On the traces of the biosocial: Historicizing “plasticity” in contemporary epigenetics

French public hygiene: A paradigm of chemical alteration of the body

By the end of the eighteenth century, the problematization of the human body as an entity modified by its environments takes an important epistemo-political turn in several national contexts. ³⁶ Here, we focus on the case of France, whose cultural tradition was dominated by a mechanistic conception of biology that postulated a materialist and deterministic understanding of the body, its environments, and their relationship. ³⁷ Within this context, the notion of “milieu” played a pivotal role in theorizing the processes of evolutionary transformations in their well-known Lamarckian formulation: “[les] animaux doivent leur forme générale aux influences du milieu dans lequel ils habitent.” ³⁸ Yet, it is by means of the coeval ³⁹ hygienist movement that systematic theories aimed explicitly at understanding “the influence of physical things on man” became concrete elements for political strategies to promote “the means of preserving health.” ⁴⁰

These two quotes are in fact the subtitle of the founding treaty “Elements of Hygiene” (1802) by Etienne Tourtelle (1756–1801). Three elements are particularly interesting in the case of French hygienists. First, the human body is conceived as a metabolic chemical entity – before the term metabolism was coined ⁴¹ – whose state is “modified” by its exposure to external factors, such as the “atmosphere”:

The human body, in the midst of the atmosphere, does not have to be thought merely as a mass upon which atmospheric influences act physically, but also as a blend within which chemical bonds are established between its principles and those of the air. At last, as organized body [. . .], the human body receives particular modifications from the atmosphere. ⁴²

Second, the hygienist movement formulates and renders operational a taxonomy of chemical alterations of the body promised to a long fortune. Through the identification of discrete “matters of hygiene” whose chemical action on the body renders them “health modifiers,” ⁴³ hygienists isolate distinct patterns of body–milieu interaction on which to act in order to preserve health:

Circumfusa: the action that bodies exert upon us, like the atmosphere, the places, water, climate.

Applicata: the things that are applied to the surface of our bodies, such as clothes, baths, frictions, cosmetics, etc.

Ingesta: the ingested substances, such as food and drinks.

Excreta: all that relates to excretions.

Gesta: physical exercise and any voluntary action.

Percepta: the influence that our perceptions exert upon the animal economy by means of the encephalon and our nervous system. ⁴⁴

Inspired by the nascent chemical episteme of Antoine-Laurent de Lavoisier (1743–94), ⁴⁵ French hygienism constitutes a strong research program devoted to the establishment of an environmental and social etiology of disease. In this program, diseases are described as mechanical and chemical phenomena emerging at the intersection of external actions and internal effects. The methodical collection of statistics about the living and working conditions of Parisian workers, as well as the recollection of systematic observations about the effects of their milieux on health, constitute a theorization of the importance of discerning healthy and unhealthy bodily states as the product of material and social determinants of pathogenic alterations. Needless to say, this view of disease etiology also has a bearing upon the conceptions of sanitary therapy developed by hygienists.

In fact, a third element worth noting in operationalizations of plasticity thinking in the hygienist movement relates to their approach to the management of these health modifiers. Their taxonomy of chemical alterations of the body gradually crystallizes in a political–moral duty to protect individuals by acting on the milieu, less to restore the health of individuals than to preserve them from external threats. Besides the fact that therapeutics were poorly developed in this period, several concurring factors contributed to the focus of hygienists on actions addressed at reducing the pathogenicity of living conditions. Primarily, medical approaches of the time – in France as well as in other contexts ⁴⁶ – largely privileged the attendance to the manifestations rather than the causes of disease on the states of mind and the body. Going under the label of “expectant medicine,” ⁴⁷ this approach to the treatment of diseases consisted in the recognition of the “natural” tendency of the body toward cure. Thus, the treating role of the physician consisted more in accompanying the body’s intrinsic vital actions to restore health (e.g. through the elimination of external threats), rather than in the administration of artificial remedies to eliminate morbid states. Secondly, before the advent of the Third Republic produced a new political elite with a large component of doctors, the first actors and theoreticians of hygiene in France were liberal chemists who tended to oppose the interference of the state in private affairs such as individual health and treatments. For these reasons, hygienists implemented what philosopher Gérard Jorland has called a “socio-clinical” ⁴⁸ approach to the protection of populations from the threats of their environments. Similarly to what characterized the emergence of public health in other national contexts, ⁴⁹ French hygienists did not focus on the treatment of disease, but rather implemented “treatment” strategies for the population that consisted in the systematic removal of all potential factors of morbidity from the living conditions, habits, and material urban environments of citizens. For instance, the nutrition of workers constituted the object of medical interventions directed at improving its quality, its cleanliness, its distribution, and its nutritional value, all for the purpose of preventing the development of diseases in this population: “Human beings are surrounded by dangers; their frail existence is incessantly threatened by thousands of destructive plagues; its organization subject to the trial of alterations that expose them to a multitude of aches at every moment.” ⁵⁰ Thus, at the beginning of the nineteenth century we observe that the hygienist movement provided an elaborate conception of the reciprocal modulations of bodies and their environments that is grounded in mechanistic explanations formulated in the grammar of nascent modern chemistry. This operationalization of a plastic conception of the body instructed, in turn, institutionalized practices of sanitation, which constituted a historical precedent of health promotion interventions taking place at the crossroad of the organic interiority of the body and the socio-material configurations of its environments. Thus, the permeability of the body to its milieu is, for nineteenth-century hygienists, not only a theorization of the chemical relationship between the organic interiority of the former and the chemical activity of the latter. Rather, it also constitutes the fundamental ground for institutional, administrative, and political actions directed at governing such biosocial nexus.

Metaphorical conjectures about “organic memory”

The question of heredity became a central issue of biological theories in the middle of the nineteenth century. ⁵¹ Besides the confrontations between Lamarckism and Darwinism, this epoch witnessed a density and proliferation of positions, arguments, and experimental practices, which resulted in numerous conceptions of heredity. Such debates straddled the biological and social conceptions of the term, and constituted a prolific epistemic space in which “taxonomies, [. . .] arguments, [. . .] architectures of hereditary knowledge, and the conjunctions of these elements” started to circulate in a variety of social arenas. ⁵² In order to navigate such space, the monumental work of the French zoologist Yves Delage (1854–1920) constitutes a remarkable milestone. In La structure du protoplasme et les théories de l’hérédité ⁵³ he proposes a useful inventory of the urgent questions on development, adaptation, and heredity still open at that time:

If the acquired characters are transmissible, how can the modifications produced in the body be transmitted, with such admirable precision, to the germ-cells, which do not yet contain any of the organs which will be affected by them? If they are not [transmissible], how can the progress of the adaptation of beings to their environment be made? ⁵⁴

At a time in which the structures and the functions of these processes remained largely unobservable at the microbiological level, Delage – and many others – tried to answer these fundamental questions essentially in two complementary ways: first, by looking for observational or experimental evidence of the transmissibility of acquired characters; second, by trying to develop general theories of heredity. One effect of this activity was the emergence of new notions accounting for the dynamics of reproduction and variation as well as stability and adaptation. Interestingly, several of these lay in a lexical space whose two coordinates are the notions of plasma (which shares the same etymology of “plasticity”) and genesis (i.e. generation, birth, descent), as illustrated in Delage’s Tableau du classement des théories générales (Figure 1).

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Figure 1.

Reproduced from Delage, La structure du protoplasme, p.409.

The epistemic space inhabited by notions such as “protoplasm,” “idioplasm,” “plastidule,” “pangenesis,” and “perigenesis” constitutes in Delage’s work a specific category of physicochemical and micromerist theories, which postulate the existence of essential particles making up the basic elements of any living being. Each of these theories forms in its own way the hypothesis of the existence of “particles [. . .] of the same nature, extending [. . .] their influence equally to the determination of all characters.” ⁵⁵ Today, one can read these theories as metaphorical accounts of phenomena that largely escaped direct empirical observations. These different notions may in fact be regarded as non-literal descriptions producing a coherent understanding of two intertwining processes: on the one hand, the transmission of stable characters; on the other hand, the effects of experiences on “organs, physiological functions, psychological aptitudes, instincts, etc.” ⁵⁶ Yet, this great variety of theories is better understood as resulting from the “deeply troubled” ⁵⁷ status of notions of heredity, development, variation, and stability in the life sciences of that time. Among the numerous attempts at solving these long-standing problems, those aiming to account jointly for several of these aspects are particularly interesting for the analyst of contemporary epigenetics. This is significantly the case of Ernst Haeckel (1834–1919).

In order to account for the physicochemical articulation between acquisition, memory, and transmission, Haeckel coined the term “Plastiden” from the abovementioned Greek plastos (molded, formed). The Plastiden designated single-cell organisms, creatures of the lowest morphological or physiological order of “individual.” Haeckel imagined these Plastiden to be filled with a substance he called “Plasson,” which in turn was composed of molecules called “Plastidules,” a contraction between “Plastid” and “Molecule” that, he argued, “must be considered as the molecular factors of the biogenetic process.” ⁵⁸ It is not surprising that this ontological invention has been interpreted as an anticipation of DNA. ⁵⁹ Yet, it is important to nuance this rapid and teleological interpretation. Haeckel’s originality lies less in having imagined a physicochemical substrate of the phenomenon of transmission of characters – many others did that, as Delage testifies – than having tried to integrate into his theory the contextual modifications (or molding) of the very material substrate of life. Haeckel called this process the “perigenesis of plastidules.” A detailed explanation of its workings can be found in the legend of his fascinating scheme (Figure 2).

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Figure 2.

“The scheme of perigenesis [. . .] is intended to illustrate, in a most subtle form, the intricate relations which, in every organic process of development, are formed between the descendants of a common stem-form by the interaction of heredity and adaptation. The transferred motion of the plastidule, which caused heredity, is indicated by red waves; the influence of the external existence conditions, which, by altering the transferred plastidul motion, causes the adaptation by black waves. The difference in the external conditions of existence, to which every organic individual must adapt, is indicated by the different form of the black bodies; the modifications in the internal plastidular movement produced by this cause are represented by black hatching in the red spheres” (Haeckel, Essais de psychologie cellulaire, p.94). Image reproduced from E. Haeckel, Die Perigenesis der Plastidule oder die Wellenerzeugung der Lebenstheilchen (Berlin, 1876), www.deutschestextarchiv.de/book/view/haeckel_plastidule_1876, p.81.

According to Haeckel, the adaptation of plastidules to external influences, and the transmission of the transformations induced by these influences, can be explained by the same “plastic activity.” ⁶⁰ The plastidules were understood mechanically as being subjected to “a ramified undulating movement, which propagates itself without interruption and that can be considered as the efficient cause of the biogenetic process.” ⁶¹ Notably, the temporalities of this process do not belong alternatively here to heredity, or contextual (phenotypic) adaptations. The modifications of the plastidular movement make it possible to account both for phenomena of contextual adaptation (i.e. modifications of the plastidular movement acquired during the life-course, which are potentially transmitted to future generations) and heredity (i.e. the accurate reproduction of the plastidular movement from one generation to another). Indeed, this unified biogenetic process is the core of his theory of organic memory: “heredity is the memory of plastidules”; variability is instead “the receptiveness” (i.e. the mnemonic capacity) of the plastidules. “The former produces stability, the latter variation of organised forms.” ⁶²

Yet, Haeckel’s theory also goes further in that it complements this view with a second hypothesis aimed at explaining another fundamental unity in the phenomenon of (human) life. The undulating movement of plastidules is not just a common explanation for ontogenetic and phylogenetic processes but also a heuristic for the continuity between the organic and the inorganic, the biological and the psychological. ⁶³ While at a molecular level the biogenetic process is characterized by the attraction and repulsion of the atoms composing it, at the level of psychic faculties this very same movement manifests itself as “ordinary acts of human intelligence” ⁶⁴ or (we would say) sociality. Haeckel’s theory affirms, in other words, a monist understanding of the biological and the psychosocial aspects of life, which postulates an additive and progressive continuity (both at the ontogenetic and phylogenetic level) between the basic functioning of life and those of a society. On the one hand, Haeckel affirms that instincts and social attitudes can be explained as manifestations of a faculty progressively accumulated through adaptation, and transmitted through heredity across species: “animal instincts are no more an exclusive property of animal brain than reason is a special privilege of humans.” ⁶⁵ On the other hand, his theory postulates a fundamental ontological unity of phenomena alternatively characterized, in present terms, as social or biological. Indeed, he argues, much as our social existence recapitulates the principles organizing our biology, the cells in our bodies can also be regarded as members of an organized society – a “cellular republic” ⁶⁶ – which is affected and shaped “by education, by exercise, by habits.” ⁶⁷ It is also “the history of human civilization,” he concludes, that “explains the history of the organization of multicellular organisms.” ⁶⁸

Haeckel’s theory of organic memory provides two conceptual elements that respectively mark a departure from the hygienist paradigm in the diachronia of plasticity thinking, and highlight another way of problematizing the entanglement of biological and social dimensions of (human) life. On the one hand, his ideas account for the articulation between contextual adaptations, their memorization in the atomic structures of plastidules, and their intergenerational transmission. The theory of the “perigenesis of plastidules” constitutes a different way of conceiving and operationalizing plasticity in that it provides a complementarist view of generation and transmission, variation and stability, adaptation and heredity. Taken at face value, ⁶⁹ Haeckel’s theory is capable of reconciling the alleged oppositions between Lamarckian and Darwinian theories of evolution. ⁷⁰ On the other hand, Haeckel’s theory also affirms a fundamentally monist view of the psychological, social, and biological aspects of (human) life. This bio–psycho–social hybridity is made possible through the recognition of a common ontology – the undulating movement of the plastidules – governing life as both a state of conscience, individual experience or social condition, and organic process of memorization and reproduction of forms in ontogeny and phylogeny. One inevitable consequence of Haeckel’s theory of organic memory is thus that the monism he defended was not merely a biological thesis rooted in expert culture, but rather constituted the ground for broader social, political, and lay culture endeavors. For instance, his drawings of developmental processes exerted a significant influence that goes beyond the field of embryology throughout the twentieth century. Haeckel’s artistic inclinations inspired views – and attracted several criticisms – regarding the notions of history, evolution, and progress they entailed. ⁷¹ At a political level, both reactionary and progressive thinkers justified in fact distinct options of social engineering on the basis of his representations of ontogeny and phylogeny, which focused respectively on the degenerative effects of social conditions and the social environment as the domain of intervention for regeneration. ⁷²

The experimental decoupling of ontogenetic and phylogenetic plasticity

Toward the end of the nineteenth century, Haeckel’s articulation of the relationships between adaptation, memory, and heredity is fundamentally challenged. The decisive factor in establishing a divide between plasticity in adaptation and heredity later became known as “Weismannism,” or – as the author himself calls it – the “doctrine of the continuity of the germ-plasm.” In commencing his second essay, ⁷³ aimed at a foundational work for a theory of heredity, August Weismann (1834–1914) affirms that:

When we see that, in the higher organisms, the smallest structural details, and the most minute peculiarities of bodily and mental disposition, are transmitted from one generation to another [. . .] we very naturally ask for the causes of such a striking phenomenon [. . .]. And the immediate answer to such a question must be given in the following terms: A single cell out of the millions of diversely differentiated cells which compose the body, becomes specialized as a sexual cell; it is thrown off from the organism and is capable of reproducing all the peculiarities of the parent body in the new individual [. . .]. ⁷⁴

The doctrine rests upon the idea that heredity entails the transfer of a cell (i.e. the germ-cell), which divides early on during development from those constituting the body (i.e. the soma) and that possesses the capacity to develop into a full-blown organism after reproduction. His doctrine was grounded on the conviction that somatic differentiation entailed a progressive loss in the contents of the nuclei (i.e. the germ-plasm – another notion sharing the same etymology of plasticity). This progressive loss of determinants favored the specialization of a given cell (i.e. the expression of cellular specificities) in a given tissue. Consequently, as the complexity of the germ-plasm “gradually diminish[es] during ontogeny,” the doctrine had to entail an early segregation of the germ-line from the somatic track. ⁷⁵ This was in fact the only way to preserve the full span of determinants from one generation to the other.

The separation between the germ and the soma was, however, in direct contradiction with those theories (among which figure prominently Haeckel’s perigenesis and Darwin’s pangenesis) holding the possibility of some inheritance of acquired characters via the progressive accumulation of somatic modifications transmitted to reproductive cells. ⁷⁶ Weismann had, therefore, the problem of reconciling continuity and variation with the proposed segregation of the germ-line from the soma. He tried to solve it by, first, making a distinction between germ cells (i.e. sperm and oocytes in sexually reproducing species) and germ-plasm (i.e. the material content of germ cells from which an individual develops). This way, he could combine the ideas that the continuity across generations lies in the “substance of the germ-cells, or germ-plasm,” and not in the immutability of germ cells, “for the germ-cells are contained in the organism, and the external influences which affect them are intimately connected with the state of the organism.” ⁷⁷ Second, in a later stage of his work he admitted variations taking place in the germ-plasm itself ⁷⁸ by means of external influences upon the development of the germ-line and through recombination during fertilization. He was in fact aware that gametogenesis entailed the loss of part of the determinants – what we would call today the transition from a diploid to a haploid genome. ⁷⁹

Weismann’s work was very influential in exposing some foundational limitations of theories linking phenotypic and evolutionary plasticity such as Lamarckism. In order to craft his own theory of heredity, he dedicated a considerable effort to discussing, experimenting with, and demonstrating the weaknesses of the available evidence for the transmission of acquired characters. However, his critique was directed at those cases of mutilations or wounds occurring during the lifetime of a parent supposedly transmitted to the progeny, such as the influential experiments conducted on guinea pigs by Charles-Édouard Brown-Sequard. ⁸⁰ These cases were problematic to him in that they entailed a modification passing from the somatic to the germ-line; that is, they were in open contradiction with his experiments corroborating the early developmental segregation of the latter from the former. So, even though he excluded the “erroneous [. . .] hypothesis, which assumes that somatic nucleoplasm may be transformed into germ-plasm,” ⁸¹ nothing prevented him from holding the idea that modifications could occur in the germ-line track. In fact, as mentioned above, he also made clear in later writing ⁸² that germ cells – in their own distinct development – may be subjected to modifications from the surrounding environment, which could produce modifications of the elements of the germ-plasm going down the phylogenetic lineage.

The appearance of Weismann’s doctrine marks, therefore, a further moment in the recent history of plasticity thinking, which brings forth a substantive distinction between ontogeny and phylogeny on experimental grounds. After Weismann, variation and stability in the germ-line require being studied in their own distinguished biological trajectory from ontogenetic processes. Weismann’s ideas about the continuity of the germ-line were thus much less conclusive than they are usually portrayed by the familiar version that constituted “Weismannism” throughout the twentieth century. ⁸³ His idea of an early separation between the soma and the germ was less monolithic than it appears in later readings of his work. Weismann himself, in other words, “was not a Weismannian.” ⁸⁴ The idea he found in need of experimental support within “the animal kingdom” ⁸⁵ was the one according to which the progressive losses of determinants from the nucleoplasm (i.e. the content of the nucleus) of somatic cells (which was conditional to cellular specification in his view) could account for the complete restoration of the germ-plasm in the germ cells. Contrary to what later became “a dogmatic faith in Weismannism,” ⁸⁶ his target was the missing mechanistic and experimental explanation that the smallest molecules of heredity can be modified by external influences on somatic cells.

Weismann’s doctrine is a case worth investigating also for the purpose of our inquiry into the ways plasticity thinking produced specific views of the entanglement between the biological and the social aspects of (human) life. As argued by Meloni, ⁸⁷ Weismann’s work entails a radical shift in the study of the interactions between experiences, social conditions, and the organic functioning of the body. After Weismann, it becomes possible to claim heredity as a biological phenomenon sharply distinguished and separated from social transmission and influences. His doctrine of the continuity of the germ-plasm is, for instance, at the origin of the distinction commonly held in psychological and behavioral sciences between innate and learned behaviors. ⁸⁸ Although such a dichotomy has been largely criticized, one of the essential foundations for the modern study of behavior – as an innate biologically driven character or as a learned, cultural phenomenon – resides in Weismann’s germ-plasm theory. Furthermore, and besides his ideas, his graphic representations of differentiation processes have also had a major influence on twentieth-century understandings and representations of the separation between social and biological processes. ⁸⁹ Weismann’s iconographic choice of describing differentiation through cell trees assigned a confined meaning to developmental processes: differentiation takes place through unidirectional relationships, which are not open to effects or feedbacks coming from external agents or lateral processes of differentiation happening across distinct branches. ⁹⁰ These powerful symbolic and theoretical implications of Weismannism suggest a specific origin of the epistemic separation between studies of our social belongings and the biological aspects of (human) life. The transformations of a society embodied into organic functionings and their implications for heredity are, starting from Weismann, two distinct processes that belong to different disciplinary specialties. As argued by Maurizio Meloni, his work inaugurates “the transcendence” ⁹¹ of social from organic life, as matters to be studied from alternative epistemic standpoints. This separation, we might add, should also be highlighted as the necessary premise for the biosocial reunification of our biological and social existence promised by contemporary epigenetics.

Plasticity without (environmental) molding of the substance of heredity

The 1930s and 40s witnessed a renewed interest in the relationship between phenotypes induced by the environment and biological inheritance, thus inaugurating a different interpretation of plasticity in the agenda of biology. As shown by Peterson, ⁹² an organicist “third way” of biological thinking proliferated across this period, which marked a departure from the alternative between mechanistic and vitalist understandings of life. In the face of such a long-standing dichotomy between life-as-complex-machine and life-as-irreducible-to-molecules, thinkers of such a third way brought to the fore the importance of expanding the language of biology beyond the nascent centrality of genes in different sociopolitical contexts. ⁹³ By opening the black box of genotype-to-phenotype transitions and pointing to development as a key process in evolution, these scientists attempted to reconcile the novel episteme of genetics with a complex understanding of organisms, their environments, and their mutual interactions. Chiefly, this was the case of Conrad Hal Waddington (1905–75). ⁹⁴

Waddington’s famous epigenetic landscape ⁹⁵ is a “representation of development as a system, whose parameters are genetic loci and whose state space is a set of phenotypic states.” ⁹⁶ Developmental processes are represented in Waddington’s landscape as a ball rolling down the landscape, whose trajectory is influenced by the (genetically determined) shape of the cliff. It is thus the whole conformation of the landscape (qua developmental system), and not any single element (i.e. any single gene) shaping it, which is at the basis of a phenotypic change. This is illustrated in the less popular “underside of the epigenetic surface” (Figure 3).

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Figure 3.

Reproduced from Waddington, The Strategy of the Genes, p.36.

Waddington’s view of genetic plasticity consists of the capacity of a complex system not to be affected by change in any of its single genetic components. Under this interpretation, plasticity is rather a property of the structure of the system itself. This is the basis of his concept of “canalization”; namely, the capacity of the genome to attain a given developmental outcome in light of environmental as well as genetic perturbations. Here, again, the author mobilizes the model of the landscape to illustrate this concept:

[. . .] the model immediately suggests that one ought to consider the degree of canalisation of any particular path of development. Has the valley a flat bottom and gently sloping sides? If so, there will be only rather a slight tendency for a developmental trajectory, when displaced from the valley centre, to find its way back there again; [. . .]. On the other hand, if the valley bottom is very narrow and the sides steep, it will be more difficult to push the trajectory away from its normal course and it will quickly return there. ⁹⁷

Waddington was not only convinced that canalization could explain phenotypic development, but he argued also for its evolutionary potential: adaptive reaction to “unusual circumstances” may in fact cause an “adaptive character [to become] so far canalised that it continue[s] to appear even when the conditions [return] to the previous norm.” ⁹⁸ In the paper just cited – published under the suggestive title “Genetic Assimilation of an Acquired Character” – Waddington reported the data from a study he conducted in Drosophila melanogaster. The results of this paper display what he calls genetic assimilation; namely, the process through which an acquired character (i.e. a variation acquired during one’s lifetime) could become an inherited one (i.e. a fixed, genetically assimilated variation). The experiment went as follows. After the administration of a heat shock to the pupae of an Edinburgh strain of wild fruit fly, a number of crossveinless specimens appeared with a certain variation, which were classified according to grades of “crossveinlessness” based on the disturbances observed in the formation of the crossveins on the flies’ wings. Two lines of selection were put in place: upward selection in which only crossveinless flies were bred, and downward selection, which encompassed only flies still showing normal wings. After a further selection to reduce genetic variability among the bred flies, the results obtained by Waddington were that flies from the upward selected line started to display crossveinless wings even in the absence of the heat shock.

Waddington did not interpret these results as supporting any form of neo-Lamarckian adaptation. ⁹⁹ Indeed, and contrary to what some of his contemporaries believed, ¹⁰⁰ his reading of the data can be thoroughly inscribed within a neo-Darwinian framework. His interpretation of these experiments was that the response to the stimulus observed was due to selection occurring at the level of the allelic variants present in the population under study. Simply put, selection in the upward line acted on the distribution of those alleles coding for the crossveinless phenotype, raising them up beyond a threshold of frequency allowing the rest of the genome to code for normal wings. As argued by theoretical biologists Eva Jablonka and Marion Lamb:

In more modern terms we would say that the variations being selected were the result of different combinations of the alleles of the many genes that are involved in the regulation of development; as a result of selection, the frequency of the initially rare combinations that contribute to an enhanced response to the stimulus increased. Eventually, selection resulted in the production of those originally extremely rare combinations that produce the crossveinless phenotype even in the absence of the temperature stimulus. ¹⁰¹

However, Waddington’s attempt to reconcile the hypothesis of acquired characters with one of the main pillars of the Modern Synthesis (i.e. Darwinian natural selection acts upon variation of Mendelian genes) had little influence (at least in genetics) for several decades. ¹⁰² As the Synthesis evolved “toward a conservative centre, with little room for more creative and complex ideas,” ¹⁰³ his views were received as a revival of Lamarckism, now viewed as a threat for both theoretical and political reasons. At a theoretical level, his interpretation of the crossveinless flies experiment was at odds with the genetic preformationism to which many of his contemporaries adhered. His view that genes do not define the emergence of a trait – but rather represent a set of potentialities to be alternatively transformed into different phenotypes depending on developmental conditions – had a Lamarckian flavor that contrasted with the received deterministic view of genotype-to-phenotype transitions. ¹⁰⁴ At a political level, explaining the demise of Waddington’s plasticity thinking requires taking into account the rise of Lysenkoism in the Soviet Union and the “morality tale” associated with such a research program in the Western genetics community of the early Cold War years. The political plot orchestrated by Lysenko – that led to the death of his adversary Nikolai I. Vavilov – was soon deployed as an argument against both the ideas (i.e. environmental determination of variation and inheritance of acquired characters) and the views on the governance of science (e.g. the centralized planning of science) associated to the Soviet scientist. In such a political atmosphere, Waddington’s alleged Lamarckism, coupled with his left-wing political leanings, ¹⁰⁵ displayed a damning resemblance to the aberrations of Lysenkoism, which negatively affected the reception of his work in genetics circles. ¹⁰⁶

Nonetheless, his contribution can be regarded as yet another key moment in the recent history of plasticity thinking. Even though the outcome of his experiments was the inheritance of acquired characters, his ideas about the genome do not require such inheritance to generate any modification of the fundamental substance of life. While the organic memory of Haeckel and the modifications of the germ-plasm evoked by Weismann all conceive plasticity as material inscription of the environment into life’s determinants, in Waddington’s work these modifications are located in a different theoretical space. Plasticity is here a property emerging from gene expression in ontogeny and from gene selection in phylogeny. Otherwise stated, plasticity in Waddington is the attribute of a complex system whose responses to perturbations do not require the material molding of the fundamental substance of heredity. Rather, adaptation and variation emerge here from a (developmental) process actualizing the several potentialities of a complex genetic machinery capable of responding to perturbations in its components and/or its environments, and of evolving across the temporalities of natural selection.

Furthermore, it is worth noting how Waddington’s operationalization of plasticity constitutes a distinct theorization of the relationship between life as biological and social phenomenon. His polemical stance toward the Modern Synthesis was in fact not merely dictated by a fundamental disagreement around the deterministic model defended by his “preformationist” colleagues. Rather, his theory of epigenesis was part of a larger philosophical project aimed at demolishing the “Bifurcation of Nature,” ¹⁰⁷ as stated in the motto of the Whiteheadian organic philosophy to which he subscribed. ¹⁰⁸ Waddington considered untenable a dualism of matter that considered the organism and its environment, the biological and the psychological, the mind and the body, as entities characterized by distinct ontologies. The tenets of his organic philosophy constituted a “scientific attitude” ¹⁰⁹ toward complexity that went beyond the understanding and representations of our biology. As argued by Susan Merrill Squier, ¹¹⁰ several of his writings and professional engagements consisted in an attempt to provide a unified theory of complexity useful to biology, philosophy, and the arts alike. His metaphor of the landscape, the author shows, has had an immense impact beyond the borders of the life sciences, reaching out into modern art, popular scientific representations, and landscape architecture. Waddington’s analogical model provided a heuristic to conceptualize systems like biological ones, but also human societies. As he points out, his organic thinking applies as well to the analysis of totalitarian political regimes, or the scrutiny of social systems as “integrated wholes” whose good depends on “the good of its individual members.” ¹¹¹ In its wide-ranging – and often unfulfilled – ambitions, ¹¹² Waddington’s organicism was thus a manifesto of scientific humanism calling for the reunification of what he ironically called “prim Science” and “harlot Humanities.” ¹¹³ In this respect, Waddington’s ideas provide us with another instance of the ways plasticity thinking in the life sciences also opened avenues for interrogating the relationship between life as biological and social phenomenon. His organic philosophy may be regarded as an ante litteram precedent to the contemporary quest for integrative biosocial approaches to the study of health and disease that could move us beyond irreducible oppositions between the social and life sciences.

Plasticity in epigenomics

A substantial part of research funding in epigenetics currently falls under the label of “epigenomics,” which exploits the power of next-generation sequencing to map the epigenetic patterns (i.e. epigenomes) characterizing the diverse tissue types in our bodies. Reference human epigenomic maps are currently a free resource available to researchers interested in the study and comparison of the epigenetic differences that characterize hundreds of cell types in a “normal” or “diseased” state. ¹¹⁷ A closer look at these maps reveals that this strand of epigenetic research employs and operationalizes an understanding of plasticity as the capacity of the genome to produce a diverse range of phenotypes. The epigenome is here characterized as a series of steady-state conformations of the genome that are specific to distinct types of cells in the body, and that determine the transitions between health and disease in a given tissue. In its current and most advanced formulation, epigenomic data are a multilayered description of the “epigenetic plasticity that enables cells to undergo [a] wide range of [cellular] lineage specifications.” ¹¹⁸ From chemical modifications of DNA not affecting the sequence (e.g. methylation), to modifications of the proteins around which DNA is compacted into chromatin (e.g. histone modifications), up to higher-level reshufflings of nuclear architecture, epigenomic maps integrate different snapshots of the material operators of regulation and expression of the genome in a complex representation. Plasticity in epigenomics is thus a distinctive combinatorial notion; namely, the result of distinct layers of genomic activity acting in concert to determine complex phenotypes, specifications, and transitions in the cells of our bodies. The different material operators of genomic differentiation (e.g. methylation, histone modifications, nucleosome positioning) build upon and extend the information potential of DNA in order to craft the diverse phenotypic characteristics of each cell type. The epigenetic profile of any given cell is in fact the result of programmed DNA arrangements, which unfold into the material structuring of distinct layers of combinations among DNA, RNAs, histones, and chromatin modifications in the nuclear genome of a cell.

Epigenomic maps permit us to describe a first conceptualization and operationalization of plasticity in contemporary epigenetics. Our genome is here regarded as a developmental resource, which possesses the capacity to unfold into various epigenomic potentials – be these the different cell types of the body, or the molecular configurations of a diseased tissue. In this respect, plasticity in epigenomics is continuous with the intellectual program of authors such as Waddington. ¹¹⁹ At the same time, the idea of genetic control of phenotypic plasticity in epigenomics appears to be imbued also with Weismannism as interpreted by the “central dogma” of molecular biology. ¹²⁰ Respectively, epigenomics goes along the same track of plasticity thinking à la Waddington in that it postulates the differentiation from the zygote to the whole range of tissues in our body (both healthy and diseased) to be captured by a panoply of steady-state cartographies of the (normal or pathological) epigenetic signatures of each different cell type. In short, epigenomic maps describe, in a Waddingtonian fashion, the behavior of the genome as a complex developmental system crafting a given phenotype. At the same time, epigenomic scientists provide an understanding of plasticity which is essentially (a) on the side of the soma by the standard of Weismann’s barrier, and (b) an intrinsic genetic property that flows from DNA to combinations of gene expression, conformations of regulatory regions, and genomic architectures of cells. In fact, plasticity is here on the side of soma because epigenomics postulates that cellular differentiation belongs to phenotypic development and does not contribute to modifications of the fundamental substance of heredity. In line with the “doctrine of the continuity of the germ-plasm,” plasticity in epigenomics is postulated as a transfer of sequential information between levels of genomic regulation, which does not involve any transmission of acquired information across the germ-line. Furthermore, the interpretation of plasticity in epigenomics is also deeply imbued with the paradigm inaugurated by classical quantitative genetics as it postulates that genetic variations are the main material operator of cellular differentiations from healthy to diseased states. State of the art epigenomic maps take, in fact, genetic variation both as a “difference maker” ¹²¹ of the transition from normal to aberrant epigenomic states, and as the “trait maker” ¹²² constituting the epigenetic profile that characterizes the phenotype of a given tissue. It is quite telling, in this respect, that the word “plasticity” occurs in the special issue of Nature comprising the first hundreds of epigenomic maps only in two specific contexts. Firstly, in relation to the effects of genetic variation on the architectural arrangements of chromatin, ¹²³ and secondly, in the context of the quantitative analysis of downregulated genes for “synaptic plasticity” in Alzheimer’s disease. ¹²⁴

Plasticity in behavioral and environmental epigenetics

Researchers in fields such as “behavioral epigenetics” and “environmental epigenetics” address the question of plasticity as “signals from the environment” that “trigger molecular biological changes.” ¹²⁵ Differently from epigenomic maps, these studies have provided an understanding of how exposures to toxic substances ¹²⁶ as well as stressful conditions ¹²⁷ can trigger germ-line-mediated inheritance of epigenetic predispositions for behavioral patterns or health conditions. In so doing, behavioral or environmental epigeneticists postulate a very precise role for plasticity, which amounts to the embodiment of environmental conditions in phenotypic development and heredity. These scientists hypothesize that the social and material environment (especially at early stages of life) has a long-term impact on mental and physical conditions via the imprinting of epigenetic signatures. ¹²⁸ The biology of complex traits (e.g. stress-coping, fear, fertility) is to be explained, under this view, by the mutual shaping of genes and their environment (from experiences, to exposures, to genes, and back to phenotypes and behaviors).

In a remarkable revival of ancient ideas of organic memory, such as Haeckel’s theory of the “perigenesis of the plastidule,” these epigenetic scientists advance a programmatic effort to dissect mechanistically how the plasticity of our genome entails environmental modifications of the very substance of development and heredity. As argued by Moshe Szyf, a prominent actor in this field, processes of epigenetic programming triggered by environmental stimuli take place over blurred temporalities of ontogeny and phylogeny:

If multigenerational transmission of ancestral experiential memory evolved to increase survival and fitness, such a mechanism should be able to modulate phenotypes crucial for survival [. . .]. It is plausible then that nongenetic inheritance would function at different timescales depending on the nature of the ancestral experience. Maintaining plasticity in response to dynamic environments requires generation-limited and reversible reprogramming. By contrast, a permanent change in habitat requires a stable multi-generational phenotypic transformation. ¹²⁹

Indeed, behavioral and environmental epigeneticists have gone even further in paralleling Haeckel’s ambition to integrate ontogeny and phylogeny, as well as Lamarckian and Darwinian evolution, in the conceptualization of their epistemic work. ¹³⁰ According to Szyf, ¹³¹ the disputed ¹³² possibility that environmental exposures could produce transgenerational adaptations via epigenetic programming (in the absence of genetic change) is a vindication of Lamarckism. In his view, the idea of the inheritance of acquired characters has been marginalized due to the lack of a plausible mechanism serving as “conduit between the environment and stable alteration of gene function that could be stably transmitted through the germline.” ¹³³ Evidence of epigenetic inheritance via the gametes provides such a mechanism, thus suggesting that evolution (in a neo-Darwinian sense) has equipped organisms with “mechanisms to respond specifically and efficiently to certain critical novel experiences,” and “to transmit this information effectively to their offspring” without necessarily involving “the typically slow process of natural selection.” ¹³⁴ In a nutshell, the plasticity of epigenetic marks enables the author to argue that Darwinian evolution has crafted at least one mechanism for Lamarckian evolution to occur.

In contrast, Michael Skinner, another influent environmental epigeneticist, argues that environmental epigenetics and transgenerational epigenetic inheritance provide grounds for integrating another “neo-Lamarckian concept” ¹³⁵ into the neo-Darwinian theory of evolution. His ideas build upon the substantial corpus of epigenetic research dissecting the involvement of epigenetic processes in disease etiology. These studies show how epigenetic mechanisms (most notably, DNA methylation) can promote genomic instability and induce genetic mutations. What emerges then as epimutation transmitted to the progeny also has, in Skinner’s understanding, a role in producing genetic changes and variations that in turn are subjected to natural selection. This way, the author can claim a dual role for epigenetic processes in evolution: one (that we encountered in Szyf’s work) pointing to the transmission of acquired phenotypic characters through germ line-mediated epigenetic inheritance. The other, instead, pointing to the role of these epigenetic mechanisms in inducing mutations on which natural selection intervenes subsequently. Briefly put, epigenetics enables the author to postulate that a neo-Lamarckian mechanism could be the driver of neo-Darwinian evolution.

Interestingly, neither a direct reference to past theories of organic memory nor the etymologically dense terminology of Haeckelian heritage can be found in the academic production of these authors. ¹³⁶ Both authors inscribe instead their views as standing in continuity with those of Waddington, who is acknowledged in their writing not just as the originator of the field of epigenetics, but as a forerunner of studies of plasticity as a mechanism of non-genetic inheritance. ¹³⁷ The word “plasticity” is explicitly problematized in only one of the texts analyzed above, ¹³⁸ although it occurs extensively elsewhere in these scientists’ production, ¹³⁹ and it is often equated with “epigenetic alterations” ¹⁴⁰ and “molecular mechanisms” ¹⁴¹ for the influence of the environment on inherited biological traits. We thus see at play here how the epistemic space ¹⁴² of contemporary epigenetics harbors distinct and often unacknowledged traditions of plasticity. While scientists’ narratives of the field and its epistemological foundations refer to Waddington to reinforce the idea of a common origin of its different epistemic programs, a thorough scrutiny of the conceptualizations and operationalizations of plasticity in this field suggests a different reading. Drawing from the four distinct historically situated understandings of plasticity we isolated above, it is in fact possible to characterize how this notion instructs distinct conceptual and experimental endeavors across different corners of epigenetics. At a closer look, plasticity in environmental and behavioral epigenetics seems to have little in common with the way this notion was conceptualized and experimented with in Waddington’s work, or the way it is currently being interpreted in the field of epigenomics. Rather, plasticity seems to be bestowed here with the capacity to account for the very same molding of the fundamental substance of heredity, which was a fundamental facet of its interpretation in Haeckel and that is still required – in these authors’ view – to explain a common biological basis for ontogeny and phylogeny.

Plasticity in molecular epidemiology and exposomics

A similar style of reasoning informs those research designs currently encompassed by the labels of “molecular epidemiology” or “epigenetic epidemiology.” These approaches – “marrying a bench science and a population science” – aim at identifying the “mechanistic link between environmental exposures and diseases’ outcomes.” ¹⁴³ Some molecular epidemiologists adopt a life-course perspective to address questions regarding the relationship between socioeconomic status and epigenetic biomarkers for susceptibility to disease. ¹⁴⁴ Some others focus instead on development and highlight the importance of epigenetics to understanding early-life exposures leading to adult diseases under the overarching hypothesis of the “Developmental origins of health and disease–DOHaD”: ¹⁴⁵ “During the critical periods of ontogenesis, [environmental] influences result in modifications connected with ontogenetic plasticity that lead to permanent changes in structure and function of different organs and systems of an organism.” ¹⁴⁶ Among the various ways of experimenting with body–environment plasticity and permeability in molecular epidemiology, the concept of “exposome” has been recently gaining traction. ¹⁴⁷ The exposome heralds a turn in the relationship between epidemiological sciences and molecular biology. First, exposomics widens the breadth of molecular approaches in epidemiology by postulating different levels of genomic regulation and expression (e.g. metabolomics, proteomics) beyond the epigenome as concurring “biosensor[s]” that modulate body–environment interactions and “hence trigger disease.” ¹⁴⁸ Second, exposomics opens up molecular epidemiology to a detailed characterization of the chemical interactions between the body and its surrounding material and social environments. ¹⁴⁹ The exposome is supposed to counter a strict focus on genetic variants and genomic plasticity as the main explananda of disease aetiology. ¹⁵⁰ The problem with this approach, according to exposomic scientists, is a consideration of disease causation as a genetic phenomenon. Studies of genetic variants, they argue, proved unable to explain how diseases develop given the prominent role of environmental exposures in producing a given phenotype. For this reason, exposomic studies revolve around a measurement of the entire set of exposures to which individuals are subjected from conception onwards throughout their lifespan. ¹⁵¹ Such a concept stresses, therefore, the importance of measuring the environment in its totality (from environmental pollutants to work-related exposures and lifestyles over the life-course) and to complement this measurement of the “external” environment with a characterization of the “internal chemical environment” where the external environment gets processed into the metabolic functioning of the body. ¹⁵² Thus, the exposome is conceived as an epistemic tool describing the biochemical processes linking the body with its surroundings, the genomic predispositions with the “endogenous and exogenous chemicals in the body at [any] given time.” ¹⁵³ Researchers in this field stress the need to combine knowledge from classical epidemiological methods (e.g. exposure matrices, dietary recalls) with a characterization of “downstream” biological events such as analyses of the chemical compounds circulating in bodily fluids (e.g. blood ¹⁵⁴ ), or the modifications of gene expression brought about by epigenetic changes. ¹⁵⁵ The complementarist view of exposomic studies is that the role of the environment in disease development should be reduced neither to a disturbance of a genetically driven process (as in epigenomics) nor to the effects of one exposure (as in behavioral or environmental epigenetics). Rather, exposomics encourages taking the plastic cross-talk between environments and the genome – the “molecular conduit” between the inner and the outer ¹⁵⁶ – as a whole, multilayered biochemical process by which the environment enters the body.

As illustrated by a recent and influential issue of the International Journal of Epidemiology (IJE), scientists across these various strands of molecular epidemiology (re)construct the history of their field against the backdrop of Waddington’s work. The issue revolves around a reprint of Waddington’s 1943 paper “The Epigenotype” and is presented as both a celebration of the importance of his ideas for the field and an overview of the various approaches that follow his ideas in epidemiology. Besides the reprint of “The Epigenotype,” the issue also includes: a) a series of commentaries on the legacy of Waddington’s work for epigenetic epidemiology written by renowned evolutionary and theoretical biologists; ¹⁵⁷ b) a number of theoretical and empirical papers that deal with the import of epigenetics for the study of prominent epidemiological questions (e.g. the association between socioeconomic status and health inequalities); ¹⁵⁸ c) a review on the translation of exposomic approaches into concrete research programs; ¹⁵⁹ as well as d) a symposium around the book by Patrick Bateson and Peter Gluckman on plasticity thinking in epidemiology across development and evolution. ¹⁶⁰ No doubt, conceptualizations of plasticity in molecular epidemiology present several analogies with its Waddingtonian interpretation analyzed above. Like Waddington, these scientists conceive and operationalize biological plasticity as the set of causal mechanisms that intervene between the genotype and the phenotype during the life-course. Furthermore, these views of plasticity are also grounded on an understanding of the genome as a dynamic network and resource that crafts the phenotype through complex processes at the crossroads of gene regulatory networks and environmental conditions. ¹⁶¹ Yet, the construction of this historical trajectory from Waddington to present molecular epidemiology also obliterates some major differences between the reflections around plasticity animating this field and those purported by the British biologist. Of note, molecular epidemiologists are only partly concerned with processes of embryogenesis and development as a matter of evolutionary significance. With the exception of some epidemiological approaches grounded on the DOHaD hypothesis, ¹⁶² the majority of scientists in this domain rather focus on the modifications to which individual bodies are subjected from conception to the adult age. Furthermore, Waddington’s epigenotype provides only a limited ground to cast developmental processes and complex genotype-to-phenotype transitions as open to environmental stimuli. As acknowledged also by the editorial introducing this special issue of IJE, this particular paper of his “says nothing about environmental modifiers of gene expression.” ¹⁶³

In this respect, the different strands of molecular epidemiology rather evoke the operationalization of plasticity animating the hygienist movement at the beginning of the nineteenth century. ¹⁶⁴ As in the case of early hygienists, these researchers take the environment as a “plastic life modifier”; namely, a variable that produces a fundamental change in biological functioning and a deviation from the normal to the pathological. Much like their nineteenth-century predecessors, they consider the body as an open metabolic entity penetrated and modified by the external world – incidentally reduced also here to a taxonomy of different types of exposures (see section on French public hygiene). Yet, it is worth mentioning how at least one major difference can be found in the articulation of these two historically distant paradigms. While public hygienists black-box the inner workings of the reciprocal modulations of bodies and environments, molecular epidemiologists attempt to unfold the fundamental mechanisms of this process thanks to an approach that draws from various facets of contemporary biology. The problem for the French hygienists was in fact less that of dissecting individual differences in the chemical interactions between bodies and milieu than the recognition of a social problem equally affecting every citizen’s body as a normal metabolic entity. By contrast, contemporary molecular epidemiologists render vivid the chemical continuum in which the body and its inner workings stand with respect to the exposures to which it is subjected. In brief, the metabolic body of molecular epidemiology is no longer an organic substrate that is essentially the same for everyone, but rather a multilayered molecular entity that combines unique genetic and metabolic predispositions with exposures and chemical alterations specific to one’s material and social environment.