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The following article was originally published here on May 6, 2019.
Recent months have witnessed a debate between Michael Behe and his supporters, on one hand, and Behe’s critics on the other, over arguments in his book Darwin Devolves about mutations in polar bear genes. The discussion has now come to end. Having heard what critics have to say and having responded extensively, we believe the evidence comes down decisively on Behe’s side.
Barring startling new revelations from the research community, nothing more needs to be said for now. But because this conversation has been intense, technical, and complex, it seems fitting to offer a concise summary. (Along with apologies if, like us, you are suffering from a bit of polar bear fatigue.) Find the full Seminar here.
- Behe’s main thesis in Darwin Devolves is that adaptive mutations tend to degrade or diminish functions at the molecular level.
- Behe gives many examples supporting his thesis, but the first ones offered are polar bear genes. About 20 genes in polar bears show strong evidence of adaptive mutations, and a computer analysis of those mutations by a 2014 paper in the journal Cell by Liu et al. found that “a large proportion (ca. 50%) of mutations were predicted to be functionally damaging.” This, Behe argues, confirms his thesis that adaptive mutations tend to be degradative.
- According to the computer study, one of the polar bears genes most strongly predicted to have experienced damage is APOB, a gene that helps regulate cholesterol in the blood. Liu et al. (2014) predicted that mutations in APOB helped polar bears deal with a high-fat diet from eating seal blubber. The question at issue is whether mutations in APOB and other highly selected polar bear genes degraded or enhanced their molecular functions.
The Critics Respond
Behe’s critics responded with four main objections:
- Objection 1: They criticized using the computer program to conclude that a gene was probably damaged. They argued the program could not detect biochemical damage because all it detects is changes to how the gene operates or phenotypic damage — but it cannot detect whether those changes were harmful or beneficial to a gene’s function at the biochemical level. Thus the objection came in two parts: (a) They claimed that when damage is detected by the program, that means “phenotypically damaging, not biochemically damaged” because “Polyphen does not attempt to predict ‘biochemical damage.’” (b) They argued that Behe misread a table in Liu et al., which over 40 times predicted a mutation was “damaging,” because “damaging in this table does not mean damaging.” Instead, they said, all the program is actually detecting is a “change in function.”
- Objection 2: Behe’s critics claimed that he exaggerated when estimating the number of polar bear genes that Liu et al. had predicted experienced damaging mutations.
- Objection 3: Some critics complained about a chart from Liu et al. that Behe showed, in part, in a blog post. The chart showed when mutations were predicted to be damaging or when they were predicted to be “benign.” These critics argued that Behe omitted important data from the table reporting benign mutations, and was therefore “deeply misleading,” “intentionally leaving out evidence that is contrary to his position,” and “deceptive to doctor the chart.”
- Objection 4: Behe’s critics also focused specifically on APOB, arguing that Liu et al. and a news article about the paper did not conclude the gene was damaged. They even claimed that the mutations “likely enhance the function of apoB” which they presumed is simply to remove cholesterol from the blood. As one critic put it, mutations in APOB “improved one of its activities, namely the clearance of cholesterol from the blood.” Critics further claimed that we misread Liu et al. since “the authors do not expect the polar bear APOB to be broken or damaged” and “There is no evidence for Behe’s claim that APOB is degraded or diminished in polar bears.” Those who claimed that Liu et al. concluded APOB was predicted to be damaged were accused of “lying.”
In Reply to the Critics
We responded to each objection in detail:
- Answering Objection 1a: Does the program examine biochemical damage? We pointed out that the computer program is precisely designed to detect biochemical damage. The technical documentation for PolyPhen-2 explains that it predicts when a mutation is “likely to destroy the hydrophobic core of a protein, electrostatic interactions, interactions with ligands or other important features of a protein,” and predicts when a mutation is “affecting protein stability or function.” That’s biochemical damage. (For our discussions, see here, here, or here.)
- Answering Objection 1b: Can the program ever reasonably predict that a protein was probably damaged? We also pointed out that the computer analysis gives a very good probabilistic estimate that the protein’s function was damaged, not simply changed. The program looks at the substituted amino acids and assesses whether they have similar chemical properties to the residues at the same position in a suite of other known homologues of that protein in other species. If they don’t, it’s safe to assume that the function of the protein is going to begin to diverge from the original function. The program can directly analyze and predict whether mutations affect protein’s stability or core function — crucial factors for assessing whether its function was damaged. The result, given in probabilistic terms, indicates when the protein’s native function is most likely being biochemically degraded and damaged. In Darwin Devolves, Behe appropriately described the program’s results as showing when a mutation was “likely” to be damaging. (We explained this here and here.)
- Answering Objection 2: Did Behe accurately estimate the number of polar bear genes that experienced damaging mutations? When Behe calculated the number of polar bear genes that experienced adaptive yet degradative mutations, he closely followed the methodology of Liu et al. (2014). Even critics admitted that Behe’s upper estimate of the number damaged polar bear genes was reasonable under Liu et al. — 14 out of 17, or 83 percent of highly selected genes probably experienced damaging mutations. As for Behe’s lower estimate, here too he closely followed Liu et al. — and followed their methodology more closely than his critics. Unlike Liu et al., these critics excluded from their lower estimate all cases where the computer program predicted a mutation was “possibly damaging.” (Even in those cases, the mutation was predicted to be damaging but was called “possibly damaging” to recognize the possibility of false positives.) Behe followed Liu et al.’s methodology and accurately calculated that the minimum number of degraded genes in polar bears was 11 out of 17, or 65 percent. You can read more about this here and here.
- Answering Objection 3: Did Behe omit contrary information from the chart? Behe’s blog post responding to Objection 2 only showed a portion of the damaging mutation chart from Liu et al., but Behe did this for good reason: The table is large (49 lines x 8 columns), and for clarity he wanted to present only the data that was required to refute the critics. In this case, critics had challenged Behe’s estimates of the number of polar bear genes that experienced damaging mutations. The chart data Behe presented was sufficient to show he was correct. One critic even admitted Behe “isn’t lying exactly” since he was just showing the “relevant information.” In a reply to the critics’ complaints, we reprinted the full table and showed why none of the data Behe left out contradicts his thesis. Some of it represented results that predicted mutations were damaging — data that clearly supports Behe! The remainder entailed mutations that were predicted to be “benign” — but this does not contradict Behe either: Behe’s “devolution” model is only challenged by “constructive” mutations, but he fully allows that benign or neutral mutations are common and even form the “the bulk of changes at the molecular level,” as he writes in Darwin Devolves.
- Answering Objection 4: Did APOB experience damaging mutations? Liu et al. reported that five mutations in APOB were “predicted to be functionally damaging.” One of those mutations received the program’s highest possible score — 100 percent likelihood — for predicting damage. Critics accused us of “quote-mining,” so we asked them to provide language from the paper indicating otherwise — that APOB mutations were not damaging. They could not do this. Instead they put words into the mouths of the authors, citing statements from the paper and from a news article that were silent about whether APOB mutations enhanced or degraded its function. While the paper certainly predicts that mutations in APOB help polar bears cope with a high-fat diet to effectively reduce cholesterol, it simply did not speculate about the exact mechanism by which this happens. Curiously, critics who argued that mutations “likely enhance the function” of APOB did not acknowledge key language from the paper which admitted: “It remains an enigma how polar bears are able to deal with such lifelong elevated levels of cholesterol.” Likewise, they failed to note that a news article about the paper stated: “It’s not clear exactly what the gene variants [of APOB] do for the polar bears.” If we don’t know the exact function of APOB in polar bears or how it helps them cope with a high-fat diet, how can we know that its function was enhanced? We can’t. Absent empirical studies of exactly what APOB does, the best evidence about the impact of APOB’s mutations is from the computer analysis which strongly predicted that it experienced damaging mutations. For details, see here, here and here.
- New evidence answering Objection 4: Degradative mutations in APOB can lower cholesterol: Most critics assumed that the function of APOB is to remove cholesterol from the bloodstream, and that polar bears cope with a high fat diet via mutations that enhance this function. They thought this made it difficult to believe Behe’s prediction that degradative mutations in APOB help reduce cholesterol. As a final point, a body of medical literature proved Behe could be right. Studies of APOB in humans show that one of its functions is to load cholesterol into the bloodstream, and that mutations that degrade this function can lead to lower cholesterol levels. In other words, degradative mutations in APOB could plausibly help polar bears deal with their high fat diet. As we explained here, functionally damaged apoB proteins can indeed lead to less cholesterol in the blood.
Mysteries remain: What exactly does APOB do in polar bears? And if it is helping reduce cholesterol (as most everyone believes), why do polar bears still have such high cholesterol, and how exactly do they cope with that? No one knows for sure what APOB is doing in polar bears and exactly how its mutations or mutations in other genes help polar bears cope with a high fat diet. But genetic analyses strongly indicate that many APOB mutations were damaging to its function, and there are plausible models by which damaging APOB can reduce cholesterol. All of this is enough to show that Behe’s arguments about APOB and devolving polar bear genes are backed by evidence and hold merit as a plausible model.
So Behe’s position has come out looking very strong. Of course, all scientists know we must be open to revising our views based upon future discoveries. We presently lack direct empirical studies of how exactly APOB functions in polar bears and how polar bears cope with high cholesterol. Perhaps studies will be done in years to come casting new light on those questions. For that matter, perhaps one day polar bears will talk, dance, watch TV, ice-skate, and drink Coca-Cola, as in the famous commercials. Who can say what the future holds?
That’s enough now. So take a deep breath, relax, and watch some polar bears: