Siddhartha Mukherjee, a physician and the author of The Emperor of All Maladies, recently published a piece in the New Yorker to promote his new book Gene: An Intimate History. While the book has already become Mukherjee’s second New York Times Bestseller, the article in the New Yorker has generated a great deal of backlash in the scientific community. Some of the criticism centered around the oversimplified explanation of complex genetic and epigenetic processes, which is prone to happen in scientific articles written for mass consumption.
The more prominent critiques of the article centered on Mukherjee’s focus on histone modification, suggesting that Mukherjee’s explanation was either (Neo-) Lamarckian in nature, or that it entirely neglected other epigenetic processes that are even more significant to epigenetic trait transmission. The Nobel Laureate Dr. Wally Gilbert wrote: “Too much of the ‘epigenetic’ discussion is wishful thinking seeking Lamarckian effects, and ignoring the role of sequence specific regulatory proteins and genes (as well as sequence specific RNA molecules).”
The Response by Siddhartha Mukherjee
After a considerable number of letters to the editor and blog posts in opposition to his piece, Mukherjee added a response to his detractors in a letter to the editor of his own in the New Yorker on May 30th. The response was not defensive in nature, but rather highlighted that the article was but a section of his new book that would offer a more comprehensive account of the different epigenetic factors involved in gene inheritance (he adds that the book devotes ample time to transcription factors and “master regulators”). There was no response to the claim that Mukherjee cherry-picked researchers who believed in the great importance of “epigenetic mechanisms,” such as histone modification in gene regulation, even though the vast majority of researchers consider those mechanisms to be more secondary in nature. Moreover, there was no response to the claim that his description of epigenetics was borderline Lamarckian (a characterization that has become the ultimate trump card in the fields of genetics and evolutionary biology).
The Epigenetic Wars Will Continue
Part of this debate (putting aside the problems arising from Mukherjee’s oversimplification, and his selection of a small portion of his book) boils down to a semantic disagreement over the meaning of the term “epigenetics.” In a conversation with Forbes’ Matthew Harper about his article, book and new Biotech Company, Mukherjee notes: “I think there’s a lot of internal debate about what epigenetics is because [sic] very ambiguous about it and it seemed that the piece got in the crossfire of that debate.” In a 2015 paper in Genetics, Deans and Maggert offer an extensive chronology of the evolution of the term from its introduction in 1942 by Waddington to its more divergent contemporary usages. The original definition offered by Waddington is “the branch of biology that studies the causal interactions between genes and their products which bring the phenotype into being.” The vagueness may initially be off-putting, but it is important to note that the term originated before Watson, Crick and Franklin ushered in the modern field of genetics with their discovery of the structure of DNA.
The authors note the first updated definition of “epigenetics” was suggested by the molecular biologist Robin Holliday in the 1980s, and was more formally formulated in a 1994 paper. Holliday suggested that there are two components to epigenetics: the first is the “study of the changes in gene expression, which occur in organisms with differentiated cells, and the mitotic inheritance of given patterns of gene expression,” and the second is “nuclear inheritance, which is not based on differences in DNA sequence.”
Not only does the dual-nature of Holliday’s definition confuse more than it clarifies, but his introduction of inheritance to the definition serves as a major deviation from Waddington’s initial usage of the term. Deans and Maggert add that “the field soon became a residence for perplexing phenomena that didn’t fit squarely into other genetic fields and, in many regards, the inability to explain these phenomena by simple genetic explanations became a defining element of epigenetics…the decoupling of genotype and phenotype exemplified by epigenetics provided an attractive refuge because it offered metaphorical language to describe the disconnect between a gene and its phenotypic properties.” The field of epigenetics has evolved into an amalgam of different perspectives, each set on explaining non-genetic phenotypic alterations. Such explains not only why even the most prominent researchers in the field disagree on the very nature of the field, but also how an article such as Mukherjee’s could receive such an extensive backlash.
A Turn Against Genetic Determinism
The medicinal chemist and acclaimed blogger Derek Lowe suggests that epigenetics has turned into a “hand-waving explanation for everything”—perhaps even as a Neo-Lamarckian response to the apparent turn toward genetic determinism. The Neo-Lamarckian movement, however, is not new, and is generally not unscientific in nature. It has evolved as a result of non-gene centered conception of heredity that was created by advances in the field of epigenetics. Jablonka and Lamb, who have written extensively on the subject, note: “Although the current gene-centered version of Darwinism—Neo-Darwinism—is incompatible with Lamarckism, Darwinism is not. In the past Lamarckism and Darwinism were not always seen as alternatives: they were recognized as being perfectly compatible and complementary.”
While the Lamarckian resurgence has yet to greatly change the discourse (as evidenced by the incredible backlash to Mukherjee’s suggestion that epigenetic mechanisms are pseudo-Lamarckian and act as a “shortcut through the glum cycles of mutation and natural selection”), it adds nuance to and further muddles conceptions of trait inheritance.
Caught in the Crossfire
Mukherjee’s piece was very likely caught in the crossfire of a semantic debate over the term epigenetics that has been going on since the inception of the field. Should the article have given more of an indication of the diversity of opinions on the role of histone modification? Probably. Should Mukherjee have tread more carefully around the Neo-Lamarckian line? Possibly.
We mustn’t, however, pretend that semantic debates are trivial. For normal science (at least in the Kuhnian sense) to progress, there is a certain level of fundamental consensus necessary in scientific disciplines. Paradigms require some form of consensus to meet the requirements for scientific maturity that allows for normal scientific progress.
The budding field of epigenetics has most probably yet to reach the state of scientific maturity, and these prominent semantic disagreements are likely contributing factors. Before tackling the debates that are more philosophical in nature, it would seem prudent for the leaders of the field to establish a shared language that can at least describe what the field exactly is.
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Deans, C., and K. A. Maggert. “What Do You Mean, “Epigenetic”?” Genetics 199.4 (2015): 887-96.
Holliday, Robin. “Epigenetics: A Historical Overview.” Epigenetics 1.2 (2006): 76-80.
Jablonka, Eva, and Marion J. Lamb. “The Changing Concept of Epigenetics.” Annals of the New York Academy of Sciences 981.1 (2006): 82-96.