted an epigenetic “code”
(Strahl and Allis 2000).
An epigenetic “program” was commonly said to contain “instructions” for
“control of gene expression”. And so an editorial entitled “Time for
Epigenetics” in the International Journal of Biochemistry & Cell
Biology told us that
The genome and epigenome [that is, the sum of all the epigenetic “marks”]
together determine the phenotype and hence, the function and
characteristics of a cell at any given point in development and during
differentiation. At the core of gene regulation are elaborate
molecular programs that alter the packaging of DNA into chromatin,
thereby regulating DNA accessibility to transcription complexes and
providing cues to the activation or repression of gene regulatory
In other words, the attempt was made to assimilate epigenetics to the
existing understanding of genetic “programs” and “instructions”. The
programs and the instructions simply became a little larger and more
But the truth, daily becoming harder to ignore, is that the entire cell
and organism are what lie “on top of” genetics, as we will be seeing in
further chapters. Once the biological community fully takes hold of this
truth, it will be realized on all sides that nothing is merely
genetic; every so-called genetic activity is an expression of its
entire context, and therefore is altogether epigenetic. The abstraction
of genetics from the rest of the organism has distorted biology on an epic
Exactly how the story of the imperial gene was false, and with what
seismic implications for the foundations of contemporary biology, is still
scarcely appreciated by the general public — or even by many of those
scientists who have been pronouncing the end of the era of the gene.
Anyone who is inclined to question the extent of this falsehood might want
to take a quick look at
where the full extent of the organism’s managerial play with its genes is
This has been the standard statement for a very long time. However, we
now know that many people have some cells derived from a different genome.
For example, a fetus may assimilate cells from its mother, and there can
be an exchange of cells between fraternal twins in the womb, even if they
are oppositely gendered. The
conventional statement, however, serves well enough for our purposes.
Anway et al. 2006
Crews et al. 2007.
Altucci and Stunnenberg 2009.
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Steve Talbott :: All Genetics Is Epigenetics