Tuesday, April 03, 2012

Evo Devo and Giants

Anything found to be true of E. coli must also be true of elephants.

-Jacques Monod (1954)
While preparing for the last lecture in my molecular evolution course I came across this quotation that explains Evo Devo.
The key to understanding form is development, the process through which a single-celled egg gives rise to a complex, multi-billion-celled animal. This amazing spectacle stood as one of the great unsolved mysteries of biology for nearly two centuries. And development is intimately connected to evolution because it is through changes in embryos that changes in form arise. Over the past two decades, a new revolution has unfolded in biology. Advances in developmental biology and evolutionary developmental biology (dubbed “Evo Devo”) have revealed a great deal about the invisible genes and some simple rules that shape animal form and function. Much of what we have learned has been so stunning and unexpected that it has profoundly reshaped our picture of how evolution works. Not a single biologist, for example, ever anticipated that the same genes that control the making of an insect’s body and organs also control the making of our bodies.

Sean B. Carroll “Endless Forms Most Beautiful: The New Science of Evo Devo” W.W. Norton & Co., New York (2005)
I've already criticized this point of view several times [Things You Didn't Know] [Sean Carroll's View of Evo-Devo] and I won't repeat them here. Read those posts to see what's wrong with Evo Devo.

If I have seen further it is by standing on ye sholders of Giants.

Isaac Newton, 1676
I want to emphasize another point. I come from a culture that praised and admired the important work that formed the background to modern discoveries. My mentors were proud of the fact that they stood on the shoulders of giants.

Someone named anthrosciguy commented on my earlier post [Sean Carroll's View of Evo-Devo] by saying ...
No one wants to stand on the shoulders of giants anymore.
That struck me as a profound commentary on much of modern biological science so I thought I'd share it with you. These days it seems like everyone wants to claim credit for discovering something that nobody anticipated. You can't be standing on the shoulders of giants if you're proclaiming a revolution. That would look silly.

I'm pretty sure I know anthrosciguy's real identity but I'll leave it to him to out himself and take credit for a very clever statement.


48 comments :

  1. It is interesting that the quote from Newton about standing on the shoulders of giants is actually lifted from an argument that he was having with another scientist that suffered from dwarfism and so is in fact a vicious personal attack. In my experience it is the rare giant that allows anyone to stand on their shoulders. I remember being at a conference as a new academic and having a “giant” in my area of research stop by my poster, the one small new idea that I had developed was totally tapped out by him and his mitarbeiters within a year leaving nothing for me to develop. Academic research in science is an excellent model for survival of the fittest. Living in the time of giants is like a tree in the forest trying to grow to the canopy, a giant must give up some of the sky or die for the small trees to flourish. Perhaps the quote should be “I have grown from the bodies of dead giants”.

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    1. "grown from the bodies of dead giants" sounds like something out of greek myth eh? Chopping up titans to make up the world around us and all. So I guess you have to castrate the experts in your field before you can become an expert then!

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  2. "Not a single biologist, for example, ever anticipated that the same genes that control the making of an insect’s body and organs also control the making of our bodies"

    How could anyone claim this with a straight face? Even a consistory understanding of evolution - in particular the concept and consequences of shared ancestry - should lead any competent biologist to the prediction that the genes regulating the development of one clade of animals will likely be very similar to those regulating development in other clades. It would have been much more surprising if that were not the case...

    ...and not to nit-pick (ok, that is exactly what I am doing), but the same genes do not control the making of an insect vs humans bodies. Some are "direct" orthologs, but we humans have many "extra" ones that have arose by duplication and subsequently differentiated. In both cases there is significant deviation in the sequences of the genes themselves - they're similar; they are not "the same genes"

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    1. How can anyone claim that with a straight face? The answer is by understanding the history of evolutionary thought because, in fact, Carroll's claim represents an accurate (albeit perhaps overstated) representation of history. Ernst Mayr is endlessly quoted in the evo-devo literature for his failed prediction that the search for parallel genes or parallel mutations would prove to be futile. He actually said it, and it actually is wrong. This is what Carroll is responding to. The question we need to ask is why Mayr et al would say such a thing when, as you suggest, it seems so obviously wrong.

      In fact, when Ernst Mayr made that failed prediction, he was representing the prevalent Modern Synthesis view. The architects of the Modern Synthesis believed that each species has a "gene pool" full of so much diversity that selection never "waits" for new variation, and that any kind of change is possible. They rejected a view of evolution as a process of incorporating new developmental mutations into a species. Instead, they saw evolution as a process of adjustment of allele frequencies at many different loci simultaneously. Evolution, for them, meant (for the most part) the deterministic movement-- in response to a change in environment-- from one extremely complex multi-locus equilibrium in the "gene pool" to another point of equilibrium. This is why they redefined "evolution" as "shifting gene frequencies".

      If organisms are infinitely malleable and there is infinite genetic variation, we just don't expect the same genes and mutations to recur. This is the basis of Mayr's prediction that is quoted so frequently in the evo-devo literature.

      Although it leads to contradiction, we can understand this view of evolution by considering that when a system reaches equilbrium, its history is lost. If someone gives you a 5% NaCl solution, you can't tell whether it was shaken or stirred, or whether the salt was added one grain at a time, or all at once. It reaches the same state, determined by conditions, not by accidents of history. Likewise, if an organism adapts to its environment fully, with no restrictions, no kinetic limitation due to mutations, under an "anything is possible" regime, then its history likewise will not be traceable.

      In fact, such an equilibrium view doesn't really make sense, because it's blindingly obvious that the tree of life is indeed discernable, QED organisms do not reach adaptive equilibrium but at best, reach some kind of quasi-equilibrium that is kinetically limited. Nevertheless, equilibrium thinking has been popular, which is why "historical contingency" sounds like a new idea relative to Modern Synthesis thinking.

      Arlin

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    2. By the time that HOX genes were being cloned and sequenced (early 1980s) there were several hundred thousand molecular biologists who never heard of Ernst Mayr. Even if they had heard of him, they never would have believed him.

      There were even prominent evolutionary theorists who disagreed with Mayr. (Perhaps you've heard of Stephen Jay Gould?)

      Sean Carroll said, "Not a single biologist, for example, ever anticipated that the same genes that control the making of an insect’s body and organs also control the making of our bodies."

      Is that really a statement you want to defend by pointing to Ernst Mayr and other field biologists?

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    3. By the early 80's the idea was emerging that development was largely due to homologous genes over all multicellular animals, and that was a large surprise even for molecular biologists. Before 1980 the idea that development was due to even somewhat similar genes was absent .
      The turnover about the history of genes and development can be fairly precisely dated. For instance by:
      Nature, 2 August 1984, Vol 310
      Developmental biology: A Rosetta stone for pattern formation in animals? Pp 364-365
      Jonathan Slack

      This is why they redefined "evolution" as "shifting gene frequencies
      Quite, and that is why defining evolution as 'shifting allele frequencies' gives the wrong idea.

      Larry Moran: S.J. Gould had nothing to do with it.
      Christiane Nüsslein-Volhard and Eric F. Wieschaus had. They might not have been interested in any specific way in what Gould said, even if they had heard of him. Mayr: same. Gould might be your hero, but I'm sorry, that is totally outdated as well as wrong on this topic.

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    4. Larry, the issue is not about Ernst Mayr. Ernst Mayr said something, and it was wrong. That fact by itself shows only that Mayr is fallible and is irrelevant to science.

      What is relevant to scientific discourse is that Mayr's statement represented the prediction of a view of evolution that was prevalent in mid-century, called the Modern Synthesis, and that still dominates.

      In the 1960s, biochemists who weren't schooled in the Modern Synthesis treated evolution essentially as a Markov process of intrinsic ongoing change, not as a process of adapting to a shift in the environment. They were ridiculed by people like Mayr and Simpson, who thought the new molecular evolutionists didn't understand a thing about evolution.

      In the 1920s, before the Modern Synthesis, the tragic Russian geneticist Nikolai Vavilov wrote an excellent paper about parallel variation and parallel speciation. Morgan, Punnett, Vavilov and other "mutationists" believed something that Ernst Mayr and the architects of the Modern Synthesis rejected. They believed that we can understand evolution as a process of incorporating "mutations" (which they viewed as phenotypic changes with a genetic basis), and that the recurrence of the same mutation in different species might result in parallel evolution.

      The mutationist view is widely accepted now, as is apparent if one reads about current work in the genetics of parallelism, e.g., Wood, et al (http://www.ncbi.nlm.nih.gov/pubmed/15881688) or Arend & Reznick (http://www.ncbi.nlm.nih.gov/pubmed/18022278).

      The point of all this, vis a vis Carroll, is that Carroll is responding to a view that dominated evolutionary thinking and that, to some extent, still dominates in a kind of subterranean way. Of course, Carroll is not omniscient and so he is not on solid grounding in claiming that no biologist ever said something. In fact, many biologists in the 20th century have rejected key claims of the neo-Darwinian "Modern Synthesis". Yet, this view still dominates. In the neo-Darwinian view, selection (not mutation) is the creative force in evolution-- it builds adaptations out of a vast number of infinitesimal differences, so we don't expect to see effects of individual mutations which are lost in the crowd. IMHO, this is the view that underlies the way evolutionary biologists talk about adaptation, even when they are trying to be critical.

      Arlin

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    5. By the early 80's the idea was emerging that development was largely due to homologous genes over all multicellular animals, and that was a large surprise even for molecular biologists.

      Nonsense. Many of us moved from studying prokaryotes to studying eukaryotes (Drosophila melanogaster, in my case) precisely because we thought that the lessons we learned from prokaryotes could now be applied to eukaryotes.

      That's why when the first HOX (homeotic) gene sequences became available they were immediately compared to prokaryote regulatory proteins. The similarities were not a surprise. They were expected.

      Before 1980 the idea that development was due to even somewhat similar genes was absent.

      Nonsense. Bacteria that diverged three billion years ago were known to have similar regulatory genes (e.g. sigma factors). It was not a surprise to some of us that much more closely related species (e.g. animals) would have similar factors.

      Now, I grant you one thing. There were many developmental biologists and molecular biologists who didn't understand evolution. (Most still don't.) They may have been surprised but you don't base your history of a field on the lowest common denominator. You base it on the best thinkers of the time.

      ... Gould might be your hero, but I'm sorry, that is totally outdated as well as wrong on this topic.

      Arlin quoted Ernst Mayr as an authority on whether homologous genes would be found in distantly related species. I pointed out that other prominent evolutionary biologists (most, in fact) disagreed with him.

      I'd also like to remind you that Gould is much more relevant than you think Have you read his book "Ontogeny and Phylogeny" published in 1977? Here's a quotation from Chapter 1.

      ... this book is primarily a long argument for the evolutionary importance of heterochrony—changes in the relative time of appearance and the rate of development for characters already present in ancestors.

      In other words, Gould expected that regulatory elements are conserved and that the development of new species depends mostly on differences in timing. Sound familiar?

      Here's another quote from that book ...

      ... those ignorant of history are not condemned to repeat it: they are merely destined to be confused.

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    6. 'Ontogeny and Phylogeny' had no relevance whatsoever to the molecular work. The book presented the end of a line, not a beginning of new thought.
      The initiation of evolutionary developmental biology had nothing to do with developmental biology, but with the scoring of embryonal lethals in Drosophila. That scoring of embryonal lethals was not because regulation was not a search for regulatory genes on the line of the bacterial genes.

      On this sort of topic, Larry Moran is systematically presenting a view that does not correspond to the actual state of affairs. Drosophila biochemistry is not identical to Drosophila development

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    7. Arlin says,

      The point of all this, vis a vis Carroll, is that Carroll is responding to a view that dominated evolutionary thinking and that, to some extent, still dominates in a kind of subterranean way. Of course, Carroll is not omniscient and so he is not on solid grounding in claiming that no biologist ever said something.

      You're referring to the adaptationist slant of the hardened Modern Synthesis. That's a view that Sean Carroll largely agrees with, even today. It's why he is comfortable publishing a book with the title, "The Making of the Fittest."

      We're discussing something different. Mayr's ideas about lack of gene homology in distantly related species were soundly rejected by those interested in molecular evolution because by the end of the 1960s we had several different trees of life showing these relationships (e.g. cytochrome c). I helped clone some Drosophila genes in 1977 and a few years later we had used those genes to isolate homologues in yeast and mice. Nobody was shocked. My grants were not rejected. Nor were scientists shocked when the Drosophila genes were used to isolate homologues from E. coli and plants.

      In fact, many biologists in the 20th century have rejected key claims of the neo-Darwinian "Modern Synthesis". Yet, this view still dominates.

      That's correct. In fact, it's often the (incorrect) view of developmental biologists, including Sean Carroll. That's why some of them write books on "evolvability" and "facilitated variation."

      The mutationist view is widely accepted now ...

      Hmmm ... I don't know whether it's fair to say "widely accepted." I think mutationism is correct and so does Arlin Stoltzfus [The Mutationism Myth, VI: Back to the Future].

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    8. Heleen says,

      Ontogeny and Phylogeny' had no relevance whatsoever to the molecular work. The book presented the end of a line, not a beginning of new thought.

      Since when is developmental biology confined to "molecular work"?

      The initiation of evolutionary developmental biology had nothing to do with developmental biology, but with the scoring of embryonal lethals in Drosophila. That scoring of embryonal lethals was not because regulation was not a search for regulatory genes on the line of the bacterial genes.

      The homeotic mutants were known in the 1930s and hundreds of genetic experiments were done before Nüsslein-Volhard and Wieschaus came on the scene in 1979. This partly explains why they shared the Nobel Prize with Ed Lewis.

      The initial targets for cloning and sequencing were genes in the Bithorax and Antennapedia clusters because those genes were well-studied. They were not discovered in the embryonic lethal screens of Nüsslein-Volhard and Wieschaus. If that's what you believe, then you are mistaken.

      On this sort of topic, Larry Moran is systematically presenting a view that does not correspond to the actual state of affairs. Drosophila biochemistry is not identical to Drosophila development.

      I attended all the important fly meetings from 1974 to 1980. I published papers with Walter Gehring and I knew many of the people who were working in the field of Drosophila development. One of the graduate students I helped supervise went on to clone the genes of the bithorax and antennapedia complexes when he was a postdoc.

      Heleen, did we encounter each other at any of those fly meetings?

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    9. Larry, you're not getting this. I agree 100% with your implicit message that Ernst Mayr is not an authority on homologous genes. He is not an authority on anything having to do with genetics, population genetics, or molecular evolution. Personally, I don't even see him as an authority on evolution, i.e., I would not read Mayr for the purpose of improving my knowledge of evolution. However, Ernst Mayr *is* an authority on *what the Modern Synthesis says about evolution*. As a scientists I don't really care if Gould or Mayr was right or wrong. I care about whether theories are right or wrong.

      The prediction about the futility of searching parallel genes or parallel mutations is based on the view that evolution is adaptation, and that adaptation is a matter of combining many separate infinitesimal changes to build biological features. Mayr made this prediction because he believed in this view of evolution.

      Arlin

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    10. Arlin says,

      Larry, you're not getting this.

      Yes,I am. You're basically arguing in favor of the anti-adaptationist position that I've been advocating for over twenty years.

      What's your point?

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    11. What's your point?

      Not Arlin, but if I may speculate: That the homology surprised a number of scientists holding the adaptationist view; that the homology can therefore fairly be said to have been surprising in relation to a widely held (perhaps dominant?) view of evolution at that time.

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    12. My point? My point in correcting you about Mayr is that you said the wrong thing. You said "Arlin quoted Ernst Mayr as an authority on whether homologous genes would be found in distantly related species", but I did not quote Ernst Mayr as an authority on homologous genes, as I explained. I could have quoted Darwin's point that adaptive characters are "valueless to the systematist" because they are shaped by selection to their ends, and don't betray the lines of descent, i.e., history. I would not be quoting Darwin as an authority on homologous genes, but as an example of a way of thinking.

      More generally, what is not widely understood in the kind of discussion we are having is that most thinking and writing in evolution is sloppy and involves enormous amounts of bet-hedging. Consequently, opinions about evolution come in an enormous variety of relatively meaningless flavors, and their relationship to facts is highly negotiable. A person's opinion is not a scientific theory, and so their rightness or wrongness is pretty much irrelevant. That you don't get this is suggested by your comment about "You're basically arguing in favor of the anti-adaptationist position that I've been advocating for over twenty years". Your opinion may have been justified all these years, but that really doesn't matter. Theories matter.

      But as I said, most discourse about evolutionary theory is hopelessly muddled. The fact that your grants were not rejected does not mean that the reviewers' beliefs were consistent with your findings. Your grants will not get rejected for finding something that flies in the face of Darwinism, because "Darwinism" is a vague and adaptable concept for evolutionists. However, your grants and papers *may* get rejected if you write "this flies in the face of Darwinism" because then you are crossing a clear line and rejecting the cultural imperative to accept "Darwinism".

      For decades now (not sure how long) we've been living in the age of the DINOs-- Darwinians-in-name-only. Check out the writings by Dean and Coyne over at Coyne's blog, in relation to Shapiro. It goes like this: if "we" the establishment accept transposable elements, and if we aren't shocked by the genetics of mutation, then there must not be anything "non-Darwinian" about these things, because we are all "Darwinians" and we are quite happy with everything about genetics. Therefore (the argument goes), no new concepts are needed to understand evolution.

      There is NO valid theoretical reasoning at work in the above argument. It is just some DINOs planting the flag on everything they see, with no underlying logic.

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    13. Arlin, stick around for a while and keep reading Sandwalk. You might learn something.

      Meanwhile you could read. Why I'm Not a Darwinist and The Modern Synthesis of Genetics and Evolution.

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    14. Thanks for the advice, Larry-- it's always a thrill to be patronized by you.

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    15. You give new meaning to the word "irony."

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  3. I think you're over-reacting. It did come as a surprise that you could insert mouse Pax6 into a fruit fly and have it work. And creationists never tire of repeating the pre-evo-devo claim that the development of homologous features is commonly induced by entirely different genetic pathways. Gavin de Beer was able to say as late as 1971 that “homology of phenotypes does not imply similarity in genotypes.” Methinks you're being a bit whiggish here.

    Also, the Monod quote is applied to housekeeping genes, not developmental ones. There's a big difference.

    de Beer, G. R. 1971. Homology: An unsolved problem.. Oxford Biology Reader No. 11, Oxford University Press, London.

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    1. I think you're over-reacting. It did come as a surprise that you could insert mouse Pax6 into a fruit fly and have it work.

      I agree. That was a surprise (still is). But a single rare example does not a generality make.

      Also, the Monod quote is applied to housekeeping genes, not developmental ones. There's a big difference.

      Monod used the phrase in several different contexts, most notably with reference to how proteins are made from a DNA sequence.

      I'm using it as a reference to the general idea, common in the late 1960s that the fundamental principles of bacterial gene regulation (repressors and activators) would apply to eukaryotes. This turned out to be correct.

      Nobody was surprised to learn that the homeotic mutations in Drosophila were located in genes that encoded transcriptional regulators. The first homeobox structures were immediately seen to be similar to the helix-turn-helix motif of bacterial transcription factors. Most molecular biologist viewed this as the fulfillment of Monod's prediction.

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    2. That was a surprise (still is).

      Yep. "Still is" is actually a key. Carroll oversells the point so badly. The list of mammalian genes that don't work in insects is much longer than those that do.

      An anecdote: a guy in the lab did a rescue of fly null with a mammalian ortholog. That was done out of pure laziness and desire to defend soon - rat clone was on hands, fly gene was not even cloned at a time. Well, it worked, kind of. The flies were viable (but weird, yet broadly consistent with "the model"). Fast forward ~15 years: turns out that mouse gene allowed survival by compensatory mechanism and the true function of that protein seems to be something completely different.

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  4. I think you're being a little unfair to Carroll -- he uses that same Monod quote in his book! I also think it's fair to say that what is true of elephants isn't necessarily true of E. coli.

    I've also criticized evo-devo, in some ways more strongly. I even gave a talk at UNLV titled "A counter-revolutionary history of evo-devo," in which I annoyed a developmental biologist or two.

    Hey! We're going to be at Eschaton 2012 in Ottawa next November: what if we proposed an evening session together -- a conversation about science and evolution and development?

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    1. I think you're being a little unfair to Carroll -- he uses that same Monod quote in his book!

      Chapter 3 in Endless Forms Most Beautiful has the provocative title "From E. coli to Elephants." Carroll begins the chapter by discussing gene regulation in bacteria (Jacob, Monod, etc.) and pointing out that biologists in the 1960s thought that the discovery of these repressors and activators had the potential to solve the mystery of development in multicellular eukarotes.

      Carroll asks (p. 80),

      We were a long way from elephants in 1965. Was Monod right? Did the logic of this tiny bacterium extend right on up to the largest, most complex creatures on Earth? It wasn't an elephant that told us, but a tiny insect, the fruit fly, from which a series of wholly unexpected and revolutionary ideas poured forth. And it started with those homoetic monsters.

      Carroll then goes on the recount the discovery of repressors and activators that control development in Drosophila, thus confirming Monod's prediction.

      Carroll obviously believes that the prediction of the 1960s were NOT borne out but, as far as I recall, he never actually spells out why he thinks this way. Perhaps you could fill in the blanks?

      Now don't get me wrong. I'm not saying that eukaryotes have lots of operons just like bacteria. And I'm not saying that introns are abundant in bacterial genes. What I'm saying is that the study of gene regulation in one tiny corner of the living world (animals) has not fundamentally altered our 1960s and 1970s view of how gene expression is regulated.

      Hey! We're going to be at Eschaton 2012 in Ottawa next November: what if we proposed an evening session together -- a conversation about science and evolution and development?

      This doesn't sound like a good idea. I don't want to embarrass you by pointing out how wrong you are about evo-devo. :-)

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    2. Speaking of speaking - Would be nice to have a permanent link on the Sandwalk home page to keep a schedule of any talks you might be giving that are open to the public. You do mention these from time to time but it would be convenient to have them at a defined location on your site.

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  5. You don't fool me. You're afraid I'll mention all the things you get wrong about evo-devo. Which means, of course, that it would be a spectacularly fun session!


    I think that Carroll does get rather self-congratulatory at times, but I don't see where he's saying the Monod predictions were false. I certainly don't think his chapter on regulatory logic is intended to apply only to animals!

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    1. You're afraid I'll mention all the things you get wrong about evo-devo. Which means, of course, that it would be a spectacularly fun session!

      If you're game then so am I, but I warn you that it won't be pretty. The number of things I might get wrong about evo-devo pale in comparison to the number of things you and Sean Carroll get wrong about evolution!

      If Carrol isn't saying the the Monod prediction was wrong then what's the point of his book? Is he criticizing all those molecular biologists of the 1960s for not recognizing that the current theory of evolution was inadequate to account for repressors and activators in phage and E. coli?

      While it's true that evo-devo applies to plants, it's also clear that Carroll sees something extraordinary in the fact that all animals (e.g. fruit flies and humans) share the same basic toolkit. He doesn't seem to realize that all animals share a common ancestor that lived only 600 million years go. What else would you expect of closely related species?

      He makes a big deal of the fact that a 60 amino acid stretch of some proteins is 90% identical in distantly related animals. Meanwhile, at the very same time, I was looking at proteins where 60 amino acid stretches were 90% identical between BACTERIA and animals.

      What's the big deal?

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    2. He makes a big deal of the fact that a 60 amino acid stretch of some proteins is 90% identical in distantly related animals. Meanwhile, at the very same time, I was looking at proteins where 60 amino acid stretches were 90% identical between BACTERIA and animals.

      What's the big deal?

      It's a book for the popular audience, which is likely to be more impressed by stuff we can see (You're made using the same basic control apparatus used to build these flies, or the weird-looking 600 million year old critters in these pictures!) than "mere" numbers describing things we can't see (60+ amino acid stretches! Do you know how impressive that is?? No?).

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    3. I think that the big deal is that few among the public, heck, few among scientists, know about those things.

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    4. Both PZ Myers and Sean B Carroll are sadly mistaken:

      1) There is no body plan encoded in the genome.
      2) None of the developmental stages are encoded in the genome.
      3) The genomes of many animals are extremely similar, negating the idea that changes in them can lead to new body plans and parts.

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  6. What I'm saying is that the study of gene regulation in one tiny corner of the living world (animals) has not fundamentally altered our 1960s and 1970s view of how gene expression is regulated.

    Except for RNA interference as elucidated by studying the animal C. elegans. This wasn't even imagined in the 60's and 70's.

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    1. The classic examples of regulatory RNAs and antisense RNAs come from studies of plasmid replication in E. coli and other bacteria. Subsequently, other examples of small RNA regulation were discovered, especially in bacteriophage lambda and the OmpF gene in E. coli.

      By 1980, we were teaching undergraduates about antisense RNA regulation using these prokaryotic examples. They started to appear in the textbooks in the 1980s and that's when synthetic antisense RNAs began to be used to regulate gene expression in eukaryotic cells.

      Wagner, E.G.H. and Simons, R.W. (1994) Antisense RNA control in bacteria, phages, and plasmids. Ann. Rev. Microbiol. 48:713-742

      http://annualreviews.org/doi/pdf/10.1146/annurev.mi.48.100194.003433

      The mechanisms that produce these small interfering RNAs are quite different in different systems. The one seen in animals (involving Dicer etc.) is not found in prokaryotes, as far as I know, but the basic idea was discovered in prokaryotes.

      It's not accurate to say that this concept "wasn't even imagined in the 60's and 70's" because the outlines were in place by the second half of the 1970s. In any case, the bacterial examples were well-known long before similar regulatory RNAs were discovered in C. elegans.

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  7. RNA interference (in animals) mediated by double-stranded RNA was first published by Fire and Mello in 1998. (Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans". Nature 391 (6669): 806–811). They were awarded the Nobel Prize for this work 8 years later. To me, that indicates a fundamental alteration in our understanding of gene regulation.

    RNA interference is not at all the same as antisense RNA, and indeed, the use of antisense RNA in animal cells as a laboratory tool for gene expression regulation has been largely ineffective. That doesn't take anything away from the work in prokaryotes in the 60's and 70's, but to imply that universal gene regulation mechanisms had been basically worked out by then is revisionist history.

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    1. We knew in the early 1980s that small interfering (antisense) RNAs in prokaryotes could interact with mRNAs forming a double-stranded region that inhibited translation. There were several different mechanisms but some of them seemed to be due to degradation of the messenger RNA. This was demonstrated in 1987 [Krinke and Wulff (1987)].

      How is the discovery of RNA interference in mammals "fundamentally different"?

      I assume you're not familiar with regulation of gene expression in bacteria. There are many examples of small (about 30-40 nucs) RNAs that are complementary to the ribosome binding sites on specific mRNAs. The regulatory RNAs form a double-stranded region that prevents the initiation of protein synthesis.

      Now that you know this, does it fundamentally alter your understanding of gene regulation because it's so different than RNA interference in animals?

      There are also examples in bacteria of small regulatory RNAs that bind to mRNA and alter it's structure so that it can't be translated. This is similar to an attenuation mechanism except that it's controlled by small RNAs. Assuming you didn't know this, does it alter your fundamental understanding of gene regulation?

      I assume you'll answer "no" because you just see these examples as variations on a theme. If that's the case, then why is RNAi in animals so fundamentally different?

      RNA interference is not at all the same as antisense RNA ...

      I understand your quibble. Here's how Andrew Fire describes it in his Noble Prize speech.

      Although the name “antisense” had initially been used to describe this process, it was clear (from the ‘sense’ results) that the phenomenon was not a simple one of antisense occlusion. There was thus a need for a new designation for the process, and after putting a few potential names to a vote, Craig chose the term “RNAi” (‘RNA interference’) to refer to the observed silencing process(es).

      Nevertheless, it is a quibble. Perhaps we should start referring to the bacterial systems as "RNA interference." Would that help?

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    2. It won't help the historical timeline for understanding gene regulation. First it was "our 1960s and 1970s view of how gene expression is regulated", then "by 1980, we were teaching undergraduates about antisense RNA regulation using these prokaryotic examples", now "degradation of the messenger RNA ... was demonstrated in 1987". It might be a quibble, but apparently it's a Nobel Prize worthy quibble. Why not give credit where it's due instead of painting newer results in animals as old news?

      The non-aficionados in the audience can start with (http://en.wikipedia.org/wiki/RNA_interference) for an accessible primer on the topic in animals (and plants) and why it is fundamentally different from what happens in prokaryotes.

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    3. I notice you didn't answer my questions. What is the "fundamental alteration in our understanding of gene regulation" that came out of RNAi work?

      My other questions had to do with the discoveries of various mechanisms where small RNAs control the regulation of gene expression in bacteria. Do those mechanisms also fundamentally alter your understanding of gene regulation?

      Why not give credit where it's due instead of painting newer results in animals as old news?

      There's a big difference between crediting scientists with a nice piece of work on a new topic that's specific to a particular group of organisms and proclaiming that the results fundamentally alter our understanding of gene regulation.

      I detest the hyperbole that's ruining today's science.

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    4. What is the "fundamental alteration in our understanding of gene regulation" that came out of RNAi work?

      Active (protein-mediated) suppression of gene networks through imperfect base pairing of regulatory RNAs with multiple mRNA targets. See also miRNA (http://en.wikipedia.org/wiki/MicroRNA). Are there any pre-1980 examples of RNA-mediated modulation of gene networks in prokaryotes?

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    5. Anonymous asks,

      Are there any pre-1980 examples of RNA-mediated modulation of gene networks in prokaryotes?

      No, and I don't know of any that have been discovered since.

      Is that what you mean by "fundamental"?

      Let's say you knew in 1980 that small regulatory RNAs in bacteria could control gene expression by blocking translation. Imagine that a paper was published in 1985 showing that one of these RNAs could actually regulate expression of two different genes.

      Would that have fundamentally altered your understanding of gene regulation?

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    6. If there is a fundamental aspect associated with RNA interference, it is that regarding its evolution and function in innate immunity, not in gene regulation, which is just a spillover role that is so confused that it appears to be part of an imaginary gene regulatory network.

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    7. I notice you didn't answer my questions. What is the "fundamental alteration in our understanding of gene regulation" that came out of RNAi work?

      There is a unifying mechanism of action of small RNAs in eukaryotes that, I believe, was not known in bacterial systems in 1980 and probably cannot be said to be anything near a universal mechanism of bacterial gene expression.

      Small RNAs are guides that bring various and sundry regulatory factors to RNAs; moreover, there is a common core machinery that mediates these mechanisms. They affect translation (by mechanisms quite distinct from the ways antisense RNA inhibit translation in bacteria), RNA stability (in ways that are not seen in bacteria), DNA structure (something that has yet to be seen in bacteria), and chromatin structure (something that also has yet to be seen in bacteria), to name a few. I don't believe there is any similar unifying mechanism in bacteria; certainly no such fundamental mechanism was known in 1980 (or 1970, or 1960).

      I'm dying to know what studies in bacterial systems presaged the fascinating story of the involvement of polIV and polV in small RNA-mediated regulation in plants. I'll admit that I may not be very current on bacterial gene expression mechanisms, but circa 1982 (when I left the world of E. coli for "greener pastures"), no such studies existed.

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    8. Pol IV and Pol V are plant multidomain RNA polymerases related to Pol II and apparently implicated primarily in silencing of transposons and viral genes (http://www.ncbi.nlm.nih.gov/pubmed/21779025). Not surprisingly, similar to other members of the RNA-based defense, or immune system, they have been co-opted, or ‘exapted’, for silencing some of the plant genes.

      Interestingly, similar to animals, the RNA silencing signals in plants can spread locally within a tissue or organ as well as move long-distance between organs as part of the plant’s circulating immune system.

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  8. If that 1985 paper also showed that multiple gene networks were actively regulated by a mechanism that involved both the positive and negative sense strand of RNA, and that this regulation significantly impacted development in animals and plants, then yes, that would have fundamentally altered my understanding of gene regulation, and I'd be thinking Nobel Prize caliber alteration of understanding, which of course, is exactly what happened. We can debate the meaning of "fundamental" but that's not a particularly interesting debate.

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    1. We'll have to agree to disagree. All I can say is that MY understanding of the fundamentals of gene regulation weren't changed by the discovery of RNAi.

      I haven't found it necessary to incorporate this phenomenon into my "Principles of Biochemistry" textbook. Some of the other, more encyclopedic, textbooks do devote a page or two to the phenomenon but you need to check the index in order to find where it's buried.

      BTW, what's your best example of RNAi significantly impacting development in mammals?

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    2. @ Anonymous,

      I have to take issue with your Nobel Prize worship. Using this to "prove" how revolutionary something is boarding on the dreaded "augment from authority".

      Check out Johannes Fibiger and his Nobel Prize....

      -The Other Jim

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    3. BTW, what's your best example of RNAi significantly impacting development in mammals?

      Why limit the discussion to mammals? There are numerous excellent examples that show clearly how small RNAs impact development in plants.

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  9. I haven't found it necessary to incorporate this phenomenon [RNA interference] into my "Principles of Biochemistry" textbook.

    How about histone methylation/acetylation and higher-order chromatin structure generally such as suppression of gene expression in genomic domains through heterochromatinization? Is that in the textbook? Does that have pre-1980's precedence from prokaryotic systems?

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    1. The question is not if RNAi is important or not in gene regulation. Clearly it is. The debate is whether the use of RNAs in regulating gene expression in eukaryal cells is fundamentally different of that in bacterial cells. Obviously, RNAs are used for the regulation of gene expression in both types of cells; so from this perspective (I think Larry’s perspective, and mine too), the eukaryal RNAi, which was discovered more recently, is old news. However, the mechanisms for producing these regulatory RNAs, and the mechanisms for gene regulation are different not only between bacterial and eukaryal cells but also between groups of organisms within the same domain. And, from this perspective, we can choose our preferred mechanism and call it (with confidence) fundamentally different form other such mechanisms. The question is: will it make it to Larry’s Principles of Biochemistry (5th edition)?

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