Monday, September 9, 2013

Exploring the protein universe: a response to Doug Axe

Original post by: Steve Matheson

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, notabout 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.


  1. Hi, Stephen! It's great to see something by you again.

    I've been interested in this general area for the longest time, due to my interest in the theme of how likely or unlikely abiogenesis is. Are we on one of a very few planets in the whole universe with advanced life forms on it, or is "life as inevitable as quartz?" as Stephen Jay Gould suggested it might be?

    I've seen one fairly detailed speculation that takes us to the threshold of the "protein takeover" and leaves us there. By this I mean that ribozymes performing such tasks as attaching the right amino to the right tRNA with great fidelity, replicating DNA, transcribing RNA and reverse transcribing DNA, and a genetic code with translation producing some simple (mostly structural) proteins. It's a fairly old article:

    AM Poole, DC Jeffares, D Penney, The path from the RNA world. J.
    Molecular Evolution 46: 1-17, 1998.

    That's as close as I ever got to a scenario for abiogenesis. I've never seen any attempt to produce one for the takeover of the vital enzymatic activity by proteins. The general observations in your essay are as close as anyone has ever gotten to a scenario--that is, not far at all. Have you ever seen anyone flesh out what you are suggesting?

  2. I hope you realize that this article isn't about the origin of life at all. It's about evolution. We start with a genome already in operation.

    1. First of all, it depends on what you mean by "life". Cells based on ribozymes, as in that old article, certainly seem to qualify as life; they simply aren't yet the kind of life that we see around us billions of years later.

      Secondly, Matheson's article is highly relevant to the origin of life, inasmuch as the usual arguments for why the protein takeover was no big deal are pretty much the same as the ones he is using. You never went beyond them in, and neither has anyone else over there AFAIK.

      Axe wasn't completely wrong in his "cat gives rise to dog" kind of experiment, by the way. Unless one hypothesizes a completely different origin for all 20 aa-tRNA synthetases, one is faced with the notion of one synthetase letting go both of the amino acid to which it is adapted and the tRNA molecules to which it is adapted, and either somehow changing both adaptations simultaneously, or undergoing an evolutionary journey via unknown intermediates of unknown utility.

    2. It seems likely that you don't understand the subject under discussion, because you don't seem to understand what subject under discussion is. I have tried to give you a heads up, but that's about all that seems useful to say.

    3. I didn't write anything about OOL in the post. It was a commentary on a specific article by Axe and colleagues, and I didn't suggest any kind of scenario for a transition from the RNA world. I'm confused about the question re the "protein takeover," as it seems unrelated to what I wrote.

      If I said anything interesting at all in that post, it was about whether "function" is incredibly rare in design space. That's an open question, I think, and my post tried to make that point. John is right that the topic of the post was protein evolution, and I guess I thought that was pretty clear.

      No, I didn't know about the existence of this blog, but reposting my work with attribution is consistent with the CC-BY license on Quintessence of Dust. It would have been nice to ask me first, but no worries.

    4. Hi Steve,

      Nice to see that you're still around. I really miss your very informative and engaging articles. I apologize for not asking for your permission to repost the article first. From now on, if I decided to copy any other material from your blog, I'll make sure to let you know beforehand.

      And just to be sure, I will never put any type of ads on this blog. It's just going to be a place where readers from the general public can see what types of objections scientists (and perhaps philosophers) raise against the arguments made in Stephen Meyer's most recent book. I noticed that these objections have been scattered on multiple blogs, and it was difficult to keep track of them. So, I thought that aggregating all the objections I've come across in one place would make everyone's life a bit easier.

  3. I'm waiting for a reply from Steve before commenting on John's strangely redundant chest-thumping.

    1. Steve isn't the person managing this blog, and I doubt that he knows that it even exists. If you'd like to discuss these issues further with him, please contact him over at his own blog: Quintessence of Dust.

      I usually put a link to the original post at the very top of the articles that I'm aggregating here. Sorry for the confusion.

    2. This comment has been removed by the author.

    3. Considering that the reply from Steve essentially repeated just what I said, perhaps you should reconsider your ability to interpret text, and might think about accepting advice next time.

    4. Steve's intent is distinct from the literal meaning of what he wrote. What he wrote included the idea of exaptation, which YOU regarded as being an obvious solution for the protein takeover.

      In fact, you even wondered aloud how I could possibly believe in evolution if I did not
      also believe THIS.

      Moral: don't count your "clueless about the text of Steve's article" chickens before they are hatched. You might find yourself with a stink bomb on your hands.

    5. So if Woody Allen pulled Marshall McLuhan out of nowhere, you'd just keep on arguing with him. Right? Your powers are amazing.

    6. Your polemical slant, acting as though I were arguing with Steve, is what is really amazing.

  4. Many thanks for the tip, and the link! Might you be the person who IS managing this blog? I could see no indication of it on the home page.