Exploring the protein universe: a response to Doug Axe

One of the goals of the intelligent design (ID) movement is to show that evolution cannot be random and/or unguided, and one way to demonstrate this is to show that an evolutionary transition is impossibly unlikely without guidance or intervention. Michael Behe has attempted to do this, without success. And Doug Axe, the director of Biologic Institute, is working on a similar problem. Axe's work (most recently with a colleague, Ann Gauger) aims (in part, at least) to show that evolutionary transitions at the level of protein structure and function are so fantastically improbable that they could not have occurred "randomly."

Recently, Axe has been writing on this issue. First, he and Gauger just published some experimental results in the ID journal BIO-Complexity. Second, Axe wrote a blog post at the Biologic site in which he defends his approach against critics like Art Hunt and me. Here are some comments on both.

1. Like my friend Todd Wood, I am encouraged by the fact that Biologic Institute is doing good scientific work and generating publishable data. Axe and Gauger seem to be smart and capable scientists, and they are asking good questions. May their Institute and its scientific work live long and prosper.

2. Axe is primarily interested in the evolution of protein folds. That question is both intensely interesting and important. And difficult.

3. Like Todd, I found the BIO-Complexity paper to be interesting technically but badly flawed in its theoretical approach and conclusions. Specifically, I note what I think any evolutionary biologist would immediately see: that Axe and Gauger did not test an evolutionary hypothesis. Todd explains this very well, but here's the basic problem. To test an evolutionary hypothesis, as I mentioned above, one must study an evolutionary transition. In other words, one must study a change or transition from an ancestral state to a current (or later) state. Joe Thornton's work is a great example: his group examined protein function in a reconstruction of an evolutionary transition. What Axe and Gauger did was study a "transition" that has never been proposed to have happened. They examined a transition from one currently-existing protein to another currently-existing protein. It's as though they analyzed the "transition" from a cat to a dog, when they should have analyzed the transition from ancestral mammals to dogs and/or cats. Their conclusions tell us something about protein structure and function but, crucially, not about the evolution of those proteins.

This does not mean that Axe and Gauger are incorrect in their hypothesis, namely that different proteins are separated by vast evolutionary wastelands that can only be traversed with the help of "design." That may be the case. But the newly-published work in BIO-Complexity gets them no closer to establishing that hypothesis as reasonable or even likely.

4. In his blog post, Axe continues to insist that evidence for rarity of function in the protein universe is evidence for isolation of individual functions in the protein universe. His arguments from probability, which have been used so many times before, simply do not convince me because, as I wrote before: isolation and rarity are not the same thing. I don't happen to think that Axe's data tell us much about the rarity of function (more on this below), but even if I did, I would find that insufficient to undermine the proposal that proteins are linked in a phylogenetic tree the way species are. Again, this is not to say that I know that Axe is wrong. I'm saying that his arguments are unconvincing to me, and that the experiments needed to test his conjecture have yet to be done.

5. Axe claims that I was wrong to describe his 2004 experiments as "whopping mutations on crippled proteins." But that's what they were. He nicely explains why that was the best way to do his experiment, and I think he's right about that. But the fact remains that his analysis doesn't help us understand evolution if his experiment involved a barely-functioning enzyme subjected to mutagenesis that changed ten amino acids at a time. As I think Art Hunt tries to make clear, this doesn't mean that his experiment was stupid or poorly designed. It does mean, clearly in my view, that the experiment tells us little about evolutionary change. And Axe himself seems to agree: he explains that he wasn't attempting to simulate evolution, only to estimate the rarity of protein function in the protein universe (or the protein-fold universe).

6. In my opinion, Axe significantly overstates his findings on the topic of "function." So for example, in both the 2004 paper and the new BIO-Complexity paper, the experiments involve measuring a single function for each enzyme. It seems to me (and I could be wrong) that when the authors see that a particular variant (mutant) of the protein stops performing that one function, they conclude that the protein "has no function." (In the BIO-Complexity paper, it's two proteins and two functions, but the point is the same.) But of course we don't know that, and evolutionary explanations would propose that new functions frequently arise when an enzyme has more than one function (or is broad-based in its function, or is modular in its structure and function). This is why I think that Axe and colleagues can't make any headway in their efforts to understand the evolution of protein function until they focus intentionally on evolutionary transitions. Instead of showing us that mutated proteins no longer do what they used to do, they should invert their reasoning to look like something like this:

Here are the proteins in a postulated evolutionary trajectory. What can we learn about the functions of the intermediates during the transition?

Those would be extensive and demanding experiments, to be sure, but they're the only kinds of experiments that can address the difficult questions that Axe wants to ask. This, by the way, is the same critique I gave Mike Behe in response to his erroneous claims in his most recent book.

7. I'm not so sure that function is as rare as Axe (and others) think. It turns out that completely novel (and foreign) protein sequences can be shown to have function, in living bacterial cells. We may be mistaken in our assumption that islands of function in the protein universe are fantastically rare.

8. Axe and his colleagues do good work, and they're asking important questions. I hope they are in close contact with scientists working on similar questions. There are many strong labs working hard on protein evolution, from various angles, and I'm sure that the scientists at Biologic Institute would profit immensely from regular interactions with the scientific community. (Consider, for example, the authors of a 2010 PLoS ONE paper on "Evolutionary Innovations and the Organization of Protein Functions in Genotype Space.") Perhaps this is happening, and if so, great. But it needs to be emphasized.

So, kudos to the scientists of Biologic Institute for working hard in the lab, and for tackling an important and formidable problem. They haven't shown us anything important about evolution yet, but I hope they keep at it, with a little more careful thought and a lot more input from colleagues.