A new paper in Proceedings of the National Academy of Sciences USA has vindicated Michael Behe in one of the central controversies over his 2007 book The Edge of Evolution. Behe already reported here on the paper, which found that multiple mutations, at least two, are required to confer resistance to the drug chloroquine on malaria parasites:

A minimum of two mutations sufficed for (low) CQ transport activity, and as few as four conferred full activity. … The findings presented here reveal that the minimum requirement for (low) CQ transport activity in both the ET and TD lineages of CQR PfCRT is two mutations.

(Summers et al., “Diverse mutational pathways converge on saturable chloroquine transport via the malaria parasite’s chloroquine resistance transporter,” Proceedings of the National Academy of Sciences USA, Vol. 111: E1759-E1767 (April 29, 2014) (emphasis added).)

Why does it matter? As Dr. Behe explained, this was a major point of contention among critics of his book. They claimed that Behe mistakenly thought chloroquine resistance required multiple simultaneous mutations, when in actuality it could arise through sequential mutations, each conferring a successively greater resistance-advantage. It can no longer be denied that the critics were dead wrong: chloroquine resistance does not arise at all until two mutations or more are present.

(To be precise, the paper found that the two minimum mutations break down as follows: one specific mutation is needed, plus a second mutation that’s also needed which can occur in one of two locations. As the paper puts it, “Given that all known PfCRT haplotypes contain either N75E/D or N326D, these results indicate that PfCRT acquires the ability to transport CQ via one of two main mutational routes, both of which entail the introduction of K76T plus the replacement of an asparagine (N75 or N326) with an acidic residue.”)

From the Beginning, the Critics Mischaracterized Behe
The critics were wrong from the outset. Behe’s argument in The Edge of Evolution didn’t depend on whether chloroquine resistance arose in a stepwise manner, or only after multiple mutations accumulated. His argument was based upon an empirically observed data point from public health studies which found that chloroquine resistance arose in about 1 in every 10²⁰ organisms. He had a strong citation for this empirical observation: Nicholas White, “Antimalarial Drug Resistance,” Journal of Clinical Investigation, Vol. 113: 1084-1092 (2004). He called the mutations (whatever they were) that caused chloroquine resistance a “chloroquine complexity cluster” or CCC. Whatever molecular mechanisms may be behind a CCC, empirical data showed that 10²⁰ cells are required in order to produce one. Behe pointed out that if a trait required the molecular equivalent of two CCC’s before providing any advantage, then that would pose major problems for Darwinian evolution.

It’s a simple calculation. Behe observed that if 10²⁰ organisms were required to obtain one CCC, then the square of that amount — 10⁴⁰ organisms — would be required to evolve a trait that required two CCC’s before providing any advantage. However, as Behe observed, a total of only 10⁴⁰ organisms have lived on Earth over the entire history of the planet. As Behe put it:

Recall that the odds against getting two necessary, independent mutations are the multiplied odds for getting each mutation individually. What if a problem arose that required a cluster of mutations that was twice as complicated as a CCC? (Let’s call it a double CCC.) For example, what if instead of the several amino acid changes needed for chloroquine resistance in malaria, twice that number were needed? In that case the odds would be that for a CCC times itself. Instead of 10²⁰ cells to solve the evolutionary problem, we would need 10⁴⁰ cells. Workers at the University of Georgia have estimated that about a billion billion trillion (10³⁰) bacterial cells are formed on the earth each and every year. … If that number has been the same over the entire several-billion-year history of the world, then throughout the course of history there would have been slightly fewer than 10⁴⁰ cells, a bit less than we’d expect to need to get a double CCC. The conclusion, then, is that the odds are slightly against even one double CCC showing up by Darwinian processes in the entire course of life on earth.

(Michael Behe, The Edge of Evolution: The Search for the Limits of Darwinism, p. 135 (Free Press, 2007).)

Behe inferred, based upon the great rarity of a CCC evolving, that it was a trait that probably required multiple mutations. Behe’s argument didn’t turn on that inference, but it was a reasonable one. Richard Dawkins himself used exactly the same sort of reasoning in other contexts to infer that a trait required multiple mutations to evolve.

Will Ken Miller, Jerry Coyne, Paul Gross, Nick Matzke, Sean Carroll, Richard Dawkins, and PZ Myers Now Apologize to Michael Behe?
Behe’s critics misread him as saying that a single CCC necessarily required multiple simultaneous mutations, and castigated Behe for allegedly ignoring the possibility of a single CCC arising via sequential mutations. For example:

• Kenneth Miller: “It would be difficult to imagine a more breathtaking abuse of statistical genetics. Behe obtains his probabilities by considering each mutation as an independent event, ruling out any role for cumulative selection, and requiring evolution to achieve an exact, predetermined result.” (Nature, 2007)
• Paul Gross: “Behe assumes simultaneous mutations at two sites in the relevant gene, but there is no such necessity and plenty of evidence that cumulativeness, rather than simultaneity, is the rule. As Nature‘s reviewer (Kenneth R. Miller) notes, ‘It would be difficult to imagine a more breathtaking abuse of statistical genetics.'” (The New Criterion, 2007)
• Jerry Coyne: “What has Behe now found to resurrect his campaign for ID? It’s rather pathetic, really. … Behe requires all of the three or four mutations needed to create such an interaction to arise simultaneously. … If it looks impossible, this is only because of Behe’s bizarre and unrealistic assumption that for a protein-protein interaction to evolve, all mutations must occur simultaneously, because the step-by-step path is not adaptive.” (The New Republic, 2007)
• Nick Matzke: “Here is the flabbergasting line of argument. First, Behe admits that CQR evolves naturally, but contends that it requires a highly improbable simultaneous double mutation, occurring in only 1 in 10²⁰ parasites. … The argument collapses at every step.” (Trends In Ecology and Evolution, 2007)
• Sean Carroll: “Behe makes a new set of explicit claims about the limits of Darwinian evolution, claims that are so poorly conceived and readily dispatched that he has unwittingly done his critics a great favor in stating them. … Behe’s main argument rests on the assertion that two or more simultaneous mutations are required for increases in biochemical complexity and that such changes are, except in rare circumstances, beyond the limit of evolution. .. Examples of cumulative selection changing multiple sites in evolving proteins include … pyrimethamine resistance in malarial parasites — a notable omission given Behe’s extensive discussion of malarial drug resistance. … [T]he argument for design has no scientific leg to stand on.” (Science, 2007)
• Richard Dawkins: “Trapped along a false path of his own rather unintelligent design, Behe has left himself no escape. Poster boy of creationists everywhere, he has cut himself adrift from the world of real science. … If correct, Behe’s calculations would at a stroke confound generations of mathematical geneticists, who have repeatedly shown that evolutionary rates are not limited by mutation.” (New York Times, 2007)
• And then of course there’s PZ Myers. He made much the same criticisms, and also wrote:
  

  Behe isn’t just a crackpot who thinks he has a novel explanation for an evolutionary mechanism — he’s a radical anti-evolutionist extremist who rejects the entire notion of the transformation of species by natural processes. … Most of the arguments are gussied up versions of the kind of handwaving, ignorant rationalizations you’d get from some pomaded fundagelical Baptist minister who got all his biology from the Bible, not at all what you’d expect from a tenured professor of biochemistry at a good university — throwing in an occasional technical gloss or mangled anecdote from the literature is only a gloss to fool the rubes.

While these comments were made a few years ago, many ENV readers who follow this debate might remember just how gleefully harsh the critics were towards Behe after his book The Edge of Evolution came out. Even if Behe had been wrong, the critics’ extreme incivility would have been unscholarly and inappropriate. But now it turns out all these critics were wrong. You get no resistance to chloroquine whatsoever unless at least two mutations are present to begin with. You might be able to get some cumulative selection after that, where successive mutations improve resistance up to a certain point. It is, however, by definition a multimutation feature.

Behe reasonably inferred that chloroquine resistance requires multiple mutations. He was right. His critics misunderstood his argument and thought this inference was a crucial plank in his reasoning. It wasn’t.

But it now turns out that the position Behe’s critics attributed to him, and then railed against, was itself correct. Even a single CCC apparently requires multiple mutations before conferring any advantage. In fact, it’s probably very close to the “edge” of evolution that Behe identified in his book.

Is an apology from Behe’s critics then forthcoming? In a world where debates were conducted with the goal of discovering truth rather than scoring points, it sure ought to be. Unfortunately, I’m not sure we live in that world.

What we’ll probably get is nothing more than PZ Myers’s concession, offered in the context of the rant quoted above:

Fair enough; if you demand a very specific pair of amino acid changes in specific places in a specific protein, I agree, the odds are going to be very long on theoretical considerations alone, and the empirical evidence supports the claim of improbability for that specific combination.

Well, that’s more or less what’s required to generate chloroquine resistance. We’ll gladly take this — i.e., simply being proven right — in lieu of an apology.