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Friday, August 08, 2014

Historical contingency and the evolution of the glucocorticoid receptor

Michael Behe is at it again. He has a freaky knack of taking scientific results that directly contradict his views and twisting them into confirmation that only god can explain the result.

This time he is revisiting an old issue. Joe Thornton's lab has published a series of papers showing that the evolution of the glucocorticoid receptor involved a number of neutral steps that were absolutely required before the receptor could acquire the ability to bind to cortisol. Each of the steps was contingent on earlier steps. This is evolution by accident.

This conflicts with Michael Behe's view of evolution because he maintains that there's an edge of evolution defined by pathways that involve multiple steps. According to Behe, all the multiple mutations have to take place at the same time because none of the intermediates are beneficial and most of them are detrimental.

Here's the abstract from the latest paper by Harms and Thornton (2014).
Understanding how chance historical events shape evolutionary processes is a central goal of evolutionary biology. Direct insights into the extent and causes of evolutionary contingency have been limited to experimental systems, because it is difficult to know what happened in the deep past and to characterize other paths that evolution could have followed. Here we combine ancestral protein reconstruction, directed evolution and biophysical analysis to explore alternative 'might-have-been' trajectories during the ancient evolution of a novel protein function. We previously found that the evolution of cortisol specificity in the ancestral glucocorticoid receptor (GR) was contingent on permissive substitutions, which had no apparent effect on receptor function but were necessary for GR to tolerate the large-effect mutations that caused the shift in specificity. Here we show that alternative mutations that could have permitted the historical function-switching substitutions are extremely rare in the ensemble of genotypes accessible to the ancestral GR. In a library of thousands of variants of the ancestral protein, we recovered historical permissive substitutions but no alternative permissive genotypes. Using biophysical analysis, we found that permissive mutations must satisfy at least three physical requirements-they must stabilize specific local elements of the protein structure, maintain the correct energetic balance between functional conformations, and be compatible with the ancestral and derived structures-thus revealing why permissive mutations are rare. These findings demonstrate that GR evolution depended strongly on improbable, non-deterministic events, and this contingency arose from intrinsic biophysical properties of the protein.
Here's the latest spin from Michael Behe: From Thornton's Lab, More Strong Experimental Support for a Limit to Darwinian Evolution.

We've been here before [Joe Thornton vs Michael Behe]. Back in 2009, Behe tried to spin an earlier paper from the Thornton lab and Carl Zimmer took an interest [The Blind Locksmith Continued: An Update from Joe Thornton]. Zimmer contacted Thornton and asked him to comment on Behe's critique.

I'm going to copy all of Thornton's letter because most of you may have forgotten what he said five years ago. I hope Thornton and Zimmer don't mind. This letter is a marvelous lesson on evolution. Read it.
Dear Carl,

Thanks for asking for my reaction to Behe’s post on our recent paper in Nature. His interpretation of our work is incorrect. He confuses “contingent” or “unlikely” with “impossible.” He ignores the key role of genetic drift in evolution. And he erroneously concludes that because the probability is low that some specific biological form will evolve, it must be impossible for ANY form to evolve.

Behe contends that our findings support his argument that adaptations requiring more than one mutation cannot evolve by Darwinian processes. The many errors in Behe’s Edge of Evolution — the book in which he makes this argument — have been discussed in numerous publications.

In his posts about our paper, Behe’s first error is to ignore the fact that adaptive combinations of mutations can and do evolve by pathways involving neutral intermediates. Behe says that if it takes more than one mutation to produce even a crude version of the new protein function, then selection cannot drive acquisition of the adaptive combination.

This does not mean, however, that the evolutionary path to the new function is blocked or that evolution runs into a “brick wall,” as Behe alleges. If the initial mutations have no negative effect on the ancestral function, they can arise and hang around in populations for substantial periods of time due to genetic drift, creating the background in which an additional mutation can then yield the new function and be subject to selection. This is precisely what we observed in our studies of the evolution of the glucocorticoid receptor (GR).

In our 2007 paper in Science, we showed that multiple mutations were indeed required for the GR to evolve its specificity for the hormone cortisol; some of the mutations that trigger the change in function are deleterious if introduced in isolation, but others are “permissive”: they have no apparent effect on the function of the protein, but once they are in place the protein can tolerate the other mutations that shift and then optimize the new function.

By experimentally characterizing the functional effect of the key historical mutations in various combinations, we showed that there were indeed pathways from the ancestral protein to the new function that passed only through permissive and beneficial intermediate states.

A path to a new function that involves neutral intermediates is entirely accessible to the evolutionary processes of mutation, drift, and selection. Our work showed that these classic neodarwinian processes are entirely adequate to explain the evolution of GR’s new function. (I should mention that pathways involving mildly deleterious intermediates are also accessible in reasonable time under some population genetic conditions; it’s just that their relative probability is lower than those involving neutral or beneficial intermediates.)

Behe’s discussion of our 2009 paper in Nature is a gross misreading because it ignores the importance of neutral pathways in protein evolution. We studied whether the key mutations that drove the “forward” evolution of GR’s new function could be reversed in a later version of the GR, restoring the ancestral conformation and function. We found that the later version of the protein could no longer tolerate the ancestral amino acids at these key sites, despite the fact that they had been present in the protein at an earlier stage of evolution.

We identified the specific “restrictive” historical mutations, which occurred after the shift in function, that either clashed with or failed to support the ancestral conformation. If these mutations are reversed first before the key function-switching mutations, the ancestral structure and function can be restored.

Reversing the restrictive mutations alone does not enhance the ancestral function, but in some orders they have no effect on the GR’s function. These restrictive mutations are simply the flip-side of permissive mutations: reversal of a restrictive mutation is a permissive mutation for reverse evolution. As Fig. 4 in our paper shows, there are several pathways back to the ancestral sequence that pass only through steps that are neutral or beneficial with respect to the protein’s functions.

Thus, all pathways to the ancestral sequence and structure are not blocked, as Behe says they are. The chance effects of genetic drift could allow the protein to “float” along such paths, producing the appropriate background in which the function-shifting mutations could be reversed. However, selection alone would not be sufficient to drive the protein deterministically through the neutral steps. If selection for the ancestral function were imposed, reversal to the same sequence and conformation as the ancestor would be unlikely, though not impossible.

Taken together, the existence of permissive and restrictive mutations indicates that neutral paths to specific adaptive combinations of mutations are opening and closing during evolution. If the clock could be turned back and history allowed to run again, it’s likely that some different path would be followed, and different protein forms would evolve by the natural processes of evolution.

This brings us to Behe’s second error, which is to confuse reversal to the ancestral sequence and structure with re-acquisition of a similar function. We showed that restrictive mutations make selection alone insufficient to drive the protein back to the same form as that found in the ancestor. But nothing in our results implies that, if selection were to favor the ancestral function again, the protein could not adapt by evolving a different, convergent, underlying basis for the function.

Indeed, directed evolution experiments in the laboratory have shown that mutation and selection alone can cause steroid receptor proteins to rapidly evolve sensitivity to new hormones; some of the mutations involved are different from those that occurred during the historical evolution of ancient proteins.

Our paper shows that re-evolution of the underlying ancestral form is unlikely, but it says nothing about the re-evolution of the ancestral function. We found that chance processes play a key role in determining which adaptive forms actually evolve under selection, but this does not mean, as Behe alleges, that no adaptive form can evolve.

Finally, Behe erroneously equates “evolving non-deterministically” with “impossible to evolve.” He supposes that if each of a set of specific evolutionary outcomes has a low probability, then none will evolve. This is like saying that, because the probability was vanishingly small that the 1996 Yankees would finish 92-70 with 871 runs scored and 787 allowed and then win the World Series in six games over Atlanta, the fact that all this occurred means it must have been willed by God.

Consider the future: there are countless possible that could emerge from our present state, making the probability of the one that actually does evolve extraordinarily low. Does this mean that the future state that will ultimately emerge is impossible? Obviously not. To say that our present biology did not evolve deterministically means simply that other states could have evolved instead; it does not imply that it did not evolve.

Consider your own life history as an analogy. We can all look back at the road we have traveled and identify chance events that had profound effects on how our lives turned out. “If the movie I wanted to see that night when I was 25 hadn’t been sold out, I never would have gone to that party at my friend’s house, where I met my future spouse….” Everyone can tell a story like this. The probability of the life we actually lead is extraordinarily small. That obviously doesn’t mean that its historical unfolding was impossible.

That we inhabit an improbably reality requires a divine explanation only if we, like Behe, take the teleological view that this is the only reality that could exist. But if we recognize that the present is one of many possibilities, then there is no difficulty reconciling the nature of evolutionary processes with the complexity of biological forms. As history unfolds, potential pathways to different futures are constantly opening and closing. Darwinian processes are entirely adequate to move living forms along these pathways to a remarkable realization – but just one realization out of many others that could have, but didn’t, take place.

I considered hard whether I should address Behe’s argument or ignore it. I am well aware that Behe and his supporters might portray my response as an indication that there is scientific debate over the possibility of adaptive protein evolution: “Look, an evolutionary biologist who actually does scientific research is arguing with me; let’s teach this controversy in public schools!” Because Behe has grossly misinterpreted the results of my research to support his position, however, I feel some responsibility to set the record straight.

Behe’s argument has no scientific merit. It is based on a misunderstanding of the fundamental processes of molecular evolution and a failure to appreciate the nature of probability itself. There is no scientific controversy about whether natural processes can drive the evolution of complex proteins. The work of my research group should not be misintepreted by those who would like to pretend that there is.

Best regards,

Harms, M.J. and Thornton, J.W. (2014) Historical contingency and its biophysical basis in glucocorticoid receptor evolution. Nature published online June 15, 2014 [doi: 10.1038/nature13410] [PubMed]


judmarc said...

This is completely wonderful - loved it the first time, happy you decided to reprint it. I particularly like the various examples Thornton uses to illustrate that Behe's notion of how probability works is completely wrong. (This is sufficiently obvious that it's one of those subjects where you ask yourself whether he understands full well it's wrong and keeps flogging it to adherents anyway; or whether he's so determined to hang on to his beliefs that he's kept himself from comprehending the simple, evident, mathematical facts.)

Mikkel Rumraket Rasmussen said...

Introduction to ID-creationist interpretations of evolutionary biology papers.

This handy little guide will help you how to become a superb ID proponent by educating you on how to interpret what you read about evolution from non-ID/creationist sources.

It will also help you understand how creationists think when they read evolution-related material.

Normal word - Cdesign proponentsist interpretation:

Rare = never ever.
Ulikely/improbable = impossible.
Likely = rare.
Theory = guess.
Guess = biased wish/materialist faith/you have no idea - therefore god!
We don't know = and you never will - therefore god!
Not fully understood = not at all understood, impossible to understand, magic/miracles required - therefore god!
Unexpected result = all naturalistic explanations ever have been falsified.
Neutral mutation = not beneficial, therefore impossiblee/doesn't exist.
natural selection = Orthodox neo-Darwinistic "party line".
It has a chance of one in 10^16 = It has a chance of one in 10^77
Maybe = biased guess.
Could have = couldn't and didn't.
Beneficial mutation = loss of function/tradeoff and/or loss of information.
New function = loss of information/information was already there.
New information = no new function.
New information and function = still belongs to the same class of enzymes (ex. hydrolases)
Improved function = no new information, ability was already there.
Mutation = destroys information, always degrades.
Gene duplication = no new information/still same information.
Gene duplication + subsequent mutation = no new information/still same information/only modified function, not new function.
Millions of years = ad hoc excuse invented to explain why we don't see 20 million year macroevolutionary change in a few months of experimental evolution.
Took billions of years = same excuse as above, just worse.
Ancestral sequence reconstruction = *crickets*
Molecular phylogeny = phyloschmylo, it's more Darwinist math-tricks.
Observation/experiment = hoax and/or only creationists properly understand the result.
Demonstration = hoax.
Statistics = Wat?
Statistically significant = NOT!
complex = impossible to evolve, must be designed.
Complexity = praise the lord
Information = immaterial soul-stuff that refutes materialism and all naturalistic expanations ever.
Quantum = immaterial soul-stuff that refutes materialism and all naturalistic expanations ever. Cannot possibly evolve.
Experiment shows how mutations can... = It's still just a bacterium/fruitfly/dog-kind.
Ape = monkey
monkey = ape
evolutionist = ape-monkey
homosexuality = bestiality and rape
evolution = materialism/naturalism/scientism/darwinism/chance/fair coin
darwinism = materialist religious faith

Diogenes said...

If you read Behe's abysmal essay on Thornton's latest work, it's so horribly short on detail that no reader can get a clear idea on what it is Thornton did, or does. Behe's writing isn't actually science writing. Even as an Op-Ed piece, it's so confusing that no reader could even determine what we're reading about. All Behe basically says is "Nyah nyah, evolution is impossible!" over and over again.

I expect Behe to be biased, but in the process of teaching his audience creationism, he doesn't even teach them any science at all, not even as an accidental side effect. His writing is worse than the old "blood clotting cascade" days.

judmarc said...

From the conclusion of Behe's essay:

The edge of evolution lies where reasonably probable, random mutation-selection runs out of steam and "dumb luck" (or -- for those willing to consider it -- purposeful design) takes over.

Leaving aside the complete and willing misrepresentation of how drift (Behe translation: "dumb luck") fits into modern evolutionary theory, he appears to be unintentionally admitting that contingency can take the place of design.

Anonymous said...

After reading Thornton's latest paper Behe concluded that Thornton's claim that the historical path taken was just one of many has now been proven wrong by Thorton's own work. Thornton showed that the permissive mutation that occurred might be the only one that can lead to cortisol sensitivity.
Its strange. After having the flaw in his thinking pointed out with several examples he goes right ahead and makes the same mistake again. He assumes that the GR was destinedto gain the function it did, so to pass through that mutational bottleneck required the help of the intelligent designer. He assumes there are no pathways to other functions that could have occurred but didn't. If he wants to continue his teleological thinking, fine. But he needs to shift his arguments and explain why that mode of thinking is justified.
Come to think of it, why would the designer, whom most IDers credit with making time, space and matter from scratch, not to mention the bacterial flagellum and Plasmodium parasite, go through this tortuous plodding route over millions of years to create this new receptor?? After all, some grad student in Thornton's lab made the same receptor in a week or 2.

Pedro A B Pereira said...

I expect Behe to be biased, but in the process of teaching his audience creationism, he doesn't even teach them any science at all, not even as an accidental side effect.

Did you really expect Behe to want to teach anything to anyone? Here's an excerpt of what his son told after coming out of the closet:

I certainly don't think it always turns out this way, but my stubbornness in maintaining and voicing my beliefs conflicted with my parents' policy of keeping the rest of my family shielded from alternate viewpoints. "Indoctrination", unfortunately, is really the word that describes it best, and I do believe that my younger brothers (the members of my family I am closest to) are truly being hurt by this. So my parents and I are in perpetual disagreement. I have, for the most part, stopped talking to my parents, and I am not allowed to speak to my little brothers at all. I don't want to complain, but this has been very painful for both them and I. Hoping to move out soon.

It's kind of funny that Behe doesn't want to "teach the controversy" to his own kids, isn't it?

Diogenes said...

Well, that's very sad-- Behe's "shunning" his son I mean. I had not seen that reddit thread before now. I know very few Catholics who are that extreme.

Gordon Davisson said...

There's an irony here, in that the fallacies Behe's falling into have actually (mostly) been solved in the latest formulation of Dembski's CSI (complex specified information) metric. The early versions of CSI had serious problems, but after Wesley Elsberry and Jeffrey Shallit's critique, Dembski revamped it significantly. The new version actually does a pretty good job (not perfect, but pretty good) of setting out what's needed to make a probabilistic case against a natural process:

- When calculating the probability of some specified result (e.g. "cortisol binding glucocorticoid receptor"), you need to calculate the total probablility of all of the ways something meeting that criterion. If there are multiple paths to multiple variant receptors, you have to sum the probabilities.

If you don't know all of the possibilities... then the best you can really do is a lower bound on the total probability. But you'd need an upper bound in order to make a case against natural processes. Oops.

- The new version also takes into account the fact that there are many possible specifications, and adjusts based on the verbosity of the specification. Basically, it multiplies the probability of that specification being met by the number of specifications of equal-or-lower verbosity.

- Finally, when calculating that probability, you must do it under the "chance hypothesis" you want to rule out. You calculated the probability of a tornado in a junkyard producing this result, and got a high CSI value from that? Congratulations, you've correctly ruled out tornadoes in junkyards as sources of new functions in glucocorticoid receptors. But if you want to rule out actual evolutionary processes producing it, you must calculate the probability of actual evolutionary processes (mutation, selection, drift, etc all acting & interacting in the same population at the same time) producing it. Oh, that's too complicated to model accurately? Then I guess you're not going to be able to rule that hypothesis out.

Also, note that this requirement interrelates with my first point as well: in order to calculate CSI correctly (under an actually relevant chance hypothesis), you need to calculate the probability of outcomes you don't know of, under a computationally intractable model. Good luck...

If the IDists actually understood & seriously used this method, it'd be immediately clear that they don't have the necessary prerequisites for building a real case. Which, of course, is why they avoid actually using it, instead preferring old versions of CSI, completely different things (that they nontheless call CSI), or (most often) just claiming to have detected CSI without having any real idea what they're talking about. Or (as in Behe's case), ignoring CSI entirely and just going ahead and making the very errors it was designed to avoid.

Pedro A B Pereira said...

Also interesting:

Your assumption about my dad's book is pretty accurate. He tends to laugh off opposing viewpoints pretty flippantly, and he also seems not to accept facts that have disproven arguments of his (such as his argument that a bacterial flagellum is 'irreducibly complex'). I think the reason many Christians love him so much is because he actually has studied science, and actually does know a fair amount about science. The problem is he tries to bend it to suit his beliefs. I saw a comic right here on /r/atheism a week or two ago which really describes him well. As I recall, the comic depicted a couple scientists examining their calculations and saying (not an exact quote), "Well, here are the facts. Let's see what conclusion we can draw from them." And in the next panel, there are a couple Christians examining their work and saying, "Well, here's the conclusion. Let's try to find some facts to support it." That about sums it up. He knows science, but he went into it trying to prove a theory that he simply grew up with that had no basis in science. As all Christians do now, he must point to the ever-smaller list of questions that science has not answered (yet) and say "There's your proof of God!"

That's a sane kid.

Unknown said...

"According to Behe, all the multiple mutations have to take place at the same time because none of the intermediates are beneficial and most of them are detrimental. "

where did Behe ever said that?

Now back to Thornton’s first point, the role of neutral mutations (which he sometimes labels “permissive” mutations). At several places in his post Thornton implies I’m unaware of the possibilities opened up by genetic drift:

“Behe’s discussion of our 2009 paper in Nature is a gross misreading because it ignores the importance of neutral pathways in protein evolution…. Behe’s first error is to ignore the fact that adaptive combinations of mutations can and do evolve by pathways involving neutral intermediates…. As Fig. 4 in our paper shows, there are several pathways back to the ancestral sequence that pass only through steps that are neutral or beneficial with respect to the protein’s functions.”

My interest in evolution by neutral mutation, however, is a matter of public record. It is an old idea that if a gene for a protein duplicates (3), then multiple mutations can accumulate in a neutral fashion in the “spare” gene copy, even if those mutations would be severely deleterious if they occurred in a single-copy gene. Four years ago David Snoke and I wrote a paper entitled “Simulating evolution by gene duplication of protein features that require multiple amino acid residues” (4) where we investigated aspects of that scenario. The bottom line is that, although by assumption of the model anything is possible, when evolution must pass through multiple neutral steps the wind goes out of Darwinian sails, and a drifting voyage can take a very, very long time indeed. But don’t just take my word for it — listen to Professor Thornton (1):

“To restore the ancestral conformation by reversing group X, the restrictive effect of the substitutions in group W must first be reversed, as must group Y. Reversal to w and y in the absence of x, however, does nothing to enhance the ancestral function; in most contexts, reversing these mutations substantially impairs both the ancestral and derived functions. Furthermore, the permissive effect of reversing four of the mutations in group W requires pairs of substitutions at interacting sites. Selection for the ancestral function would therefore not be sufficient to drive AncGR2 back to the ancestral states of w and x, because passage through deleterious and/or neutral intermediates would be required; the probability of each required substitution would be low, and the probability of all in combination would be virtually zero.” (my emphasis)

Let’s quote that last sentence again, with emphasis: “Selection for the ancestral function would therefore not be sufficient … because passage through deleterious and/or neutral intermediates would be required; the probability of each required substitution would be low, and the probability of all in combination would be virtually zero.” If Thornton himself discounts the power of genetic drift when it suits him, why shouldn’t I?

Mikkel Rumraket Rasmussen said...

Thank you for demonstrating that you are able to mindlessly copy-paste Behe. Now do us a favor and quote individual passages from Thornton, and the accompanying "refutation" from Behe, so that we can see you understand what you're reading.

John Harshman said...

At several places in his post Thornton implies I’m unaware of the possibilities opened up by genetic drift

Who is this? It would appear to be Michael Behe talking about himself in the third person.

Sean Boyle said...

Can't tell if this is actually a schizophrenic Behe or some creationist chatbot pasting together sentences into a ransom-note style argument.

Piotr Gąsiorowski said...

It's just an Unknown Idiot quoting something written by Behe five years ago and unable to mark it as a quotation, provide a comment from him/her/it-self, or even a proper link:

Unknown said...

"According to Behe, all the multiple mutations have to take place at the same time because none of the intermediates are beneficial and most of them are detrimental. "

you all missed the question. Where did Behe said that? I just quoted Behe to show that all you (professor Moran and Thornton inlcluded) say about is all wrong.