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A Pretty Sharp Edge: Reflecting on Michael Behe's Vindication

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I am writing a post that shouldn't have to be written. It's about Dr. Michael Behe's book The Edge of Evolution, what it predicted, how that prediction was confirmed, and how his detractors continue to quibble and obfuscate, claiming that even if he was right he was still somehow wrong. That's not the way scientists are supposed to operate.

behe1.jpgIn science, theory that explains data and makes a prediction that is experimentally verified is considered to be confirmed. That's the way it is supposed to work. Einstein's general theory of relativity, Mendeleev's periodic table, and many other theories have been verified this way.

Now let's look at Behe's theory. Malaria is a devastating disease caused by the parasite P. falciparum. These parasites are quick to develop resistance to most drugs, but they have had a hard time overcoming chloroquine, requiring more than ten years to develop resistance. In fact, sixty years since the drug's introduction, and after more than 1020 malarial parasites total, resistance to chloroquine has developed fewer than ten times. Why?

In The Edge of Evolution, Behe proposed an answer. His explanation -- his hypothesis, if you will -- is simple. The mutation rate of P. falciparum is roughly 1 in 108 mutations per base pair per parasite. There are on average 1012 parasites in the human body -- that's enough for more than a thousand copies of every possible single mutation to exist somewhere in each infected person. So if resistance required only one mutation, it should have appeared in a few days. However, it took more than a decade for resistance to emerge. Behe argued that therefore at least two mutations must be required for the parasite to develop resistance to chloroquine. Furthermore, those two mutations must each be of no use as single mutations, and those two mutations must be present together in the same organism in order to confer resistance to the drug.

Why did Behe make these predictions? It's a simple calculation, really. If two simultaneous mutations are required for resistance, the rate of that double mutation occurring can be calculated by multiplying the single rates together. That makes the rate for two mutations roughly 1 in 1016 mutations per base pair per parasite. To find those two mutations would require many more trials than are available among the 1012 parasites in each person infected. However, 1020 parasites (the total present in a single year) represent more than enough opportunity for that double mutation to occur.

His critics focus on Behe's use of the word "simultaneous." Getting two simultaneous mutations is ridiculous, they say, and so multiplying two rates together is ridiculous. 

Maybe the two mutations happened simultaneously, meaning together in the same molecule in one generation. It is possible. Maybe the mutations happened one at a time. We don't know. Parasites carrying single mutations on the path to resistance (meaning they have no resistance yet) are sickly, though, because those single mutations have damaged an essential function. They and their offspring might survive and reproduce long enough for a second mutation to occur, but it seems unlikely. Most of the time they will simply be out-competed by their non-mutant siblings.

Another critique Behe's opponents offer is that Behe just doesn't understand evolution. There must be some cumulative adaptive path that would take the parasite to drug resistance. In support they offer Joe Thornton's work with hormone receptors, where his lab evolved a hormone receptor from its "ancestral" form by a series of selective steps. Thus there can't be an edge to evolution as sharp as just two mutations, they say. What the critics don't say is that the first step is not a selectable step. It's a gully across the road to new function that must be crossed by jumping.

The same is true about the path to chloroquine resistance. First of all, common sense says if there were a selective path with each mutation conferring increasing resistance, it would happen quickly, much more quickly than in a decade. But more importantly, a recent paper by Summers et al. has shown by experiment that two mutations, neither of them conferring any resistance by themselves, are the first steps of chloroquine resistance. (One mutation is required by all pathways; then either of two other mutations can be used to bring about resistance.) This is a more like a canyon than a gully. Two mutations must be present together in the same molecule to confer resistance to chloroquine. Call it "occurring simultaneously" or not. The effect is the same, and Behe is right and his critics are wrong. 

Ironically, recent work has shown the same thing with regard to hormone receptors. Carroll et al. (2011) reported that at the base of the pathway to evolve the ancient hormone receptor there are two mutations (a gene duplication plus point mutation) that must occur before any further evolution is possible. Harms and Thornton then showed that these mutations are the only way forward. There is no other road to take, no way around the canyon. It sounds remarkably like the malarial resistance pathway, doesn't it?

So how sharp is the edge of evolution? For the malarial parasite P. falciparum, the edge of evolution for chloroquine resistance is two mutations: one specific mutation and either one of two other mutations. These mutations have to occur together, and they have to be there before any other mutations can have any effect. If the parasite doesn't have these two mutations, it remains chloroquine-sensitive. But as we have seen, getting two mutations can take a long time. It happens relatively quickly for malaria because of its huge population size. For us and other animals it may take an extremely long time.

That sounds like a pretty sharp edge of evolution to me.

Behe predicted this requirement for two mutations seven years ago. All continuing criticism now sounds like sniping and quibbling over terminology. Maybe those quibbling and sniping can't see they are wrong. Maybe they don't understand how science works and what counts as evidence. Or, and this is more likely, they will never admit that Behe is right and they are wrong.

Photos: Christ Stickley/Flickr and Lehigh University.