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Real-World Data and the Lesson of Chloroquine Resistance

Photo: Plasmodium falciparum, by Dr Graham Beards, CC BY-SA 4.0 , via Wikimedia Commons.

Editor’s note: In 2020, Michael Behe published A Mousetrap for Darwin, a collection of his essays and responses to critics. Professor of biochemistry Laurence Moran argued that Behe had misinterpreted evidence and had misunderstood the significance of chloroquine resistance. This is the second in a two-part response. Find the first part here, “How Much Can Evolution Really Accomplish?

Following the publication of his 2020 book, A Mousetrap for Darwin, I had the privilege of interviewing Michal Behe in a series of podcasts. What came across clearly in our discussions is that Behe is interested in data. Whether we are talking about gene duplication, neutral evolution, or the specific route to chloroquine resistance, we need to take the data seriously. It is easy to make up stories about how this or that mutation might result in this or that outcome. Just-so stories are a dime a dozen and have long been a staple of evolutionary rhetoric. Whether a tall tale about the giraffe’s impressive neck or a microscopic tale about mutations of the miniscule nucleotides composing the stringy stretches of Plasmodium falciparum’s DNA, the stories are of little relevance unless constrained by the data.

In short, there is little question that we can imagine several different routes to chloroquine resistance, but these efforts need to be subject to the data. So let’s step back for a minute and examine the logical possibilities in light of the data.

One logical possibility — the simplest case — would be that chloroquine resistance is a piece of cake and that a single point mutation, such as in the cast of atovaquone, will do the trick. However, such a simple scenario doesn’t fit with the immunological data and after 2014 has been effectively refuted by Robert L. Summers et al., writing in PNAS, so we can strike it off the list.

Another logical possibility would be that chloroquine resistance requires two mutations. Not just any two mutations; the immunological data soundly refutes that. However, two specific coordinated mutations might potentially do the trick, fitting relatively well with the data. The data can be reasonably squared with two coordinated mutations under either Behe’s estimated Plasmodium mutation rate of 10^-8, perhaps along with a third mutation in PfCRT, or under Laurence Moran’s estimated mutation rate of 10^-10 alone. In either case, this possibility of two coordinated mutations is roughly in line with White’s estimate of chloroquine resistance in the field.

Readers will remember that, in rough outline, this was essentially Behe’s proposal back in 2007 when he wrote The Edge of Evolution: the simplest and most parsimonious explanation for the rarity of chloroquine resistance was that it required at least two coordinated mutations. Based on the subsequent research from Summers et al., Behe’s prediction turned out to be correct and the need for at least two coordinated mutations has now been settled.

Roads Leading to Rome?

A third logical possibility would be that even more mutations are required — three, four, perhaps even five. Such a scenario might plausibly fit with the data if there are multiple potential pathways to chloroquine resistance. Summers et al. had shown that at least two coordinated mutations were required to initiate chloroquine resistance. Once the initial benefit had been conferred by these coordinated mutations, then additional mutations were able to improve the resistance through a few different pathways. It is these pathways that interest Moran and where he thinks Behe has gone astray.

At his blog, Sandwalk, Moran argues based on his reading of Summer et al. that “four separate mutations were required for effective chloroquine resistance and the mutations had to occur in a particular order.” He then insists on drawing his line even deeper in the sand, stating that “the particular combination of mutations are probably the only possible routes to resistance.”

This is a rather odd argument to level against Behe. Certainly Behe agrees that multiple mutations are required and that getting resistance isn’t a trivial affair, with numerous available pathways, as some critics had argued.

Just to clarify Moran’s statement for readers, he isn’t arguing that all four mutations are required in order to gain any beneficial outcome. Were that the case, then the hurdle for chloroquine resistance would skyrocket to something on the order of 10^40, flatly contradicting the data and representing a hurdle that even the aggressive and quickly-reproducing Plasmodium could not overcome.

On the other end of the spectrum, Moran is not arguing that each individual mutation confers a meaningful selective benefit to Plasmodium, as that would contradict Summers et al. and would be largely irrelevant to the question at hand. To my knowledge, Behe has never argued that a Darwinian process cannot build up a complex feature if every single step on the path represents a meaningful advantage to the organism. That isn’t the question. The entire question on the table is whether evolution has a reasonable ability to construct systems where the intermediate steps are not, each individually, advantageous.

In spite of Moran’s reference to four mutations for “effective” chloroquine resistance, Moran again reminds his readers that he is not disagreeing about the rarity of chloroquine resistance, but that he disagrees with Behe’s explanation of how it came about. Watching Moran agree with Behe’s main point, but quibble about a side issue, one might be forgiven for wondering if we’re again witnessing someone argue against Behe just on the principle of disagreeing with a critic of evolutionary theory.

Casey Luskin notes that:

…Behe’s greater argument in The Edge of Evolution… did not turn upon whether a CCC [chloroquine complexity cluster] required one mutation, two mutations, or fifty mutations in fifty different genes. He said that a CCC “presumably” required two simultaneous mutations, but it wasn’t a crucial plank in his argument.

Behe’s argument was simply to observe, on the basis of White’s public health data, that chloroquine resistance arises in 1 in 10^20 cells. That’s a data point. He then asked a hypothetical question: If one CCC requires 10^20 replications, what would happen if there were a trait that was as complex as a “double-CCC”? Such a trait, Behe argued, would require 10^40 cells to arise, which is more cells than have lived over the course of the history of the Earth. This, he concluded, would pose a problem for Darwinism…

Although acknowledging Behe’s main point about the “edge of evolution,” Moran downplays Behe’s (correct) prediction that a multi-mutational event was required to confer chloroquine resistance and instead insists that “effective” resistance requires four mutations. Moran seems to be missing the forest for the trees.

Mice Still Trapped

Moran appears to believe that Behe has underestimated the power of evolution. Enamored with the idea of neutral evolution, Moran writes that “effects that require only two mutations will be common if the first one is effectively neutral (or nearly-neutral) and that’s the real lesson of chloroquine resitance [sic].”

Unfortunately, despite Moran’s enthusiasm, this most certainly is not the real lesson of chloroquine resistance.

Summers et al. showed that two mutations are indeed required in Plasmodium prior to achieving a beneficial effect (as Behe argued). Remember though, that in Plasmodium we are dealing with huge numbers of organisms and a fast reproductive cycle, and we are also dealing with a rather simple biological change. The problem for evolution is that it has to build sophisticated biological systems with a limited number of organisms in a limited amount of time. (There are other problems with the evolutionary story that are more problematic and run even deeper, but we’re focusing here on what evolution is supposed to be able to accomplish even within the optimistic evolutionary narrative.)

The real take-home lesson is that evolution, on its best day, is an embarrassingly anemic process. In the face of real-world data, it’s evident that no matter what ideas we throw at the wall to try to help the story along, we still need massive numbers of organisms with rapid reproductive cycles to achieve even modest results by evolutionary means. We can argue about whether “effective” chloroquine resistance should be defined as requiring exactly four mutations. We can quibble about whether the mutations are beneficial or neutral. We can debate the math and even be off by an order of magnitude or more. Yet none of this alleviates the significant challenge the real-world data poses to the evolutionary story.

This is the real lesson of chloroquine resistance. This is Behe’s real point. And once we recognize this point the exchange between Behe and his critics descends into something almost comical. After we strip away all the debating rhetoric and the fancy math and the intimidating biological terminology and look at the bottom line of the exchange, it goes something like this:

Behe: It was difficult for Plasmodium to evolve resistance to chloroquine. The evolutionary mechanism isn’t very effective if coordinated mutations are required. Thus, to explain what we see in biology, evolution doesn’t seem to work very well.

Moran and Friends: Oh yeah? Well here are additional pathways that show evolution doesn’t work very well. Take that!

Listen to the Parasites

Behe is quite right to argue that if we need something like 10^20 cells to confer a relatively simple trait like resistance to chloroquine (however arrived at), then the evolutionary story is in dire straits. To his credit, Moran correctly acknowledges that developing chloroquine resistance “is an event that is close to the edge of evolution.” Now he just needs to pause and appreciate the implications for the evolutionary story.

Are there functions in biology that are as complex or as difficult to achieve as chloroquine resistance? Of course there are. A brief look around the biosphere confirms that it would be irrational to think otherwise. Behe’s critics seem easily impressed by Plasmodium’s development of resistance to chloroquine as a shining example of the power of evolution. Yet remember, we’re not talking about forming a new organ or a new body plan, or constructing a new molecular machine, or building a new regulatory network, or even a single new gene. As Behe dryly observes, we’re only talking about “a few crummy point mutations in a pre-existing protein.”

Yet evidently this is about all we can expect from evolution.