Ford Doolittle talks about transposons, junk DNA, ENCODE, and how science should work

Here's more from the interview with Ford Doolittle [The Philosophical Approach: An Interview with Ford Doolittle].

Gitschier: I want to close with what you describe as your “latest rant.” How did you get on function?

Doolittle: Well, I’ve always been on that.

Back in 1980, people were talking about transposable elements as if their function was to speed evolution; that they exist because of their future utility. And I’ve never liked that kind of idea. I didn’t like it in terms of introns. And Dawkins had just published The Selfish Gene in 1978.

Carmen Sapienza, a student of mine who now works on eukaryotic imprinting, and I wrote a paper which was rejected by Science after seven referees. But we heard that Leslie Orgel and Francis Crick were working on something like this, so we sent it to them. They said, “If you submit it to Nature, we will tell Nature not to publish ours without publishing yours, and to publish yours first,” etc., which was very nice.

That paper, seemingly now very simplistic, said you don’t need to suppose that transposable elements are there for the purpose of speeding evolution. These are selfish things, and natural selection will favor such elements that can make copies of themselves in genomes and then spread horizontally to other genomes within the species. These are basically parasites. I think many people would now accept this, but it was radical at the time.

People don’t like to think that the human genome has junk in it. This came back when the ENCODE papers came out a few years ago and were touted as spelling the “demise of junk DNA.” That got my dander up.

I wrote a perspective in PNAS, and Dan Graur had a much more vituperative thing in Genome Biology and Evolution. I don’t think the ENCODE people have given up; they had a kind of semi-apology in PNAS, which wasn’t really an apology.

It is the same as the tree of life issue, but until we actually have some agreement about what we mean by words we are going to get into these arguments, and in my mind, there are two devastating things you can say about the ENCODE people.

One is that they completely ignored all that history about junk DNA and selfish DNA. There was a huge body of evidence that excess DNA might serve some structural role in the chromosomes, but not informational. They also ignored what philosophers of biology have spent a lot of time asking: what do you mean by “function?” And you can mean one of two things: we might mean either what natural selection favored, which is what I think most biologists mean, or we might mean what it does. Some people might say, “Well the function of this gene is in the development of cancer,” but they don’t really mean that natural selection put it there so that it would cause cancer. These are not-so-subtle differences.

I think many molecular biologists and genomicists, in particular, think that each and every nucleotide is there for a reason, that we are perfect organisms. It is almost as if we were still theists thinking God doesn’t make junk; we just now think natural selection doesn’t make junk. I think there is a deep issue about the extent to which we are noisy creatures and the extent to which we are finely honed machines. I think the latter view informs much of genomics, and I think it is false.

ENCODE wouldn’t have got funded had they said 80% of the human genome is just junk, transposable elements.

Gitschier: It is justifying itself, post hoc. They are the big players with a lot of money. It’s like a machine—“We can do it, so let’s just do it!”

Doolittle: It’s a juggernaut is what you are saying.

My other objection is that it is false ontology. I think all of our science suffers not only from the big science motivation, but from what I call “positivism.”

A couple of times we submitted papers saying, “Everybody’s doing something this way, and it doesn’t work, and it is wrong to do it this way.” And Nature would write back, “We’re not interested in negative reports like this. What does work?” And we say, “We don’t give a damn what does work, it is important to know that what people are doing now is not working.”

There is no critique in science, very little. You can’t actually say, “This doesn’t mean what people say it means.” You’ve got to be “positive;” you’ve got to be moving the program forward all the time. I don’t think that is right.

Now, and down the road, we’re going to tackle directly relevant questions, like what is the meaning of function in the concept of genomics? There are legitimate evolutionary constructs in which you can address transposable elements, and people have not really explored that. Questions about the tree of life, again, and some of the questions we’ve been through are things that continue to interest me and which have a strong philosophical component as well as a data-related component. That’s what I’m interested in pursuing.

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