## An Open Letter to Kenneth Miller and PZ Myers

Dear Professors Miller and Myers,

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 10^{20} malaria-cell replications. Okay, if you don't like that, what's *your *estimate? Let's see *your *numbers.

The malaria literature shows strong population genetics evidence for fewer than ten independent origins of resistance. The riddle is, why so few? Show us all *your *calculation for that. Here's a number to keep in mind -- 10^{12}. That's roughly the number of malarial cells in one sick person. Here's another -- 10^{-8}. That's a generous rounding-up of the mutation rate for malaria. (Multicellular eukaryotes are an order of magnitude less.) That means on average *ten thousand copies of each and every point mutation *of the malarial genome will be present in *every person *being treated with chloroquine.

Here's another -- 3. That's the number of patients it takes for spontaneous resistance to atovaquone to appear. That makes a lot of sense since resistance to atovaquone needs only one point mutation. If atovaquone were used as widely as chloroquine, we'd expect about a billion or more origins of resistance to it by now, not a measly handful. So how do you quantitatively account for that difference -- give or take an order of magnitude?

Your chief complaint against my ideas seems to be this:

That the malaria parasite needs two mutations was never a point of contention, nor was it particularly worrisome. What was wrong with Behe's work is that he na�vely claimed that the two mutations had to occur

simultaneouslyin the same individual organism, so that the probability that could happen was the product of multiplying the two individual probabilities. That's ridiculous.

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 10^{20}. 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 10^{20}, perhaps 1 in 10^{15} to 10^{16} of it (roughly from the square of the point mutation rate up to an order of magnitude more than it). So how do your calculations account for it?

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.

From the recent work of Summers *et al*. 2014 it's possible that a third mutation in PfCRT may also be needed (perhaps already segregating in the population as a nearly neutral or marginally deleterious mutation) to allow the parasite to survive at therapeutic levels of chloroquine. That may contribute another factor of 1 in 10^{3} to 10^{4} or so to the probability, to reach an aggregate factor of approximately 1 in 10^{20}. After that minimally functioning foundation is established, further mutations could rapidly be added individually and cumulatively -- the way Darwinists like -- to help balance the complex demands on PfCRT for its native activity plus chloroquine transporting, as Summers *et al*. discuss.

If you folks think that direct, parsimonious, rather obvious route to 1 in 10^{20} 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.

Or, Ken, tell us how that ARMD phenotype you like to mention affects the math. Just make sure it all works out to around 1 in 10^{20}, or let us know why not.

Everyone is looking forward to seeing your calculations. Please keep the rhetoric to a minimum.

With all best wishes (especially to Professor Myers for a speedy recovery),

Mike Behe

*Image credit: Gabri�l Metsu, "Man Writing a Letter"/Wikicommons.*