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#4 of Our Top Ten Evolution Stories of 2014: A Key Inference of The Edge of Evolution Has Now Been Experimentally Confirmed

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Published originally on July 14, 2014.

A recent paper in PNAS confirms a key inference I made in 2007 in The Edge of Evolution. Summers et al. conclude that "the minimum requirement for (low) [chloroquine] transport activity ... is two mutations." This is the first of three posts on the topic.

behe edge.jpgLet me start with some background. Darwinian theory proposes that the astoundingly intricate machinery of the cell developed step by excruciatingly tiny step, by natural selection acting on random mutation. I argued against that in 1996 in Darwin's Black Box, contending that much cellular machinery was, like a mousetrap, irreducibly complex, could not be made gradually, and required purposeful design. Some Darwinists parried with breezy scenarios, imagining intricate systems forming at the drop of the proverbial hat. Vague as the stories might be, though, they often had a surface plausibility that provided an excuse for the reluctant to not look too deeply. For the case against Darwinism to advance, I thought, it had to move beyond descriptive arguments (which too often are deflected with specious yarns) to quantitative ones (which call for numerical replies that can be tested). So, as far as possible, hard numbers had to be attached to the probabilities of the events Darwinists blithely ask of unaided nature. That was the goal of The Edge of Evolution.

A major point of the book was that if evolution has to skip even one baby step to attain a beneficial state (that is, if even one intermediate in a long and relentlessly detailed evolutionary pathway is detrimental or unhelpful), then the probability of reaching that state decreases exponentially. After discussing a medically important example (see below), I argued that the evolution of many protein interactions would fall into the skip-step category, that multi-protein complexes in the cell were beyond the reach of Darwinian evolution, and that design extended very deeply into life.

However, at the time the book's chief, concrete example -- the need for multiple, specific changes in a particular malarial protein (called PfCRT) for the development of resistance to chloroquine -- was an inference, not yet an experimentally confirmed fact. It was really an excellent, obvious inference, because resistance to chloroquine arises much, much less frequently than to other drugs. For example, resistance to the antimalarial drug atovaquone develops spontaneously in every third patient, but to chloroquine only in approximately every billionth one. About PfCRT I wrote, "Since two particular amino acid changes [out of four to eight total changes] occur in almost all of these cases [of chloroquine resistance in the wild], they may both be required for the primary activity by which the protein confers resistance." The result would be that "the likelihood of a particular [malarial] cell having the several necessary changes would be much, much less than the case [for atovaquone] where it needed to change only one amino acid. That factor seems to be the secret of why chloroquine was an effective drug for decades." Still, the deduction hadn't yet been nailed down in the lab.

Now it has, thanks to Summers et al. 2014. It took them years to get their results because they had to painstakingly develop a suitable test system where the malarial protein could be both effectively deployed and closely monitored for its relevant activity -- the ability to pump chloroquine across a cell membrane, which rids the parasite of the drug. Using clever experimental techniques they artificially mutated the protein in all the ways that nature has, plus in ways that produced previously unseen intermediates. One of their conclusions is that a minimum of two specific mutations are indeed required for the protein to be able to transport chloroquine.

(Interestingly, one of the two mutations I discussed in The Edge of Evolution as possibly required, at position 76 of the protein chain, is in fact one of the two that Summers et al. proved to be needed. But the other one I discussed, at position 220, isn't. Although that change can help, Summers et al. found that the second required mutation is at either position 75 or position 326. They also showed that, although proteins with just the two required mutations could pump chloroquine past a cell membrane in their test system, the rate was significantly less than for some proteins with additional mutations. What's more, the two required ones weren't necessarily enough to allow malarial parasites to survive better in the presence of chloroquine in the lab. What that means for malaria in the wild is still unclear.)

The need for multiple mutations neatly accounts for why the development of spontaneous resistance to chloroquine is an event of extremely low probability -- approximately one in a hundred billion billion (1 in 1020) malarial cell replications -- as the distinguished Oxford University malariologist Nicholas White deduced years ago. The bottom line is that the need for an organism to acquire multiple mutations in some situations before a relevant selectable function appears is now an established experimental fact.