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 to coin epigenetics (Waddington 1942). He initially argued that the new field would be limited to ‘the causal interactions between genes and their products which bring the phenotype into being’ (a subject that Julian Huxley had previously worked on), but broadened his argument very quickly.
Waddington’s position was influenced by the dawning realisation of several researchers of his day that development of the embryo must involve networks of interactions among genes that form a complex integrated system, and that the completely bifurcated subjects of genetics and embryology should be brought closer together, even though many embryologists feared that their field would be completely overtaken by genetics if such a move took place (Waddington 1940). Waddington was trained in both fields; he had worked in Germany with the Nobel Laureate embryologist, Hans Spemann, and with the geneticist Thomas Hunt Morgan in California, and made the very idea of ‘development’ central to his arguments specifically because of its double meaning: the growth of individuals and evolutionary change.
For Waddington, development denotes the set of conditions that enable so-called ‘multi-potent stem cells’ to become differentiated in tissues that develop into cells with specific functions. He insisted that genes are responsible for guiding only ‘the mechanics of development’, and argued that genotypes and environments function together to produce phenotypes. An appreciation of what continues to be recognised as ‘critical periods’ in developmental processes is also embedded in Waddington’s thinking. He adamantly rejected reductionist neo-Darwinianism, and described himself expressly as a Darwinian.
In his book Organisers and Genes, published in 1940, Waddington topologically depicted ‘the epigenetic landscape’ as a symbolic representation of embryonic development. The image is of a ball rolling down an undulating plateau in concert with other balls, in which one of several possible pathways is taken before it eventually comes to rest at a lowest point. In the case of a pathway or ‘creode’ which is deeply carved into the hillside, external disturbance is unlikely to prevent normal development. The balls depict developing eggs and the gradual transformation of their pluripotent cells into tissue types, the process of which is controlled by genes interacting with each other that modulate the manner in which the egg/ball descends the slopes and select specific intersections (Figure 1.1). Waddington’s point was that development is ‘canalised’ – thus ‘buffering’ the outcome of natural selection, understood today as a measure of the ability of a population to produce replicable phenotypes regardless of variability in genotypes or the environment.
Waddington’s intention was to demonstrate that there is no straightforward relationship between a gene and its phenotypic effects, and furthermore that, should a mutation arise, its effects may well be moderated or buffered by other genes – a process he termed ‘genetic assimilation’ that he explicitly linked to Darwinian thinking. Waddington was emphatic that genetic variation and phenotypic expression are not coupled. He acknowledges that change can be random, but at the same time he argued that evolution occurs primarily as a result of mutations that affect developmental anatomy. His theorising influenced debates of his day about both embryology and evolution. See Petryna, this volume, for influences on Waddington’s thinking by the Scottish biologist and mathematician, D’Arcy Thompson.
Waddington was clear that the metaphor of the epigenetic landscape had limitations (Waddington 1940, 92); nevertheless, this image is usually taken as the starting point for a genealogy of epigenetics. His argument that synchronic processes, both among genes and in the larger intra-cellular environment, must be incorporated into and modify linear unidirectional accounts of developmental processes and evolutionary change was in effect a paradigmatic shift. In the preface to the first edition of his book, Waddington notes that his greatest debt goes to the biochemist Joseph Needham, also an extraordinarily influential sinologist best known for his monumental seven-volume work on the history of science in China. It is reasonable to assume that the image of the epigenetic landscape was influenced to some extent by discussions with Needham who, in the 1940s, was teaching himself Chinese, and would have been well acquainted with classical understanding of disease causation in China in which inductive thinking is dominant, and bodies are embedded in encapsulating spheres of the individual, society, environment and cosmos. This type of thinking persists in modified form to the present day in the practice of traditional Chinese medicine (Farquhar
