At the heart of the disagreement lies a deceptively simple question: how much of the variation observed between individual epigenomes is actually driven by genes rather than by environment? Zaina’s reply leaned heavily on evidence that genetic differences between individuals exert a powerful influence on epigenetic patterns, particularly DNA methylation, the chemical modification of cytosine bases that is the most widely studied epigenetic mark. He pointed to studies such as work by Husquin and colleagues, published in Genome Biology, which explored the genetic basis of human population differences in DNA methylation and their causal impact on immune gene regulation. If, as Zaina contends, the individual characteristics of the epigenome are for the vast majority dependent on interindividual genetic differences, he asks whether the field should really invest so heavily in understanding the social and environmental ramifications of those differences.

Zaina’s answer is a firm no, and he offers two distinct reasons for it. The first is that he believes there is little to be learnt from studies of environmentally driven variation in epigenetic predispositions to disease, because what he calls the grip of genetics over epigenetics is so strong that the field should, in his view, be renamed paragenetics. The term is deliberately provocative: it suggests that epigenetics is not an autonomous discipline studying environmental regulation of the genome, but essentially a satellite of genetics, a layer of molecular detail whose variation is predetermined by underlying DNA sequence. The second reason is more subtle and more philosophical. Zaina warns that by calling for a complexification of the biosocial tools of epigenetics, researchers run the risk of reifying the social differences under study, converting them into the genetic differences that supposedly have a grip on them. In other words, the very act of tracing social disparities to molecular marks might end up naturalizing those disparities as biological facts.

Chiapperino and Paneni’s response does not dismiss these concerns. They concede that Zaina’s reading of the relationship between genetics and epigenetics contains several elements of truth, and they note that these elements can also be found in a well-established thread of philosophical, historical and sociological scholarship on the subject. Epigenetic differences, they acknowledge, may not simply be the marks, the product, or the biological correlates of one’s unique exposures to ecological, material and social environments. The epigenome is also the result of developmental trajectories, meaning the timing of events during an organism’s development, and of individual genetic differences, meaning variation in DNA sequence. The authors are explicit that they never intended to suggest otherwise, and they credit Zaina for acknowledging that dialogue around the biosocial aspects of epigenetics is worth the community’s effort.

But the authors argue that a wrong conclusion is often drawn from this acknowledgment. Claiming that the presence of genetics’ grip on the epigenome proves either that environmental determinants are unimportant, or that the epigenome is in essence under the control of the genome, is, in their view, just as problematic as the opposite claim that the epigenome sits entirely at the mercy of its environments. The reason, they insist, is that this is not an either/or matter. Drawing on extensive scholarship in developmental epigenetics and on decades of analysis of the nature-nurture debate, they argue that the dichotomous framing itself is the problem. Genetic and non-genetic factors, they write, constitute a dynamic, mutually dependent, relational developmental system within which different components and levels of organization coact to promote the emergence, maintenance, or modification of phenotypic traits. On this view, asking whether genes or environment matter more is a category error, because both are constitutive of the developmental process rather than competing causes of it.

From this diagnosis flows what Chiapperino and Paneni describe as a pragmatic call towards methodological symmetry. Their complaint is not that epigenetics ignores biology, but that the sophistication of its methods, tools and questions is strikingly lopsided. When researchers study biological variables of developmental systems, they deploy elaborate molecular assays, statistical models and experimental designs of considerable complexity. Yet when it comes to socio-environmental variables and their biological ramifications, the same level of methodological rigor is rarely matched. Why, the authors ask, should the measurement of social exposures, life conditions and environmental contexts remain so comparatively crude when the molecular readouts they are supposed to explain have become so refined? This asymmetry, they suggest, is a genuine scientific weakness, not merely a sociological observation, because poorly characterized environmental variables undermine the very inferences that epigenetic studies are designed to support.

The second half of their reply tackles Zaina’s warning about reification more directly. Chiapperino and Paneni state plainly that they do not believe the complexity of the phenotypes and human conditions studied in epigenetics will ever be amenable to genetic differences, let alone be bound to be reframed as genetics-related phenomena. Crucially, their reasoning is not that misinterpretation is impossible. They fully acknowledge that genetic or epigenetic differences can be misread as privileged informational sources, obscuring the deep social, historical and environmental ramifications behind them, and they cite a body of critical scholarship that has repeatedly raised the alarm about risky revivals of sociobiological ideas within epigenetics. Scholars such as Maurizio Meloni, who has written on race in an epigenetic time, and Dupras, Saulnier and Joly, who surveyed the ethical, legal and social dimensions of the field, have hammered this nail on its head, in the authors’ words. The concern that epigenetics could become a vehicle for old biological determinism dressed in new molecular clothing is taken seriously rather than waved away.

Instead, the authors ground their confidence in a different principle: the impossibility of reducing complex phenotypic differences to either one of their components, whether the genome or the environment. There may be specific phenotypes for which a genetic difference is more instructive for understanding the roles and contributions of a given epigenetic difference, including those relating to environmental exposures or developmental trajectories. Yet even these phenotypes, they argue, must ultimately be explained as the product of the biosocial components of the system, that is, of the organism as a whole embedded in its conditions of life. Once this distinction is recognized, the authors write, they cannot share Zaina’s caution about the risk of affirming the primacy of the genome through the epigenome. A risk of misinterpreting the biosocial dimensions of the epigenome certainly exists, but they pose a pointed counter-question: is that risk enough of a reason to give up on what Zaina himself called the noble and useful enterprise of reducing the daylight between epigenetics and fine-grained mapping of the social milieu?

The exchange closes on a note that is part challenge and part invitation. Experimenting with the epistemic foundations and political undertones of a biosocial epigenetics, the authors concede, is no easy task, and it may carry a controlled and relative risk of discomfort. But they believe there exist few alternatives to walking into this territory, a peregrination metaphor they borrow from Zaina himself, without taking that risk of thinking and writing about these issues with colleagues from different trajectories, if not different worldviews. It may be far from the comfort zone of pipettes and tubes, they write, but it may nonetheless be a productive and exciting stroll. Their closing line, urging scientists to take a walk on the wild side, captures the stakes of the debate: whether epigenetics will retreat into a purely molecular, genetically anchored discipline, or embrace the harder, messier work of integrating rigorous social science into its study of how lives become biology. The correspondence, published as open access in Epigenetics Communications and supported by a Swiss National Science Foundation Ambizione grant, makes clear that this conversation is far from over, and that its outcome will shape how a generation of researchers interprets the molecular traces of human difference.

Subject of Research: The debate over genetic versus environmental influences on epigenetic variation and the biosocial ambitions of epigenetics

Article Title: Walk on the wild side: a response to Zaina

Article References: Chiapperino, L., & Paneni, F. (2023). Walk on the wild side: a response to Zaina. Epigenetics Communications, 3(1), Article 3. https://doi.org/10.1186/s43682-023-00019-z

Image Credits: AI Generated

DOI: 10.1186/s43682-023-00019-z

Keywords: epigenetics, DNA methylation, biosocial science, nature and nurture, developmental epigenetics, genetics, gene-environment interaction, social epigenetics, biological determinism, Epigenetics Communications, Chiapperino, Zaina