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ENCODE and the Truth


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is just in the abstract.

Graur (I’ll italicize papers to prevent confusion with the author) is a snarky paper throughout, causing titters amongst many scientists. One compared it to a vulture picking apart a wildebeest carcass.

A vivid metaphor but one usually applied to movie reviews, not dry research papers.   There are reasons most scientific discussions are impersonal and use the passive voice.

The peculiar nature of the paper – its direct attack on the work of others; its use of first person; its heavy discussion of semantics – is more a personal argument than a logical one.

To me, it is harmful in its hubris, in its personal tone and in its seeming surety that ENCODE is not only wrong science but bad science, done by bad scientists; disparaging both the results and the researchers.

Now, that is just my opinion and has nothing to do with the data. Nature always wins and the truth will come out, without regard for the character of the researchers or how personal their arguments.

So let’s look at the data.

A major area of disagreement between Graur and ENCODE is something Mark Minie focused on in our Xconomy article.  ENCODE resolves some complex issues by “re-defining the gene of a multi-cellular organism as a simple, easily studied biomolecular unit—the RNA transcript of the DNA sequence.”

Graur disagrees with this, feeling that transcription is not sufficient to show function. For example, from the paper (my bold):

“The human genome is rife with dead copies of protein-coding and RNA-specifying genes that have been rendered inactive by mutation. These elements are called pseudogenes (Karro et al. 2007). Pseudogenes come in many flavors (e.g., processed, duplicated, unitary) and, by definition, they are nonfunctional. The measly handful of “pseudogenes” that have so far been assigned a tentative function (e.g., Sassi et al. 2007; Chan et al. 2013) are, by definition, functional genes, merely pseudogene look-alikes. Up to a tenth of all known pseudogenes are transcribed (Pei et al. 2012); some are even translated in tumor cells (e.g., Kandouz et al. 2004). Pseudogene transcription is especially prevalent in pluripotent stem cells, testicular and germline cells, as well as cancer cells such as those used by ENCODE to ascertain transcription (e.g., Babushok et al. 2011). Comparative studies have repeatedly shown that pseudogenes, which have been so defined because they lack coding potential due to the presence of disruptive mutations, evolve very rapidly and are mostly subject to no functional constraint (Pei et al. 2012). Hence, regardless of their transcriptional or translational status, pseudogenes are nonfunctional!”

A pseudogene, even if transcribed or translated, can never be functional. Let’s look at this definition and how it might affect real world decisions – such as requests for funding.

Say a researcher came to you with a proposal examining pseudogenes. Searching genomic databases, using some algorithmic magic, they found at least 15,000 pseudogenes in the human genome. About 1,500 of these “dead copies of protein-coding and RNA-specifying genes” might be transcribed into RNA.

Do any of the pseudogenes have a biological function? There are no data yet. They want to look and need money to continue. Would you fund it?

Following the Graur view, this proposal should be denied, because it looks at something worthless. A pseudogene is a dead copy of a functional gene, even if it is transcribed.  Looking for function is bad science, done by poorly trained technicians.

Now, if that proposal was taken to ENCODE, they would have a different view. Transcription is very important. A transcribed pseudogene could be functional; let’s find out what it really does.

I am glad that Graur devotees were not responsible for funding such proposals, that they were not able to deny funding for the projects, to prevent us from learning more about Nature.

Because guess what? When we look at supposedly nonfunctional pseudogenes, we find function.

The very Chan paper Graur pooh-poohs above as “measly” is the example I just used.

The authors hypothesized that … Next Page »

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  • Great article on one of the most important current scientific debates.

    One lesson of biology is that it’s a lot safer to say “we don’t know what that does” than it is to say “that doesn’t do anything.” That’s one of the things that makes biology fun. Graur (the person and the article) comes across as a vicious defender of a incompletely-articulated orthodoxy. For pseudogenes, he’s sure that if he doesn’t know what they do, they don’t do anything. In the abstract, his position is implausible; in this specific case, he has to do some very fancy arguing to avoid being obviously wrong.

    I don’t really understand what Graur wants done different. How are we supposed to find his “pseudogene look-alikes” without looking at what we now think of as pseudogenes? Gayle correctly points out that Graur is moving the goal posts. His attack on people is unambiguous. His attack on ideas lacks clarity.

    Asking Graur’s question backwards is also likely to be interesting: what might be the biological importance of DNA sequences with high mutation rates? Graur seems genuinely horrified that the human genome might have *important* regions of instability. Well, nature wasn’t put here to satisfy anybody’s sense of esthetics. There is no a priori reason that DNA regions not under evolutionary pressure for a highly-conserved sequence can’t have biochemical importance. ENCODE is a reasonably cheap way to find things we otherwise won’t get much data on.

    Graur makes it easy for his critics to paint him as a dogmatic bully. In the TV movie version of history, these people lose in the end. Of course, if the dogmatic bully is right, the TV movie never gets made. As Gayle points out, we’ll get the right answer, and probably fairly soon, petty games or no.

    • Erik, you make a great point about the decision regarding what to look at. The idea of purposefully looking for function in areas that do not look like they are being selected for is a wonderful paradigm-shifting way of breaking through imposed constraints in our enquiries.

      As Heisenberg said, “What we observe is not nature itself, but nature exposed to our method of questioning.” The method is as important as the question.

      The approach from some ENCODE critics seems to greatly limit the questions and perhaps constricts just what we can learn.

  • Pedro Fernandes

    This is an important article about two subjects: the attitude of scientists and the ENCODE debate itself. I was delighted to review the Richard Feynman quotations through the links, some of them I had forgotten, and I agree wit the author’s vision of the ENCODE subject. Nature itself will disentangle it,but in the meantime this article sheds some light onto important aspects of the debate.

    • Pedro, Thanks for the kind words. I entered CalTech in 1974 and that commencement speech was one of the first things I read in the campus paper. It had a huge impact on me and on how to actually do science. I love excuses to connect others to his words.

  • “Because Nature is always right. The truth will come out.” Yes, true, and Nature doesn’t give a rat’s twitch about much of the other stuff that you wrote prior to this statement. An ego-driven a-hole can be right or can be wrong. A humble work-a-bee can be right or wrong.

    It’s fascinating how people get carried away with all this psychological/sociological babble as if it has anything to do with the scientific argument at hand. The truth comes out, Nature wins, everything else is yadda-yadda-yadda…

    One sector that has been able to overcome getting caught in such nonsensical “shrink” talk is – you may be surprised – sports. Kobe Bryant is a recognised a-hole; Tim Duncan is the nicest guy on Earth. To basketball people they are both just great players. Ron Artest, Dennis Rodman, weird guys as they come, found work for years… Choirboy Tim Tebow is out of the NFL… And vice versa.

    I am not taking a side in the argument, at all. It’s just that you cant judge merit by how bellicose or egocentric, or nice or humble the author is. You just can’t.

    • Which is exactly what I said. The personality of the researcher does not affect the data. However, science does not happen in a vacuum, Bullying behavior can be harmful because it can prevent work from being done. It can slow down how long it takes for the truth to come out.

      As Max Planck observed “A scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die and a new generation grows up that is familiar with it.” Science often advances one funeral at a time. Why? Because personalities can muck up the works.

      Feynman discussed this. He showed how simply the authority of Millikan prevented the correct value of the charge on an electron from being determined.

      The discussion is not whether we should only believe science from nice guys. It is that the behavior can affect how rapidly our investigations reveal truth.

      • Oh, great points, great points. However, our generation, we have this “new age”-ism that sometimes brings the same harmful effects from the opposite direction. Where somebody’s argument can be impugned because the person is rough and uncouth.

        Let science and data speak. You have a platform the other side has a platform; leave style and personality aside, focus on substance.

        • We are on the same page. Problems arise when people use purely rhetorical approaches to make their arguments. And we are a very argumentative species where winning makes more of a difference than being right. We both know that things like grants are seldom prey based on substance, for example. So we just need to recognize it and work to minimize its impact.

  • Curt Malloy

    Nicely done, Richard — thoughtful and provocative.

    • Thanks, Curt. It is very hard for to be both thoughtful and provocative in just a few thousand words ;-)

  • Martin Hafner

    Aren’t you aware of ENCODE’s press releases and the interviews Ewan Birney et al gave in September 2012? Aren’t you aware of the other two papers criticizing ENCODE befor Graur et al. appeared? Didn’t you read Ford Doolittle’s PNAS paper? Without Graur’s paper they would have gone unnoticed. If you listen to Birney’s BBC interview (http://www.bbc.co.uk/iplayer/episode/b01qwhtp/Material_World_Junk_DNA_mine_fires_Homer/) you may get the feeling that he is squirming not to having agree to that ENCODE’s “no junk et all” claim was wrong, uneducated and stupid.

    • I was responding to a narrow part of the matter because I only had a couple of thousand words of allotted space. So I focussed on, what in my opinion, are the faulty rhetorical points – both scientific and ad hominem – from one particular group. The article was not meant to be authoritative on the entire controversy.

      Do I believe that ENCODE is completely correct and has accurately described Nature? Unlikely, as I state in the article. Do I think that Graur and his paper is completely correct and has accurately described Nature? Unlikely, as I state in the article.

      Do I think either side of the controversy is stupid and uneducated? Do I think either are bad scientists? Or even badly trained technicians? Nope, because I feel those are inappropriate rhetorical arguments when dealing with a scientific controversy. Those arguments have nothing to do with the data, the hypothesis or the theory. I believe that those sorts of bullying approaches, using ad hominems and other logical fallacies, do little to enhance our knowledge of the world around and are, in fact, part of the tools used to diminish our understanding. They are great in a court room but not useful for those people truly interested in knowing more about the natural world around us.

      • Martin Hafner

        My impression is that you only mean Dan Graur when you refer to Asshole Scientists. Who actually claimed that textbooks have to be re-written? Actually, Nature has Junk-DNA proven right 40 years before ENCODE. Birney et al. could submit a rebutal. However, instead they are actively ingoring the four critical papers and rather try to detract from the core of the discussion by repeating again and again how important the data are. However, they still don’t accept that 80% of their data should at least be considered as noise rather than signal.

  • Roger Shrubber

    There’s a very reliable way to distinguish the hype artists from the real scientists. The hype artists never directly address their critics. The ENCODE project is trailed by a legacy is critics that cite prior work and the recent ENCODE publications have simple ignored that criticism. They don’t even seem to understand the published definition of “Junk” DNA that they claim to be overturning.

    • Part of the point is that it does not matter if the work is done by hype artists or by ‘real’ scientists. Nature wins no matter who is hyping or who is a ‘real’ scientist. What does matter is whether the work, the theory or the hypothesis being examined moves our understanding forward or stops it dead. ENCODE could very well be wrong but its approach – including the controversy it may engender – moves us forward. Some of the arguments of Graur fail to do that, in my opinion.

      Whether someone responds in a proper rhetorical fashion or not – and I feel that ad hominem arguments as espoused by Graur are not a proper rhetorical response – has little real bearing on the underlying data and science.

      I tell hype artists from ‘real’ scientists partly by the types of rhetorical tools they use to make their arguments. Ad hominems, appeal to authority, ad hoc arguments and other fallacies are not the proper tools of scientists interested in understanding Nature. As the saying goes, when the law is on your side, argue the law. When the facts are on your side, argue the facts. When neither is on your side, holler. I do not value arguments that resort mostly to hollering.

      • Roger Shrubber

        I could take issue with many of your points but why quibble. The key point to consider rests on reading on understanding Feynman’s address on “Cargo Cult Science”. In particular, Feynman addresses the requirement that we first be our own harshest critic, and that we address ways we can be wrong. That is what ENCODE utterly failed to do. And more than failing to be introspective critics, they failed to, and continue to fail to, acknowledge well reasoned and thoughtful criticisms. To those _in the know_, it is so glaringly obvious that it sparks up the sort of frustration seen in Gaur’s response. And frankly, it’s time to stop putting up with Charlatans who never learned that most essential lesson that Feynman spoke of. They damage the process. People look at them and think that hyping results is OK and that ignoring your critics, and avoiding being a self-critic is OK.
        It isn’t, and they deserve a public spanking.