Mukherjee takes confusing positions about epigenetics in Nature and in Forbes

Believe me, I really am tired of this affair and didn’t want to post more on Siddhartha Mukherjee and his New Yorker article, a piece that, to many scientists, distorted what we know about gene regulation (see here for background).  But I did note that I’d discuss press coverage of our disagreement, and we have some. Yesterday, two articles appeared that are worth reading if you’re following this debate. The first was in Nature, “Researcher under fire for New Yorker epigenetics article“. The other was in Forbes, “Siddhartha Mukherjee, author of bestselling cancer book, starts biotech company and answers criticism.” Both are free online.

To reprise briefly: Mukherjee’s New Yorker piece maintained that the specificity of gene action—how individual genes are targeted for activation and inactivation in a way that makes cells differentiate during development—resides in the controlling action of the histone proteins that help package DNA into chromosomes, as well as in “epigenetic marks” (DNA bases that have added methyl groups). Other scientists in the field argued that the dominant factor in specific gene regulation involves both small RNA molecules and, importantly, “transcription factors”: proteins that target specific genes in a way that can turn them on and off. Specific gene regulation has long been known to be produced by transcription factors and RNAs, but Mukherjee omitted that completely in his piece, arguing that epigenetic markers and histones are the exciting, newly discovered ways that genes are activated and inactivated.

The argument, then, is about whether Mukherjee and the New Yorker misrepresented what we know about how genes are turned on and off in favor of telling an exciting story—a story for which there is virtually no evidence. To a layperson this may seem like a tempest in a beaker, but do remember that many scientists are deeply concerned that the state of knowledge in their field be properly understood by the public. I get upset, for instance, when creationists foist their palaver on the public, or when misguided real scientists proclaim that “Darwin was wrong” on erroneous grounds.

The Nature article is the first piece whose writer doesn’t try to excuse Mukherjee and The New Yorker on the grounds that it’s impossible to convey the known story of gene regulation within the limited space of a magazine article. If you’ve followed the controversy, you’ll know that part of Mukherjee and the New Yorker‘s defense was that the article really did allude to transcription factors. That defense didn’t hold, and Nature gives some new quotations about it:

Coyne’s two blog posts about The New Yorker article each gathered more than 100 comments, many of them from scientists. Richard Mann, a molecular biologist and biophysicist at Columbia University Medical Center in New York City, noted that the article mentioned histones 26 times without a single mention of the word transcription. “Only a talmudic-like reading can reveal a hint that something other than histone modifications are at play.”

Mann is right: transcripti0n factors and RNA control molecules aren’t mentioned a single time in the New Yorker article, and I can’t find an allusion to them, either.

Mukherjee, however, does seem to recognize a misstep, and I have to give him credit for that:

In a response published on the website of the Scripps Translational Science Institute in La Jolla, California, Mukherjee thanked his critics for their “immensely detailed comments”. Speaking to Nature, Mukherjee says that, after re-reading the story, he felt that he put too much emphasis on the “speculative” roles of histone modification and DNA methylation. “This was an error,” he says, adding that a mention of transcription factors could have helped to avoid “an unnecessarily polarizing reading of the piece”. He says that The New Yorker is “very likely” to run a response.

I’d be heartened if the New Yorker‘s response was a clarification saying that important science was omitted from the article. But Nature‘s next paragraph suggests that the magazine is digging in its heels:

The New Yorker says that it stands by the article, saying in a statement that it had a “narrower focus” than Mukherjee’s upcoming book, which it says goes into detail about the history of gene-regulation research.

Perhaps the book gives a correct picture of what we know about gene regulation, but the excuse that the article had a “narrower focus” won’t wash. It’s not a narrower focus, but a focus on the wrong thing—giving the lay reader a misleading view of how genes act during development. The New Yorker piece really does need a clarification and a bit of retraction.

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The Forbes piece, on the other hand, gives a rather different view, for in it Mukherjee appears to stand by his piece, maintaining that his article was fine and that the story of transcription factors really is in there somewhere—it’s just hidden. (The article also reports that he’s starting a biotech company to work on cancer treatments, but you can read that bit for yourself.) He’s interviewed by Matthew Herper (MH), and here is an except. The bold bits are my emphasis.

MH: Sid, I also wanted to take a moment just to ask you about the feedback you’ve gotten on your recent piece inThe New Yorker on the field of epigenetics. Scientists including Tom Maniatis and Jerry Coyne have been very critical. Are the calls for corrections to the piece correct?

SM: It’s a longer and separate conversation. I’m going to give you some quick thoughts about it. I want to make two points.

Number one is that the piece is an excerpt from a six-hundred-page book, and when an editorial excerpt is created, it’s impossible to cover the rich detail that’s in the book. [JAC: There’s that excuse again!] This piece had a relatively specific focus on histones and methylation and changes in gene expression, and we tried to keep that focus. Otherwise, we didn’t want to give a re-hash of the entire history of regulation. That’s point one.

Point two is that contrary to what everyone is saying, because I’m not sure they’ve read the piece, the idea that transcription factors are denied their role in the piece is wrong. There are four or five references to transcription factor genes being turned on and off in cells that are explicitly in the piece. There’s an incredible sensitivity to that idea. That’s why these things were put in, and if you look at the piece carefully, you’ll see that every time we talk about histone modification, we talk about transcription factors. I’ll give you one example and you can look for the rest.

Number one, one example I tell you is that in discussing one sentence says, “Genes are turned on and off in response to these cues and epigenetic marks are laid subsequently or later, whatever they might be.” That’s just one example of how we make it very clear, because we knew the field, I knew the field very well. Genes are turned on and off and transcription factors turn on and off, and epigenetic match factors are secondary. .

But this isn’t correct. I went back and read the New Yorker piece again, and found not a single mention of transcription factors. Nor do I see any reference or allusion to them, or an “incredible sensitivity” to their importance.  As Richard Mann said, you’d have to have the between-the-lines parsing ability of a Talmudic scholar (or a Sophisticated Theologian™) to get from Mukherjee’s piece any notion that he’s talking about—or even aware of—transcription factors.

I’ll just give three excerpts from the New Yorker article, and you tell me if you see transcription factors in there:

#1:

“The remarkable thing about workers and gamergates [sexually reproducing worker ants]” Yan told me, “is that they are almost genetically identical.” The gene sequence before and after the transition is the same. Yet, as DNA methyl groups or histone modifications get shifted around those gene sequences, the worker transforms into a gamergate , and virtually everything about the insect’s physiology and behavior changes. “We’re going to solve how the change can have such a dramatic effect on longevity,” Reinberg said. “It’s like one twin that lives three times longer than the other”—all by virtue of a change in epigenetic information.

#2

I’ve bolded a bit below because it’s a bit of a howler: Yamanaka’s experiment actually showed the primacy of transcription factors as “most important” (see below)

Yamanaka was taken by the idea that chemical marks attached to genes in a cell might function as a record of cellular identity. What if he could erase these marks? Would the adult cell revert to an original state and turn into an embryonic cell? He began his experiments with a normal skin cell from an adult mouse. After a decades-long hunt for identity-switching factors, he and his colleagues figured out a way to erase a cell’s memory. The process, they found, involved a cascade of events. Circuits of genes were activated or repressed. The metabolism of the cell was reset. Most important, epigenetic marks were erased and rewritten, resetting the landscape of active and inactive genes. The cell changed shape and size. Its wrinkles unmarked, its stiffening joints made supple, its youth restored, the cell could now become any cell type in the body. Yamanaka had reversed not just cellular memory but the direction of biological time.

What Yamanaka (and his collaborator Takahashi) actually showed, which won him the Nobel Prize in 2012, was that adding four genes that produced transcription factors, and then activating them in an already-differentiated fibroblast cell, de-differentiated that cell, turning it back into a “pluripotent stem cell” that could then further differentiate into many types of cells. This showed the key role of transcription factors in cell differentiation.

The abstract of his paper is below (click to go to paper), and note that the four genes mentioned in the abstract are those that make transcription factors. Therefore Mukherjee completely distorted what Yamanaka showed, which was that the most important factor here in de-differentiating cells were transcription factors, not epigenetic marks. Mukherjee doesn’t mention those transcription factors. Some “sensitivity”!

Behold a really cool and Nobel-Prize-winning result!:

#3

Chance events—injuries, infections, infatuations; the haunting trill of that particular nocturne—impinge on one twin and not on the other. Genes are turned on and off in response to these events, as epigenetic marks are gradually layered above genes, etching the genome with its own scars, calluses, and freckles. Prospero, raging against the deformed Caliban in “The Tempest,” describes him as “a devil, a born devil, on whose nature/Nurture can never stick.” Caliban is destined to remain a genetic automaton, a windup ghoul—vastly more pathetic than anything human. He experiences the world, but he has no capacity to be changed by it; he has a genome that lacks an epigenome.

Again, I defy you to find an “incredible sensitivity” to the crucial action of transcription factors in any of the three passages above. And note the complete mischaracterization of the paper by Takahashi and Yamanaka.

But at the end of the Forbes piece, Mukherjee does come around a bit, saying this:

I think there’s a lot of internal debate about what epigenetics is because very ambiguous about it and it seemed that the piece got in the crossfire of that debate. It was not intentional. If people want me to say, transcription factors are important in epigenetic regulation or gene regulation, I’d be delighted to say it. I work on transcription factors myself, so if that’s what it takes, I’d be delighted to say that transcription factors.

You can quote me: “Transcription factors are crucially important in epigenetic regulation.” I welcome people to get beyond that point and look at where their downstream effects on histones and methylation can also be important in gene expression.

That seems a bit petulant, but I’ll take it. Yes, Dr. Mukherjee, I don’t want to put words in your mouth, but I do want you to give an accurate picture of the field.  It’s laudable to change your mind when the facts show you wrong; that is, after all, what science is about. I only wish that the New Yorker had that attitude!