Abstract: This is a two part-post about a science piece on gene regulation that just appeared in the New Yorker. Today I give quotes from scientists criticizing that piece; tomorrow I’ll present a semi-formal critique of the piece by two experts in the field.

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Yesterday I gave readers an assignment: read the new New Yorker piece by Siddhartha Mukherjee about epigenetics. The piece, called “Same but different” (subtitle: “How epigenetics can blur the line between nature and nurture”) was brought to my attention by two readers, both of whom praised it. Mukherjee, a physician, is well known for writing the Pulitzer-Prize-winning book (2011) The Emperor of All Maladies: A Biography of Cancer. (I haven’t read it yet, but it’s on my list.) Mukherjee has a new book that will be published in May: The Gene: An Intimate History. As I haven’t seen it, the New Yorker piece may be an excerpt from this book.

Everyone I know who has read The Emperor of All Maladies gives it high praise. I wish I could say the same for Mukherjee’s New Yorker piece. When I read it at the behest of the two readers, I found his analysis of gene regulation incomplete and superficial. Although I’m not an expert in that area, I knew that there was a lot of evidence that regulatory proteins called “transcription factors”, and not “epigenetic markers” (see discussion of this term tomorrow) or modified histones—the factors emphasized by Mukherjee—played hugely important roles in gene regulation. The speculations at the end of the piece about “Lamarckian evolution” via environmentally induced epigenetic changes in the genome were also unfounded, for we have no evidence for that kind of adaptive evolution. Mukherjee does, however, mention that lack of evidence, though I wish he’d done so more strongly given that environmental modification of DNA bases is constantly touted as an important and neglected factor in evolution.

Unbeknownst to me, there was a bit of a kerfuffle going on in the community of scientists who study gene regulation, with many of them finding serious mistakes and omissions in Mukherjee’s piece. There appears to have been some back-and-forth emailing among them, and several wrote letters to the New Yorker, urging them to correct the misconceptions, omissions, and scientific errors in “Same but different.” As I understand it, both Mukherjee and the New Yorker simply batted these criticisms away, and, as far as I know, will not publish any corrections. So today and tomorrow I’ll present the criticisms here, just so they’ll be on the record.

Because Mukherjee writes very well, and because even educated laypeople won’t know the story of gene regulation revealed over the last few decades, they may not see the big lacunae in his piece. It is, then, important to set matters straight, for at least we should know what science has told us about how genes are turned on and off. The criticism of Mukherjee’s piece, coming from scientists who really are experts in gene regulation, shows a lack of care on the part of Mukherjee and the New Yorker: both a superficial and misleading treatment of the state of the science, and a failure of the magazine to properly vet this piece (I have no idea whether they had it “refereed” not just by editors but by scientists not mentioned in the piece).

Let me add one thing about science and the New Yorker. I believe I’ve said this before, but the way the New Yorker treats science is symptomatic of the “two cultures” problem. This is summarized in an email sent me a while back by a colleague, which I quote with permission:

The New Yorker is fine with science that either serves a literary purpose (doctors’ portraits of interesting patients) or a political purpose (environmental writing with its implicit critique of modern technology and capitalism). But the subtext of most of its coverage (there are exceptions) is that scientists are just a self-interested tribe with their own narrative and no claim to finding the truth, and that science must concede the supremacy of literary culture when it comes to anything human, and never try to submit human affairs to quantification or consilience with biology. Because the magazine is undoubtedly sophisticated in its writing and editing they don’t flaunt their postmodernism or their literary-intellectual proprietariness, but once you notice it you can make sense of a lot of their material. . . . Obviously there are exceptions – Atul Gawande is consistently superb – but as soon as you notice it, their guild war on behalf of cultural critics and literary intellectuals against scientists, technologists, and analytic scholars becomes apparent.

I agree. All too often the magazine takes an anecdotal rather than data-driven approach to research, and I’ve clearly detected an attitude that science is but one “way of knowing”—just as fallible as any other of the touted “ways of knowing”, including literature and the fine arts. There seems to be a lack of rigorous vetting of the science, as shown not just by Mukherjee’s piece, but by Jonah Lehrer’s earlier superficial treatment of scientific data and his ultimate firing for plagiarism (see my posts here and here on Lehrer’s superficial discussion of science). In the New Yorker, slickness and good writing seem to substitute for scientific accuracy and incisive analysis. What we have, then, is a lot of sizzle from a very tiny steak. And the whole problem is compounded, as it was in this case, by the magazine’s refusal to even consider that they might do a better job with their science pieces.

This post will be long, but only because it’s full of quotes from scientists (and a science-journal editor) who commented on the Mukherjee piece: people willing to go on the record with their opinions.

Tomorrow I’ll present a detailed critique of the article written by two experts on gene regulation. If you haven’t read Mukherjee’s piece, you have another day to do it.

When you read these comments, remember that The New Yorker is famous for fact-checking. Perhaps that reputation is not fully deserved with respect to science. Remember, too, that these are reactions of experts who read the Mukherjee piece with expert eyes. I’ve given the affiliations of the researchers. We’ll start with the Nobel laureates since those folks always get more attention. The last few “quotes” are longer, but will give you a preliminary idea of the piece’s scientific problems. Those problems with be discussed in a lot more detail tomorrow.

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Wally Gilbert, Nobel Laureate, biochemist and molecular biologist, Harvard University (retired). The New Yorker article is so wildly wrong that it defies rational analysis. 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).

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Sidney Altman, Sterling Professor of Molecular, Cellular, and Developmental Biology and Chemistry at Yale University, Nobel Laureate: I am not aware that there is such a thing as an epigenetic code. It is unfortunate to inflict this article, without proper scientific review, on the audience of The New Yorker.

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Tom Maniatis, Isidore Edelman Professor of Biochemistry and Molecular Biophysics at the Columbia University College of Physicians and Surgeons in New York: Remarkable that his article made it through the New Yorker editorial review, and was apparently not vetted by unbiased scientific experts. A real setback for the accurate communication of science to the readership of the New Yorker.

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Richard Mann, Professor of Biochemistry and Molecular Biophysics, Columbia University Medical School: It is really sad and embarrassing that something as awful as this appeared in such a respected magazine, and by a (formerly) respected author. Ugh

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John Greally, Professor, Depts. of Medicine, Genetics, and Pediatrics; Director, Center for Epigenomics, Albert Einstein College of Medicine: It really is a horribly damaging piece.

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Oliver Hobert, Professor of Biological Sciences, Investigator, Howard Hughes Medical Institure, Columbia University: A truly painful read. But funny to see the Yamanaka experiment described as proof for something that it disproves. Sad that the author lets himself be fooled by people who really should know better and that he propagates what is an intellectually dishonest perspective of the problem of gene regulation.

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Steve Henikoff, Division of Basic Sciences at Fred Hutchinson Cancer Research Center, Investigator, Howard Hughes Medical Institute: When the New Yorker issue appeared on my iPad early this past week, I noticed in the contents sidebar that there was an article by Siddhartha Mukherjee, the author of one of my favorite non-fiction books – Cancer: Emperor of all maladies. Contrary to my usual habit, I skipped over Talk of the Town to see what Mukherjee had to say, and was at first delighted that it was on my own speciality: epigenetics. But as I read it I became increasingly dismayed by the lack of scholarship and the misinformation about central concepts in the field, shrouded in soaring prose. The problems began when Mukherjee made a leap from the existence of differences between his mother and aunt to how there must be something written on the genome to remember these differences. He made it seem as if a healed broken ankle, and even a mere callus, become “etched” into the genome. I first thought that maybe he was describing some sort of immunological memory. But as the remainder of the article made quite clear, his subject was covalent histone and DNA modifications. And when it came to mentioning actual evidence for phenotypic specification and memory, he cited the Yamanaka factors, seeming not to realize that these are transcription factors, not the etching of marks on histones or DNA, or enzymes responsible for these modifications, or anything else about DNA packaging proteins or their modifications. Mukherjee seemed not to realize that transcription factors occupy the top of the hierarchy of epigenetic information, that this has been widely accepted in the broader chromatin field, and that histone modifications at most act as cogs in the machinery that enforces the often complex programs specified by the binding of transcription factors. In no case that I recall is there an example of a change in gene expression that can be attributed to histone hyperacetylation to the exclusion of non-histone substrates, of which many have been identified. DNA methylation might be doing some interesting things, but despite decades of effort there is still no hard evidence that implicates DNA methylation in the kinds of processes that underlie differences between Mukherjee’s mother and aunt. Indeed, epigenetic processes analogous to those performed by the Yamanaka factors are performed by bacteria that entirely lack histones and DNA methylation. Mukherjee’s description of evidence for Lamarckian inheritance through the germline is no better, implying that phenotypic effects passed through the germline may be somehow mediated by histone and DNA modifications. But the best evidence is contrary to this view. For one thing, nearly all the histones are removed when sperm is packaged, and DNA methylation is erased and reset between generations. More to the point, the only informational components that have been shown to be transmitted with sperm to the next generation are small RNAs, which like transcription factors, are not referred to at all in this article. These errors and omissions coming from such a highly regarded author are especially unfortunate, as aside from the science, the piece is entertaining and well-written, and as a result will likely misinform the educated public about an area of biology that has great potential for making a positive social impact.

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Geoffrey North, Senior Editor, Current Biology: I have observed this phenomenon over more than 30 years now: in the 80s, studies of transcriptional regulation fell into two clear camps, one the biochemists/geneticists, carrying on the work started by Jacob and Monod to show how transcription factors activate and repress genes, and how the basic mechanisms are conserved between prokaryotes and eukaryotes; the other, influenced strongly by structural biologist/chemists such as Gary Felsenfeld (a student of Linus Pauling), investigating “chromatin structure”, identifying features that correlate with gene expression such as hypersensitive sites (I guess this group was inspired by structural biology’s one unambiguous huge success: the DNA double helix and the subsequent molecular biology zeitgeist of biological insights from structure.) I always felt the former were inclined to look for conservation of fundamental mechanisms (yay!) and the latter hoping to show a fundamental difference due to chromatin, somehow related to the greater “complexity” (ill-defined term in biology, frankly) of eukaryotes, metazoans in particular. Of course, DNA methylation was known about then, but the phylogenetic distribution has always been a bit puzzling and despite huge efforts over many years I am not sure the real “function”/role has ever become very clear (perhaps it is in the case of mammalian “imprinting”, not sure off hand). Things seemed to die down a bit, the “chromatin project” not really getting very far—and then it reared its head again with a vengeance with discoveries about histone modifications and emergence of “epigenetics” as THE buzzword for the transcription/gene regulation field, taking over peoples minds and seemingly leading to a mass loss of memory of the history of the field, and a mass loss of clear perspective on how DNA/histone modifications fit into an over all process of differential gene regulation.

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Dr. Florian Maderspacher (a letter submitted to the New Yorker): In his piece, Dr. Mukherjee paints a grotesquely distorted picture of how the environment influences our genome and of how genes are regulated. Not only does he represent the ideas propagated by Dr. Allis and Dr. Reinberg as set in stone, which they are not; in fact, many researchers actively debate whether the ‘epigenetic’ processes they study have indeed a causative, instructive role in gene regulation or whether they are just cogs downstream of proteins, known as ‘transcription factors’, that determine which genes get turned on or off. Ironically, the Yamanaka experiments mentioned in the text clearly argue for the latter. To say the least, the jury is still out on these matters. And there is certainly no evidence whatsoever that epigenetic mechanisms play a role in evolutionary adaptation. More disconcertingly, however, Dr. Mukherjee also ignores the vast body of work that scientists studying gene regulation have accumulated over the past half century. This includes areas like the regulation of gene activity through transcription factors, which aren’t mentioned once in the article, and external signals, such as growth factors or hormones, that can change the appearance of a cell or an entire organism without changing its DNA sequence. The fruits of this research can be found in any undergraduate biology text book, and countless Nobel Prizes have been awarded. And of course, cancer, which Dr. Mukherjee should be very familiar with, is nothing but gene regulation through signals and transcription factors gone awry. Finally, even Dr. Mukherjee’s account of the origins of the term epigenetics as meaning ‘above genetics’ is wrong. Conrad H. Waddington coined the term as an adjective, ‘epigenetic’, pertaining to ‘epigenesis’, the de novo origin of structures of the embryo, as opposed to ‘preformation, a mere unfolding of already pre-existing structures. All of these inaccuracies and omissions are far from marginal. In a lay reader, they install the impression that ‘epigenetics’ is providing new answers to an unsolved problem in biology, when we really already have a very good understanding of how the environment influences the genome. They also gloss over the fact that, no matter what, the cellular machinery that controls gene activity, including the ‘epigenetic’ machinery, is encoded in the genome, hence is ultimately genetic. Such lopsided reporting, which only confuses readers who aren’t well versed in biology, would certainly not be tolerated in any other realm of public life, such as the arts or politics. Why should it be tolerated in an important domain of science that touches so deeply onto who we are as biological beings?

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There you have it, and stay tuned till tomorrow at the same time.

Will the New Yorker take this criticism on board, and the letters they’ve received, and perhaps issue a correction or modification? I’d like to see that, but I’m sure not counting on it. I predict they’ll ignore the whole issue, or maybe dig in their heels and assert that every word of Mukherjee’s piece was right. After all, they have a gazillion more subscribers than does this site!

I want to add one last comment. Mukherjee is celebrated as a great science writer, and that may well be true for his first book. But to me, great science writing means more than just fluid and attractive prose: it means a respect for the facts, unstinting accuracy, and the ability to convey the state of the art in an area to an educated lay audience. Neither I nor the commenters above see the latter qualities in the New Yorker piece.