Michael Behe has published a book containing most of his previously published responses to critics. I was anxious to see how he dealt with my criticisms of The Edge of Evolution but I was disappointed to see that, for the most part, he has just copied excerpts from his 2014 blog posts (pp. 335-355).

I think it might be worthwhile to review the main issues so you can see for yourself whether Michael Behe really answered his critics as the title of his most recent book claims. You can check out the dueling blog posts at the end of this summary to see how the discussion evolved in real time more than four years ago.

Many Sandwalk readers participated in the debate back then and some of them are quoted in Behe's book although he usually just identifies them as commentators.

My Summary

Michael Behe has correctly indentified an extremely improbably evolution event; namely, the development of chloroquine resistance in the malaria parasite. This is an event that is close to the edge of evolution, meaning that more complex events of this type are beyond the edge of evolution and cannot occur naturally. However, several of us have pointed out that his explanation of how that event occurred is incorrect. This is important because he relies on his flawed interpretation of chloroquine resistance to postulate that many observed events in evolution could not possibly have occurred by natural means. Therefore, god(s) must have created them.

In his response to this criticism, he completely misses the point and fails to understand that what is being challenged is his misinterpretation of the mechanisms of evolution and his understanding of mutations.

The main point of The Edge of Evolution is that many of the beneficial features we see could only have evolved by selecting for a number of different mutations where none of the individual mutations confer a benefit by themselves. Behe claims that these mutations had to occur simultaneously or at least close together in time. He argues that this is possible in some cases but in most cases the (relatively) simultaneous occurrence of multiple mutations is beyond the edge of evolution. The only explanation for the creation of these beneficial features is god(s).

An important part of The Edge is defining the edge and this is where he discusses the development of chloroquine resistance in the malaria parasite, Plasmodium falciparum. He relies heavily on a guesstimate made by Nicholas White some years ago. Here’s how Behe describes it [An Open Letter to Kenneth Miller and PZ Myers].

... considering the number of cells per malaria patient (a trillion), times the number of ill people over the years (billions), divided by the number of independent events (fewer than ten) — the development of chloroquine-resistance in malaria is an event of probability about 1 in 10²⁰ malaria-cell replications.

None of us have a serious problem with this guesstimate but several of us have objected to the way Behe interprets it. Here's how he thinks chloroquine resistance evolves.

From the sequence and laboratory evidence it’s utterly parsimonious and consistent with all the data — especially including the extreme rarity of the origin of chloroquine resistance — to think that a first, required mutation to PfCRT is strongly deleterious while the second may partially rescue the normal, required function of the protein, plus confer low chloroquine transport activity. Those two required mutations — including an individually deleterious one which would not be expected to segregate in the population at a significant frequency — by themselves go a long way (on a log scale, of course) to accounting for the figure of 1 in 10²⁰, perhaps 1 in 10¹⁵ to 10¹⁶ of it (roughly from the square of the point mutation rate up to an order of magnitude more than it).

He is assuming that the frequency of a single mutation is approximately 10^-8 and, since two mutations are required, they have to occur together within a very short time. For the sake of simplicity I'll say that the two mutations have to occur simultaneously althought Behe will quibble that this is not a strict requirement. The probablity of these two mutations occuring simltaneously is 10^-8 × 10^-8 = 10^-16 or one in 10¹⁶. This is what he means when he says that simultaneous mutations account for most of the observed frequency of chloroquine resistance.

The rest of Behe's argument is based on this explanation of chlroquine resistance. He argues that the simultaeous occurrance of two different mutations is required to achieve a beneficial effect and this is possible in single cell organisms like Plasmodium because they have huge populations. The probablities drop significantly if more than two mutations are required and/or the populations are much smaller, as in humans. He claims that in humans and other species there are many observed examples of beneficial effects where mutlple mutations are necessary. Given the upper limit seen in chloroquine resistance, it would be impossible to evolve such beneficial effects because they are beyond the edge of evolution.

Ken Miller and PZ Myers tried to explain to Behe that his assumption of simultaneous mutations is unnecessary and probably incorrect. The observed frequency of chloroquine resistance is compatible with other explanations including explanations assuming that some of the required muations are neutral and fixed by random genetic drift. Behe didn't seem to understand why this is important because in the post quoted above he says, "What’s puzzling to me is your thinking the exact route to resistance matters much when the bottom line is that it’s an event of probability 1 in 10²⁰." But, in fact, it matters a great deal since Behe's argument depends on his explanation being correct.

He then doubles down on his explanation ....

It’s also entirely reasonable shorthand to characterize such a situation as needing "simultaneous" or "concurrent" mutations, as has been done by others in the malaria literature, even if the second mutation actually occurs separately in the recent progeny of some sickly, rare cell that had already suffered the first, harmful mutation. Guys, please don’t hide behind some dictionary or Einsteinian definition of "simultaneous." It matters not a whit to the practical bottom line. If you think it does, don’t just wave your hands, show us your calculations.

This is where I stepped in to answer Behe's challenge and try to come up with calculations based on realistic assumptions. I began with the results of Summers et al. (2014) who showed that many chloroquine resistant lines of Plasmodium had multiple different mutations (usually four) that contributed to the resistance phenotype. Several of these mutations were effectively neutral and were segregating in the popluations long before the parasites ever encountered chloroquine. Another complication includes the fact that you have to account for fixation, or at least an increase in frequency, by random genetic drift, so you can't just assume that the observed frequency (10^-20) is mostly due to mutation alone.

I also pointed out that the real mutation rate is probably closer to 10^-10 which makes the probablitly of two simultaneous mutations even more unlikely. This really confused Behe, who thought that I was making an even stronger case for his explanation when, in fact, I was challenging his explanation.

There are lots of other complications and many unknown variables. Some of these were discussed in the comments under my post(s) and others were discussed in the Summers et al. paper. I concluded that it's quite possible to explain some versions of chloroquine resistance without ever assuming that two simultaneous mutations are required and without ever assuming that one of the mutations is deleterous.

Thus, I believe I answered Michael Behe's challenge to Ken Miller and PZ Myers as he (Behe) described it. I can provide estimates but I can't give precise calculations but, then again, neither can Behe. Here's the Behe challenge.

If you folks think that [my] direct, parsimonious, rather obvious route to 1 in 10²⁰ isn’t reasonable, go ahead, calculate a different one, then tell us how much it matters, quantitatively. Posit whatever favorable or neutral mutations you want. Just make sure they’re consistent with the evidence in the literature (especially the rarity of resistance, the total number of cells available, and the demonstration by Summers et al. that a minimum of two specific mutations in PfCRT is needed for chloroquine transport). Tell us about the effects of other genes, or population structures, if you think they matter much, or let us know if you disagree for some reason with a reported literature result.

Not only did I (we) meet the challenge of providing a reasonble alternative route, we also showed why Behe's route to 10^-20 is unresonable. Naturally, Behe didn't like this and he responded on that well-known scientific website, Evolution News and Views, where comments are forbidden. These are the responses that he incorporated into his latest book.

Behe's first attempt was extremely disingenuous. He agreed that we could provide alternative routes to 10^-20 by postulating neutral, or nearly-neutral, mutations that did not have to occur simultaneously. In other words, we met the challenge but he dismisses this in his blog post [Laurence Moran’s Sandwalk Evolves Chloroquine Resistance] by saying ...

The bottom line is that numbers can be tweaked and a few different scenarios can be floated, but there’s no escaping the horrendous improbability of developing chloroquine resistance in particular, or of getting two required mutations for any biological feature in general, most especially if intermediate mutations are disadvantageous. If a (selectable) step has to be skipped, the wind goes out of Darwin’s sails.

This is disingenuous because what we showed was that Behe's simple calculation using two simultaneous mutations doesn't take into account lots of variables that he simply ignored. We also showed a reasonable pathway to chloroquine resistance based on single mutations occuring in a background of a population with lots of variation due to segregating nearly-neutral alleles.

Effects that require only two mutations will be common if the first one is effectively neutral (or nearly-neutral) and that's the real lesson of chloroquine resitance. That's not a lesson that Behe likes because he wants to argue that it's difficult to get "two required mutations for any biological feature in general."

I do not deny that the observed routes to chloroquine resistance were highly improbable (10^-20) but I account for this low probabilty by trusting the results of Summers et al. (2014) who showed that four separate mutations were required for effective chloroquine resistance and the mutations had to occur in a particular order. In addition, there are several other factors that contribute to the low overall probability; the most important is the demonstration that the particular combination of mutations are probably the only possible routes to resistance.

Michael Behe tries really hard to counter my objections but as so often happens his best laid schemes go agley (awry). He never really grasps the objections to the chloroquine frequency data: it's not that we are disagreeing with the frequency of chloroquine resistance (about 10^-20), it's that we are disagreeing with his explanation of that frequency. That's why I was surprised to see him admit defeat but then claim that it didn't matter [How Many Ways Are There to Win at Sandwalk?]

...it matters not a whit for the prospects of Darwinian theory whether the pathway consists of two required mutations that are individually lethal to a cell and must occur strictly simultaneously (that is, in the exact same replication cycle), or whether it consists of several mutations each with moderately negative selection coefficients, or consists of, say, five required mutations that are individually neutral and segregating at some appreciable frequency in the population, or some other scenario or combination thereof. The bottom line for all of them is that the acquisition of chloroquine resistance is an event of statistical probability 1 in 10²⁰. It is the outlandish improbability of the pathway — not its particular features — that is the crux. It puts strong limits on what we can expect from Darwinian processes. And that is an important point for any biologist — whether in a medical field or not — to appreciate.

I can assure you that we all agree with Michael Behe that the development of chloroquine resistance in Plasmodium falciparum is an extermely rare event that puts strong limits on what we can expect of evolution. That's not the issue: the issue is his incorrect interpretation of that observation and, subsequently, his conclusion that events requiring two or more mutations in humans are beyond the reach of evolution by nautural means.

You have to read The Edge of Evolution carefully to see how he develops his argument. For example, he says on page 112 ...

Suppose, however, that the first mutation wasn't a net plus; it was harmful. Only when both mutations occurred together was it beneficial. Then on average a person born with the mutation would leave fewer offspring than otherwise. The mutation would not increase in the population, and evolution would have to skip a step for it to take hold, because nature would need both necessary mutations at once. ... The Darwinian magic works well only when intermediate steps are each better ("more fit") than preceeding steps, so that the mutant gene increases in number in the population as natural selection favors the offspring of people who have it. Yet its usefullness quickly declines when intermediate steps are worse that earlier steps, and it is pretty much worthless if several intervening steps aren't improvements.

Behe is trying to convince his readers that evolution ("Darwinism") can only work if every single step in a pathway is beneficial. There are a few exceptions, such as chloroquine resistance, but these are such low probabilty events that they can only occur in species with huge population sizes and short generation times. He then goes on to propose the "Two-Binding-Sites" rule, which states that it is very unlikely that a new protein-protein interaction could rise by chance if two mutations are required for binding and it is beyond the edge of evolution for complexes of three or more interactions to evolve.

In short, complexes of just three or more different proteins are beyond the edge of evolution. They are lost in shape space.

And the great majority of proteins in the cell work in complexes of six or more. Far beyond that edge. (p. 135)

---

The immediate, most important implication is that complexes with more than two different binding sites—ones that require three or more different kinds of proteins—are beyond the edge of evolution, past what is biologically reasonable to expect Darwinian evolution to have accomplished in all of life in all of the billion-year history of the world. (p. 146)

... With the criterion of two protein-protein binding sites, we can quickly see why stupendously complex structures such as the ciliumm, the flagellum, and the machinery that buids then are beyond Darwinian evolution.

At the risk of beating a dead horse, allow me to state the obvious, once again. Behe's entire argument in The Edge of Evolution is founded on a false understanding of evolution because he assumes that most of evolution requires a "Darwinian" mechanism where each new mutation has to confer a beneficial effect. This allows for the sequential evolution of effects with multiple mutations. However, according to Behe, most effects require several mutations where one of the steps is deleterious and those effects are beyond the edge of evolution. Here's how he summarizes the argument ...

Although two or three missing steps [mutations] doesn't sound like much, that's one or two more Darwinian jumps than were requried to get chloroquine resistance in malaria. In Chapter 3 I dubbed that level a "CCC," a "chloroquine-complexity cluster," and I showed that its odd were 1 in 10²⁰ births. In other words (keeping in mind the roughness of the calculation):

Generating a single new cellular protein-protein binding site is of the same order of difficulty or worse than the development of chloroquine resistance in the malarial parasite. (p. 134-135)

It is ridiculous to claim that creating a new protein-protein interaction is as difficult as a CCC.

That's because lots of spurious protein-protein interactions are already present inside the cell. These can be due to single mutations that are effectively neutral, especially in small populations where the effects of negative selction are diminshed (drift-barrier hypothesis). It then takes only one more mutation to make the interaction strong enough to make a difference. This is the essential point in constructive neutral evolution. We tried to explain this to Behe using the development of chloroquine reistance because that also involves neutral mutations but he failed to understand why that pathway was relevant.

I'm disappointed that in this particular instance Behe did not answer his critics. What this means is that A Mousetrap for Darwin is Behe's fourth book and his fourth failed attempt to come up with a decent scientific argument against evolution.