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Ken Miller, the honest Darwinist

Salvador Cordova
June 27, 2007
Intelligent Design
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Ken Miller just published a review of Michael Behe’s book, Edge of Evolution. Here is Miller at his best:

but Behe has built his entire thesis on this error. Telling his readers that the production of so much as a single new protein-to-protein binding site is “beyond the edge of evolution”, he proclaims darwinian evolution to be a hopeless failure. Apparently he has not followed recent studies exploring the evolution of hormone-receptor complexes by sequential mutations (Science 312, 97–101; 2006),

Ken Miller
Falling over the edge

Miller falsely accuses Behe of not following the Science (2006) paper, yet it’s hard to imagine that Miller missed the widely available public response by Behe of that very study. How could Miller accuse Behe of not following the study, when Behe said:

The study by Bridgham et al (2006) published in the April 7 issue of Science is the lamest attempt yet — and perhaps the lamest attempt that’s even possible — to deflect the problem that irreducible complexity poses for Darwinism
….

The fact that such very modest results are ballyhooed owes more, I strongly suspect, to the antipathy that many scientists feel toward ID than to the intrinsic value of the experiment itself.

In conclusion, the results (and even the imagined-but-problematic scenario) are well within what an ID proponent already would think Darwinian processes could do, so they won’t affect our evaluation of the science. But it’s nice to know that Science magazine is thinking about us!

Michael Behe
The Lamest Attempt Yet to Answer the Challenge Irreducible Complexity,

Despite Behe’s public and widely available commentary on this study, Miller falsely accuses Behe of not following it. Miller asserts boldly, “Apparently he [Behe] has not followed recent studies exploring the evolution of hormone-receptor complexes by sequential mutations (Science 312, 97–101; 2006)“.

I get it, Miller didn’t realize Behe has indeed followed this study and that Behe has even publicly commented on the Discovery Institute’s website. Miller couldn’t possibly have been so dastardly as to actually know Behe published responses to the study, and then falsely accuse Behe of not following the study.

Miller couldn’t possibly be that dastardly. We can therefore attribute it to Miller’s ignorance and simply presume, even though Miller has been obsessed by ID activities, he missed Behe response on the DI website. That can only be the explanation since Miller, being the honest Darwinist he is, can’t possibly do such a dastardly thing. We must chalk this up to his honest ignorance.

[UPDATE:

I found more examples of Ken’s Honesty:

1. Miller falsely insinuates Behe waves away “evidence”

2. Miller’s case against a non-220 CQRs self-destructs by the very paper he cites against Behe

3. Ken Miller needs to know 2004 does not equal 2005

4. Ken Miller reapeats the same misrepresentation he made under oath in Dover

]

Notes:

1. Ken Miller is the guy who has taken various bruisings from scientific evidence and continues his misrepresentations and story telling as he did under oath in the Dover trial. [See: Ken Miller may face more embarrassing facts, Behe’s DBB vindicated and Ken Miller caught making factually incorrect statements under oath]

2. Miller has not (to my knowledge) retracted yet another misrepresentation he made of Behe some time back.

Mike Gene observes in 9+2 = Straw:

In his book, Finding Darwin’s God, Miller finds himself “amused” at Behe’s argument regarding the eukaryotic flagellum, adding, “A phone call to any biologist who had ever actually studied cilia and flagella would have told Behe that he’s wrong in his contention that the 9+2 structure is the only way to make a working cilium or flagellum.” (p.141).
….
But I can’t find where Behe ever raised this contention.
….
what is annoying is that Miller uses this misrepresentation as part of a carefully crafted ad hominem. He begins with “amusement” that leads up to his “A phone call to any biologist” schtick.

Mike Gene

Comments
Jehu: You are completely wrong on everything you post.
So when I posted the following, it was wrong? "White himself says that host immunity plays a central role in preventing the emergence and spread of resistance." How was that wrong, precisely? Here's a section heading from the review Behe cites: The central role of immunity in preventing the emergence and spread of resistance in high-transmission settings
Behe doesn’t rely on himself as an authority in Malaria. He relies on N.J. White, who has over 400 publications in the field.
Behe doesn't agree with White. Behe claims that the 10E-20 frequency represents a mutational limit, while White patiently goes through all the relevant factors in detail, such as host immune response and sexual reproduction, both of which Behe omits. Go back to my totally dishonest polio argument above. If you attack my conclusion that animal experiments don't work, I can simply deflect your attack by pretending that you are attacking the authority of the Nobel laurates who did the research instead of attacking my utterly dishonest argument. Would you buy such a deflection as valid? Did you figure out why that argument is dishonest yet?
Your claim that White’s review to article ratio is too high is an unbelievable absurdity that leads me to believe that you are a complete neophyte.
Are you willing to test the sincerity of your belief by putting some real money on it?
White takes into consideration all of the factors you raise and still comes up with a 1 in 10^20 probability of CQR emerging de novo.
And White, unlike Behe, discusses those factors so that anyone who reads his review with an open mind sees the complexity. Behe pretends that it is much more simple than it is.
Your criticism that Behe doesn’t discuss these same factors is therefore pointless.
Behe attributes the rarity of emergence to only one of the factors discussed by White, just as my completely dishonest polio argument attributes all the success of the Nobel laureates' research to their use of human cells in culture. I'm telling you that my polio argument is designed to deceive in precisely the same way, but apparently you can't see the deception. Cognitive dissonance is an amazing thing.
It has been repeatedly explained to you why the evidence best supports CQR requiring two or more amino acid changes from the wild type.
And you clearly aren't bothering to read what I post. It is clear that many changes contribute, and I predict that more will arise in the mutant haplotypes. I am challenging Behe's explicit claim that two are required in a "single mutation." I am challenging any claim that any two have to occur in the same clone, because sexual reproduction recombines them at the same time it preserves wild-type alleles. The selective forces act in different directions, at different times. Behe, through negligent or deceptive omissions, leads his audience to conclude that selection is in one direction only and unchanging over time, so that the reader concludes that this represents a limit to evolution, instead of the complexity of population genetics in sexually-reproducing organisms subject to ever-changing selection pressures. Now, Jehu, can you spot the dishonesty in my polio argument? Above, you said that my argument was laughable, and all you've done is misunderstand and misrepresent my argument. I can tell you up front that my polio argument is dishonest and laughable, and you can't tell me the reason why.JAM
July 11, 2007
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JAM continues to argue: Except that you are ignoring recombination, so the probability of getting two independent mutations together is many orders of magnitude higher.
Well then, how do you account for the fact CQR too longer to evolve than other forms atovaquone. You're persistent, JAM, and dialogue with you has been good practice at rhetoric, but I think you're not persuading the ID side, and I'm not so sure your side is believing what you have to say. The bottom line is that Darwinism, in light of the very large number trials, was relatively slow to evolve resistance to CQ.scordova
July 11, 2007
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JAM, You are completely wrong on everything you post. Your arguments have been thoroughly refuted and yet you repeat them. Behe doesn't rely on himself as an authority in Malaria. He relies on N.J. White, who has over 400 publications in the field. Your claim that White's review to article ratio is too high is an unbelievable absurdity that leads me to believe that you are a complete neophyte. White takes into consideration all of the factors you raise and still comes up with a 1 in 10^20 probability of CQR emerging de novo. Your criticism that Behe doesn't discuss these same factors is therefore pointless. It has been repeatedly explained to you why the evidence best supports CQR requiring two or more amino acid changes from the wild type. You apparently do not understand the arguments because when they are raised you agree with them but then immediately go back to pretending like they were never raised. At this point you are raising one pointless absurdity after another and reverting back to already refuted arguments.Jehu
July 11, 2007
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Bad formatting--the end of the dishonest argument should go like this: viruses; and (c) by identification of the agents grown in tissue culture in virus neutralization tests.” 4) This clearly shows that animal experiments aren’t needed, and that the nonanimal alternative of cell culture gives superior results.JAM
July 11, 2007
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Jehu: It has repeatedly been pointed out to you that when White made his calulation he took into consideration the standard population genetics factors that a de novo mutation for CQR will not be selected when it occurs, including sexual recombination.
I agree completely. For example, White goes into great depth about the role of the host immune response in restricting the spread of resistance, which Behe completely ignores, along with his neglect of sexual reproductive factors.
He takes these factors into consideration and still arives at the number that Behe accurately cites.
"He" being White, yes. But Behe completely misrepresents this probability as the product of only one of those factors (mutation), and claims that two residues must be changed in the absence of evidence supporting his claim, while ignoring evidence that does not support his claim.
As I have pointed out White has over 400 peer review publications on Malaria.
And Behe has zero! Thus, when White discusses the roles of the immune system and sexual reproduction in retarding the spread of CQR and Behe ignores those factors completely, which one has more credibility with you?
You made the utterly trivial argument that 50 of them were reviews. (I am not sure how you know that unless you read them.)
It's easy. They are all identified as reviews, so one simply uses the search term "review." The conflation of reviews with the primary literature (and quoting conclusions with citing the data) is not trivial. In fact, it's one of the best markers for determining whether the quoter's goal is to inform or to deceive.
Regardless 350 articles is still a staggering number and 50 reviews is also impressive.
Yes and no. I'd say his proportion of reviews among his papers is too high. Whether you agree with that or not, when White tells you how the host immune response restricts the spread of CQR in a population, what do you think when Behe ignores that?
With a CV like that, White is undoubtedly one of the World’s leading authorities on the topic. For you to sit here and claim that White doesn’t know the basics of how drug resistance emerges and is selected is absurd.
I haven't claimed anything of the sort. I pointed out that he mislabeled one thing that he correctly labeled elsewhere, probably because he isn't comfortable with the terminology of population genetics.
That is exactly wrong. What you are trying to do is suggest an argument with out actually making one. In this case, the argument you are suggesting is laughable.
Well, since you got the false idea that I was claiming that White doesn't understand how CQR evolves, I'm curious to see what you perceive this argument as being. Let me offer a parallel, totally dishonest argument on a different subject. 1) Animal experiments and tests are misleading. 2) The biggest advance in making a polio vaccine used human cell culture. 3) Here's a quote to prove it: "...the decision was taken to use a mixture of human embryonic skin and muscle tissue in suspended cell cultures in the hope that the virus of varicella might multiply in the cells of its natural host. In this way such cultures were made available while close at hand in the storage cabinet was the Lansing strain of poliomyelitis virus. Thereupon it suddenly occurred to us that everything had been prepared almost without conscious effort on our part for a new attempt to cultivate the agent in extraneural tissue...It is evident that under these conditions significant quantities of virus appear only after a period of eight days and that the maximal yield is obtained between the 12th and 16th days. These findings were soon confirmed and extended: (a) by continued serial passage in human embryonic skin and muscle tissue of this as well as another strain of Lansing virus; (b) by the successful propagation of representatives of Types I and III viruses; and (c) by identification of the agents grown in tissue culture in virus neutralization tests."4) This clearly shows that animal experiments aren't needed, and that the nonanimal alternative of cell culture gives superior results. Jehu, can you spot the defect in the reasoning that makes this a massively, cynically dishonest argument whose sole purpose can only be to deceive? Given your tactics above, is it fair to say that if I pointed out that this argument was totally dishonest, you'd disagree and claim that the argument has to be right because it employs a quote from the ultimate expert in the field--a Nobel laureate?JAM
July 11, 2007
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jerry: I will ask again. Isn’t a main conclusion of the book that given all the reproductive events of the malarial organism, HIV and bacteria that not much has happened to any of these organisms?
I'd call it a contention, not a conclusion. You'd need to review the evidence exhaustively to come to such a conclusion, and Behe clearly hasn't done that. Does Behe discuss the evolution of the HIV Vpu protein, or does he conclude that it was added by a designer? Would you call this case of observed evolution "not much"? Nature 412, 334-338 (19 July 2001) Evolution and transmission of stable CTL escape mutations in HIV infection Philip J. R. Goulder et al.JAM
July 11, 2007
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JAM
The reason that resistance takes so long to emerge is the same reason that we will never be rid of cystic fibrosis alleles–population genetics, particularly the ability of sexual reproduction to maintain polymorphism in a population.
That is exactly wrong. What you are trying to do is suggest an argument with out actually making one. In this case, the argument you are suggesting is laughable.Jehu
July 11, 2007
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JAM; It has repeatedly been pointed out to you that when White made his calulation he took into consideration the standard population genetics factors that a de novo mutation for CQR will not be selected when it occurs, including sexual recombination. He takes these factors into consideration and still arives at the number that Behe accurately cites. As I have pointed out White has over 400 peer review publications on Malaria. You made the utterly trivial argument that 50 of them were reviews. (I am not sure how you know that unless you read them.) Regardless 350 articles is still a staggering number and 50 reviews is also impressive. With a CV like that, White is undoubtedly one of the World's leading authorities on the topic. For you to sit here and claim that White doesn't know the basics of how drug resistance emerges and is selected is absurd.Jehu
July 11, 2007
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gpuccio: I don’t see how sexual reproduction could increse the probabilities, and make Behe’s number “exponentially wrong”.
I suggest a genetics textbook, then. They cover recombination in detail. Sexual reproduction both makes it more likely to recombine independent events and less likely for them to be transmitted, both human->mosquito and mosquito->human. It's much more complicated than Behe's presentation suggests it is.
I can’t answer your objection at this regard, because that is not my field and I could easily be wrong.
It's not Behe's field either, so I I don't understand why you accept his oversimplification of White's position by ignoring the host immune response and sexual reproduction. White himself says that host immunity plays a central role in preventing the emergence and spread of resistance. Whom do you believe?
I think magnan has well answered some of your objections, but I agree that the subject is complex.
Do we agree that Behe oversimplifies it?
Indeed, I have read the article you cite (Arch Biochem Biophys. 2006 Aug 15;452(2):119-28), and my impression is that it does not demonstrate at all what you say, that the single K76T mutation is sufficient to confer, if isolated, clinically significant CQR.
It doesn't have to confer clinically significant CQR by itself. All it has to do to falsify Behe's claim is to confer a selective advantage in the presence of CQ.
I would like to add again, anyway, that Behe’s central idea, that if two or more independent mutations have to be present at the same time in an individual to confer a selective advantage,...
But Behe has shown no evidence to support his claim. Why did you lower the goalpost from "clinically significant" above to a mere "selective advantage" here?
...that should offer a self-evident impossibility for causal role of RM + NS in most significant biological information building.
Why? We've seen that evolution can co-opt an existing pathway in a very short time. The reason that resistance takes so long to emerge is the same reason that we will never be rid of cystic fibrosis alleles--population genetics, particularly the ability of sexual reproduction to maintain polymorphism in a population.
Finally, I can’t share your indignation at citing from reviews, especially in a book aimed at the general public.
The problem is in quoting from reviews instead of citing the actual data. I don't see why the target audience excuses the failure to go to the data, as books aimed at the general public cite the data all the time. Quoting from reviews enables obfuscation.
Anyway, Behe gives many direct references in the notes.
But not on the central point in what Behe calls his "centerpiece example."
Reviews, metanalyses, and in general intellectual discussions about data are, in my opinion, a very important part od scientific knowledge.
Reviews are used to introduce people to a field. They are not used as sources of quotes by practicing scientists looking to bolster their position in a controversy.
Peer reviewed lab work is not necessarily the hallmark of scientific truth.
Then what is the hallmark, if not evidence (by evidence, I don't mean only lab work; it includes field work)? And why do reviews cite the data published in these manuscripts, and why is their primary function to point interested parties to them? --------
Patrick Caldon: the probability of a sequence of mutations occurring in a particular generation cannot be calculated directly from the number of distinct times a particular phenotype (e.g. CQR) been observed to arise and become predominant in a population in the real world. These are chalk and cheese; the one question is essentially molecular biology, the other essentially population genetics.
Precisely. It's clear that White understands this but none of that is conveyed in Behe's book.JAM
July 11, 2007
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mangan: This is an excellent conceptualization, and I think it explains why “simultaneous” or “sequential” for the mutations conferring CQR are irrelevant to the issue.
It's not even close to excellent, because it completely ignores the role of meiotic recombination in combining substitutions in a haplotype.
Under these conditions the net probability is still approximately the product of the two mutation frequencies even when the two occur sequentially.
Except that you are ignoring recombination, so the probability of getting two independent mutations together is many orders of magnitude higher.
This analysis neatly fits with White’s estimates of mutation frequencies for resistance.
How does a discrepancy of almost 1000-fold become a neat fit in your estimation? Your whole position consists of promoting White's mislabeling of something (a single time), because despite his expertise, he clearly is uncomfortable with the language of population genetics.
He considers multiple mutations in his description of Table 1:
No, that's only one of the things that White lists in his Table 1: Factors determining the probability of selection of de novo antimalarial drug resistance 1. The frequency with which the resistance mechanism arises 2. The fitness cost to the parasite associated with the resistance mechanism 3. The number of parasites in the human host that are exposed to the drug 4. The concentrations of drug to which these parasites are exposed (i.e., the doses used and pharmacokinetic properties of the antimalarial drug or drugs) 5. The pharmacodynamic properties of the antimalarial drug or drugs 6. The degree of resistance (the shift in the concentration-effect relationship) that results from the genetic changes 7. The level of host defense (nonspecific and specific immunity) 8. The simultaneous presence of other antimalarial drugs or substances in the blood that will still kill the parasite if it develops resistance to one drug (i.e., the use of combinations) All these factors contribute to the 10E-20 frequency. You and Behe simply pretend that most of these factors do not exist.
Behe realized this and just describes the two as being necessary in one parasite at the same time without specifying whether this acquisition was simultaneous or sequential.
No. Behe clearly stated that a "single mutation" causing a "shift of two amino acids" is "required": "...single mutation of the kind required for malaria to become resistant to chloroquine–not the easiest mutation, to be sure, but still only a shift of two amino acids..."
White notes that mutation frequencies are considerably higher in vitro than in vivo.
Wrong again. White carefully qualifies the in vivo frequency as an APPARENT mutation rate, because of all those factors listed above. Why is it that when White writes something you like, you claim, "It is what White says it is," but when he writes something you don't like, you omit the qualifications that he includes that you don't like?
This would be because in the body as opposed to in vitro the single mutation is not sufficient for expanding clonal selection against the drug.
Here's what White (and nobody else) says: "Mutations may be associated with fitness disadvantages (i.e., in the absence of the drug they are less fit and multiply less well than their drug-sensitive counterparts). Another factor that may explain the discrepancy between in vitro and much lower apparent in vivo rates of spontaneous mutation is host immunity....there is only a 2–3% chance that the genetic event causing resistance would arise in the antigenically variant subpopulation that will expand to reach transmissible densities." So, mangan, is that 50-fold reduction a part of White's "per-parasite probability of developing resistance de novo" that Behe touts as a simple mutation rate?
For this it appears to need several additional mutations, which have to occur either simultaneously or soon thereafter in the clone of the first mutation.
False; neither requirement exists. You are simply denying the existence of sexual reproduction in Plasmodium.
Thus, again, the net frequency of in vivo CQR acquisition is approximately the product of the mutation frequencies (or even lower), and corresponds closely to the estimates used by Behe.
Read the list White offers. Those are the factors that contribute to the low frequency of in vivo CQR acquisition, and Behe is trying to pretend that all those factors represent only one: a mutation rate. Then, he takes that rate and applies it to humans, despite the fact that we can and have measured mutation rates in humans. Why extrapolate from the complex population genetics of primitive eukaryotic parasites? Why not look at the mutational events underlying mammalian evolution to see if Behe's limits hold? Do small genetic changes mediate large morphological changes?JAM
July 11, 2007
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jam I also recall you saying that it has been empircally established that the single point mutation rate in prokaryotes is ~10^9. You then go on to argue that the possibility of two simultaneous mutations is ~10^18 and then ask how it became 10^20 in malaria parasites. The answer is simple and I'm surprised you (or anyone else I read here) didn't know the answer. The answer is that each single point copy error can be to any one of four nucleotides (ACTG). The CQR mutation requires a specific one of those four possibilities while the other three are useless for CQR. Thus it raises the improbability of the right mutation occuring by a factor of 4 or ~4*10^9. Since the 10^9 number is approximate to begin with (it varies by environment, genetic loci, and species) a multiplication by four could very conceivably bump the base rate up to ~10^10. The 10^20 number for CQR was empirical, not calculated. Not surprisingly it roughly agrees with the calculated probability of two specific simultaneous point mutations. It also agrees nicely with the empirical observation of atovaquone resistance (AQR) arising in 10^10 malaria parasites. AQR requires only one single point mutation (again the right one of four possibilities). In your ancillary argument that CQR resistance could be two sequential point mutations - that is correct - it theoretically *could* be. Facts however say it doesn't happen that way. Virtually every person treated with atovaquone ends up with a resistant bug. If two sequential mutations could confer CQR then we should expect that it would arise at about half the rate of AQR. But in fact CQR is exceedingly rare. That CQR requires two simultaneous mutations is thus a virtually indisputable inference from real world data. Behe is on very solid ground here and your critique has now been shown to be fatally flawed. I suggest you move on to another avenue of attack. DaveScot
July 10, 2007
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jam I recall you asking, more than once IIRC, where Behe got a particular number: 10^20. I glanced at his Amazon blog where he addresses it in a response to Jerry Coyne.
Here is where Professor Coyne and other Darwinist reviewers really miss the boat and overlook the considerable power of the malaria results. The number I cite, one parasite in every 1020 for de novo chloroquine resistance, is not a probability calculation. Rather, it is a statistic, a result, a data point. (Furthermore, it is not my number, but that of the eminent malariologist Nicholas White.) I do not assume that “adaptation cannot occur one mutation at a time”; I assume nothing at all. I am simply looking at the results. The malaria parasite was free to do whatever it could in nature; to evolve resistance, or outcompete its fellow parasites, by whatever evolutionary pathway was available in the wild. Neither I nor anyone else were manipulating the results. What we see when we look at chloroquine-resistant malaria is pristine data — it is the best that random mutation plus selection was able to accomplish in the wild in 1020 tries. Let me elaborate that last point. The fact that de novo chloroquine resistance is observed to be an event of frequency 1 in 1020 means that mutational events of greater frequency are of little help, because events of greater frequency would have been expected to occur many times in the same time interval. For example, if a single point mutation such as K76T alone in PfCRT in the wild were sufficient to confer chloroquine resistance, then resistance would occur de novo in virtually every person treated with chloroquine, as it does in almost every person treated with atovaquone. In 1020 parasites that single mutation would have been expected to have occurred about 1010 times or more. What’s more, every other possible single point mutation, at every position of the parasite’s genome, would also be expected to have occurred roughly the same number of times. And enormous numbers of other types of mutations — deletions, insertions, gene duplications, and more — in every gene of the parasite, would also have occurred. The result: a very few mutations helped the parasite a bit; the overwhelming number of mutations did not help at all.
DaveScot
July 10, 2007
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Now, let's revisit something I asked repeatedly.
JAM said: what matters is that Behe claims that two changes are required simultaneously.
And then I asked:
1. one particular kind of CQR malarial strain 2. ANY conceivable CQR malarial strain. 3. You don’t know how to answer Why don’t you answer the question? Afraid to respond. Or will you just quote-mine passages out of Behe’s book to avoid answering? It’s not that hard a question.
And then you said:
I do know what you’re asking. That’s why I don’t simply say #3.
Ok, let's try again with a different approach. When Behe says:
The likelihood that Homo sapiens achieved any single mutation of the kind required for malaria to become resistant to chloroquine–not the easiest mutation, to be sure, but still only a shift of two amino acids
Was he saying the only abosolute possible route to CQR is via 2 mutations, or was he referring to the two most important mutations in the primary form of CQR observed and studied so far? If you don't know, say so. But let me point out, Behe has made the appropriate qualifiers in other parts of the book, and you should have taken them into account if you were willing to render a charitable reading:
different mutations have been found in PfCRT from different regions of the globe… The mutant PfCRTs exhibit a range of changes, affecting as few as four amino acids to as many as eight. .... some other mutations in some other proteins are thought to contribute to chloroquine resistance, none are nearly as effective as that in PfCRT Michael Behe
What's this, Behe refers to 4 mutations, and then to 8 mutations for CQ resistance? Apparenlty, the number 2 was referring to the apparent minimal number needed for the CQRs observed, not that 2 mutations are the only absolute possible route.. JAM, I'm afraid, you're unwilling to see what Behe is trying to communicate. In light of this, even the 3 amino acid Philippine CQR which I cited does not refute the idea trying to be conveyed. The number 2 was referring to the minimum of 2 mutations needed, not that that was the only path to CQR. PS You're participation here shows a great degree of resolve and valor, and I respect that, but it is badly misplaced. You're quibbling over words, and mis-reading what is said. You badly misread Behe's work and you tried to criticize his ideas with your misreading of the Fidock paper. Your valor is commendable, but your making one mistake after another at this point.scordova
July 10, 2007
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JAM wrote: Sal, My mistake. I missed that they had put K76I it into the Dd2 context.
Gracious of you to acknowledge your egregious error. The mistake you made was to assume K76I is sufficient to confer CQR. But that was not the mutation Behe was speaking of. Thank you for the offer of the PDF to the other paper, but even that was a bit of a suspect argument as this was not a study of real malaria but only parts of it inserted in yeast. The issue is whether K76* mutations by themselves are sufficient, and it appears they are not.scordova
July 10, 2007
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I will ask again. Isn't a main conclusion of the book that given all the reproductive events of the malarial organism, HIV and bacteria that not much has happened to any of these organisms? And that their number of reproductive events dwarf the number of reproductive events of all mammals since their inception. JAM did not answer the question but deflected to another argument being the center piece of the book.jerry
July 10, 2007
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Patrick Caldon, One thing that gets a comment held up is a link. The longer the link the more likely the comment will not make it through. There are times when I cannot even reference another thread at UD.jerry
July 10, 2007
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Some of my comments seem to be ending up in the bit-bucket, so it seems I must be violating the comment policy and being boring. I shall try to be less boring! Patrick (with no last name), "what is the source of novelty" is an excellent question. But there are two questions here: * what is the source of "novel adaptive function of the organism occurring as a result of a new allele arising, and subsequently fixing into a sizable sub-population", which will of course depend on what the adaptation is to, what the population is and what environment the population is exposed to. and, * "what is the source of new alleles", which is a question about molecular biology. JAMs consistent point (and argued with much more technical knowledge than I or anyone else here possess) is that the probability of a sequence of mutations occurring in a particular generation cannot be calculated directly from the number of distinct times a particular phenotype (e.g. CQR) been observed to arise and become predominant in a population in the real world. These are chalk and cheese; the one question is essentially molecular biology, the other essentially population genetics. From my limited knowledge of genetics JAMs point seems an eminently sensible, and entirely consistent with standard references/ textbooks on the subject. I'm not qualified to say that he's right, but for instance his careful insistence on the importance of the notion of haplotype has given me a lot of insight into these kinds of mechanisms which I did not previously have.Patrick Caldon
July 10, 2007
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JAM: my note: The two mutations could well appear sequentially, for instance one in a single plasmodium and the second in its immediate descendants. your comment: I agree…or they can be combined in a haplotype by recombination during sexual reproduction. All these things happen billions of times more frequently than one in 10E20. So we agree that Behe’s number is exponentially wrong. No, I don't think we agree on that last concept. The fact is that, if two independent mutations have to be simultaneously present in an individual plasmodium to confer resistance, be selected and expand, then the probability of the event is the product of the two single probabilities, however and whenever and wherever the two single mutations happende. I don't see how sexual reproduction could increse the probabilities, and make Behe's number "exponentially wrong". I appreciate your discussion about the fundamental "if". Indeed, Behe's argument, or at least his main argument in the book, rests on the assumption that both mutations are necessary for CQR. I can't answer your objection at this regard, because that is not my field and I could easily be wrong. I think magnan has well answered some of your objections, but I agree that the subject is complex. Indeed, I have read the article you cite (Arch Biochem Biophys. 2006 Aug 15;452(2):119-28), and my impression is that it does not demonstrate at all what you say, that the single K76T mutation is sufficient to confer, if isolated, clinically significant CQR. But again, this is not my field, and so I will let this discussion to others. I would like to add again, anyway, that Behe's central idea, that if two or more independent mutations have to be present at the same time in an individual to confer a selective advantage, then the probabilities of the event are extremely low, whatever the random mechanism by which the single mutations arise. Given the very complex nature of practically every new biochemical function, that should offer a self-evident impossibility for causal role of RM + NS in most significant biological information building. Finally, I can't share your indignation at citing from reviews, especially in a book aimed at the general public. Anyway, Behe gives many direct references in the notes. Reviews, metanalyses, and in general intellectual discussions about data are, in my opinion, a very important part od scientific knowledge. Peer reviewed lab work is not necessarily the hallmark of scientific truth.gpuccio
July 10, 2007
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gpuccio: "In other words, the chances of having the two mutations sequentually in the same individual plasmodium line are not so different from those of having them arise “simultaneously”, that is in the same cell,in a short time, because anyway the clone of the original mutation remains a small clone, does not expand, and can well die, and so the chances of having the specific second mutation in that specific clone are extremely low, and should be multiplied to the equally low chances of the first mutation to obtain the total chances of the double event in a same individual." This is an excellent conceptualization, and I think it explains why "simultaneous" or "sequential" for the mutations conferring CQR are irrelevant to the issue. Under these conditions the net probability is still approximately the product of the two mutation frequencies even when the two occur sequentially. This analysis neatly fits with White's estimates of mutation frequencies for resistance. He considers multiple mutations in his description of Table 1: "If the resistance mechanism is multigenic then this represents the frequency of the parasite becoming resistant and thus it is the product of the individual mutation frequencies." He doesn't mention simultaneous or sequential because in this situation it is irrelevant. Behe realized this and just describes the two as being necessary in one parasite at the same time without specifying whether this acquisition was simultaneous or sequential. White notes that mutation frequencies are considerably higher in vitro than in vivo. This would be because in the body as opposed to in vitro the single mutation is not sufficient for expanding clonal selection against the drug. For this it appears to need several additional mutations, which have to occur either simultaneously or soon thereafter in the clone of the first mutation. Thus, again, the net frequency of in vivo CQR acquisition is approximately the product of the mutation frequencies (or even lower), and corresponds closely to the estimates used by Behe.magnan
July 9, 2007
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I wonder what survival advantage is incurred by snideness. Do the mutations need to be simultaneous, or is it likely to be conferred sequentially, through single mutations for sneering and sarcasm?Apollos
July 9, 2007
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The relative fitness of CQR strains of malaria, in the absence of Chloroquine, has been calculated at .76 and .86, depending on the study.
Then why not cite those studies directly, instead of a review that cites them? You wouldn't be denigrating them as insignificant if you did.
The population of CQR malaria in a single individual necessary to produce illness is at least 10^7. At that point, the gametocytes carrying the CQR genes have reached transmissible densities and will not get lost due to sexual reproduction in the mosquito.
Why are you assuming that the infection and population growth occurred in the presence of CQ?
White, who has published over 400 peer review articles on malaria, appears to have already taken all of these factors into consideration in making his calculations.
False on both counts: 1) Fifty-two of his papers are reviews. They are rarely peer-reviewed. In fact, Behe is avoiding the primary, peer-reviewed literature in favor of quoting from a review. Can you guess why? 2) White clearly tells you that not all of the factors can be quantitated or estimated.
It is also being claimed that Behe is assuming two simultaneous mutations are required to confer CQR. This is false. What Behe is saying is that a minimum of two mutations are required before CQR arises, not that the mutations must occur simultaneously.
Behe is very clear: “The likelihood that Homo sapiens achieved any single mutation of the kind required for malaria to become resistant to chloroquine–not the easiest mutation, to be sure, but still only a shift of two amino acids–the likelihood that such a mutation could arise just once in the entire course of the human lineage in the past ten million years, is minuscule–of the same order as, say, the likelihood of you personally winning the Powerball lottery by buying a single ticket.” We know that the probability of getting a substitution at a specific nucleotide is 10E-9. The probability of getting two substitutions simultaneously at two specific nucleotides is the square of that, or 10E-18. Where does Behe derive 10E-20 if, as he claims, he is looking at mutation frequencies? Are you saying that Behe was in error when he wrote this? --------
gpuccio: It seems to me that the question should be viewed as follows: what Behe means is, as Jehu correctly states, that for resistance to CQR to arise, it is necessary that at least two independent mutations be present in the same individual plasmodium. That does not mean that the two mutations must arise simultaneously, in the sense that they must happen “at the same time”, or even in the same individual plasmodium.
That's not what Behe wrote, though.
The two mutations could well appear sequentially, for instance one in a single plasmodium and the second in its immediate descendants.
I agree...or they can be combined in a haplotype by recombination during sexual reproduction. All these things happen billions of times more frequently than one in 10E20. So we agree that Behe's number is exponentially wrong.
But the point is that neither one nor the other confer resistance to CQR if isolated,..
But the hallmark one, K76T, has been isolated experimentally, and you're wrong: Arch Biochem Biophys. 2006 Aug 15;452(2):119-28 Functional reconstitution of purified chloroquine resistance membrane transporter expressed in yeast. Tan W, Gou DM, Tai E, Zhao YZ, Chow LM. This is an isogenic experiment, as clean as it gets.
... and therefore even if they appear sequentially, the clone with the first mutation cannot in any way be selected, fixed or expanded, although it certainly has the same chances to survive as any other CQR sensitive clone (not many, if CQR is administered).
But that assumption is wrong. You're also trying to pretend that CQR/CQS is simple and binary. Real people have all sorts of different CQ concentrations, changing over time.
...That is not only a theoretical calculation, but is strongly supported by the observation of the extreme rarity of CQR resistance (two mutations)
Not two mutations. Two haplotypes with multiple mutations. Why won't anyone think about the definition of "haplotype" here? --------
jerry: But I read the book through once and it seemed to me the main conclusion was that the malaria eukaryote represented more reproductive events than the reproductive events in a lot of classes such as mammals since the beginning of their existence. And given this enormous number of reproductive events, very little has happened to change the organism compared to the zillions of changes that have taken place in mammals.
But you can only derive that probability if you assume that two simulaneous changes are required in a single event, and that event is still ~1000x more frequent than Behe's "centerpiece example" of 10E-20.
So the argument over when and how a couple mutations may or may not have happened is a sideshow argument over irrelevant minutiae. Or am I not understanding something which is always possible. If I am misunderstanding the connection of the minutiae with the overall conclusion then maybe someone could discuss the connectionns.
Behe calls it the "centerpiece example" of the book, so if you call its derivation "irrelevant" and a "sideshow," you are clearly disagreeing with Behe. --------
magnan: JAM: “Since the detection of it (spontaneous resistance mutation)...
This is the second time you've inserted "mutation" where it wasn't used. Why not argue the actual evidence? The antecedent of "it" is not a "spontaneous resistance mutation," it is a resistance HAPLOTYPE that contains multiple substitutions. Why do the experts use the word "haplotype," mangan?
Since the inference is based on White’s research results that he clearly described,
Behe's inference was definitely not based on White's research results. It was cynically based on a quote Behe took out of context from a REVIEW. That tells you just how weak it is.
...then both of White’s papers and probably many of his others are also fatally flawed, despite his apparently being accepted as an expert in the field with a large number of published research papers.
You're citing a review, not a research paper.
You need to point this out in the scientific arena by a letter to the Royal Society to be published in its Proceedings.
Why? I don't object to anything in that review.
White et. al. first present an analysis of the genetic events conferring drug resistance including the estimates of de novo per parasite resistance mutation frequencies with the 10^-19 figure for CQR (Table 1).
Wrong, mangan. You omitted the qualifications White included in the title: "Approximate per-parasite frequencies for genetic events (mutations or gene amplifications) which lead to the emergence of clinically significant drug resistance of Plasmodium falciparum in vivo." So you omitted "lead to," "clinically significant," and the plural on "mutations." How come? Wishful thinking? Why not take a peek at Figure 3 while looking at Table 1?
The next paragraph is on “De Novo selection of resistance” in which he discusses the probability that the genetic event conferring resistance will be selected for and expand in the body population. After this he covers all the factors reducing individual parasite survival probability and whether resistant strains reach transmissable populations. This includes reverse selection in the mosquito part of the life cycle.
Yes. This is just one of the reasons why the probability of emergence in a population is so much lower than the mutation frequency.
White and Pongtavornpinyo are analyzing de novo emergence of antimalarial drug resistance, as they say predominantly in areas of low malaria transmission.
No, it's a review, not an analysis. Do you understand the purpose of reviews?
This means spontaneously occurring resistance in individuals, not transmitted resistance.
They introduce you to the reasons why resistance in individuals is rarely transmitted. You apparently missed that. And if they are only discussing resistance in individuals, what is the relevance of the rate of transmission? Face it, mangan, they are doing epidemiology and population genetics, not analyzing mutation frequencies, which are much more easily measured for humans as rates of sporadic dominant lethals.
Thus the Table 1 estimate of “per parasite resistance mutation frequency” for CQR is clearly distinguished from host selection and transmission factors. It is what White says it is.
Yet at least one of the authors says that it is something different in the title. Do you realize how pathetic this is, mangan? How do you know that Pongtavornpinyo didn't write the column heading and White didn't write the far more accurate title for the table? Do you see that if you are reduced to quoting a column heading as evidence, you are deliberately ignoring the actual evidence?
Later in the paper White continues to make clear his (to you misguided) conclusions: “By contrast, for drugs such as chlorquine or artemisinin, the genetic events conferring resistance are much rarer (they may have happened only a few times in the case of chlorquine, and significant resistance has not yet been detected for artemisinin). Assuming an equal distribution of probabilities throughout the life cycle, the genetic event is likely to take place in only a single parasite at the peak of infection.”
I don't claim that he's misguided. I also don't claim to be certain that White wrote that. And it's clear that they are writing about clinically-significant resistance, which involves multiple, clinically-undetectable steps.
Notice that he...
He? Funny, I noticed that there were two authors, not one. I just sent the first draft of a ms out to my coauthors, and they are finding plenty of ambiguities. Of course, because this paper, unlike a review, will be peer-reviewed, it is much more important to correct them.
What do you think the following quote means from the White paper (in section 5. Transmission intensity and the selection of resistance)?: “In low-transmission areas the majority of malaria is symptomatic and selection therefore takes place in the context of treatment.”
It means that the emergence of resistance is so rare because it doesn't emerge in areas of high transmission. It doesn't help you to address my question, which is about whether any real-world malaria outbreak has had all patients treated throughout infection with CQ. Why not just admit that the answer is no? Show some courage and do the math. 10 CQR sporozoites (fitness 0.86) and 10 CQS sporozoites (fitness 1) infect an untreated human. Three weeks later, what is the typical number of merozoites in the blood and what is the calculated ratio of CQR to CQS merozoites?JAM
July 9, 2007
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The Other Patrick,
Most modern biologists apparently don’t subscribe to the view “that evolution is the result of mutation and natural selection” as you state, but would state rather that adaptation (as opposed to evolution) is the result of natural selection.
The real question is what is the source of novelty. Two years ago at the World Summit on Evolution it appeared that the "old camp" of Neo-Darwinists was still strong but that other camps were growing. I asked around at the time if anyone knew of a study or poll on what modern biologists believed but no one knew. I'd still like to know the size of the various "camps". Debating with someone who is in the same camp as Dawkins is very different from, say, Margulis or MacNeill. They're all coming from a different point of view on "how evolution really works". This leads to confusion when someone in the two sides debating doesn't know the other's position. It'd be like if someone here were to attack DaveScot with an argument commonly targeted at Creationists. Oh, and there has been much discussion about neutral theory in the past. Try googling "neutral site:www.uncommondescent.com". Here's one from Sal: https://uncommondescent.com/intelligent-design/what-are-the-speed-limits-of-naturalistic-evolution/Patrick
July 9, 2007
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DaveScot, It's not hard to see that the vast majority of mutations in eukaryotes will be neutral, since they will occur in regions which don't code for anything or regulate anything. In this way we can confidently predict that the vast majority of mutations will be neutral. Synonymous mutations will all be neutral. Indeed I understand that the majority of coding mutations are neutral or nearly neutral, and the empirical studies which have been done indicate a preponderance of neutral mutations, a good many detrimental mutations but a small but still noticeable number of beneficial mutations. For instance this paper found that 12% of a sample of random mutations on E. Coli were beneficial: http://www.pnas.org/cgi/content/abstract/98/20/11388 The big problem is in fact: how do the neutral mutations become fixed? I'm no expert in this area as I've only read a couple of textbooks on this material, but Kimura and Ohta described how neutral and nearly neutral (i.e. in some cases mildly detrimental) mutations can and necessarily will become fixed over time. Indeed it's possible to predict the degree of heterozygosity which comes from drift (i.e. related to the number of unfixed mutations hanging around) and predict it will be a function of the rate of mutation and the population size. Most modern biologists apparently don't subscribe to the view "that evolution is the result of mutation and natural selection" as you state, but would state rather that adaptation (as opposed to evolution) is the result of natural selection. In summary, we can confidently predict that the majority of random mutations will be neutral or nearly neutral, and have good theoretical models which have been empirically tested to show how both these mutations become fixed in populations. I've suggested this to you before, that you'd do very well to read an undergraduate textbook on evolution, and get a better grasp of the theory you're criticizing. Try Mark Ridley's book, "Evolution", it explains how the neutral and nearly neutral theories work very well, and then discusses in depth how it matches up with empirical data.Patrick Caldon
July 9, 2007
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JAM: "Since the detection of it (spontaneous resistance mutation) is only possible after many life cycles of selection for alternating with selection against this, your inference is fatally flawed." Since the inference is based on White's research results that he clearly described, then both of White's papers and probably many of his others are also fatally flawed, despite his apparently being accepted as an expert in the field with a large number of published research papers. You need to point this out in the scientific arena by a letter to the Royal Society to be published in its Proceedings. White et. al. first present an analysis of the genetic events conferring drug resistance including the estimates of de novo per parasite resistance mutation frequencies with the 10^-19 figure for CQR (Table 1). The next paragraph is on "De Novo selection of resistance" in which he discusses the probability that the genetic event conferring resistance will be selected for and expand in the body population. After this he covers all the factors reducing individual parasite survival probability and whether resistant strains reach transmissable populations. This includes reverse selection in the mosquito part of the life cycle. White and Pongtavornpinyo are analyzing de novo emergence of antimalarial drug resistance, as they say predominantly in areas of low malaria transmission. This means spontaneously occurring resistance in individuals, not transmitted resistance. Thus the Table 1 estimate of "per parasite resistance mutation frequency" for CQR is clearly distinguished from host selection and transmission factors. It is what White says it is. Later in the paper White continues to make clear his (to you misguided) conclusions: "By contrast, for drugs such as chlorquine or artemisinin, the genetic events conferring resistance are much rarer (they may have happened only a few times in the case of chlorquine, and significant resistance has not yet been detected for artemisinin). Assuming an equal distribution of probabilities throughout the life cycle, the genetic event is likely to take place in only a single parasite at the peak of infection." Notice that he is referring to the "genetic event" as occurring in a single parasite probably at the peak of infection (because of the higher population numbers). Notice that this event "May have happened only a few times" (for CQR since introduction of the drug). This is the occurrence of the mutations conferring CQR. Magnan: So during an outbreak RM (and other sources of random variation) + NS in infected humans can be expected to vastly predominate over any reverse selection during the mosquito reproductive life cycle. JAM: Why? Can you point me to a malaria outbreak in the real world in which all the infected humans were treated with CQ? What do you think the following quote means from the White paper (in section 5. Transmission intensity and the selection of resistance)?: "In low-transmission areas the majority of malaria is symptomatic and selection therefore takes place in the context of treatment."magnan
July 9, 2007
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I have a question. I have not followed all the detailed wrangling over the timing and sequences of mutations. This is not my background and I hadn't the time to concentrate on who is consistent or not and what the book actually says. But I read the book through once and it seemed to me the main conclusion was that the malaria eukaryote represented more reproductive events than the reproductive events in a lot of classes such as mammals since the beginning of their existence. And given this enormous number of reproductive events, very little has happened to change the organism compared to the zillions of changes that have taken place in mammals. So the argument over when and how a couple mutations may or may not have happened is a sideshow argument over irrelevant minutiae. Or am I not understanding something which is always possible. If I am misunderstanding the connection of the minutiae with the overall conclusion then maybe someone could discuss the connectionns.jerry
July 9, 2007
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I have received TEOE juast a few days ago, and I have already almost finished it. I am really very, very enthousiastic about the book. It is, in my opinion, a very important book, clear, precise and deep, full of pertinent information, balanced, and very well written. I really shoul catch up with all the discussions here. For the moment, I woul like to add a brief comment about the problem of the "two mutations", simultaneous or not, which seems to be at the center of many posts, including the last one from Jehu. It seems to me that the question should be viewed as follows: what Behe means is, as Jehu correctly states, that for resistance to CQR to arise, it is necessary that at least two independent mutations be present in the same individual plasmodium. That does not mean that the two mutations must arise simultaneously, in the sense that they must happen "at the same time", or even in the same individual plasmodium. The two mutations could well appear sequentially, for instance one in a single plasmodium and the second in its immediate descendants. But the point is that neither one nor the other confer resistance to CQR if isolated, and therefore even if they appear sequentially, the clone with the first mutation cannot in any way be selected, fixed or expanded, although it certainly has the same chances to survive as any other CQR sensitive clone (not many, if CQR is administered). In other words, the chances of having the two mutations sequentually in the same individual plasmodium line are not so different from those of having them arise "simultaneously", that is in the same cell,in a short time, because anyway the clone of the original mutation remains a small clone, does not expand, and can well die, and so the chances of having the specific second mutation in that specific clone are extremely low, and should be multiplied to the equally low chances of the first mutation to obtain the total chances of the double event in a same individual. That is not only a theoretical calculation, but is strongly supported by the observation of the extreme rarity of CQR resistance (two mutations) compared to the much higher frequency of other resistances to other antimalaric drugs (one mutation).gpuccio
July 9, 2007
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The relative fitness of CQR strains of malaria, in the absence of Chloroquine, has been calculated at .76 and .86, depending on the study. The population of CQR malaria in a single individual necessary to produce illness is at least 10^7. At that point, the gametocytes carrying the CQR genes have reached transmissible densities and will not get lost due to sexual reproduction in the mosquito. White, who has published over 400 peer review articles on malaria, appears to have already taken all of these factors into consideration in making his calculations. It is also being claimed that Behe is assuming two simultaneous mutations are required to confer CQR. This is false. What Behe is saying is that a minimum of two mutations are required before CQR arises, not that the mutations must occur simultaneously.Jehu
July 9, 2007
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Patrick Caldon I think it's misleading to say mutations are random with relation to phenotype. Random is synonymous with unpredictable. Saying random mutations are unpredictable is like saying state lottery results are unpredictable. The state wouldn't have lotteries if the results were unpredictable. They don't know precisely who will win and lose but they can confidently predict losers will vastly outnumber winners. If there's one chance in 10 million of winning a given lottery you can point to any individual ticket and predict it won't win with a confidence level of 99.99999 percent! Random mutations are on a par with that. We can confidently predict that any given random mutation won't be beneficial. If you scrutinize Darwin's Origin of Species you'll find two places in it (Chapters 1 and 5 IIRC) indicating Darwin believed in Lamarckian inheritance of acquired characters. If Lamarck was right then it becomes much more credible that evolution is the result of mutation and natural selection. The crux is that Lamarckian mutations aren't random but rather are direct responses to environmental pressure. If mutations are indeed random, and we know that random mutations are rarely beneficial, and even a beneficial mutation in organisms with long reproductive cycles and few offspring stand little chance of becoming fixed due to slightly higher selection value, then it's reasonable to seriously question whether random mutation is the true source of novelty that natural selection acts upon. DaveScot
July 8, 2007
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Phinehas: Is that similar to how the lack of randomness in coin flips and die rolls is largely predicted by physics?
No, it's very different, as I explained and you predictably ignored.
So then, what would count as a random process once we’ve set the standard for randomness so high? Or was that the point?
Well, you set the standard at PURELY random, remember? Again, mutations aren't random wrt location, direction, type, etc. They are random wrt fitness, so that can't meet any rational definition of "purely random," especially when you're applying that label to a process that includes selection, which isn't random by any criterion.
Jehu pointed out earlier: “the relative fitness of CQR strains is .76 or .85, so it is not immediately deselected for lack of fitness in an environment without selective pressure for CQR.”
First, Jehu didn't cite any data for that, and the speed depends on how you define "immediately." Why don't you try a calculation, then? Fitness is per generation. If a mosquito infects you with 10 CQR sporozoites and 10 CQS sporozoites. The proportion of CQR after n generations is then calculated as: (0.5)(0.86)^n Remember, the n is an exponent. How many generations are there in a single human host? And which one of us is engaging in wishful thinking in claiming that 0.86 isn't a significant reduction in fitness?
So, what is the relative fitness of atovaquone resistant strains?
It's the ratio of fitnesses with/without drug, not the absolute value. You really need to think about the math before you do a victory dance. The relative fitnesses will be different at each stage of the life cycle, with the wild card of sexual reproduction thrown in.
magnan made a similar point: “Concerning the rapidly reversing fitness landscape argument. White says the fitness factor of the CQR strain is 75%-85% that of the wild type. This is weak selection compared to the very strong selection for CQ resistance in a multiplying population in a sick human.
1) White doesn't say that anywhere in the JCI review. 2) What White says doesn't matter. What matters is what the data show. Besides, if you want to hold up White as the ultimate authority, he doesn't share Behe's hypothesis about simultaneous mutations. 3) The only fitness paper I found was about pfmdr, the secondary locus, not the primary one (pfcrt), with a relative fitness of 0.75 in an isogenic in vitro experiment with four substitutions: Hayward, Rhys, Saliba, Kevin J. & Kirk, Kiaran pfmdr1 mutations associated with chloroquine resistance incur a fitness cost in Plasmodium falciparum. Molecular Microbiology 55 (4), 1285-1295. 4) Guess how many days of culturing a 50:50 mix of Plasmodium carrying the resistant and sensitive haplotypes it took to reduce the level of resistant ones to an undetectable level. 5) Even if the haplotypes with 4-8 substitutions had a relatively high fitness, I'm talking about the initial steps. Obviously, if resistant bugs have swept the population, many of those substitutions (how does White think they got put together in haplotypes, btw?) help with fitness in the absence of the drug.
In addition, the population in a human victim is vastly greater than in the mosquitoes.
The number is not the critical thing--it's the number of generations, which is an exponent for the fitness. What's (0.86)^1000, for example? Is the number of generations in EACH human host typically more than 1000? Are all humans treated with drugs? What's the fitness of these haplotypes through sexual reproduction? For that matter, does Behe even bother to tell you about the sexual reproduction?
So during an outbreak RM (and other sources of random variation) + NS in infected humans can be expected to vastly predominate over any reverse selection during the mosquito reproductive life cycle.
Why? Can you point me to a malaria outbreak in the real world in which all the infected humans were treated with CQ? And in every life cycle, there's a bottleneck in mosquitoes, with differential fitness at multiple steps, including competition during sexual reproduction, all occurring in the absence of CQ.
Given these points, your assertion seems awfully speculative to me, but I’d be happy to consider any math or data you have to back up the claim that the difference between every third person and only 10 persons in the last fifty years can be explained solely by appealing to differences in relative fitness.
Solely? That's a straw man. You seem to have forgotten the multiple genes involved and the complexity of the haplotypes. How were the haplotypes assembled? What does White say? Do you realize that ethical scientists, when they disagree with dogma, cite the papers with data, and don't quote passages from reviews to try to fool people into thinking that the author of the review agrees with the ethical maverick?
That sounds like wishful thinking to me.
Sounds like projection to me. Why won't you be brave and answer my questions?JAM
July 8, 2007
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Phineas, As a broad analogy, (and I'm a non-expert in this area) think about what happens when you throw several dice. If you throw one, the probabilities of 1,2,3,4,5,6 are equal. If you throw three, there is a good chance of the sum being 9,10,11, or 12 but a very low chance of the sum being 3,4,17, or 18. I believe the point of the word "randomness" in this context is "not-correlated with the fitness of the phenotype". The mutations which happen just happen, without having an eye to what the ultimate effect of the mutations are on the critter. The mutation probabilities are on the other hand correlated with other things; e.g. the organism's exposure to mutagenic processes and substances, the particular place on the chromosome, and so on.Patrick Caldon
July 8, 2007
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