Researchers criticize the Mukherjee piece on epigenetics: Part 2

Trigger warning: Long science post!

Yesterday I provided a bunch of scientists’ reactions—and these were big names in the field of gene regulation—to Siddhartha Mukherjee’s ill-informed piece in The New Yorker, “Same but different” (subtitle: “How epigenetics can blur the line between nature and nurture”). Today, in part 2, I provide a sentence-by-sentence analysis and reaction by two renowned researchers in that area. We’ll start with a set of definitions (provided by the authors) that we need to understand the debate, and then proceed to the critique.

Let me add one thing to avoid confusion: everything below the line, including the definition (except for my one comment at the end) was written by Ptashne and Greally.

_______________

by Mark Ptashne and John Greally

Introduction

Ptashne is The Ludwig Professor of Molecular Biology at the Memorial Sloan Kettering Cancer Center in New York. He wrote A Genetic Switch, now in its third edition, which describes the principles of gene regulation and the workings of a ‘switch’; and, with Alex Gann, Genes and Signals, which extends these principles and ideas to higher organisms and to other cellular processes as well.  John Greally is the Director of the Center for Epigenomics at the Albert Einstein College of Medicine in New York.

 

The New Yorker  (May 2, 2016) published an article entitled “Same But Different” written by Siddhartha Mukherjee.  As readers will have gathered from the letters posted yesterday, there is a concern that the article is misleading, especially for a non-scientific audience. The issue concerns our current understanding of “gene regulation” and how that understanding has been arrived at.

First some definitions/concepts:

Gene regulation refers to the “turning on and off of genes”.  The primary event in turning a gene “on” is to transcribe (copy) it into messenger RNA (mRNA). That mRNA is then decoded, usually, into a specific protein.  Genes are transcribed by the enzyme called RNA polymerase.

Development:  the process in which a fertilized egg (e.g., a human egg) divides many times and eventually forms an organism.  During this process, many of the roughly 23,000 genes of a human are turned “on” or “off” in different combinations, at different times and places in the developing organism. The process produces many different cell types in different organs (e.g. liver and brain), but all retain the original set of genes.

Transcription factors: proteins that bind to specific DNA sequences near specific genes and turn transcription of those genes on and off. A transcriptional ‘activator’, for example, bears two surfaces: one binds a specific sequence in DNA, and the other binds to, and thereby recruits to the gene, protein complexes that include RNA polymerase. It is widely acknowledged that the identity of a cell in the body depends on the array of transcription factors present in the cell, and the cell’s history.  RNA molecules can also recognize specific genomic sequences, and they too sometimes work as regulators.  Neither transcription factors nor these kinds of RNA molecules – the fundamental regulators of gene expression and development – are mentioned in the New Yorker article.

Signals:  these come in many forms (small molecules like estrogen, larger molecules (often proteins such as cytokines) that determine the ability of transcription factors to work.  For example, estrogen binds directly to a transcription factor (the estrogen receptor) and, by changing its shape, permits it to bind DNA and activate transcription.

Memory”:  a dividing cell can (often does) produce daughters that are identical, and that express identical genes as does the mother cell.  This occurs because the transcription factors present in the mother cell are passively transmitted to the daughters as the cell divides, and they go to work in their new contexts as before.  To make two different daughters, the cell must distribute its transcription factors asymmetrically.

Positive Feedback: An activator can maintain its own expression by  positive feedback.  This requires, simply, that a copy of the DNA sequence to which the activator binds is  present  near its own gene. Expression of the activator  then becomes self-perpetuating.  The activator (of which there now are many copies in the cell) activates  other target genes as it maintains its own expression. This kind of ‘memory circuit’, first described  in  bacteria, is found in higher organisms as well.  Positive feedback can explain how a fully differentiated cell (that is, a cell that has reached its developmental endpoint) maintains its identity.

Nucleosomes:  DNA in higher organisms (eukaryotes) is wrapped, like beads on a string, around certain proteins (called histones), to form nucleosomes.  The histones are subject to enzymatic modifications: e.g., acetyl, methyl, phosphate, etc. groups can be added to these structures. In bacteria there are no nucleosomes, and the DNA is more or less ‘naked’.

“Epigenetic modifications: please don’t worry about the word ”epigenetic”; it is misused in any case. What Mukherjee refers to by this term are the histone modifications mentioned above, and a modification to DNA itself: the addition of methyl groups. Keep in mind that the organisms that have taught us the most about development – flies (Drosophila) and worms (C. elegans)—do not have the enzymes required for DNA methylation. That does not mean that DNA methylation cannot do interesting things in humans, for example, but it is obviously not at the heart of gene regulation.

Specificity Development requires the highly specific sequential turning on and off of sets of genes.  Transcription factors and RNA supply this specificity, but   enzymes that impart modifications to histones  cannot: every nucleosome (and hence every gene) appears the same to the enzyme.  Thus such enzymes cannot pick out particular nucleosomes associated with particular genes to modify.  Histone modifications might be imagined to convey ‘memory’ as cells divide – but there are no convincing indications that this happens, nor are there molecular models that might explain why they would have the imputed effects.

Analysis and critique of Mukherjee’s article

The picture we have just sketched has taken the combined efforts of many scientists over 50 years to develop.  So what, then, is the problem with the New Yorker article?

There are two: first, the picture we have just sketched, emphasizing the primary role of transcription factors and RNA, is absent.  Second, that picture is replaced by highly dubious speculations, some of which don’t make sense, and none of which has been shown to work as imagined in the article.

(Quotes from the Mukherjee article are indented and in plain text; they are followed by comments, flush left and in bold, by Ptashne and Greally.)

In 1978, having obtained a Ph.D. in biology at Indiana University, Allis began to tackle a problem that had long troubled geneticists and cell biologists: if all the cells in the body have the same genome, how does one become a nerve cell, say, and another a blood cell, which looks and functions very differently?

The problems referred to were recognized long before 1978.  In fact, these were exactly the problems that the great French scientists François Jacob and Jacques Monod took on in the 1950s-60s.  In a series of brilliant experiments, Jacob and Monod showed that in bacteria, certain genes encode products that regulate (turn on and off) specific other genes.  Those regulatory molecules turned out to be proteins, some of which respond to signals from the environment.  Much of the story of modern biology has been figuring out how these proteins – in bacteria and in higher organisms  – bind to and regulate specific genes.  Of note is that in higher organisms, the regulatory proteins look and act like those in bacteria, despite the fact that eukaryotic DNA is wrapped in nucleosomes  whereas bacterial DNA is not.   We have also learned that certain RNA molecules can play a regulatory role, a phenomenon made possible by the fact that RNA molecules, like regulatory proteins, can recognize specific genomic sequences.  

In the nineteen-forties, Conrad Waddington, an English embryologist, had proposed an ingenious answer: cells acquired their identities just as humans do—by letting nurture (environmental signals) modify nature (genes). For that to happen, Waddington concluded, an additional layer of information must exist within a cell—a layer that hovered, ghostlike, above the genome. This layer would carry the “memory” of the cell, recording its past and establishing its future, marking its identity and its destiny but permitting that identity to be changed, if needed. He termed the phenomenon “epigenetics”—“above genetics.”

This description greatly misrepresents the original concept.  Waddington argued that development proceeds not by the loss (or gain) of genes, which would be a “genetic” process, but rather that some genes would be selectively expressed in specific and complex cellular patterns as development proceeds.  He referred to this intersection of embryology (then called “epigenesis”) and genetics as “epigenetic”. We now understand that regulatory proteins work in combinations to turn on and off genes, including their own genes, and that sometimes the regulatory proteins respond to signals sent by other cells.  It should be emphasized that Waddington never proposed any “ghost-like” layer of additional information hovering above the gene.  This is a later misinterpretation of a literal translation of the term epigenetics, with “epi-“ meaning “above/upon” the genetic information encoded in DNA sequence.  Unfortunately, this new and pervasive definition encompasses all of transcriptional regulation and is of no practical value.

Waddington’s hypothesis was perhaps a little too inspired. No one had visualized a gene in the nineteen-forties, and the notion of a layer of information levitating above the genome was an abstraction built atop an abstraction, impossible to test experimentally. “By the time I began graduate school, it had largely been forgotten,” Allis said. . . Had Allis started his experiments in the nineteen-eighties trying to pin down words like “identity” and “memory,” he might have found himself lost in a maze of metaphysics.

By the 1980’s there had been significant advances in our understanding of the biological problems of “identity and “memory”.  We had learned not only how regulatory proteins bind specific sequences in DNA, but also how such proteins can work together, in response to extracellular signals, to make a “switch” in turning one set of genes on and another off. It was apparent by that time that these ideas and findings were applicable to the study of development in higher organisms, and explained different cell identities.  The problem of cellular “memory”—then and now—can be explained by positive feedback mechanisms involving regulatory proteins, as discussed in the Introduction.

But part of his scientific genius lies in radical simplification: he has a knack for boiling problems down to their tar. What allows a cell to maintain its specialized identity? A neuron in the brain is a neuron (and not a lymphocyte) because a specific set of genes is turned “on” and another set of genes is turned “off.” The genome is not a passive blueprint: the selective activation or repression of genes allows an individual cell to acquire its identity and to perform its function. When one twin breaks an ankle and acquires a gash in the skin, wound-healing and bone-repairing genes are turned on, thereby recording a scar in one body but not the other.

As noted above, this would hardly have been news at the time. The specificity of cellular identity and the response to stress has been known for decades to be due to the actions of specific DNA binding proteins (and, more rarely, RNA molecules) that regulate gene transcription.

But what turns those genes on and off, and keeps them turned on or off? Why doesn’t a liver cell wake up one morning and find itself transformed into a neuron? Allis unpacked the problem further: suppose he could find an organism with two distinct sets of genes—an active set and an inactive set—between which it regularly toggled. If he could identify the molecular switches that maintain one state, or toggle between the two states, he might be able to identify the mechanism responsible for cellular memory. “What I really needed, then, was a cell with these properties,” he recalled when we spoke at his office a few weeks ago. “Two sets of genes, turned ‘on’ or ‘off’ by some signal.”

The question raised in the first sentence here had, as we have noted, already been answered. The lambda phage switch mechanism is one well-known example of how regulatory proteins can be used to switch a gene “on”, with the gene then persisting in this ‘on’ state in the absence of the protein/signal that first switched it on.  The mechanism is an instantiation of positive feedback (see Introduction).  The more detailed explanation is readily apparent, and does not involve extra layers of information. The mechanism has been well-established in many cases in higher organisms as well.

In 1996, Allis and his research group deepened this theory with a seminal discovery. “We became interested in the process of histone modification,” he said. “What is the signal that changes the structure of the histone so that DNA can be packed into such radically different states? We finally found a protein that makes a specific chemical change in the histone, possibly forcing the DNA coil to open. And when we studied the properties of this protein it became quite clear that it was also changing the activity of genes.” The coils of DNA seemed to open and close in response to histone modifications—inhaling, exhaling, inhaling, like life.

This attributes an autonomy to and an effect of histone modifications that is grossly misleading. And there is no evidence that coiling and uncoiling of DNA has a causal effect on gene activity.   

“Two features of histone modifications are notable,” Allis said. “First, changing histones can change the activity of a gene without affecting the sequence of the DNA.” It is, in short, formally epi-genetic, just as Waddington had imagined. “And, second, the histone modifications are passed from a parent cell to its daughter cells when cells divide. A cell can thus record ‘memory,’ and not just for itself but for all its daughter cells.”

There is no evidence, despite years of research, that nucleosome states can be “copied” for transmission to daughter cells.  The one experiment performed in yeast that appeared to show persistence of histone modifications was performed using mutant strains lacking the enzyme that erases the modification tested. In the Introduction, we describe how states of expression are transmitted from as cells divide.   

By 2000, Allis and his colleagues around the world had identified a gamut of proteins that could modify histones, and so modulate the activity of genes. Other systems, too, that could scratch different kinds of code on the genome were identified (some of these discoveries predating the identification of histone modifications). One involved the addition of a chemical side chain, called a methyl group, to DNA. The methyl groups hang off the DNA string like Christmas ornaments, and specific proteins add and remove the ornaments, in effect “decorating” the genome. The most heavily methylated parts of the genome tend to be dampened in their activity.

It is true that enzymes that modify histones have been found—lots of them.  A striking problem is that, after all this time, it is not at all clear what the vast majority of these modifications do.  When these enzymatic activities are eliminated by mutation of their active sites (a task substantially easier to accomplish in yeast than in higher organisms) they mostly have little or no effect on transcription.  It is not even clear that histones are the biologically relevant substrates of most of these enzymes.  

 In the ensuing decade, Allis wrote enormous, magisterial papers in which a rich cast of histone-modifying proteins appear and reappear through various roles, mapping out a hatchwork of complexity. . . These protein systems, overlaying information on the genome, interacted with one another, reinforcing or attenuating their signals. Together, they generated the bewildering intricacy necessary for a cell to build a constellation of other cells out of the same genes, and for the cells to add “memories” to their genomes and transmit these memories to their progeny. “There’s an epigenetic code, just like there’s a genetic code,” Allis said. “There are codes to make parts of the genome more active, and codes to make them inactive.”

By ‘epigenetic code’ the author seems to mean specific arrays of nucleosome modifications, imparted over time and cell divisions, marking genes for expression.  This idea has been tested in many experiments and has been found not to hold.  

But Reinberg sought a more advanced instance of epigenetic instruction—a whole animal, not just a cell, whose form and identity could be shifted by shifting the epigenetic code. “So imagine that you tighten some parts of the DNA and loosen other parts by changing the structures of the histones,” Reinberg said. “Can you change the form or nature of an animal simply by coiling and uncoiling various parts of its genome?”

This is once again subscribing to the view that chromatin structure is the primary determinant of cellular and organismal states.  If that is the view, then the question must be asked – if you could magically change chromatin structure at specific genomic locations, why would cell physiology alter?  If the answer is that “this will allow regulatory proteins to bind at these specific sequences,” then the question becomes why invoke a mysterious mechanism for targeted chromatin structure changes with secondary binding of regulatory proteins, when a primary event of binding of these proteins accomplishes both steps?

Perhaps the most startling demonstration of the power of epigenetics to set cellular memory and identity arises from an experiment performed by the Japanese stem-cell biologist Shinya Yamanaka in 2006. 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.

This is an extremely inappropriate example to use in a story about the supposed primacy of histone modifications.  The Yamanaka experiment, in fact, showed the opposite: that you can change cell identity by expressing certain DNA-binding proteins that bind to and activate specific genes.    Any changes in chromatin organization—presumably the “epigenetic marks” referred to, given the context of the entire piece—found during this process are the result of the activities of the DNA-binding regulatory proteins Yamanaka used. There are now many examples of cell “reprogramming” elicited by expression of specific DNA-binding regulatory proteins.  This reprogramming example is used by Mukherjee in attempting to establish a primary role for ‘epigenetic’ regulation, but instead provides an excellent example of the higher level control by regulatory proteins.

Both Allis and Reinberg understand the implications of transgenerational epigenetic transmission: it would overturn fundamental principles of biology, including our understanding of evolution.

. . . . Conceptually, a key element of classical Darwinian evolution is that genes do not retain an organism’s experiences in a permanently heritable manner. Jean-Baptiste Lamarck, in the early nineteenth century, had supposed that when an antelope strained its neck to reach a tree its efforts were somehow passed down and its progeny evolved into giraffes. Darwin discredited that model. Giraffes, he proposed, arose through heritable variation and natural selection—a tall-necked specimen appears in an ancestral tree-grazing animal, and, perhaps during a period of famine, this mutant survives and is naturally selected. But, if epigenetic information can be transmitted through sperm and eggs, an organism would seem to have a direct conduit to the heritable features of its progeny. Such a system would act as a wormhole for evolution—a shortcut through the glum cycles of mutation and natural selection.

We agree with the author that this is highly speculative and not currently supported by any mechanistic studies involving so-called epigenetic regulatory processes.

 _______

JERRY’S ADDENDUM:  Yes, and until there is evidence for this kind of evolutionary transformation—ANY evidence—people should stop yammering about this kind of “Lamarckian” evolution. 

 

 

145 Comments

  1. merilee
    Posted May 6, 2016 at 10:19 am | Permalink

    sub

  2. George
    Posted May 6, 2016 at 10:25 am | Permalink

    The good part of the Mukherjee piece is that I have been educated. When I read the New Yorker article, I immediately had my qualms because of the reliance on epigenetics. I am not really sure what epigenetics really are. Deepak Chopra uses the term. As does Robert Wright. The term seems to be used by a variety of people to add some scientific luster to their arguments.

    When Mukkherjee made references to Lamarck, the alarm bells really started to go off. But then I thought why was I so suspicious. I really did not understand the mechanism at all. So I have been reading.

    I will have to read Ptashne and Greally numerous times. My ignorance on this subject is embarrassing.

  3. Posted May 6, 2016 at 10:31 am | Permalink

    I love this! I’m so glad you all who put this together saw the teachable moment and took the time to engage.

    • ken
      Posted May 6, 2016 at 10:42 am | Permalink

      +1

      • somer
        Posted May 8, 2016 at 9:35 am | Permalink

        Riveted all weekend reading these articles and associated material also – really appreciate such a gift to lay readers! Thank you

    • rickflick
      Posted May 6, 2016 at 11:34 am | Permalink

      Agree.

    • darrelle
      Posted May 6, 2016 at 12:12 pm | Permalink

      Yes indeed. Many thanks to Mark Ptashne and John Greally for their clear, easy to understand critique, and to Jerry for hosting them and providing definitions and additional insightful comments.

      • Posted May 6, 2016 at 12:59 pm | Permalink

        Let me correct one thing; the definitions came from Ptashne and Greally, not from me. I’m sorry if there’s confusion there.

        • darrelle
          Posted May 6, 2016 at 1:06 pm | Permalink

          Not at all Jerry, the confusion was mine alone. Your article is very clear that the definitions are from Ptashne and Greally.

      • Merilee
        Posted May 7, 2016 at 6:04 pm | Permalink

        +3
        Very disappointed in Mukherjee, whose cancer book I thought was very good.

    • FiveGreenLeafs
      Posted May 6, 2016 at 1:11 pm | Permalink

      +1

      Sincere thanks to all involved!

    • Posted May 6, 2016 at 1:48 pm | Permalink

      Agreed. I learned a LOT. Thanks PCCE!

    • Diane G.
      Posted May 7, 2016 at 2:13 am | Permalink

      Booyah!

  4. George
    Posted May 6, 2016 at 10:43 am | Permalink

    A critique of Mukherjee from Inverse (never heard of it before), crediting and sourcing PCC.
    https://www.inverse.com/article/15271-how-badly-did-the-new-yorker-screw-up-its-article-on-identical-twins

    • George
      Posted May 6, 2016 at 11:05 am | Permalink

      I have been trying to find more critiques of the New Yorker piece. So far, other than Inverse, I have found one from the Unz Review which had a minor criticism – but posted early on April 28.
      http://www.unz.com/gnxp/the-new-yorker-has-fact-checkers-they-should-use-them/

      Other publications have linked to the article, either positively, sometimes without comment. I am afraid that what Mukherjee wrote may become the conventional wisdom. We need to comment on these links, linking to PCC’s posts.

      Carl Zimmer has done his part on Twitter.

      • Posted May 6, 2016 at 1:49 pm | Permalink

        Nice to see the Ceiling Cat Ikon prominently displayed. All hail CC! 🙂

  5. Posted May 6, 2016 at 11:04 am | Permalink

    I really appreciate the efforts, and it looks very interesting.
    Honestly, however, I have to admit that I was unable to fully understand what’s going on.
    Jerry’s posts usually make things more understandable for us laypersons. Maybe the subject is more complicated or Ptashne and Greally aren’t as good.

    • Diane G.
      Posted May 7, 2016 at 2:26 am | Permalink

      I think Ptashne and Greally are quite good at explaining what’s what and where Mukherjee goes off the rails, but to do so requires practically trying to teach a whole course in transcription/development in one article. A noble effort, but to grasp it all it’s probably helpful to already have a pretty good grasp of genetic processes at the molecular level in the first place. It is not so much hard to understand, just quite detailed and quite loaded with discipline-specific terms.

      (Now if you’re a molecular geneticist yourself, apologies for insulting your intelligence!)

      • Posted May 7, 2016 at 2:29 am | Permalink

        HEH
        I’m not a biologist, nor am I insulted 🙂
        You’re probably right. I found it difficult to follow the details of a subject of which I have superficial understanding at best.

    • Mark Ptashne
      Posted May 7, 2016 at 7:22 pm | Permalink

      Yep, sorry. Hard to explain in a few sentences

      • Posted May 8, 2016 at 12:34 pm | Permalink

        No need to apologise! I thought you did fantastically well to summarise such complex ideas so succinctly. I’ve copied this article into my lecture notes on genetics and I have learnt a lot. You have clarified so much for me. Thank you.

      • Vijay Varma
        Posted May 10, 2016 at 8:15 pm | Permalink

        No, it was a lucid description of complex mechanisms with bits of relevant history. I remember listening to your lecture a long time ago, that left me admiring–he really knows how to get to the heart of the matter. Thanks both, for taking the time.

  6. Edward Hessler
    Posted May 6, 2016 at 11:11 am | Permalink

    Thanks for posting these. When I first read/heard that Mukerjee was writing a book on genetics my reaction was “what does he know about genetics?” (I know him only as an oncologist and then cancer researcher) but then I wondered whether he’d switch field/careers several years ago and maybe was going to write about cancer genetics.

    When I read the article the word epigenetics made me very leery but then I thought just maybe there had been some tremendous advances, breakthroughs of which I was unaware. I knew though that I needed some help. I scouted around the few blogs I know looking for reactions/critiques but to my great surprise I couldn’t find any until your post and the promise of another by experts. One huge problem with his article as others have pointed out is that he writes like a whiz. This can be seductive.

    It has made me wonder about the fascination of Lamarckian explanations. Clearly, they have a hold on some. I hope sometime you might write about this but I think you have better things to do with your time so please don’t.

    I’m a science educator so on my good days I’m a decent generalist (I think). I’m far, far, far from being a specialist in anything. I try to keep in mind a question that the late science educator Mary Budd Rowe once asked: “Suppose all students learned to ask the following questons routinely (she was talking mostly K-8 but physics educators have used similar ones, e.g., the late Arnold Arons)? Here are a few.

    On Evidence: What do I know? What are the reasons I think that they are true? What is the evidence? Do I have it all? Where did the evidence come from? How good is it.

    Inference: What do I make of it? What are all the possible interpretions?

    Evaluation: What does it all mean? Do I value certain outcomes over others? What are the reasons.

    There is a similar and much more extensive list in Lipman’s “Philosophy for Children.”

    And so on.

    I’m genuinely disappointed in Mukerjee (but still recommend his book on cancer) in his handling of the science and also as a writer. I thought he was the kind of bioscientist who would warn readers on the edginess of this field, its nature (I still don’t think there is much controversy but in any event the reactions of a few other researchers would have helped but then I don’t think the article would have been published. There would be nothing there. The science to date seems clear).

    Well, thanks again.

    • Mark Ptashne
      Posted May 7, 2016 at 7:24 pm | Permalink

      then I don’t think the article would have been published. There would be nothing there. The science to date seems clear).

      Yessir

  7. Pliny the in Between
    Posted May 6, 2016 at 11:22 am | Permalink

    Fantastic summary. thx!

  8. darrelle
    Posted May 6, 2016 at 11:35 am | Permalink

    That point by point critique is devastating to Mukherjee’s article. I’m trying to give him the benefit of the doubt, that he was enthusiastic, well meaning and merely sloppy and over-confident.

    Overall it looks to me like someone bullshitting their way through something that they think they have an understanding of but they really don’t. Or maybe even a bit worse. For example . . .

    ““Two features of histone modifications are notable,” Allis said. “First, changing histones can change the activity of a gene without affecting the sequence of the DNA.” It is, in short, formally epi-genetic, just as Waddington had imagined.

    . . . the part in bold. It sure does hit the mark for standard story telling format 101, but it doesn’t necessarily follow even if you grant the inaccurate premises he previously established. It makes me wonder if he was predisposed to accept or conjure inaccurate conceptions of these issues in the service of creating a good mystery -> prediction -> eureka moment validation story.

    I was never in agreement with the commonly held opinion that regardless of accuracy this article was well written in a literary sense. The more I read it the more I disagree.

  9. Chemist
    Posted May 6, 2016 at 11:42 am | Permalink

    Great response clearly addressing the specific errors in Mukerjee’s piece. Has there been any indication that the article’s editor or author will address the identified errors (given it’s basis in science, one would expects errors corrections are mandated)? Or does The New Yorker believe itself to be above the confines of science reality or facts in their publishing efforts?

    • darrelle
      Posted May 6, 2016 at 12:14 pm | Permalink

      It may be that The New Yorker considers themselves a literary magazine above all else, and that literature trumps science.

      • Diane G.
        Posted May 7, 2016 at 2:33 am | Permalink

        But by what standards do they judge this article to be “literary?”

        I find that just the fact that this appeared in the New Yorker says everything about this article in terms of its scientific cred, but I’m still trying to figure out why this mag published this piece in the first place.

        • rickflick
          Posted May 7, 2016 at 7:20 am | Permalink

          I’m guessing it has to do with the clever way the author combined the story about his mother the twin with the sciency stuff. It had a first person appeal. Also, he pulled out David Allis as the scientific sleuth. A great protagonist. The vocabulary is kind of right too.

        • darrelle
          Posted May 7, 2016 at 8:26 am | Permalink

          If you mean the article didn’t impress you even from a literary perspective I entirely agree! But I’ve always thought the New Yorker to be a bit pretentious so I might be biased.

  10. Armando
    Posted May 6, 2016 at 11:43 am | Permalink

    Thank you very much for this series.

    These days, in the field of Evolutionary Ecology, epigenetics indeed seems to be the buzz word. Yet, it seems to mean many different things to different people.

    It does seem to be that environmental exposure can have an effect on the patterns of DNA methylation in the genome, and that these can sometimes be inherited. Some argue that this leads to a plastic response that is adaptive. That being said, it seems that this New Yorker piece goes much further than that. If the field is often hard to navigate even by researchers, it must be much much harder for the general public that the New Yorker caters to.

    Again, thank you very much- this series does what I think your blog does best- raise awareness and educate.

    Keep it up and don’t stop the science related posts just because they get less comments. We read them.

    • darrelle
      Posted May 6, 2016 at 12:35 pm | Permalink

      “It does seem to be that environmental exposure can have an effect on the patterns of DNA methylation in the genome, and that these can sometimes be inherited.

      I suppose it depends on exactly what is meant by “inherited.” To date experimental evidence indicates that some degree of change due to environmental causes experienced by a parent organism have been detected no further than 2nd generation offspring.

      There is, to date, no solid evidence of any permanent changes (as would typically be meant in the context of inherited characteristics), due to any proposed epigenetic mechanisms.

      I don’t think there is any doubt that some very interesting things that we don’t know much about are happening, and that they have some affects. But I think “inherited” is overstating things at this point in time.

      • Armando
        Posted May 6, 2016 at 1:59 pm | Permalink

        Correct! Perhaps it would have been best phrased as transmitted.

  11. Posted May 6, 2016 at 11:57 am | Permalink

    It seems to me that Ptashne and Greally should not be leveling their attack on Mukherjee…he’s merely a doctor. Mukherjee seems to be passing on the claims of 2 prominent researchers; C David Allis and Danny Reinberg. From Allis website, and the part on ‘indexing of H3 variants’ I get the impression that he would not consider Mukherjees claims to be wildly unsupported.
    If my impression is incorrect then Mukherjee’s greatest sin was not misrepresenting the science but misrepresenting Allis and Reinberg.

  12. Posted May 6, 2016 at 12:01 pm | Permalink

    Jerry, your own takedowns here of deluded views on evolution have been classics. Now that you are hosting informed and incisive critiques by no less than Mark Ptashne, things have been carried to a new, and even higher, level.

    • ritebrother
      Posted May 6, 2016 at 1:47 pm | Permalink

      That was my thought, as well. I enjoy Ptashne’s regular editorials bashing the misplaced “epigenetics” euphoria and the collective memory loss in the field of transcriptional regulation regarding the primacy of transcription factors. I knew this article would rile him as soon as I saw it.

  13. Joe Dickinson
    Posted May 6, 2016 at 12:01 pm | Permalink

    Ptashne and Greally’s critique is, of course devastating. I would only add that there is more than a half-century of relevant work even before Jacob and Monod. A case can be made the the entire discipline called experimental embryology, beginning in the late 19th century, emerged from trying to distinguish between two models: differential distribution of information (called “determinants” before the concept of “gene” was available) on the one hand and differential utilization (expression) on the other. The question was pretty well settled in favor of the second option the first few decades of the 20th century. In other words, it was known that, in modern terminology, diverse cell types all contain the same set of genes and that cell specialization results from differential gene expression. The history recounted by Ptashne and Greally picks up at that point to explain how that actually works. One other noteworthy point: it clear that cells can become committed to a specific fate well before they show any overt morphological specialization. In other words, determination is distinct from and typically precedes differentiation.

    • Mark Ptashne
      Posted May 7, 2016 at 7:27 pm | Permalink

      Excellent points.

    • Ian Dworkin
      Posted May 10, 2016 at 7:22 pm | Permalink

      I think it is worth pointing out that “determinants” in the old usage (again before a modern concept of the gene) was agnostic to the molecular basis. In fact, during the first few cell divisions (cleavage) many proteins and sometimes mRNA’s are localized and asymmetrically distributed to daughter cells. These are usually deposited maternally (as zygotic transcription often does not start immediately after fertilization, depending on the organism).

      In (relatively) modern parlance, we often describe these as cytoplasmic determinants.

      • Mark Ptashne
        Posted May 10, 2016 at 7:44 pm | Permalink

        Excellent.

  14. Chemist
    Posted May 6, 2016 at 12:05 pm | Permalink

    Just came across a horrible article with the National Post on epigenetics titled:

    Can trauma be passed through generations?

    http://news.nationalpost.com/health/can-trauma-be-passed-through-generations-author-says-making-link-to-past-may-be-key-to-healing?

    Not sure how to stop this utter nonsense, but I can see a whole lot of ineffective or harmful woo using “epigenetics pathway” to “help” desperate people.

  15. Dominic
    Posted May 6, 2016 at 12:08 pm | Permalink

    Ah – Lysenkoism is still alive! That reminds me of the Japanese Waltzing Mice which were at one time thought to be the result of being kept in cages…

    I fee sorry for Lamarck. I think he deserves his place in the pantheon, but he was doing the best with what he had in the way of information and ideas.

    • Petrushka
      Posted May 6, 2016 at 12:41 pm | Permalink

      It moves from Lamarck to Lysenko when the movement refuses to listen to evidence.

      It is now in sight of creationism.

      In fact, it is strongly applauded by creationists.

    • Mark Sturtevant
      Posted May 6, 2016 at 12:52 pm | Permalink

      I have a soft spot for Lamarck. He had two rather elegant theories of evolution, both destroyed by a barrage of ugly facts, but they were clever and they had what I like to call ‘explanatory power’.

      • Jiten
        Posted May 6, 2016 at 1:07 pm | Permalink

        His day will come once again when AI is here. They will be Lamarkian creatures. One could make the case that Darwinism is only a temporary case before Lamarkian creatures arrive.

        • Mark Sturtevant
          Posted May 6, 2016 at 2:00 pm | Permalink

          A movement in that direction is where we are all wearing Google implants, and have nano-bots in our blood. Soon we can re-write our phenotype by just downloading the latest update into our USB-2000 port. Don’t ask me where it will be. You don’t want to know.

          • W. Benson
            Posted May 6, 2016 at 4:40 pm | Permalink

            🙂

          • Allan Miller
            Posted May 10, 2016 at 1:03 pm | Permalink

            A movement in that direction is where we are all wearing Google implants

            Haha! I read that first as “Google underpants” 🙂

      • Posted May 6, 2016 at 5:14 pm | Permalink

        Yes, I feel bad for Lamark – that he is remembered not for his contributions but for an error which was not even his own invention.

        • nicky
          Posted May 6, 2016 at 11:59 pm | Permalink

          indeed, I’m sure that if Lamarck were alive now he would not be a “Lamarckian” at all.

          • Diane G.
            Posted May 7, 2016 at 2:37 am | Permalink

            🙂 Nicely said.

  16. Posted May 6, 2016 at 12:12 pm | Permalink

    While agreeing with the criticism of the “epigenetic” Lamarckian pseudoscientific fad, I think that DNA methylation is very important in vertebrates, particularly mammals (maybe also in plants, but I know too little about them). In mice, homozygous knockouts for the maintenance methyltransferase DNMT1 die before birth. Knockouts for the de novo methyltransferase DNMT3a have the same fate, while whose without the related enzyme DNMT3b are born alive but die before adulthood. In humans, mutations in the X-linked methylation-related gene MECP2 are usually lethal for boys, while heterozygous girls develop Rett syndrom, a severe regressive autism spectrum disorder. Mammalian zygotes with 2 female or 2 male pronuclei produce embryos that show opposite abnormalities and cannot develop to term. This effect is thought to be based on sex-specific methylation of certain genes resulting in differential expression (genomic imprinting). In light of this, I think that it is an underestimation to say that DNA methylation can do interesting things in humans but is not at the heart of gene regulation.

    • daveyc
      Posted May 6, 2016 at 12:17 pm | Permalink

      The vast majority of organisms are not vertebrates (or plants).

      • Posted May 6, 2016 at 12:24 pm | Permalink

        True! But as a vertebrate, I am biased.

    • Posted May 7, 2016 at 7:28 am | Permalink

      I think the “not at the heart of gene regulation” refers to the fact that it is not DNA methylation that is driving REGULATION of gene expression. It is very important for MAINTAINING patterns of gene expression following regulation by something else. X-inactivation, for example, is heavily dependent on DNA methylation but it is “regulated” (i.e. triggered) by an RNA, Xist, expressed from a specific DNA locus.

      Even in genomic imprinting, I do not think the methylation is necessarily the specific regulator of gene expression, although it does seem to play a crucial role in identifying which are the maternal and paternal alleles. (If I remember/understand it correctly.) In other words, the methylation state is probably the consequence of the activity of the regulator, and not itself the regulator.

    • Mark Ptashne
      Posted May 7, 2016 at 7:20 pm | Permalink

      Good points. Why is mechanism so hard to pin down? Why can flies etc do without it?

      • Posted May 9, 2016 at 4:23 pm | Permalink

        Let me share my thoughts though by trying to discuss things outside my area of expertise I must be making a fool of myself, like Dr. Mukherjee.
        I checked what is reported about the presence of DNA methyltransferases among various groups of eukaryotes. What impressed me most is that animal DNMT1 and plant MET1 not only perform similar functions but are considered structural homologs. That is, unless there has been a horizontal gene transfer, the enzyme is very ancient; in fact, it must be fairly ancient even if there has been a horizontal gene transfer.
        I found 2 main hypotheses about the main role of eukaryotic DNA methylation: that it is a tool to regulate transcription, particularly in differentiation, and that it is a tool to silence parasitic DNA. In fact, I see these hypotheses as similar. How does the cell “view” the DNA parasites within its genome? As far as I know, there is no way for the eukaryotic cell to recognize a piece of DNA as “foreign”, once it is in the genome. So the way to deal with such sequences is to label them as “not to be transcribed”; in cell differentiation (in the broadest sense), the “not to be transcribed” label can be applied also to other sequences.

        • Mark Ptashne
          Posted May 9, 2016 at 4:33 pm | Permalink

          Good points.

          (Tho notice that flies have lots of silent elements but not methylation).

          I could well imagine, for example, that reiterated sequences somehow make small RNAs that recruit DNA methylases, and that those methyls “silence” the transposons. I am only puzzled by why it seems so hard to pin this sort of thing down. Maybe i have missed something?

          • Posted May 9, 2016 at 4:59 pm | Permalink

            My idea: DNA methylation originally used by all eukaryotes to control parasitic DNA, utilized by many in cell differentiation (maybe independently).
            Vertebrates have long life spans and contain many cells that must retain both their differentiated (to some degree) state and their ability to proliferate. For them, DNA methylation seems an ideal label of tissues.
            Both Drosophila and Caenorhabditis have short life spans. Somatic cells of adult C. elegans are all postmitotic and, as far as I know, the same is true for Drosophila. They do not need as much as we do.
            I initially thought that DNA methylation may have been secondarily lost by the entire ecdysozoan clade including both model animals. 5 minutes of search, however, produced reports of methylation in many arthropods. So it must have been lost independently by smaller clades.
            Differentiation in an animal with short life span and rigid development apparently can be achieved very well without methylation. Drosophila, however, may have problems with losing the universal role of methylation, to control genome parasites.
            Cnidarians are not very advanced in cell differentiation, but those of them that reproduce by budding have longer life spans than any vertebrate, they are practically immortal. So I was delighted to read that they have relatively high level of DNA methylation. I think this is derived: sexual reproduction is a more fundamental trait than multicellularity, so the direct transfer of the tissue structure to the progeny in budding must be a later development. But the cnidarians, unlike the ancestor of Drosophila, had kept the methylation “package” and could easily utilize it.

      • Posted May 9, 2016 at 4:42 pm | Permalink

        I suppose that DNA methylation of “not to be transcribed” sequences may have been introduced very early in eukaryotic evolution to control genomic parasites.
        I do not think that eukaryotic DNA methylation systems evolved directly from the restriction modification systems of prokaryotes (except maybe DNMT2, which I am leaving aside as irrelevant and too enigmatic). Because they are not only different, they are diametrically opposed. Prokaryotes methylate DNA to be preserved, eukaryotes methylate DNA to be suppressed.
        I think that an increase in size predated most other peculiarities of the eukaryotic genome. With the increase of total size, it became more and more probable that restriction enzymes would cut the cell’s genome (either as a result of 2 rounds of replication in some region before the methylase caught up, or as a result of too-often integration of parasitic DNAs before the restriction enzyme could cut them.) So, the old restriction modification systems started to bring more harm than good and had to be abandoned.
        How could the cell recognize where to put the “not to be transcribed” label? It must have been easier to leave unlabeled the sequences to be transcribed, hence the overall gene expression pattern of eukaryotes with specific activation and widespread, “default” non-active state. The eukaryotic ancestor may already have been predisposed to such management of the genome by the presence of histones, inherited from archaeans and good for non-specific silencing.

        • Mark Ptashne
          Posted May 9, 2016 at 4:46 pm | Permalink

          Sure, why not.

          One striking fact is that if you grow cells in culture, lots of genes get methylated. Is that a cause (of what?) or a consequence? And lets ask John Greally: isn’t it true that eliminating methyls (with 5AZAC) has little effect on gene expression genome-wide?

  17. daveyc
    Posted May 6, 2016 at 12:16 pm | Permalink

    This post was far from being too long. I enjoyed the entire thing, and would love to read more!

  18. Posted May 6, 2016 at 12:32 pm | Permalink

    I understood just enough of it to make me want to reread it and understand … some more.

    Great posts! Keep ’em comin’.

  19. Petrushka
    Posted May 6, 2016 at 12:38 pm | Permalink

    Not simply Lamarckian.

    Lysenkoist. This is a quasi political movement.

    It’s going to affect medicine and education.

    Adversely.

    • Posted May 6, 2016 at 2:22 pm | Permalink

      It may affect education, but i don’t think it will affect medicine. Most of us don’t take Deepak Chopra very seriously. There are very high hurdles to overcome before a new medical treatment along these lines will be approved – and it will have to be real.

  20. Posted May 6, 2016 at 12:46 pm | Permalink

    “Trigger warning: Long science post!”

    Hee hee hee! 🙂

    • Marilee Lovit
      Posted May 6, 2016 at 3:08 pm | Permalink

      More like click bait.

  21. Mark Sturtevant
    Posted May 6, 2016 at 12:47 pm | Permalink

    First and foremost – wow.
    This has been an enjoyable trip thru the ghostly forest of epigenetics. What becomes clear even part way through this journey is that the subject may at first seem to be spooky and mysterious, but after a time one should realize that its’ all just different ways that gene products control expression of other genes. A bit like a walk through a foggy forest, but once the sunlight has a chance to do its work, lifting the fog, one can see that those dark and creepy forms are just trees.

    • Mark Ptashne
      Posted May 7, 2016 at 7:30 pm | Permalink

      Bingo. Let’s just agree to never utter the word “epigenetic” again.

      • Diane G.
        Posted May 8, 2016 at 3:38 am | Permalink

        😀

        Suits me!

  22. BobTerrace
    Posted May 6, 2016 at 12:49 pm | Permalink

    Mukherjee’s QED – not.

    Lamarck is still lying undisturbed in his grave.

  23. Larry Moran
    Posted May 6, 2016 at 12:55 pm | Permalink

    Knowing the historical context of a field is very important as Ptashne and Greally point out.

    It reminds me of something that Stephen Jay Gould said in his 1977 book “Ontogeny and Phylogeny,” which, incidentally, advertised the case for developmental regulation by transcription factors.

    He said,

    “… those ignorant of history are not condemned to repeat it; they are merely destined to be confused” (p. 4)

    • Mark Ptashne
      Posted May 7, 2016 at 7:31 pm | Permalink

      Lovely.

  24. Nell Whiteside
    Posted May 6, 2016 at 12:58 pm | Permalink

    Excellent. Many thanks.

  25. mecwordpress
    Posted May 6, 2016 at 1:07 pm | Permalink

    Many thanks, Dr. Coyne, et al.

  26. John Conoboy
    Posted May 6, 2016 at 1:25 pm | Permalink

    Fascinating! I had just started reading Mukherjee’s early New Yorker article about his family and schizophrenia, but set it aside to read this article. I have not had a genetics course in almost 50 years but I found his article to be somewhat believable, although I am always skeptical of articles like this, until reading these critiques. I haven’t checked, but I fully expect to see posts on facebook that use this article to support all kinds of woo. Glad to have some evidence to try and thwart that. Thanks.

  27. christiandelrosso
    Posted May 6, 2016 at 1:31 pm | Permalink

    Great blog post,thank you for highlighting the scientific misinterpretation of epigenetics and keep us informed. It would be great to hear from Mukherjee and from the researchers he mentioned.

    By the way, Mukherjee is a great writer and his book was excellent. I have ordered the forthcoming one on genetics. Looking forward to seeing your review on that.

  28. Steve Brecher
    Posted May 6, 2016 at 1:51 pm | Permalink

    First quote from Mukherjee: “In 1978 … Allis began to tackle a problem that had long troubled geneticists and cell biologists …”

    The first sentence of the response: “The problems referred to were recognized long before 1978.” I am quite willing to believe that this redundant remark is due to an inadvertent misreading.

    • Diane G.
      Posted May 7, 2016 at 2:46 am | Permalink

      I see what you mean. But when I read it, I just assumed that Ptashne and Greally meant that those “troubled geneticists and cell biologists” had also tackled the problem, well before Allis came along. Definitely could have been written more clearly!

    • Mark Ptashne
      Posted May 7, 2016 at 7:32 pm | Permalink

      Yes, good point.

  29. Posted May 6, 2016 at 1:58 pm | Permalink

    Great post, thanks to PCCE and Mark Ptashne and John Greally.

  30. Mark Ptashne
    Posted May 6, 2016 at 2:07 pm | Permalink

    I wish now I had made this point more strongly: arguments over the “definition” of the word “epigenetics” usually throw up a smoke screen. The challenge is to discuss whatever is of interest here without using that word!

    • Posted May 6, 2016 at 3:16 pm | Permalink

      Thanks for your detailed reply to Mukherjee (I really loved his first book). I really learned a lot from it!

    • Diane G.
      Posted May 7, 2016 at 2:48 am | Permalink

      What J. Blilie said; also, thank you for dropping in on our discussion here!

  31. Mark Ptashne
    Posted May 6, 2016 at 2:11 pm | Permalink

    Quoting Evelyn Waugh, from WSJ today:
    Never send off any piece of writing the moment it is finished. Put it aside. Take on
    something else. Go back to it a month later and re-read it. Examine each sentence and
    ask “Does this say precisely what I mean? Is it capable of misunderstanding? Have I
    used a cliché where I could have invented a new and therefore asserting and
    memorable form? Have I repeated myself and wobbled round the point when I could
    have fixed the whole thing in six rightly chosen words? Am I using words in their
    basic meaning or in a loose plebeian way?” . . . The English language is incomparably
    rich and can convey every thought accurately and elegantly. The better the writing the
    less abstruse it is. Say “No” cheerfully and definitely to people who want you to do
    more than you can do well.
    All this is painfully didactic—but you did ask for advice—and there it is.

    • Posted May 6, 2016 at 2:17 pm | Permalink

      Orwell gave similar advice. And though I haven’t read his book of the topic, I believe Pinker agrees as well.

      • Posted May 6, 2016 at 3:17 pm | Permalink

        As did A. Lincoln.

        I’ve felt this bite myself on re-reading things posted in haste. Yikes!

    • Diane G.
      Posted May 7, 2016 at 2:53 am | Permalink

      Excellent advice, to be sure. But sometimes an article is needed sooner and one doesn’t really have the luxury of putting it aside for a month. Especially in journalism, timeliness is critical.

      But that’s immaterial, as I thought your article was great in the first place. 😉

  32. Posted May 6, 2016 at 2:12 pm | Permalink

    This (and yesterday’s post on this topic) is great. Thank you so much. In the immortal words of Flavor Flav, when it comes to the subject of epigenetics, Don’t Believe The Hype!

    youtube.com/watch?v=9vQaVIoEjOM

  33. Doug Gray
    Posted May 6, 2016 at 2:35 pm | Permalink

    In the now distant past I was a postdoctoral fellow at the Whitehead Institute, and had the pleasure of hearing a lunchtime performance by Mark Ptashne on his beloved Guarneri violin. If the New Yorker positions culture on a higher plane than science they must take Dr. Ptashne’s trenchant critique very seriously – he is a clearly a cultured man! To confirm this they can check their own archives:

    http://www.newyorker.com/magazine/2008/11/24/financial-instruments

  34. Posted May 6, 2016 at 3:12 pm | Permalink

    Greetings from the Twittersphere! I wanted to report that Siddhartha Mukherjee has sent a detailed response to Eric Topol, who has posted it as screen grabs attached to a couple tweets:

    • Posted May 6, 2016 at 3:15 pm | Permalink

      Thank you! Is there anywhere we can read his response in regular text? Cheers!

      • Posted May 6, 2016 at 3:34 pm | Permalink

        Not that I’m aware of.

      • George
        Posted May 6, 2016 at 5:43 pm | Permalink

        Mukherjee has posted his response online:
        http://www.stsiweb.org/an-epigenetics-controversy/

        • Curt Nelson
          Posted May 7, 2016 at 9:19 am | Permalink

          No admission of error and he concludes: “This was written precisely to express skepticism to the idea – growingly popular in the world – that epigenetic information can be transmitted across generations.”

          Precisely the opposite.

          And he signs: Dr Siddhartha Mukherjee MD, D.Phil

          Double-dosing on Dr – calling yourself Dr while listing your Dr-conferring degrees – is such a tell for an egotist.

    • Posted May 6, 2016 at 3:57 pm | Permalink

      Yeah, I’ve seen it. Mukherjee wrote me several times demanding that I put it on my website. I wouldn’t do that until the New Yorker publishes the criticisms of Mukherjee that scientists made. Such chutzpah!

      And the criticisms are obscurantist and misguided anyway. I’ll let him promulgate his reply as he wants, and readers (or scientists) can be the judge.

      The letter, BTW, is not a direct response to my own posts, but mainly to the emails that the New Yorker got from the scientists who wrote to them about the piece. As far as I know, the NYer sent those emails to Mukherjee, and he wrote a long response to the critics before I even put up my first post, admitting NOT ONE ERROR on his part. He and the NYer are apparently taking the stand that because it’s an excerpt, they had to leave all the clarifying information out. Like TRANSCRIPTION FACTORS! Oy!

      Anyway, I’m done here. Nothing to see; move along.

      • Posted May 6, 2016 at 9:11 pm | Permalink

        I dunno. Refusing to publish his response seems a little unscientific in terms of spirit of transparent inquiry. Unless you wish to truly make the case that even displaying his response would do harm, I don’t get not putting it up here. Why not continue? Why not meet him in broad daylight?

        • Posted May 6, 2016 at 9:16 pm | Permalink

          1. Sorry, but he has places he can publish his response, and he already has, both on twitter and a Scripps site.; the link is above and everyone can go there.
          2. Mukherjee’s response is not a “response” to what I wrote on this site, but to the emails he got from various people. It’s not my responsibility to post something written in response to a different set of comments.
          3. We’d have to respond to the response, and it would never end.
          4. Finally, are you going to call out the New Yorker for deciding to publish NO criticism of that article?

          • Posted May 6, 2016 at 9:27 pm | Permalink

            Burden of inquiry and transparency falls heavily and perhaps unfairly to science, and you know what is at stake. Practically lifelong subscriber to the magazine, and glad to call them out but I have a 30-year-old degree in English literature from a regional religious college, and not sure I have the goods to make a dent.

  35. Posted May 6, 2016 at 3:33 pm | Permalink

    The problem is that this kind of nonsense is creeping well into education. I’m under the impression that opinions as presented in the
    Mukherjee piece are almost mainstream.
    Many biologists use the term epigenetics carelessly: “pick, choose and mix” is quite often the motto. Have a look on coursera for example: There is a MOOC on the topic.

    I’m convinced that Mukherjee acted in ‘good faith’ and felt that he did his homework. He probably talked to a few ‘experts’ who offered him a sufficiently coherent picture, so he didn’t feel the need to read by himself.
    No excuse though.

    P.S.
    In that context an other recommendation to read:
    Weismann Rules! OK? Epigenetics and the Lamarckian temptation
    Biology & Philosophy
    June 2007, Volume 22, Issue 3, pp 415-428
    By David Haig

    P.P.S.
    Thanks to Prof. Ptashne for his groundbreaking contributions!
    In Cologne (in the mid 1990ties) we had a journal-club-series on his papers (mainly papers together with Jun Ma & Norbert Lehming) and a seminar based on ‘a genetic switch’

    • Kopper
      Posted May 6, 2016 at 4:32 pm | Permalink

      Ptashne is an ace. In 1990 I took Intro to Mol and Cel Biol, where we discussed his paper about inhibiting gene expression using antisense mRNA in E. coli. I kept using that paper when I was instructor in the same class 10 years later. Now I teach mol biol (another country, another language) but I still use one of the figures from that paper to introduce RNAi in my lectures…

      • Posted May 6, 2016 at 5:02 pm | Permalink

        Could you please give the paper’s details?

    • jaxkayaker
      Posted May 7, 2016 at 5:39 am | Permalink

      Thanks for the reference. I have not yet read it, but I will just point out that Weismann’s barrier does not apply to plants, protists, bacteria, or fungi. Not even all animals have germ/soma distinction, e.g. sponges.

  36. Scientist
    Posted May 6, 2016 at 4:00 pm | Permalink

    Great posts. Pardon if this has already been mentioned, but what Allis originally discovered was the more global mechanism of transcriptional control in the ciliate Tetrahymena. It is typical of ciliates that transcription occurs only in the large macronucleus, not (except for conjugation) in the small, diploid micronucleus. Allis group (Vavra et al., J. Biol. Chem. 257, 2591–2598) showed that histones H3 and H4 of the macronucleus were acetylated and those of the silent micronucleus were not. Historically, this was the first link between histone acetylation and transcriptional control. It was not, and never has been to my knowledge, associated with control of specific genes in Tetrahymena. Incidentally, histone acetylation is associated with micronuclear transcription during conjugation, but it is global, producing the scanRNAs used in macronuclear development. Interested readers are referred to this review: Karrer, K. M. 2012. Chapter 3 – Nuclear Dualism. In: Collins, K. (ed.) Methods in Cell Biology. Academic Press. Volume 109:29-52.

    • Hempenstein
      Posted May 6, 2016 at 10:24 pm | Permalink

      When I read the assignment I couldn’t imagine how the histone modification seminars I used to sit thru hadn’t made any of Mukherjee’s claims. Or how I had managed to miss them. Or how that could possibly work.

      Glad this sets things straight, but sad for the amount of effort needed to do that.

  37. Craw
    Posted May 6, 2016 at 4:34 pm | Permalink

    Whew.

    I would like to get a good book on this stuff on the level of De Duve’s Living Cell or the like. It’s not hard to spot the woo in arguments and articles but I at least find it hard to respond with facts. As was done here.

    I am feeling chuffed btw as seemingly the only Mukherjee skeptic who was not so impressed with Emperor!

  38. W. Benson
    Posted May 6, 2016 at 4:35 pm | Permalink

    There is much food for thought here, several pages in fact. One interesting point is that Mukherjee uses the word “memory” 13 times in the essay whereas “natural selection” glumly appears but twice. There seems to be no mention of adaptation.

    • Diane G.
      Posted May 7, 2016 at 3:02 am | Permalink

      Interesting observation.

      I can’t see how epigenetics doesn’t involve at least a little natural selection anyway. If it were deleterious, surely it would no longer occur.

      • Posted May 7, 2016 at 7:02 am | Permalink

        Quite so. Either “epigenetic modifications” are (1) stably inherited and thus ARE subject to natural selection, but NOT to the whims of environmental influence, and thus NOT Lamarckian evolution; or (2) ARE changed in direct response to relevant environmental cues and thus cannot (by definition!) be stably inherited and therefore do not constitute evolution, Lamarckian or otherwise.

        The Lamarckians seem to invoke some magic in which epigenetic modifications are set by the environment once and then somehow become fixed – rather than just accepting the simpler explanation that they are products of a naturally selected genetic switch that is thrown into the on position until off (or vice versa).

  39. kelskye
    Posted May 6, 2016 at 5:37 pm | Permalink

    Nice article. I’m trying to figure out just what kinds of epigenetic claims are reasonable and which ones are fanciful, so this article really helped.

  40. squidmaster
    Posted May 6, 2016 at 6:33 pm | Permalink

    This was excellent. I’m a neuroscientist,not a geneticist, but I found the arguments easy to follow and quite informative. Most of the popular treatment of ‘epigenetics’ is of the ‘Darwinism overturned!!!!’ variety and I pay little attention to it. I’ve appreciate PCC’s posts on the subject and really liked this one. Thanks!

  41. Posted May 6, 2016 at 9:09 pm | Permalink

    Thank you. Thank you. Thank you. I think I will make this required reading for all my genetics undergrad students.

  42. Dale Franzwa
    Posted May 7, 2016 at 12:03 am | Permalink

    Great two posts, Jerry. I echo the admiration of the other commenters.

  43. Darwinian Demon
    Posted May 7, 2016 at 2:13 am | Permalink

    Reposted over at Metafilter…

    http://www.metafilter.com/159324/An-Epigenetics-Controversy

  44. jaxkayaker
    Posted May 7, 2016 at 5:34 am | Permalink

    Thanks for taking the time to explain, Prof. Ptashne and Prof. Greally.

  45. Chris G
    Posted May 7, 2016 at 7:01 am | Permalink

    I delayed reading the New Yorker article and the three associated posts Jerry wrote, until I had a good chunk of free-time to properly concentrate and read all in one sitting – many cups of tea have been drunk this Saturday morning.
    Here are my resulting comments:
    – It’s really hard for us lay-folk to read, digest, and fully understand material on these kinds of topics, which I’m sure goes a long way to explaining why the more technical posts Jerry writes get fewer reads and comments (and I have maths and science A Level qualifications, and a degree in Computing and Information Systems).
    – Particularly when there’s so many other non-technical posts (here, and by other writers) that also call for our limited attention.
    – Those other posts being perhaps more relevant to wider issues/topics/politics that affect our daily lives and experiences i.e. we have to pick and choose and prioritise.
    – However, I learned a great deal from careful concentrated reading of this material. I bought a couple of books some time ago (Steve Jones’s ‘Y: The Descent of Men’, and Matt Ridley’s ‘Genome’), but not yet got round to reading them for similar reasons to those outlined above.
    – It’s awe inspiring to get some insight to the advances dedicated scientists are making in understanding these aspects of molecular-biology, even when I don’t understand much of it. And great to know there are others who dedicate their lives to this work.
    – Would be interesting to hear further thoughts of other readers (and Jerry, of course) on the ‘politics’ of this article i.e. building on Jerry’s earlier comments about the poor approach of The New Yorker towards science in general, their postmodernism etc. By politics, I mean the wider context and hidden-agenda that may be at play e.g. why the desire to ‘challenge’ evolution by natural selection, and promote Lamarckism. I’m assuming there isn’t any hidden religious motivation, but is there something akin to the regressive/authoritarian left lurking behind all this, which may explain The New Yorker’s deliberate reluctance to fact-check and peer review before publication?
    Chris G

  46. peepuk
    Posted May 7, 2016 at 7:24 am | Permalink

    Siddhartha Mukherjee’s article is a nice example of the fact that good stories and truth don’t combine very well.

    So he bends the science just a little bit to tell us in many words nothing new. Personally I really don’t like his writing style; couldn’t get through his first book.

    To his credit in his response he says:

    “This was written precisely to express skepticism to the idea – growingly popular in the world – that epigenetic information can be transmitted across generations. Oliver Hobert’s studies suggest that small RNAs can play some role in this – but the transmission of information across generations in other systems remains minimal and dubious. As the piece points out, Darwin – far from falling under any bus – emerges vindicated by epigenetic research.”

    Would be nice if he would add this to his article.

    • Posted May 7, 2016 at 5:32 pm | Permalink

      If people would just write “epigenetic signals” (or “states”) rather than “epigenetic information”, I think a lot of the controversy and confusion would disappear. Inheriting expressed RNA is NOT transmission of “information” in the same way that inheritance of DNA is transmission of information – the RNA is not being replicated.

  47. Posted May 7, 2016 at 7:33 am | Permalink

    Reblogged this on cabbagesofdoom and commented:
    Required reading if you have ever been tempted by the epigenetics hype.

  48. Posted May 7, 2016 at 8:35 am | Permalink

    Dear Dr. Coyne,

    thanks so much to you, Mark Ptashne and John Greally, for putting this critique together. Reading a utterly wrong and misleading popular article on one’s area of expertise is really excrutiating. Almost feels like a personal insult. So I am really glad you took the time to get some unquestionable experts to set the record straight.

    btw. I agree about the constant yammering about Lamarckian evolution in popular articles as well.
    Having said that… The Crisp/Cas system that bacteria use to store a record of selfish DNA elements that previously invaded them, as part of an immune mechanism against such elements, is really awfully close to Lamarckian. But that’s of course not the kind of thing the yammerers had in mind.

  49. Posted May 7, 2016 at 8:37 am | Permalink

    Great post!

    A question: Has anyone tried to analyse exactly why some people are so attracted to the idea of resurrecting Lamarck (or Lysenko)? What intellectual problem do they consider that Darwinian evolution has? I really don’t see what they are after.

    I notice at the end of Mukherjee’s article a reference to “glum cycles of mutation and natural selection”. Is that a clue to why these folk so desperately try to find ways around Darwin?

    If anyone has a reference to a text about this, I would be much obliged.

    • Torbjörn Larsson
      Posted May 7, 2016 at 10:59 am | Permalink

      I think pomos don’t like the finding that behavior is ~50% (or more) nature, ~50% (or less) nurture.

      Osculating their woo stick, they can pretend it may be 100 % cultural.

    • Posted May 7, 2016 at 5:52 pm | Permalink

      I think it’s the same as the reluctance to accept that free will is an illusion. There is a tendency to think that if something – such as IQ – is predominantly determined by your genes, not your environment, you are “doomed” to some ill-fated destiny beyond your control.

      They don’t seem to realise that many of things like intelligence and physique may set boundaries – I will never be Miss Universe – but there is a lot of room to do different things with what you have.

      Either that or guilt/reluctance to admit that their success is not all down to their own hard work – the genetic (and social) hand they are dealt is a major part of it. If they are lucky, rather than special, do they really deserve that enormous salary?

    • Mark Ptashne
      Posted May 7, 2016 at 7:44 pm | Permalink

      Yes. Florian Madersbacher wrote a very fine article on exactly this question for Current Biology. Should be easy to find.

  50. Torbjörn Larsson
    Posted May 7, 2016 at 10:55 am | Permalink

    Catching up … but well worth taking some extra time studying. Thanks a lot, to jerry and to the informative critics.

    As a side note, the modern New Yorker seems to lack subscription factors.

    • Torbjörn Larsson
      Posted May 7, 2016 at 10:56 am | Permalink

      Jerry [sp}.

  51. Posted May 7, 2016 at 2:00 pm | Permalink

    Thanks, to PCC, Ptashne and Greally. I feel that these posts have really helped me understand why I should dismiss many of the popular articles (not just the NYer article) about epigenetics.

  52. George
    Posted May 7, 2016 at 2:02 pm | Permalink

    Interesting story in Vox on this entire imbroglio –
    http://www.vox.com/2016/5/7/11606886/scientists-angry-new-yorker-epigenetics

    Resnick is too kind to the New Yorker. He says – “The print New Yorker only has so much space.” My take – if space constraints mean you print a story that is factually wrong, do not print the story.

  53. Giamila
    Posted May 8, 2016 at 9:08 am | Permalink

    In the midst of all this discussion about the specifics of epigenetics and signal transduction, I would like to point out the sentence in the article that mentions that autism is “the result of genetic mutation”. Is there any solid proof for this claim?

    This from a NIH 2014 news release:”About 52 percent of the risk for autism was traced to common and rare inherited variation, with spontaneous mutations contributing a modest 2.6 percent of the total risk.” https://www.nih.gov/news-events/news-releases/common-gene-variants-account-most-genetic-risk-autism

    Is this been disproved by more recent evidence I am not aware of?

    Thanks, Giamila

  54. Posted May 8, 2016 at 12:11 pm | Permalink

    Thanks for the trigger warning – it persuaded me that this article was well worth devoting a lot of time to, and the effort has been amply rewarded!

  55. Posted May 9, 2016 at 7:36 pm | Permalink

    Please see Structural diversity of supercoiled DNA http://dx.doi.org/10.1038/ncomms9440

    Serious scientists have linked the epigenetic landscape to the physical landscape of supercoiled DNA via everything known about the innate immune system and energy-dependent changes in hydrogen-atom transfer in DNA base pairs that link angstroms to ecosystems via metabolic networks and genetic networks.

    The problem for pseudoscientists is this report: Evolutionary resurrection of flagellar motility via rewiring of the nitrogen regulation system http://www.sciencemag.org/content/347/6225/1014.abstract

    Weekend evolution of the bacterial flagellum is not consistent with any theoretical approach, which means it must be ignored. But then, you have Siddhartha Mukherjee who refuses to let neo-Darwinism die without more obfuscation of facts.

  56. Kim Dalton
    Posted May 10, 2016 at 11:09 am | Permalink

    Would it be fair to characterize so-called epigenetic phenomena (DNA methylation, changes in chromatin configuration, etc.) as INTERMEDIATE in their effects on cell function? That is, more enduring or “solid” than those of transcription factors and less enduring than those of genes.

    • Mark Ptashne
      Posted May 10, 2016 at 11:56 am | Permalink

      Well you illustrate a commen problem by your use of the word “epigenetic” as encompassing chromatin configuration, DNA methylation, etc. NO – we must study each of these and all the other supposedly relevant factors to see what they do or don’t do. See John Greally’s bit about chromatin folding and unfolding in our original piece).. and DNA methylation continues to be a very interesting and elusive problem..see comments above..

      Everything would be better if we all just stopped using the word “epigenetic” and said what we mean..

  57. Allan Miller
    Posted May 10, 2016 at 1:32 pm | Permalink

    But, if epigenetic information can be transmitted through sperm and eggs, an organism would seem to have a direct conduit to the heritable features of its progeny.

    Unfortunately for this notion, the spouse also has ideas, in sexual species. Which partner has primacy?

    Every time I encounter such ideas, I go into “but … but …” mode. I simply can’t see how it would work. Say you could record your experiences and pass them on to your progeny (and overcome the wife’s own experiences). If offspring experience the same conditions, why couldn’t they just make the same modifications themselves, independent of inheritance? Conversely, if they experience different conditions, what use are they?

    • Mark Ptashne
      Posted May 10, 2016 at 1:39 pm | Permalink

      Better have Jerry chime in here on the general question. The only example I know of is transfer in the sperm of RNA acquired as a result of infection by a virus.

    • Posted May 11, 2016 at 7:21 am | Permalink

      Let’s say that there is a drive in evolution to create an information transfer mechanism other that DNA from parents to child. And let’s ignore the fact that culture does this nicely for humans and some other species.

      In the mother’s case it seems that there would be ample opportunity: Firstly the stuff (protein, RNA, whatnot) that goes into the egg, secondly the influence possible during pregnancy, thirdly lactation, and maybe more. For the father, some non-DNA agents in the sperm (RNA, I believe), at least.

      But none of this compromises Darwinian evolution, does it? After all, the mechanism itself must have arisen through Darwinian evolution, and must be encoded in the genome.

      It seems to me that those who wish to see inheritance of acquired characteristics from parent to child have not thought through the mechanistic aspect. It can’t just be an indiscriminate jumble of experiences that is to be transferred, it has to be a selection. And that cannot happen unless there is a mechanism for transfer of some experiences but not others. That mechanism must have evolved in a Darwinian fashion. Lamarck cannot arise except in Darwinian fashion, and only then as a monitor for certain experiences and traits dependent on them.

      Does this make sense? I am thinking aloud here…

      • Mark Ptashne
        Posted May 11, 2016 at 10:53 am | Permalink

        Seems intelligent to me. Just sayin..

  58. Archimedes Castro
    Posted May 11, 2016 at 12:13 am | Permalink

    “Keep in mind that the organisms that have taught us the most about development – flies (Drosophila) and worms (C. elegans)—do not have the enzymes required for DNA methylation. That does not mean that DNA methylation cannot do interesting things in humans, for example, but it is obviously not at the heart of gene regulation.”

    This is NOT correct. There are many evidences that either Drosophila and C elegans DO have DNA methylation enzymes.
    Refs:
    S. Takayama, J. Dhahbi, A. Roberts, G. Mao, S.-J. Heo, L. Pachter, D. I. K. Martin, D. Boffelli. Genome methylation in D. melanogaster is found at specific short motifs and is independent of DNMT2 activity. Genome Research, 2014;

    Lyko F1, Ramsahoye BH, Jaenisch R. DNA methylation in Drosophila melanogaster. Nature. 2000 Nov 30;408(6812):538-40.
    DNA methylation in Drosophila melanogaster.

    Shilatifard A. The COMPASS family of histone H3K4 methylases: mechanisms of
    regulation in development and disease pathogenesis. Annu Rev Biochem 2012;
    81:65–95

    Guoqiang Zhang, Hua Huang, Di Liu, Ying Cheng, Xiaoling Liu, Wenxin Zhang, Ruichuan Yin, Dapeng Zhang, Peng Zhang, Jianzhao Liu, Chaoyi Li, Baodong Liu, Yuewan Luo, Yuanxiang Zhu, Ning Zhang, Shunmin He, Chuan He, Hailin Wang, Dahua Chen, N6-Methyladenine DNA Modification in Drosophila, Cell, Volume 161, Issue 4, 7 May 2015, Pages 893-906,

    Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro GS, Han S,
    Banko MR, Gozani O, Brunet A. Members of the H3K4 trimethylation complex
    regulate lifespan in a germline-dependent manner in C. elegans. Nature 2010;
    466:383 –387.

    Katz DJ, Edwards TM, Reinke V, KellyWG. A C. elegans LSD1 demethylase contributes
    to germline immortality by reprogramming epigenetic memory. Cell 2009;
    137:308 –320.

    • Posted May 11, 2016 at 6:40 am | Permalink

      Several of your references are to histone methylation, which is not the same as DNA methylation!
      In Drosophila, the position has been controversial: people have found some evidence for DNA methylation, but even there we see big differences from what you see, for example in mammals—differences that would cast doubt on a conserved mechanism essential for forming a complex metazoan. Fly DNA methylation is rare, not nearly as ubiquitous in the genome as in other species, visible only in early embryos, and there is doubt whether even that methylation is essential for transcription. There is, further, no work that implicates fly DNA methylation in doing anything, as far as I know.

      That said, yes, I stand correct on its COMPLETE absence in flies.

      However, there is virtually NO DNA methylation in Caenorhabditis: it’s not biochemically detectable except for a rare amount in adenine, and there are no methylating enzymes coded in the genome. As I said, some methylation of adenine (but not cytosine) has been described, but that paper is considered controversial because of the lack of enzyme and because of other technical weaknesses.

      • Michael Ailion
        Posted May 23, 2016 at 2:42 am | Permalink

        Sorry that I am late to this discussion. I agree that DNA methylation is not central to gene regulation and I do not dispute the major points made. However, I question one detail. I had been reasonably convinced that the trio of papers in Cell last year (Cell 161: 868, 879, 893) had shown that there are low levels of N6 methylation of adenine in eukaryotes, including Drosophila and C. elegans. I found the C. elegans paper particularly compelling as it reported the identification of putative enzymes that perform methylation and demethylation of adenine, assayed the biochemical activity of the demethylase enzyme, and showed that genetic mutations knocking out these enzymes had expected effects on the levels of N6 mA in the animals. Though I am not an expert in this field, I found the papers convincing that there is some low level of adenine methylation in eukaryotes (though function is less clear), and I would be interested to know what the technical flaws were and why this is still considered controversial.


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