Etymology of Epigenetics

That is a charming exchange of letters between the 1910 traveler Mr. Bacon and two modern geneticists in “Genes, genetics, and epigenetics: a correspondence” by C.-t. Wu and J. R. Morris (Viewpoint, special issue on Epigenetics, 10 Aug., p. [1103][1]). The authors might be correct about Waddington as the originator of the term epigenetics, but only in the modern sense of the origin of the phenotype from the genotype. The root term epigenesis goes back more than two millennia to Aristotle, as Waddington acknowledged, and was proposed in opposition to preformation, the concept favored by the Greek philosophers Democritus and Leucippus. In epigenesis, there were no preformed equivalents in the fertilized egg for later developing structures. Preformation maintained its hold in the popular mind for millennia, even capturing the attention of the great 17th-century anatomist Malpighi. The advent of the microscope and the discovery of the germ layers in the chick embryo by Pander, and their generalization by von Baer, settled the issue in favor of epigenesis in the 18th century. Of course, genetics was unknown as such until the 20th century; until then, “epigenetics” implied the workings of epigenesis, as studied by Roux and his school of experimental embryologists in the 19th century. Waddington's adaptation of the term epigenetics to modern genetic concepts was an advance in one sense, but has apparently allowed many to forget the root and original intent of the term. While we search for reactions that persist through mitosis, we forget that hierarchical structures maintain tissue stability. We might well contemplate as the starting point for a deeper understanding of epigenetics the insight of Sewall Wright, a founder of population genetics: “Persistence may be based on interactions among constituents which make the cell in each of its states of differentiation a self-regulatory system as a whole, in a sense, a single gene at a higher level of integrations than the chromosomal genes” ([1][2]). Such hierarchical thinking would help structure the many molecular interactions certain to accumulate under the current rubric of epigenetics and give them deeper biological significance. 1. [↵][3]1. S. Wright , Am. Nat. LXXIX, 289 (1945). [OpenUrl][4] # Response {#article-title-2} I agree with Rubin that, for many, the history of the term epigenetics has been lost and, with it, useful viewpoints. A colleague has further alerted me to an early discussion of “Development as an epigenetic process” by C. H. Waddington in his book An Introduction to Modern Genetics ([1][5]). This discussion is a forerunner to Waddington's 1942 paper ([2][6]) introducing “epigenetics” and has clarified for me how the author might have progressed from the original theory of epigenesis to “epigenetics.” In this earlier piece, Waddington explicitly mentioned epigenesis and preformation, putting each into the context of development. With respect to epigenesis, he said that as “the interaction of these constituents [of the fertilized egg] gives rise to new types of tissue and organ which were not present originally,…development must be considered as ‘epigenetic.’” Waddington then considered the manner in which tissues and organs are induced during development. He discussed the concepts of genotype and phenotype but noted that they “are not adequate or appropriate for the consideration of the development of differences within a single organism.” That is, “the difference between an eye and a nose, for instance, is clearly neither genotypic nor phenotypic.” Instead, the difference “is due…to the different sets of developmental processes which have occurred in the two masses of tissue.” Waddington suggested that the terms epigenetic constitution or epigenotype be used to refer to the “set of organizers and organizing relations to which a certain piece of tissue will be subject during development.” These terms in hand, he then urged that we consider “the appearance of a particular organ [as] the product of the genotype and the epigenotype, reacting with the external environment.” Thus, in this manner, Waddington drew the original concept of epigenesis closer to those of genotype, phenotype, and development. With regard to the quotation from Wright that Rubin mentions, I would also agree. We must keep in mind the context in which a gene works and that, as we broaden our understanding of the gene, the boundary of the gene might become less obvious. By way of thanks, I append a quotation from a paper published by H. J. Muller in 1938. Its focus, the phenomenon of position effect, differs from the issue addressed by Wright, but its flavor seems reminiscent of Wright's message. > In the production of phaenotypic effects the gene must begin by interacting with cellular substances so as to produce a highly specific product or products, which must diffuse out from the locus of activity of the gene and in turn cause (or affect) further physio-chemical changes. In the course of one of these chains of reaction, that has its origin in an individual gene, there will be many opportunities for interaction with other chains of reaction present in the complicated mixture; thus, the reactions will really form a kind of multi-dimensional net, rather than a simple chain. The final phaenotypic manifestations lie at the ends of the net furthest removed from the inner gene ends, and their quality depends upon the character and strength (including speed) of all the intermediate reactions and interactions ([3][7], 1938, p. 588). 1. [↵][8]1. C. H. Waddington , An Introduction to Modern Genetics (Allen & Unwin, London, 1939), pp. 154-156. 2. [↵][9]1. C. H. Waddington , Endeavour 1, 18 (1942). [OpenUrl][10][CrossRef][11] 3. [↵][12]1. H. J. Muller , Proceedings of the 15th International Physiological Congress, Leningrad-Moscow, 1935 State Biological and Medical Press, 587-589 (1938) Reprinted in Studies in Genetics: The Selected Papers of H. J. Muller (Bloomington, IN, Indiana Univ. Press, 1962) 137–140. 4. I thank M. Green at the University of California, Davis, for alerting me to Waddington's 1939 discussion of epigentics. 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