Biosocial Worlds. Группа авторов
An important shift in orientation that commenced decades before the HGP, but which had remained largely quiescent, started to attract significant attention boosted by the post-genomic surprises. This shift was towards an investigation of the way in which environmental stimuli influence molecular activity. Today the majority of biologists, whatever their specialty, accept that cellular differentiation associated with human development is governed by processes akin to what was first described by the developmental biologist, embryologist, and philosopher Conrad Waddington in the mid-twentieth century as the epigenetic landscape; that is, a complex panorama of networks and feed-forward loops that determine when exactly stem cells are activated to form a lineage (Ramirez-Goicoechea 2013, 66). In other words, a chronological process that is context-specific. Numerous scientists also agree that these changes are not only initiated inside the body, but that external stimuli interact directly with individual genomes, resulting in epigenetic changes, or markers. Many such changes are stable, while others are reversible. Over the past decade molecular epigenetics has added numerous insights to this complex picture.
The assertion that multiple mechanisms of inheritance exist, and that variation in genomic sequences alone cannot account for phenotypic differences (Ramirez-Goicoechea 2013, 66–7) inevitably raises ontological concerns similar to those apparent in the days of Lamarck, regardless of the question of intergenerational inheritance, and epigenetics has been described as neo-Lamarckian by some researchers. Of course, given that neo-Lamarckism is grounded in molecular biology, its original claims are significantly modified, but the central tenet that environment makes a major contribution to the characteristics that are passed along to ensuing generations informs the foundational thinking of the burgeoning discipline of epigenetics.
The philosopher of science Evelyn Fox Keller sums up the situation thus: ‘The role of the genome has been turned on its head, transforming it from an executive suite of directional instructions to an exquisitely sensitive … system that enables cells to regulate gene expression in response to their immediate environment’ (Keller 2014, 2425). We live now with a ‘reactive genome’ (Gilbert 2003, 92). Furthermore, if genes are conceptualised as in effect ‘real’ entities, then they should be understood as composite rather than as unitary, somewhat analogous to ‘the solar system, or a forest, or a cell culture’ as Barnes and Dupré put it (Barnes and Dupré 2008, 53). A dynamic epigenetic network with a ‘life of its own’ – a context-dependent reactive system of which DNA is just one part has been exposed. Thus, contingency displaces determinism.
Gene regulation – above all how, and under what circumstances, genes are expressed and modulated – is central to epigenetic investigation, and whole cells, rather than DNA segments, are the primary targets of investigation. Effects of evolutionary, historical, and environmental variables on cellular activity, developmental processes, health, and disease have, in theory, become central to the research endeavour in epigenetics, although, to date, this is by no means the case in most basic science investigations into genomics.
Over the past decade, then, a profound shake-up has occurred in connection with knowledge about genes and how they function. The consolidation of the field of molecular epigenetics has brought about a demotion of the gene, and challenges the unexamined assumption held by many geneticists, researchers in human development, certain social scientists, and members of the public, that genes determine who we are.
Two decades ago, the neurobiologist Steven Rose argued that we must be concerned above all with the dynamics of life, that is, with process, and the continuous interchange between organisms and their environments. Our ‘lifelines’, he argued, constituted by life processes, generate our sense of self (Rose 1997).
Sculpting the genome
We must now ask to what, precisely, is the genome reactive? This forces us to consider the concept of ‘environment’. Lewontin noted long ago: ‘An egg, before fertilisation, contains a complete apparatus of production deposited there in the course of its cellular development. We inherit not only genes made of DNA but an intricate structure of cellular machinery made up of proteins’ (Lewontin 2001, 143). For genes to function, they must be activated (switched on) and, when appropriate, deactivated (switched off) by means of complex processes bringing about differentiation that takes place at the cellular level throughout the life cycle.
The epigenetic mechanism best researched to date is methylation, a process uncovered in 1975 in which methyl groups are added to a DNA molecule. DNA methylation is found in all vertebrates, plants and many non-vertebrates and is highly conserved, indicating that it has long been involved with evolutionary change and developmental processes. Enzymes initiate such modifications that do not alter the actual DNA sequence, but simply attach a methyl group to residues of the nucleotide cytosine, thus rendering that portion of DNA inactive.
Epigenetic researchers are careful to point out that the identification of mechanisms that transmit signals from social environments external and internal to the body resulting in DNA methylation have yet to be fully worked out. But it is incontrovertibly demonstrated that methylation functions so that any given genome is able to code for diversely stable phenotypes. In other words, although every cell at the time of formation is ‘pluripotent’, that is, it has the potential to become any kind of mature cell, methylation brings about so-called ‘cell differentiation’ resulting in liver, neuronal cells, or skin cells, for example. Methylation also determines whether an embryo bee will become a drone or a queen bee, and many other such examples exist. Furthermore, methylation does not take place only in utero and early postpartum years, as was formerly believed, but continues throughout the life span (Meaney 2010).
An additional hypothesis that attracts environmental epigeneticists posits that DNA methylation and other related mechanisms have a second very important function, namely that these processes are not solely the result of endogenous stimuli, but are also direct responses to environmental signals external to the body that modulate patterns of cellular activity; a substantial body of research of this kind now exists (Cortessis et al. 2012; Feil and Freger 2012). In recent years, it has been recognised that such environmental exposures bring about changes to the three-dimensional chromatin fibre that compacts DNA inside cells. The idea of an epigenome as a distinct layer over and enveloping the genome is no longer acceptable. The genome and epigenome is a flexible, commingled entity, orchestrated by shape-shifting chromatin that may result in hereditable changes (Lappé and Landecker 2015). In addition, strips of DNA can be damaged, often during replication, some of which changes result in mutations that may or may not be hereditable. Epigenetic mechanisms other than methylation, such as histone modifications of various kinds, also regulate gene expression, but these are as yet poorly understood. A comprehensive Wikipedia article summarises the incredible complexity and uncertainties involved in the unfolding field of epigenetics.
In summary, it is clear that genes are ‘catalysts’ rather than ‘codes’ for development (Meloni 2014), and it is the structure of information rather than information itself that is transmitted. DNA is not changed directly by environmental exposures. Rather, whole genomes respond ceaselessly to a wide range of environments and exposures, and chromatin mediates many such responses that, in turn, modulate DNA expression. The methylation processes described above are manifest in several timescales – evolution; transgenerational inheritance; individual lifetimes; life-course transitions (including infancy, adolescence, menopause, and old age), in addition to which are seasonal change modifications. The effects of these passages of time become miniaturised in individual bodies, making them researchable at the molecular level. This was first demonstrated using rats, discussion of which is set out below following an account of the consolidation of the field of epigenetics.
The epigenetic explosion
The word epigenetics was first used in 1942 by C. H. Waddington, described in the Encyclopædia Britannica as an embryologist, geneticist and philosopher of science. While teaching at Cambridge University, he taught himself palaeontology and eventually became known as the founder of systems biology. Waddington wrote that the Aristotelian word epigenesis, even though the term ‘was now more or less in disuse’, was the stimulus for him