BBC interview with Ewan Birney.

Say what you want about the tone of the Graur et al. (2013) paper in Genome Biology and Evolution, but it has people talking. Including Ewan Birney, the lead scientist of the ENCODE project and the primary spokesperson for ENCODE in the media fiasco describing the “death of junk DNA”. Most recently, Birney was interviewed by Quentin Cooper on the BBC Radio 4 program Material World, along with Oxford biologist Chris Ponting. You can listen to the show here.

I have also transcribed the parts in which Birney discusses the ENCODE findings and the flap around the claims of “80% function” of the human genome. Again, remember that Birney himself said several times in prior interviews that the ENCODE results undermine the idea of junk DNA and that the genome is jam packed with “switches” (see here, here, here, and here).

Quentin Cooper (host): Ok, well, Ewan, we’ll get on to what this paper says and doesn’t say, but can you just give us a quick precis of why ENCODE’s findings are in such contrast to a lot of conventional thinking and clearly a lot of current thinking about junk DNA?

Ewan Birney (Lead scientist, ENCODE): I don’t think the findings are in such stark contrast. It’s more about the interpretation of the words, in particular when the words get used in, um, out of context, out of the scientific paper context and propagated. So, what exactly do we mean by this word “junk”?.

Quentin Cooper: But are you sure it’s all about the context. Because I mean, one of the reasons why these findings attracted so much interest was because it didn’t seem to fit the conventional thinking. It can’t just be down to a bit of phraseology and saying actually confirms what we already knew, can it?

Ewan Birney: Ah, so, I don’t — It’s interesting to reflect back on this. For me, the big important thing of ENCODE is that we found that a lot of the genome had some kind of biochemical activity. And we do describe that as “biochemical function”, but that word “function” in the phrase “biochemical function”is the thing which gets confusing. If we use the phrase “biochemical activity”, that’s precisely what we did, we find that the different parts of the genome, [??] 80% have some specific biochemical event we can attach to it. I was often asked whether that 80% goes to 100%, and that’s what I believe it will do. So, in other words, that number is much more about the coverage of what we’ve assayed over the entire genome. In the paper, we say quite clearly that the majority of the genome is not under negative selection, and we say that most of the elements are not under pan-mammalian selection. So that’s negative selection we can detect between lots of different
mammals. [??} really interesting question about what is precisely going on in the human population, but that’s — you know, I’m much closer to the instincts of this kind of 10% to 20% sort of range about what is under, sort of what evolution cares about under selection.

Quentin Cooper: But this paper that’s appeared in the journal Genome Biology and Evolution, Dan Graur from the University of Texas, professor there, all these lines, do you think they’re reacting more to the press coverage around the story rather than what’s actually in your paper itself?

Ewan Birney: That’s my belief. And of course in some sense our responsibility to help that press coverage do the right thing and that’s what I worked very hard in September, in particular in the UK context where I’m based, to try and make that press coverage work. It is quite complicated, because you want to be excited about what you’re doing, but you don’t want people to get the wrong — draw the wrong interpretation of it. So, it’s not an easy job to do, but I believe that most of the heat in this debate is about the definitions of the words, and not the data or the interpretation of the data.

Chris Ponting (Oxford University): Ewan, my question to you is, how much of the genome do you think is vital for life?

Ewan Birney: Yeah, I don’t, I would do that on a, as you know I’ve blogged about this. You know, certainly everything that’s under negative selection in the human population, that evolution cares about right now in humans, that if it changes then the person has less reproductive fitness, that’s clearly vital for life. I think there is a chance of there being a small amount of additional things that we find interesting about differences between people that are not under selection. So, those may be phenotypes that are late-onset such as neurodegenerative diseases or things like that. So, I think there’s a little addition to that but those are the kind of boundary components to that.

Chris Ponting: So I think we can probably agree between us that between 10% and say 20% is vital for life.

Ewan Birney: I mean, I think we would agree with that. I think, you know, refining that percentage down is quite interesting. I think also the other components that we — biochemical events that we see in the genome, sort of, each one of them are equally likely to be part of that 10% to 20% that we’re looking for. It’s important to realize that it’s not the case that we can spot the 10% to 20% just by looking harder. Each of these different places in the genome that have some biochemical activity associated with it, when there’s some phenotype screen that’s directed there or some evolutionary screen that’s directed to that point, ENCODE can now say “Ah ha! Here is a biochemical thing that this piece of DNA looks like it could be doing”.

Quentin Cooper: Ewan, just briefly, what about another aspect of the criticism, the idea that the ENCODE project lacked anyone with any real knowledge of evolutionary biology?

Ewan Birney: Well, I’m sure we could have, um, ahhh, had, um, many other people join us. There were a number of us who have worked — I do know quite a bit about evolutionary biology. Whether everybody considers me to be an expert, I don’t, you know, that’s for other people to say. If you read the paper, and not the press reports, there is a lot detail spent on what is under different aspects of evolutionary biology, ah, selection. So, I think again, a lot of this is not about the paper, but is more about the words used to describe the paper.

Quentin Cooper: Finally though, Ewan, is there any of the criticism you do take on the chin, think well perhaps we did let the story get a bit away from us at times?

Ewan Birney: Well, hindsight is a fairly cruel thing. And one of the things which I regret about being in this situation, arguing about words in the press, is I just wish there was a way of us not talking about this. I think ENCODE already is being used by many, many different groups, in particular disease biology groups having their phenotypes screened against it, and other people worldwide. And the whole point of this for the data by the project to be used by many, many other groups. I’m really happy about that, um, and hindsight being such a cruel thing, makes me think about what I could have done to minimize this kind of rather heated debate.


16 comments to BBC interview with Ewan Birney.

  • RBH

    That’s a whole lot of bobbing and weaving there.

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  • Roger Shrubber

    Ewan does himself more damage with every interview. If he was surprised to find this “biochemical” function covering so much of the genome he was poorly informed to start with. We knew that 20 years ago from ESTs. Moreover, he still does not seem to understand basic biochemistry, that transcription is a fundamentally sloppy process, and again this has been known for a long time. And we know, and have known for a long time, that the genome is littered with broken transposeable elements. It’s embarrassing. It really is.

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  • Do you think that Nature and the ENCODE leaders are ever going to admit that they misled the public? Do you think that any of the ENCODE leaders are going to admit that they didn’t understand junk DNA and the evidence that supports the concept ?
    I don’t understand why there haven’t been one or two project leaders speaking out in favor of a different interpretation of the ENCODE results.
     
     

      (Quote)

  • Please note that Dr. Birney speaks of ‘differences between people that are not under selection.’ What could he have meant by this? Well the batches of variable region genes that collectively are ‘vital for life’  (e.g antibody formation), would profitably vary between individuals, thus creating a greater challenge to prospective pathogens. But an individual V region gene could be dispensed with in one person without any necessary negative selection effect.
    By analogy, there is now growing evidence that host ‘antibody RNAs’ that can hybridize with the RNAs of intracellular pathogens, would be adaptively advantageous. The corresponding genes would benefit by diversification, so that pathogens could not anticipate the ‘antibody RNA’ spectrum of its next host. These ‘biochemical events’ (their transcription), would not be under conventional negative selection.

      (Quote)

  • Ewan Birney says,
    <blockquote> I think there is a chance of there being a small amount of additional things that we find interesting about differences between people that are not under selection.</blockquote>
    Most of the binding sites that ENCODE identified are spurious binding sites with no biological function. Single nucleotide substitutions could change those into non-binding sites. There are millions of differences between individuals that could be detected in this way.  I wonder how ENCODE leaders will react when this happens?

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  • gillt

    Birney’s explanations sound reasonable. What we knew 20 years ago were estimates and predictions based on limited data. Now that these large consortiums are churning out huge amounts of data there’s this ugly pushback from those scientists on the outside, which is where most evolutionary biologists are, feeling left out. The only criticism with substance has been how ENCODE communicated with the media. Where have the ENCODE papers gone so horribly wrong? Are there any good critiques of the actual literature yet? And please don’t quote Gaur at me. His piece mostly an opinion on the proper place of big science with heated rhetoric. 
    “Ewan, just briefly, what about another aspect of the criticism, the idea that the ENCODE project lacked anyone with any real knowledge of evolutionary biology” 
    See what I mean? 

      (Quote)

    • Well, the ENCODE papers go wrong in the abstract and the first item in the list of findings by using either an inflated figure of 80% and/or a misleading definition of “function”. That formed the basis of the (mis)communication with the media.

      Graur et al. had some valid scientific points if you look deeper than just the tone. However, I tend not to agree that *only* conserved sequences can be functional in a biologically meaningful sense.

      If you don’t like Graur, you can read Doolittle’s critique in PNAS.

      http://www.pnas.org/content/early/2013/03/06/1221376110.abstract

       

        (Quote)

    • <i> … there’s this ugly pushback from those scientists on the outside, which is where most evolutionary biologists are, feeling left out.</i>

      The ENCODE leaders are taking their results and using them to draw conclusions about the evolution of genomes. In doing so, they pretty much ignored thirty years of data on the subject of junk DNA. most of the ENCODE leaders are biochemists and bioinformaticians. 

      Explain to me again which scienitsts are on the outside of this field? Are you referring to Dan Graur, Ryan Gregory, Ford Doolittle, Sean Eddy, and Michael Eisen as outsiders? Maybe you should read: <a href=”http://blogs.scientificamerican.com/the-curious-wavefunction/2012/09/13/three-reasons-to-like-junk-dna/”>Three reasons why junk DNA makes evolutionary sense</a>.

       

        (Quote)

    • Dan Graur

      You ask: Where have the ENCODE papers gone so horribly wrong? 

      Let us look at the HeLa cells that were used in ENCODE. Fortunately, the genome and the transcriptome have been published, although for reasons unrelated to ENCODE, the sequences are no longer public.

      http://www.g3journal.org/content/early/2013/03/14/g3.113.005777.full.pdf+html

      Pay particular attention to their figure 3 (the karyotype of the cell line). Do you think we can learn anything from this cell on humans. Do humans, in your opinion, have 64 chromosomes (including 5 copies each of chromosome 1 and 5)? 

      The entire edifice of ENCODE was based on the assumption that whatever happens in cancer cell lines (some very very old) is relevant to human cells. Well, guess what? They aren’t and with the exception of the hype, nothing will be left of ENCODE.

      I am merely a population geneticist and molecular evolutionist, so I cannot comment on the many experimental sins of ENCODE, including a complete and utter lack of controls in all their transcription experiments. Fortunately, other people are not as ignorant, and their forceful rebuttals are making their way up in the publication pipeline.

       
       
       

        (Quote)

  • Ewan Birney is trying to give the impression that the problem is that people have misinterpreted him. But <b>he was the one who put forward the 80% figure</b>. It was not added by the popular science press, he wanted it out there and wanted it noticed. And when there was a huge blaze of publicity centered on the (purported) death of junk DNA, publicity that Ryan has done us the great service of listing, I didn’t notice Birney jumping up saying that he had been misinterpreted.
    Large numbers of laypeople and other scientists are now persuaded that there never was any junk DNA. It will probably take 10 years to unpersuade them. We have Birney to thank for this situation. I’m saddened to see him dance around and try to give the impression that someone else came up with the Death of Junk DNA.

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  • sparc

    I have the feeling that ENCODE, not only Birney, is currently trying to envoke the impression that their data are valuable irrespective of the junk DNA debate that they try not to mention. They behave as if none of the critiques have ever been published. However, if taken seriously 80% junk DNA means a lot of what they measured is noise. Obviously, until now they don’t have filters to isolate the real meaningfull signals. How could they if they are not aware of the problem. As the saying goes: Garbage in, garbage out.

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  • Dan Graur

    I wish it was “garbage in, garbage out.” Unfortunately, it was “gazillions of dollars in, and garbage out.”

      (Quote)

  • Dr. Graur is puzzled by the karyotype. But cells with 64 chromosomes may well be under ‘stress,’ a condition likely to be accompanied by increased transcription (initiated in Alu elements, etc.). This may be of adaptive value, but, for reasons I have already given, the corresponding genomic regions may not be conserved,

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  • gillt

    Thanks for the Doolittle opinion piece. This sounds reasonable: “the publicity surrounding ENCODE reveals the extent to which these understandings [of biological function] have been eroded. However, theoretical expansion in other directions, reconceptualizing junk, might be advisable.” And by this he means of the architectural and structural sort. If you want to flash freeze the word function in time, okay fine, but you have to make the case of why it shouldn’t evolve in light of new data (e.g., comparing FEs among Plethodons with small genomes and those with much larger genomes). I’m wondering if Rachel Mueller would agree with me here.
    Michael Eisen’s main lament is against big science in general where ENCODE is within easy reach. 
    Dan Graur: That’s an interesting paper. And the disparity shown in FIG3 is a legit criticism, but I don’t think I’m being too charitable in saying that the consortium were aware of the peculiarity of immortalized tumor cell lines, as they’ve been microarrayed into oblivion. And I don’t think it’s fair to single out ENCODE from all the other research relying on HeLa cells. 

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  • Claudiu Bandea

    @gillt
    Generating data (“churning out huge amounts of data”) is only half of the science process; the other, is the interpretation of the data. And, that’s where the “opinion pieces” by Graur at al. and Doolittle make their science contribution, which dwarfs the contribution of the ENCODE’s leaders. I’m pointing at the leaders, because I think most ENCODE scientists, like the rest of the field, have also been victimized.

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  • Claudiu Bandea

    Ryan, what is your position on ‘junk DNA’? Are you still in favor of Bennett’s nucleotypic theory?

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