"The ENCODE debacle"

“Where is the wisdom we have lost in knowledge? Where is the knowledge we have lost in information?”  T. S. Eliot. 1934. The Rock.
“Where is the wisdom we have lost in knowledge? Where is the knowledge we have lost in information?” T. S. Eliot. 1934. The Rock.

Below, we list excerpts from about 50 e-mails that were send to Dan Graur in reference to our 2013 paper in GBE. Since it was impossible to ask all writers for permission to make their comments public, the authors of the e-mails are only identified by the initial of their first name, and we erased as much as possible all identifying details. It seems that my colleagues and I have channeled the frustrations of many in the scientific community, who were either too polite or too busy to bring attention to the fact the emperor wears no clothes.

1. “Bravo! I have nothing to add to your Genome Biology & Evolution paper, except: Hooray! Sharp in a field often dull, quantitative in otherwise sloppy terrain, witty in an often pedestrian culture, and immensely fascinating to an interested but largely ignorant outsider. (And ignore the crap that is certainly raining down upon you. Remember William Blake's dictum that a fool's reproach is a kingly title.)” C

2. “Read your wonderful paper in Genome Biology and Evolution. It made my week, and gave me faith there are still people thinking out there in the land of big and small science.” D

3. “Congratulations on your demolition of the ENCODE paper! What a load of drivel it was (along with most human genomics in fact, certainly 95% by amount of funding), but nobody dares to say anything because of the impact through the grant panels!” P

4. “Ah, a breath of sanity! Thank you for writing this article. FB passed your article on to me, which I read with great interest even though I know nothing about human genomes. He was wild about your article, including the humour. As was I. I have one minor comment about wanting to be on the committee who designed the E. coli genome. In my opinion, your colleague was mistaken because it is only marginally better than the human genome and the E. coli field is plagued by the same functionalist philosophy that exists at ENCODE. Salmonella enterica is a bit more rational, but only a bit.” M

5. “Thank you for publishing your paper about ENCODE in GBE. It was a great read, and you proved what many of us thought, but didn’t have the time or the courage to state.” P

6. “As someone who was mystified by the claims and hype that accompanied the ENCODE publications in Nature - I very much appreciate your courage in publicly drawing attention to some of the shortcomings of this project.” T

7. “You have written a superb critique of the ENCODE people in GB and E. I call them Technodrones. Any minimal understanding of comparative evolutionary genomics reveals that the ENCODE figures are bogus. Unfortunately, this is not obvious to the technodrones, whose knowledge of evolutionary principles is near zero. One only has to compare two closely related species of bats, or the Xenopus series, or invertebrates that discard massive amounts of genomic material during early cleavage stages of embryogenesis, to see that most of the genomic DNA cannot be under selective constraint. Anyway, this brief note is simply to encourage you to stay firm in the face of the abuse that the Technodrones will throw your way. Your first class scientific principles and clear logic are much to be admired.” G

8. “I enjoyed very much reading your superb critique of the ENCODE hype. Thank you for holding up the banner for evolutionary genomics!” E

9. “Good news is that Graur et al. paper created a huge storm, and will hopefully affect brain map and other grandiose (wasteful) projects.” S

10. “Your recent GBE paper regarding ENCODE is brilliant and hilarious... and no doubt the topic of every evolutionary biology journal club this week.” B

11. “ENCODE had it coming. Maybe we can create a DECODE consortium.” B

12. “My group has chosen Dan Graur and Company's diatribe against ENCODE as our journal club paper this week. Very rarely does a scientific paper cause me to snort with laughter, but this one has caused it, several times.” J

13. “I loved your spanking of ENCODE, from beginning to the end, not only because of the scientific content but also because of the humor.” A

14. “It's nice to read a scientific article in plain English instead of pompous journalese.” D

15. “Ha! Great paper! Keep it up. Wish more science writing was like this!” D

16. “Thank you so much for expressing in writing what so many of us think!” D

17. “Thank you for your slow roasting of ENCODE. It is so wrong in so many ways that it infuriates me.” D

18. “On behalf of many scientists, and my own sanity when it comes to disillusionment with modern science - thank you for your article questioning the gospel of ENCODE, and the dangers of big science in general. If only it could actually make a difference to current trends!!!” A

19. “The paper is excellent; very well-argued, informative, entertaining and frankly, devastating. I think this paper should emerge as a major critique of the ENCODE project, pointing out the extremely liberal and flawed (and as you say in the paper, not even consistently flawed) definitions of "functional" used by the ENCODE researchers.” A

20. “It's wonderful! That's the kind of science we need more of these days. It annoys me greatly that there's a myth out there concerning predictions of human gene number. The real experts (i.e. the ones who actually studied genomes as opposed to sequencing them) knew that there had to be a lot fewer than 50,000 genes. There was abundant data pointing to a consensus (among the real experts) of about 30,000 gene. I agree with your conclusion that many scientists just can't deal with the idea that we may not be more complex than a fruit fly, or an onion. I call this "The Delfated Ego Problem" and it's very real. I think it influences a lot of data interpretation. Wouldn't it be nice if modern biochemists and molecular biologists actually understood evolution? “ L

21. “Excellent article. Well done.” D

22. “Congratulations on your superb article in GBE (On the immortality of television sets...)! If someone had given it to me to read with authors' names removed, I would have known it immediately as yours. I'd had BS sessions w/ friends over beer trashing out ENCODE for its many sins late last year, but left it at that. Anyway, enjoy life!” D

23. “I really enjoyed reading your article on the “evolution-free gospel of ENDCODE”. It is very unfortunate that these days the factory men posing as scientists dominate biological sciences. Be it ENCODE or the human EPIGENOME, we are being inundated by the sea of largely meaningless data. Not a pretty picture.” R

24. “I just wanted to write and thank you for your article 'On the immortality of television sets: “function” in the human genome according to the evolution-free gospel of ENCODE' I really really enjoyed it and I am so glad you wrote it. Science is far better off, and the actual winner due to your article being published. I also shudder to think how you were treated by reviewers and editors during the process of publishing it and I am sure you will get a few less invitations to birthday parties this year. I (and I am sure countless others), have wanted to write similar articles about bad science but never had the guts or support, to do it. Your article makes me re-think whether keeping quiet about bad science is as scientifically correct as it is 'politically correct'. I am curious if you were reviewed at Nature and Science or just palmed off. Certainly, and especially through my recent dealings with some journals, the option seems to favour a great story rather than sound science which is very unfortunate. Unless you stumble across a brave editor. Thanks again for your article. Everyone I have spoken to who knows the ENCODE publications has really really enjoyed it. I wish more scientists had the guts to do what you did.” E

25. “Thanks for supplying some juicy material to our journal club this semester. I tried to explain to my students who you are in person, but was met with utter disbelief. You are as far removed from the Midwestern mentality as possible within our species. In any case, I appreciate your critique of ENCODE.” I

26. “I very much enjoyed your recent article discussing the ENCODE publications - very important, brilliant, and entertaining. I think the problems of ENCODE and its claims even start with the experiments themselves, the methods' shortcomings and the lack of appropriate controls.

For example, we have been discussing the claim that nearly 80% of the genome are transcribed in the context of very deep sequencing potentially detecting genomic DNA contamination: Imagine incomplete DNase digestion results in genomic DNA not being 100% removed before to the reverse transcription step that converts RNA into cDNA prior to sequencing (and of course nothing is ever 100%). Very deep sequencing might then detect remaining genomic DNA contamination, which would be impossible to distinguish from "very lowly abundant transcripts". A negative control to exclude this possibility, i.e. a "non-RT" control - standard for qPCRs - has not been done (in fact, I have not seen this anywhere but for this particular claim it would have been absolutely necessary). I therefore find it not inconceivable that the 80% "transcribed" regions merely correspond to the "mappable" fraction of the genome, while the remaining 20% are non-mappable (i.e. deep sequencing reads cannot be mapped uniquely to these regions) - a scenario that renders the entire claim unsubstantiated and artifactual.

It is interesting in this context that the authors find that the newly discovered lowly abundant transcripts are typically (1) unspliced and (2) enriched in the nuclear versus the cytoplasmic fraction when such RNA-seq datasets are created separately and then compared. I.e. ENCODE finds the genome where it belongs. I hope that we get around to actually do the "no-RT" RNA-seq experiment in our lab some day - I have a very clear expectation regarding the outcome...

I have been comparing this entire situation with the way the physics community handled the "faster-than-light neutrinos": given the very unexpected finding, they did their homework and found the result to be due to bad wiring (e.g. http://www.guardian.co.uk/science/2012/feb/23/faster-light-neutrinos-faulty-connection). ENCODE instead wrote 30 something papers and created a big media hype. I wish ENCODE had also done their homework first. Thanks again to you and all your co-authors.” A

27. “I just read your article in GBE dealing with over- and miss-interpretations of the ENCODE project: it's jubilant! It's sad too note how scientific journals are victim of the quest for buzz. Reversing the interpretations that have been established in broad-audience media will require a longer time…” C

28. “Like many, I most enjoyed your article. Did you see Current Biology’s quick guide last November, which I think made some similar points? http://www.cell.com/current-biology/fulltext/S0960-9822(12)01154-2. The main point of my email was not to tout our quick guide (though I couldn't resist that), but to add to the plaudits for your paper, not just because it is such a relief to see that critical analysis and proper biological thinking are still extant, but also because of the intelligent fun in the writing... Bravo! My immediate feeling on reading about the ENCODE papers - in particular the "spin" in the media - was: but what about the C-value paradox? This just cannot be right…” G

29. “This is the kind of important commentary similar, I think, to that of Joseph Terwilliger at the outset of the HapMap. Pretty much every word of an article he wrote in 2002 could be published today verbatim and still holds true. In that sense, ENCODE has been a boondoggle.” R

30. “Thank you for a wonderful reminder that evolutionary thinking is rigorous, and highly needed in the era, or for that matter anytime, of "high-throughput" x-omics.” A

31. “Loved it!!!” Y

32. “Very DANish title and lovely reading!” P

33. “Nice article. Just got back from a lecture at the annual AAAS meeting in Boston in a session pounding on the necessity of solid evolutionary analysis when interpreting the molecular details of modern biology.” S

34. “I just want to express my maximum respect for your recent comment on ENCODE in GBE. Boy, this hits the core. If there is one reason to stick to what I'm doing and trying to be successful with it, than it is because of one day being able to put something so honest (and very true) out there. I do not know however, if I'll grow the necessary balls, too. I cannot express enough how much this is the way that I wish we could more often deal with the rubbish that is out there, and unfortunately very often in the "big" journals.” S

35. “I'm delighted to see a formal yet passionate response to the breathless, sweeping PR claims of the ENCODE project. I'm intensely aware that biology resides very much in the details, and I think "big science" is a potentially useful dipping well, but full of noise and artifacts that need to be carefully sifted. The trumpetings that ENCODE "changes paradigms of genomic function" were frankly appalling.” A

36. “I recommend Graur et al.’s paper to all biologists, evolutionary or not, because it deals with some of the most fundamental concepts in biology with unusual clarity and wit. It also prompts one to ponder on the pros and cons of big science vs. small science. Last but not least, if you are intelligent, you will enjoy reading this 43-page PDF.” J

37. “Looking forward to the movie.” R

38. “Brilliant, wonderful article!! Your article has zapped around the Internet like no other. And it came at a nice time. Tomorrow night I will give the first talk in a symposium noting the 6oth anniversary of the DNA structure, and I will be inspired by, though can hardly live up to, your article!” M

39. “I read "On the immortality of television sets: “function” in the human genome according to the evolution-free gospel of ENCODE". Great work!” C

40. “I enjoyed reading your amazing (bitter) critique of the "next generation Big Science". It is surprising that famous guys from prestigious institutions produced so many wrong interpretations and misleading conclusions.” D

41. “Kudos! I just want to say that I just read a preprint of your paper on the ENCODE project and found it tremendously entertaining - and on the money. I wish papers were always this fun!” D

42. “I really enjoy your article: On the immortality of television sets. I think that beside the fact that you are correct saying that the encode project costs too much, the problem is the definition of function.” P

43. “Wonderful article in GBE, thank you for putting some reasonable perspective on the ENCODE data. As a PhD student of Sydney Brenner it's nice to see him correctly quoted on 'junk' DNA too?” G

44. “Like you, I have been watching the events of the whole ENCODE media spectacular with much Incredulousness. However, I have enjoyed watching the backlash, as it is not only providing a teaching moment about the perils of overhyping results, but it is also delivered an opportunity to bring to light some important issues that have long been ignored by molecular biologists, such as population genetics.” A

45. “I am writing to congratulate you on a shrewd and amusing article. I have to say that I could not understand the claims being made by the authors in regard to 'junk', and I am pleased to see the underlying reasoning in this regard exposed so witheringly.” I

46. “Well done for tearing into ENCODE. Made me laugh a lot. Keep up the good work! You've said aloud what so many of us thought, and it's time to make Big Science a bit more humble... Well done. D

47. “Nicely done!” T

48. “Nice work.” M

49. “I thoroughly enjoyed and appreciated your recent article on the ENCODE project.” In this context, I'd like to bring to your attention a small commentary of mine on one of the papers that accompanied the main publication, that, if I may say so, is even worse (yes, that is possible). Thought you might find it interesting (http://arxiv.org/abs/1212.3076). The journal Science, unsurprisingly but disappointingly, did not agree to publish it as a technical comment. Y

50. “I very much enjoyed reading your devastating, educational and entertaining critique of the ENCODE functionality conclusions.” B

51. “I salute you! I just read your article titled: "On the immortality of television sets: “function” in the human genome according to the evolution-free gospel of ENCODE” Needless to say I love your (and your co-writers) article. I've been skeptical of the ENCODE project from inception and have always wondered: WHAT IS THESE PEOPLES QUESTION? Much of this is hype, a wave of fashion in science, if you will. Your paragraph about the meaning of the word function should be mandatory reading for all biology undergraduates. Gentlemen, I salute you!” B

52. Many of my colleagues and I very much enjoyed your article on junk DNA. You and your colleagues have a gift for very witty writing and also clear thinking. Well done for standing up against the tide of hype and thanks for providing one of the best papers I have read in a while. M

53. I don't usually do this but I feel that I have to convey to you how much I enjoyed your paper. Your arguments were brilliant and your exposition was incredibly cogent and clear. However what struck me the most was that this was a scientific paper with attitude. I believe that we should conduct our research with passion and not perpetuate the myth that our work is more objective when we make it devoid of emotion. Your passion is clearly evident and deeply appreciated. I don't think I have enjoyed a paper this much in years because it shows that you (and your coauthors) really care about the topic and its significance. Your passion was not a substitute for a critical and thoughtful analysis of the data. You won't get the media hype that was granted to the ENCODE papers, but for those of us in the field, this was truly a worthy contribution. M

As of June 2013, the list is no longer updated. My granddaughter, Lilla Keshet Graur, gives ENCODE the finger (2013)
My granddaughter, Lilla Keshet Graur, gives ENCODE the finger (2013)