Miller: Axe Decisively Confirmed?

I ratify this concern. If we have already discovered all folds we don’t expect to find new folds, and that doesn’t matter at all. What matters is new functions. Novelty isn’t measured by folds.


The challenge is finding novel folds from distant nonfunctional sequences. At some point, an entirely new fold had to appear even if one has to go back to the origin of life. In the middle of sequence space, none of the processes you cite will help a search find an exceedingly rare functional island.

No, it isn’t. The challenge is only to find novel functions. You’re conflating folds and functions in a way that makes absolutely no sense. They aren’t the same thing.

This is silly. Random sequences fold. It’s what proteins generally do.

Yet catalytic antibodies have been found for the last 32 years, but never cited by Axe nor Gauger. Multiple hits in a library of 10^8 isn’t rare at all, and destabilizing existing proteins is not a model for a forward search.


So @bjmiller there is the Turf13 example put forward by @art, which appears to arise by constructive neutral evolution.


I promise to cite you by name in my next article. Please keep listing your thoughts on counterexamples and other related issues, and I will respond to all of the points at once.


I don’t see how that makes up for the lack of attribution in the previous one. Do you not know that web pages can be edited?

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Thanks @bjmiller, with the current blitz from ENV, it is important to me that we continue to highlight positive dialogue between us. This is an example of such positive dialogue. Peace.

There is five things I would like you address.

  1. The first one is T-urf13 which has been put forward by @art, and is an example of a three part irreducibly complex system that appears to have arisen without selective benefit, by Constructive Neutral Evolution. This is not Darwinism, but neutral evolution, so you may need to reorient your rhetoric.

  2. How are you going to account for the point that @Rumraket has made, legitimately, that you are not taking negative selection into account in your analysis?

  3. It does appear that an irreducibly complex beta-lactamase can arise out of an unselected library of less than 10^-10 sequences. We discussed this at length with @Agauger here: Antibody Enzymes and Sequence Space. If this is true (and I believe it is), it appears you are back to square one. This substantiates all the critique @Mercer has been making with hard evidence.

  4. I want to know your situation here, as a proxy for Axe. If you found that Axe was wrong would you be able to and willing to publicly admit it? Or do you need approval to do so? Or do you honestly plan to argue his case no matter what the evidence shows? I ask this question without judgement, but to understand what we can realistically expect from you in this exchange. If you can’t or wouldn’t ever admit error, even if you were convinced of it, it would be good to just know up front.

  5. Getting to the point on #4, can you acknowledge any errors in your own reasoning or in Axes reasoning that you can acknowledge? If not about this, can you provide any evidence of a place where you personally have admitted error publicly? This would go a long way to calming concerns I have, and making much more hopeful for progress.

I do not mean any of this as insult or to be invasive. Answering this last question for myself, I plan to be writing up in a blog post soon for myself. I have admitted error more than once after being corrected by ID proponents. I would like to know if we are being fair to each other now.

Finally, there is one personal question I have.

  1. Why is it that the DI has repeatedly called me a Darwinist? I am not a darwinist and have explained this recently: Do they mean this as an insult? Are they intentionally trying to misrepresent me? What do you think should be done about this.

These are all the questions I have, and they are each important to me. Thank you for addressing them. I very much look forward to your response.


@bjmiller, please keep in mind that this field is immense. Do not fixate on merely the three papers under question in that thread. We are seeking understanding with you. I encourage you to bring your objections to @mercer privately or publicly, and allow him to present additional papers if required. This is a body of work that @agauger and Axe are not familiar with, so please accept our help.


Doesn’t the existence of orphan genes in humans (that have non-coding homologs in chimps) decisively refute the notion that new protein sequences are vanishingly rare?

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Why is that the challenge? You wrote in an earlier post that the challenge was to evolve, for example, a flagellum protein from a protein with another function. But a protein with another function would not constitute a “distant nonfunctional sequence”. it’s not clear that a protein with another function would even be distant.

You brought up the example of the filament proteins of the flagellum as a supposed example of one of these proteins that would have been too unlikely to evolve from some other function because you could find homologoues of the filament protein with as little as 20-30% amino acid sequence similarity.

I then pointed out that there are filament proteins that simultaneously function as adhesive proteins, and even more hilariously, there are filament proteins that are active enzymes. Filament proteins (flagellin), just like antibodies, have a hypervariable region which mutates a lot (for the reason that filament proteins are often the target of immune system antibodies in multicellular eukaryotes).
Moens S, Vanderleyden J. Functions of bacterial flagella. Crit Rev Microbiol.
1996;22(2):67-100. Review. PubMed PMID: 8817078.

Eckhard U, Bandukwala H, Mansfield MJ, Marino G, Cheng J, Wallace I, Holyoak T, Charles TC, Austin J, Overall CM, Doxey AC. Discovery of a proteolytic flagellin family in diverse bacterial phyla that assembles enzymatically active flagella. Nat Commun. 2017 Sep 12;8(1):521. doi: 10.1038/s41467-017-00599-0

This is evidence that the “islands” constituting different functions in “sequence space” considerably overlap, and evidence against the claim that they are impossibly rare and isolated. This means three known functional “islands” overlap in the flagellum flagellin protein. It’s a filament protein, an adhesive protein, and an enzyme at the same time.

At some point, an entirely new fold had to appear even if one has to go back to the origin of life.

An entirely new fold is not the same as a new function. But proteins with novel folds typically evolve de novo from non coding DNA.

In the middle of sequence space, none of the processes you cite will help a search find an exceedingly rare functional island.

This idea that functional islands are exceedingly rare and isolated is a fantasy. Taking an existing enzyme, then mutating it until it stops working doesn’t say anything about how frequent functional proteins are in sequence space.

More importantly, you have still not acknowledged your complete misunderstanding of the Bershtein et al 2006 paper you keep referencing.


I’m sorry but this is false and it appears you have again completely ignored my earlier response to this same assertion of yours. It is only true that proteins will necessarily destabilize in response to accumulating mutations if it happens in the absence of purifying selection. You simply cannot extend the conclusions about what the effects of accumulating mutations in the absence of selection is like on protein function and stability, to protein evolution in general. As should be obvious from the Bershtein et al 2006 paper you’ve referenced.

  1. The number of “sequence families”/single domain architectures (SDAs) is increasing very slowly/“becoming saturated”, and the few hundred thousand “close families” which have been identified are typically combinations of the small number of SDAs. Therefore, a search through sequence space would never even enter the neighborhood of any protein families. The number of SDAs is far too small to find even one.

But that simply doesn’t follow. It is not even implied at all. How many folds have been so far discovered and utilized life on Earth is not itself any indication of how many possible folds are “out there”. It could just as well be the case that because species share common descent, even if there are still many new organisms to be discovered, they’re going to be related to already discovered life, so chances are they will just have variants of already discovered folds.

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This is another important point I want to “second” here. There is no reason to think that evolution must proceed by evolving proteins from distant sequences.