Real-world data and the next lesson of chloroquine resistance

Real-world data and the next lesson of chloroquine resistance Editor's Note: In 2020 Michael Behe published The Mousetrap of Darwin, a collection of his articles and his responses to critics. Biochemist Lawrence Moran has argued that Behe has misinterpreted the evidence and misunderstood the importance of chloroquine resistance. Here is the second part of the response. The first part can be read here: "How much can evolution really achieve?" After the publication of Behe's 2020 book (Darwin's Mouse Trap) I had the privilege of interviewing Michael Behe in a series of audio interviews. It was clearly shown in our discussions that Behe is interested in data. Whether we are talking about gene multiplication or neutral evolution or the specific route to resistance to chloroquine, we need to take the data seriously. It's easy to make up stories about how this mutation or this storyline can lead to happen. Whether it's a long tale of the giraffe's impressive neck, or a microscopic tale of small nucleotide mutations that make up the chord extensions of sickle cell DNA, the tales are irrelevant if not bound by data. In short, we can imagine several different ways to resist chloroquine, but these efforts must be subject to data. So let’s take a step back and examine the logical possibilities in terms of data. One logical possibility – the simplest case – is that chloroquine resistance is a piece of candy and that a single point mutation, as in the case of atovaquone, will do. But such a simple scenario doesn’t fit the immunological data, and was completely refuted after 2014 by Robert L. Summers and colleagues in their paper published in PNAS Academic, so we can cross it off the list. Another logical possibility is that resistance to chloroquine requires two mutations. Not just any two mutations; the immune data refutes this. But two specific coordinated mutations may work, and they fit relatively well with the data. The data can reasonably correspond to two coordinated mutations either at the perceived mutation rate, estimated by Behe at a 10 ?-8 rate, possibly along with a third mutation in PfCRT, Readers will recall that this was essentially Behe’s suggestion in 2007 when he wrote Edge of Evolution, the basis of which was almost entirely that the simplest and most plausible explanation for the scarcity of chloroquine resistance was that it required at least two coordinated mutations. Behe’s prediction turned out to be correct based on subsequent research from Summers and colleagues, and it has now been agreed that at least two coordinated mutations are needed. Roads to Rome? A third logical possibility is that more mutations are needed – three, four, maybe even five. Such a scenario might fit reasonably well with the data if there are multiple potential pathways to chloroquine resistance. Summers et al. have shown that at least two coordinated mutations are needed to initiate chloroquine resistance. Once the initial benefit is given by these two coordinated mutations, additional mutations will be able to improve resistance across a few different pathways. Moran argued in his blog Sandwalk based on his reading of Summers et al.'s research that "four separate mutations are needed for effective chloroquine resistance and mutations must occur in a certain order." He then insists on confirming this noting that "the particular combination of mutations is probably the only possible ways to resist". This is a rather strange argument against Behe. Behe undoubtedly agrees that multiple mutations are needed and that getting resistance is not a trivial affair, with many paths available, as some critics have argued. Just to illustrate Moran's phrase to readers, he does not argue that all four mutations are required in order to get any useful result. If so, the obstacle to chloroquine resistance will rise to a probability of around 10-40, which is completely incongruous with the data, and represents an obstacle that even the rapidly multiplying aggressive perception cannot overcome. On the other end of the spectrum, Moran does not argue that each individual mutation confers a meaningful selective benefit to plasmodium, as that would contrast with Summers and his colleagues. It would have no relevance to the topic of research here. To my knowledge, Behe never argued that the Darwinian process could not build a complex advantage if every step of the way represented a meaningful advantage for the organism. The whole question at hand is whether evolution has a reasonable ability to build systems in which intermediate steps alone would not be useful. Despite Moran's reference to four "effective" mutations of chloroquine resistance, Moran again reminds his readers that he does not disagree about the scarcity of chloroquine resistance, but he does not agree with Behe's explanation of how they occur. Thus, watching Moran agree with Behe's main point, but argue about a side issue, may allow one to wonder if we are again witnessing someone arguing against Behe simply for the principle of disagreeing with a critic of evolutionary theory. Casey notes to Skin: ... the most important argument presented by Behe in his book Edge of Evolution ... did not turn on whether the CCC [Chloroquine Complexity Group] requires one, two, or fifty mutations in fifty different genes. He said that the CCC is "supposed" to require two simultaneous mutations, but it was not a decisive pillar of his argument. Behe's argument was simply an observation, based on White's public health data, that chloroquine resistance arises in 1 out of every 10 x 20 cells. This is a data point. He then posed a hypothetical question: if a single mtk requires a 10 x 20 multiplication, what would happen if a complex trait such as "double mtk" existed? Such a trait, Behe argued, would require 10 x 40 cells to arise, which are more cells. Despite acknowledging Behe's main idea in the book The Edge of Evolution, Moran downplays Behe's (correct) prediction that a polymorphic event was required to confer chloroquine resistance and instead insists that "effective" resistance requires four mutations. Moran does not seem to see the bigger picture. The rats are still trapped. Moran seems to believe that Behe has underestimated the power of evolution.[citation needed] Moran, fascinated by the idea of neutral evolution, wrote that "effects requiring only two mutations would be common if the former were effectively neutral (or semi-neutral) and that is the real lesson of chloroquine resistance [as reported]". Unfortunately, despite Moran’s enthusiasm, this is certainly not the true lesson of chloroquine resistance. Summers and his colleagues have shown that two mutations in the perceived are indeed needed before a beneficial effect can be achieved (as Behe has argued). Remember though, that in the perceived we are dealing with huge numbers of organisms and a fast reproductive cycle, we are also dealing with a fairly simple biological change. The problem for evolution is that it has to build sophisticated biological systems in light of a finite number of organisms within a finite amount of time. The real lesson is that evolution at best is an awkwardly meager process. Against real-world data, it is clear that no matter what ideas we throw at the wall to support the story, we still need vast numbers of organisms with fast reproductive cycles to achieve modest results using evolutionary means. This is the real lesson of chloroquine resistance. This is Behe’s real idea. Once we realize this idea, the exchange between Behe and his critics descends into something almost comical. Having stripped down all the rhetoric, fancy mathematics and scary biological terms and looking at the conclusion of the controversy, it goes something like this: Behe: It was difficult for the perceived to develop resistance to chloroquine. The evolutionary mechanism is not efficient enough if coordinated mutations are needed. Thus, to explain what we see in biology, evolution does not seem to work very well. Moran and his friends: Oh yeah? Well, here are additional tracks that show that evolution isn’t working very well. Take that! Listen to the parasites. Behe is absolutely right in saying that if we need a 10 20 cell quantity to give a relatively simple trait such as chloroquine resistance (however reached), the evolutionary story is in tatters. Moran calculates that he correctly acknowledges that the development of chloroquine resistance "is an event close to the edge of evolution." A brief look at the biosphere confirms that it would be illogical to think otherwise. Behe’s critics seem to have liked the ease with which the concept of chloroquine resistance is developed as a shining example of the power of evolution. But remember, we’re not talking about forming a new organ or a new body plan, building a new molecular machine, building a new regulatory network, or even just one new gene. It is quite clear that this is all we can expect from evolution. Source: Real-World Data and the Lesson of Chloroquine Resistance - Eric Anderson - Translated by Abdullah Dabgen — Source: Brahin Center website - Published 2022-08-03 (archived at the Internet Archive) https://braheen.com/articles/evolution-design/بيانات-العالم-الحقيقي-والدرس-القادم-من-مقاومة-الكلوروكين