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 genome.1 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 stream” (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 Chapter 4. It must also bring about and orchestrate the elaborate performances of its chromosomes we saw in Chapter 3 — 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 Chapter 20, “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 (Chapter 2).
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?” (Ledford 2015). 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?
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 exist.
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 laboratory rats.2 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.
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 laboratories.
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 programs. 3
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 complex.
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 scale.
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 17, where the full extent of the organism’s managerial play with its genes is powerfully suggested.
1. 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.
2. See Anway et al. 2006 and Crews et al. 2007.
3. Altucci and Stunnenberg 2009. Emphasis added.
Altucci, Lucia and Hendrik G. Stunnenberg (2009). “Time for Epigenetics”, International Journal of Biochemistry & Cell Biology vol. 41, no. 1, pp. 2-3. doi:10.1016/j.biocel.2008.09.010
Anway, Matthew D., Charles Leathers and Michael K. Skinner (2006). “Endocrine Disruptor Vinclozolin Induced Epigenetic Transgenerational Adult-Onset Disease”, Endocrinology vol. 147, no. 12 (Dec.), pp. 5515-23. doi:10.1210/en.2006-0640
Crews, David, Andrea C. Gore, Timothy S. Hsu et al. (2007). “Transgenerational Epigenetic Imprints on Mate Preference”, PNAS vol. 104, no. 14, pp. 5942-6. doi:10.1073/pnas.0610410104
Cervantes, Marlene and Paolo Sassone-Corsi (2019). “Modification of Histone Proteins by Serotonin in the Nucleus”, Nature vol. 567 (March 13), pp. 464-5. doi:10.1038/d41586-019-00532-z
Dolinoy, Dana C., Dale Huang and Randy L. Jirtle (2007). “Maternal Nutrient Supplementation Counteracts Bisphenol A-induced DNA Hypomethylation in Early Development”, PNAS vol. 104, no. 32 (Aug. 7), pp. 13056-61. doi:10.1073/pnas.0703739104
Ledford, Heidi (2015a). “The Genome Unwrapped”, Nature vol. 528 (Dec. 3), pp. S12–S13. doi:10.1038/528S12a
Lillie, Frank R. (1927). “The Gene and the Ontogenetic Process”, Science vol. 46, no. 1712 (Oct. 21), pp. 361-8. https://www.jstor.org/stable/1651140
Nature editors (2010). “Time for the Epigenome”, Nature vol. 463, no. 7281 (Feb. 4), p. 587. doi:10.1038/463587a
Poulter, M., L. Du, I. Weaver, et al. (2009). "GABAA Receptor Promoter Hypermethylation in Suicide Brain: Implications for the Involvement of Epigenetic Processes", Biological Psychiatry vol. 64, no. 8, pp. 645-52. doi:10.1016/j.biopsych.2008.05.028
Rassoulzadegan, Minoo, Valérie Grandjean, Pierre Gounon et al. (2006). “RNA-mediated Non-Mendelian Inheritance of an Epigenetic Change in the Mouse”, Nature vol. 441 (May 25), pp. 469-74. doi:10.1038/nature04674
Strahl, B. D. and C. D. Allis (2000). “The Language of Covalent Histone Modifications”, Nature vol. 403, no. 6765 (Jan 6), pp. 41-5. doi:10.1038/47412
Technau, Ulrich (2008). “Small Regulatory RNAs Pitch In”, Nature vol. 455 (Oct. 30), pp. 1184-5. doi:/10.1038/4551184a
Weaver, Ian C. G., Nadia Cervoni, Frances A. Champagne et al. (2004). “Epigenetic Programming by Maternal Behavior”, Nature Neuroscience vol. 7, no. 8 (Aug.), pp. 847-54. doi:10.1038/nature04674
Steve Talbott :: All Genetics Is Epigenetics