Michael Behe's final thoughts on the edge of evolution

We've been having an interesting discussion about chloroquine resistance and the Edge of Evolution. It began last month when Michael Behe started bragging that his "prediction" had been confirmed by a recent paper [A Key Inference of The Edge of Evolution Has Now Been Experimentally Confirmed]. It didn't take long for Casey Luskin to jump on the bandwagon [So, Michael Behe Was Right After All; What Will the Critics Say Now?]. Luskin demanded an apology from Behe;s critics.

It turns out that Behe and Luskin are wrong and the recent results published by Summers et al. (2014) actually refute most of Micheal Behe's calculations. PZ Myers pointed out that Behe's critics were mostly¹ right when they criticized the original calculations in The Edge of Evolution [Quote-mined by Casey Luskin!].

Behe responded by issuing a challenge [An Open Letter to Kenneth Miller and PZ Myers] where he said ...

Talk is cheap. Let's see your numbers.

In your recent post on and earlier reviews of my book The Edge of Evolution you toss out a lot of words, but no calculations. You downplay FRS Nicholas White's straightforward estimate that -- 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. Okay, if you don't like that, what's your estimate? Let's see your numbers.

I responded to the challenge [Taking the Behe challenge!]. I pointed out that these calculations are very difficult because there are many variables and many unknowns. I tried my best but, as it turns out, Behe wasn't satisfied. Now he's given us his final word on this topic [Drawing My Discussion with Laurence Moran to a Close].

Why is this important? Well, in a certain sense, it's not important because the main point in Behe's book is that some evolutionary scenarios are so improbable that they will not occur in lineages leading to large multicellular animals (like humans). That's because the population sizes are far too low—unlike the situation with malarlia parasites that have huge populations, fairly short generation times, and higher mutation rates. Nobody questions this point. It's true that the probability of many complex, specific, evolutionary pathways is so low that they are never going to happen in some species.

On the other hand, it's important because Behe describes something he calls a "chloroquine-complexity cluster" (CCC) that represents the probability of a cluster of mutations arising that confers chloroquine resistance. It's equal to 10^-20—a number based on a guesstimate by Nicholas White (White, 2004). His earlier estimate was 10^-19 where he says that "the estimates for chloroquine and artemisinin are speculative" (White and Pongtavornpinyo. 2003). Only ten chloroquine resistant strains have been detected.

There are many factors that affect the development of chloroquine resistant strains and only one of them is the frequency of mutation to resistance. White (2004) gives us a table that is quite revealing ....

A lot of different things have to happen before a chloroquine resistant strain becomes established. The combined probabilities, according to Nicholas White is 10^-20. Behe uses this number as his estimate of the rate that the resistant genotype occurs (item #1 in the Table). This error has been pointed out to Michael Behe several times and here's how he responds in his latest post.

It takes chutzpah to deride a value calculated by one of the world's foremost malariologists -- a Fellow of the Royal Society, who lives and works in the middle of malarious regions of the world, who reasons deeply and quantitatively about the development of drug resistance -- as a "guesstimate." White's calculation was based on intimate knowledge of many details of the biology and epidemiology of the parasite.

Malaria is a horrendous scourge, and so is followed closely by international health organizations. In this age of easy and rapid sequencing, one would expect independent strains of malaria to be detected quickly by the many researchers in the area. If Professor Moran has any actual evidence that a large number of de novo origins of malaria have gone undetected, we would all love to see it. Otherwise it's reasonable to assume that the number so far identified is close to the number that have in fact arisen.

Keep in mind that Behe's calculations are critically dependent on the idea that the probability of the mutation occurring is 10^-20. That's where he gets his CCC and that's the number he uses to discuss the probability of similar mutations during the evolution of complex species.

If it turns out that White's guesstimate incorporates a number of other factors then Behe's calculations are incorrect. Let's see what this famous malariologist says about whether parasites carrying the resistence genotype will automatically be detected as Behe says. I quote from page 1089 of White's 2004 paper.

Even if the resistance-bearing parasites do establish themselves in the anopheline mosquito, they must still be transmitted to a susceptible recipient for resistance to spread. In areas where the majority of the population is immune, the individual probability of propagation is reduced, as inoculation in a subsequent mosquito-feeding event often does not result in an infection capable of being transmitted (i.e., an infection generating sufficient gametocytes for onward transmission).

In high-transmission areas, where malaria-associated illness and death are largely confined to young children, the chance of a drug encountering large numbers of parasites in a semi-immune host is confined to the first few years of life. The net result is considerable reduction in the probability of de novo selection and subsequent transmission of a resistant parasite mutant in high-transmission compared with low-transmission areas. Historically, chloroquine resistance emerged in low-transmission areas, and antifol resistance has increased more rapidly in low-transmission than in high-transmission areas.

So, the expert that Michael Behe quotes says unequivocally that in high transmission areas a great many of the newly mutated organisms will not become established as a drug resistant strain. So it's reasonable to assume that the number detected is NOT close to the "number that have in fact arisen" as Behe claims. Somebody has chutzpah but I don't think it's me.

In my response to the Behe challenge, I tried to show some different calculations that gave different values for the mutation rate to chloroquine resistance. My guesstimates assume that at least two independent mutations are required and I arrive at double mutation rates that are much closer to 10^-20 even if both mutations are neutral on their own. What this means is that chloroquine resistant individuals should be even rarer than Behe or White estimate.

I don't know how to explain this. It's a very complicated scenario and many of the estimates could be off by an order of magnitude.

One of the points of contention is whether the pathway to chloroquine resistance must involve a single mutation that is deleterious. If so, this would lower the probability of a resistant strain arising in the first place because the parasite with the first single mutation will likely die before the second mutation occurs.

This is where the data in the Summers et al. (2014) paper becomes relevant. They have a nice figure showing how the chloroquine resistant stains arose from a series of strains that acquired different mutations. The seven resistant strains are underlined (e.g. GB4). If you look at the group of strains on the left, you will see that there are two possible mutational routes to strain D32, which is not significantly resistant to chloroquine in the field even though it carries two essential mutations in the PfCRT gene.

In one pathway, the mutation N75E occurs first giving rise to strain D39 and then the K76T mutation occurs in that strain creating D32. The order of the mutations is reversed in the other pathway. In either case, the first mutation has no effect on the chloroquine uptake while the addition of the second mutation produces a significant effect.

It is important for Behe's argument that the "first" mutation is deleterious and he claims that the K76T mutations is, in fact, deleterious on its own. He says ....

Close your eyes and envision a pathway to a malaria parasite that has four mutations. The first mutation is deleterious, the second rescues the first and makes the parasite marginally chloroquine resistant. Subsequent steps are all beneficial by dint of either improving chloroquine resistance or of stabilizing the structure of the mutated PfCRT, which is required for malaria survival. Once a parasite can survive at least marginally in the presence of chloroquine, further mutations can be added one at a time (no longer two at a time) in each cycle of infection because the population size (10¹²) greatly exceeds the inverse of the mutation rate.

In the argot of chemical kinetics, getting beyond the deleterious mutation is the "rate-limiting step." After that hurdle is passed further mutations can be added singly -- the way Darwinists like -- and comparatively rapidly. Since they would be added rapidly, they would be difficult to detect in the wild. Hence the pattern described by Summers et al. fits the scenario I described perfectly.

Assuming that Behe is correct about the K76T strain (this is not certain), then the pathway N75E → K76T → strain D32 does not have an intermediate that is "rate-limiting" because the K76T mutation is never present on its own. It seems to me that ALL the pathways have to have a deleterious intermediate in order for Behe's scenario to make sense. In other words, both N75E and K76T have to be deleterious.

This neutral pathway to resistance has been observed. There's a strain in the wild called 106/1 that contains several different allelic variants in the PfCRT gene but it's sensitive to chloroquine. That strain becomes full-blown resistant to chloroquine in a single step when it acquires the K76T mutation (Cooper et al. 2007). Contrast this with Behe's explanation that requires two mutations to occur together in a single infected individual before you can get a resistant parasite.

Isn't that strange? Am I missing something?

As I said above, this quibbling about chloroquine resistance isn't very important to Behe's main complaint about evolution. We can all agree that some pathways are improbable and if he wants to use 10^-20 as a point of departure then that's fine by me. Let's just make sure he describes it accurately and let's make sure he isn't claiming to have made an important prediction that was subsequently verified.²

But that's exactly what happened. Behe and his supporters (I called them sycophants, but Behe says that's childish) made it into a big deal by claiming that recent published results confirmed Behe's predictions. The implication here is that if Behe was so right about the science of chloroquine resistance then it's likely that he's right about the improbability of evolution.

As it turns out, he's wrong on both counts.

Let's look at how Behe describes his main thesis in his latest post. Keep in mind that this is his final position after seven years of debate and discussion since his book was published.

I wrote in my last post that I had cited chloroquine resistance in Edge as a likely example of the two-mutation phenomenon, and that Summers et al. recently "confirmed" that it did need two mutations to pump chloroquine. Moran responds, "This is a little bit misleading and possibly a little bit disingenuous. Everyone understood that chloroquine resistance was rare and that it almost certainly required multiple mutations."

I'm afraid it is he who is playing the ingénue. There's a big difference between simply requiring serial additive mutations for some maximal effect and requiring multiple mutations before you get an effect at all. The first is a run-of-the-mill, gradualist Darwinian scenario: one mutation comes along, helps a bit, spreads in the population by selection, which increases the base from which the second mutation may arise; the second appears, helps a bit more, spreads, and so forth. Lather, rinse, repeat.

But if the first required mutation (or second, or third) doesn't help, or positively hurts, then the gradualist scenario is interrupted. The first mutation does not spread in the population (in fact it's actively kept in check by negative selection), so the number of organisms with the mutation does not increase and can't provide a larger base within which the second mutation can arise. The Darwinian magic is turned off.

How Much Does that Hurt?

Enormously. For most species, missing even one such baby step increases the required population size/waiting time by a factor of millions to billions. If even one step in a long and relentlessly detailed evolutionary pathway is deleterious, then a Darwinian process is woefully impaired. If several steps in a row are deleterious, you can kiss the Darwinian explanation goodbye.

I'm afraid Michael Behe is confusing me with some of his other critics. I never suggested that chloroquine resistance could arise by stepwise addition of two mutations where each one added a little bit of resistance and was, therefore, favored by natural selection.

I am not a Darwinist and I don't usually rely on adaptationist explanations for complex phenomena with low probabilities. I'm not a big fan of natural selection. In fact, I think I've mentioned other mechanisms on this blog. I think I've even talked about things like Neutral Theory and population genetics and tried to get IDiots to understand how neutral alleles and deleterious alleles can contribute to evolution.

It's sad that Intelligent Design Creationists keep referring to Darwinism and "Darwinian magic" because it confuses their readers. If Behe is simply objecting to a strict Darwinian process as an explanation of chloroquine resistance then I completely agree with him. It seems pretty clear to me that the pathway to a chloroquine resistant strain involved neutral alleles and possibly even slightly deleterious ones.

That's easily explained by modern evolutionary theory but not by the kind of Darwinism that Behe describes. Is that what this is all about? Is Behe's entire point just an argument in favor of random genetic drift and evolution by accident?

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1. The debate gets a little complicated because some of Behe's critics really did misinterpret Behe's calculation and proposed a silly scenario for chloroquine resistance that doesn't agree with the data. There were, in fact, several reviews of Michael Behe's book that completely missed the mark. That's embarrassing.

2. I have a small stack of papers from prominent journals that propose multiple mutations behind chloroquine resistance. They were published BEFORE Behe's book appeared in 2006.

Cooper, R.A., Lane, K.D., Deng, B., Mu, J., Patel, J.J., Wellems, T.E., Su, X. and Ferdig, M.T. (2007) Mutations in transmembrane domains 1, 4 and 9 of the Plasmodium falciparum chloroquine resistance transporter alter susceptibility to chloroquine, quinine and quinidine. Molecular microbiology 63:270-282. [doi: 10.1111/j.1365-2958.2006.05511.x]

Summers, R. L., Dave, A., Dolstra, T. J., Bellanca, S., Marchetti, R. V., Nash, M. N., Richards, S. N., Goh, V., Schenk, R. L., Stein, W. D., Kirk, K., Sanchez, C. P., Lanzer, M. and Martin, R. (2014) Diverse mutational pathways converge on saturable chloroquine transport via the malaria parasite’s chloroquine resistance transporter. Proceedings of the National Academy of Sciences. published online April 11, 2014. [doi: 10.1073/pnas.1322965111]

White, N.J. (2004) Antimalarial drug resistance. The Journal of clinical investigation 113:1084-1092. [doi:10.1172/JCI21682]

White, N. J. and Pongtavornpinyo, W. (2003) The de novo selection of drug-resistant malaria parasites. Proceedings of the Royal Society of London. Series B. Biological Sciences 270, 545-554.[doi: 10.1098/rspb.2002.2241]