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Ken Miller, the honest Darwinist

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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
Patrick: "I think someone needs to summarize the argument and conclusions in this thread." I have tried to summarize my take on this discussion with a further elaboration of the numerical argument: Nicholas White in his 2004 paper makes an estimate of the rate of appearance of chloroquine resistance in malaria Plasmodia. "Resistance to chloroquine in P. falciparum has arisen spontaneously less than 10 times in the last 50 years (14). This suggests that the per parasite probability of developing resistance de novo is on the order of 1 in 10^20 parasite multiplications." This is cited by Behe in TEOE. An estimate for the actual parasite multiplication rate per 48 hours (PMR) is given as about 8. With the exponential growth curve and no die off this leads to a 1 trillion population in about 28 days. There are in any year about 42-43 million people sick with malaria. If it takes about 5 years worldwide to develop resistance somewhere, this is about 70 periods of multiplication to a 10^12 population in 4.25 x 10^7 people. This is 1 in a total of 7.0 x 10^13 x 4.25 x 10^7 = 2.3 x 10^21 parasite multiplications. The initial stages of parasite multiplication may be against the full uncompromised immune system attack, where White's 2-3% figure applies. This will stretch out the time required for the clone to reach "transmissable densities". During this preliminary period of the infection the immune system will destroy some percentage of spontaneously occurring CQR mutated parasites before they can multiply by many times. So this is an attrition factor that stretches out the time to achieve the 1 trillion population. To be conservative, we could assume it increases the time period to a 10^12 population from 28 days to 280 days. This would reduce the number of multiplications to 2.3 x 10^20. But this number still does not reflect the CQR parasites that were killed by the immune system. We can assume that the immune system was not significantly weakened up to the point of transmissible densities. This would be up to say a population of 500 million. During this period say 98% die. But during this stage the immune response factor is insignificant because it takes place in relatively small populations - the vast bulk of the multiplications take place after this point, in the acute phase leading from 500 million or so to 1 trillion. In this latter part of the progression of the disease the population expands by a factor of about 2000. In the latter stages of the infection leading to the 1 trillion population the host's immune system is compromised, so during this stage which includes most of the total multiplications the immune system kill off is much less than 98-97%. There is one more factor: partial reversal of fitness selection due to the CQR parasite being some percentage less fit than the wild variety in a non drug environment. This also would reduce the chances of a CQR mutant surviving to propagate into a large population. This factor is also insignificant because the people being considered in the estimate are all being treated with chloroquine, in order to clinically observe chloroquine resistance. As a result, in this human population sick with malaria during the time being considered, the CQR parasites are always favored over the normal type. This reasoning attempts to figure in all the objections, but it still results in approximately 1 in 10^20 to 10^21 multiplications.magnan
July 14, 2007
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I should have said "...2-3% of the parasites in each parasite life cycle (not each multiplication) to generate a variation of the cell surface antigen"magnan
July 14, 2007
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PaV " I took that for a maximum number. But, of course, if you multiply 5 years (avg. time for resistance to develop) and 183 (365 divided by the two-days needed to develop the 10^12 parasites in each of the severely ill malarial patients), this leads to 0.915 x 10^20 malarial parasites needed for CQR to develop." It is good to try to come up with a more rigorous estimate. I would differ from this a little. The parasite life cycle of invading a red blood cell, multiplying inside and then bursting to spread more parasites is about two days. I found an estimate for the actual parasite multiplication rate per 48 hours (PMR). This is given as about 8. With the exponential growth curve and no die off at all this leads to a 1 trillion population in about 28 days. If it takes about 5 years worldwide to develop resistance somewhere, this is about 70 periods of multiplication to a 10^12 population in 4.25 x 10^7 people. This is 1 in a total of 7.0 x 10^12 x 4.25 x 10^7 = 2.3 x 10^21 multiplications.magnan
July 14, 2007
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Jehu: "You say White put the odds of selection at 2-3%? If White really believed that he should have estimated the number of de novo CQR events at 250 instead of “less than 10.” I think the odds of selection in a sick person is about 50%, which fits with White’s calculation." This is a good point. But he is clear on the immune response factor. "It is likely that this specific immune response directed against the immunodominant surface antigens will reduce the probability of the usually single mutant parasite ever multiplying sufficiently to transmit as for P. falciparum; 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 transmissable densities." The parasite apparently has a systematic way of evading the host immune response. This is by programming 2-3% of the parasites in each multiplication to generate a variation of the cell surface antigen that the immune system responds to. Very clever. Perhaps White didn't figure this in to his calculation because he was mainly considering acute phase infections, after the parasite has already reached "transmissible" densities (apparently that is in the order of hundreds of millions to a few billion Plasmodia, not the trillion or so for acute phase. During the latter period presumably the host immune system is weakened considerably, so the 2-3% survival rate no longer applies.magnan
July 14, 2007
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gpuccio: "....any contribution of other factors (immune system of the host, reversal of mutation for fitnell loss, etc.) cannot explain the great difference in orders of magnitude between observed CQR and other observed resistances." The host immune response and (partial) fitness reversal effects can be considered to in principle commonly apply to both single and double mutation resistance genetic events. So the observed huge difference of frequencies of occurrence would not be expected to be affected. gpuccio: " But, even if one of the alternative views were partially true, Behe’s thesis is more than valid." I agree. I just think it is prudent to carefully examine all possible criticisms. As I mentioned, I think this particular objection is actually technically valid. It directly follows from the way White apparently did his calculation of the frequency of "de novo" resistance genetic events. But it is a minor point that still doesn't affect Behe's thesis. gpuccio: "It could, alternatively, have developed a metabolic way of destroying the drug “chloroquinase”, or something like that)......Or the plasmodium could have developed a new pump system, out of the blue, with the only function of getting rid of the drug." The only way critics could deal with this would be to show that there are no more elaborate strategems possible to the parasite, presumably due to its basic structural design. In other words, that your suggestions are impossible without fundamentally redesigning the whole organism. This is ridiculous on the face of it.magnan
July 14, 2007
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Is there some resistance in other animals to malaria that is no present in humans? Could it be that we "thin-skinned" humans are easy targets for the probing mosquito proboscis?PaV
July 14, 2007
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I think someone needs to summarize the argument and conclusions in this thread and post it as a front page thread.Patrick
July 14, 2007
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You might be confusing the total number in a year with the total number on any given day. White gives the number of between 10^16 and 10^18 as the population in sick people in any two-day period, not over the course of a year.---------Jehu I was working off of Figure 5 from White's "Antimalarial Drug Resistance". It shows 10^17 as the number of parasites "in the world today". I took that for a maximum number. But, of course, if you multiply 5 years (avg. time for resistance to develop) and 183 (365 divided by the two-days needed to develop the 10^12 parasites in each of the severely ill malarial patients), this leads to 0.915 x 10^20 malarial parasites needed for CQR to develop. Seems awful close to 1 in 10^20, doesn't it? :) So I'm much more comfortable with the numbers. And, alas, for the Darwinists: they've got to come to terms with these numbers.PaV
July 14, 2007
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I have a question. What is unique about human blood that makes the malaria parasite go after it and not other animal's blood? Is there some resistance in other animals to malaria that is no present in humans?jerry
July 14, 2007
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jehu and magnan: thank you for your very thoughtful attempts at verifying thsoe calculations. I appreciate them very much, and they have certainly contributed to clarify some points. I think that the important thing is that Behe's thesis is based essentially on a fact: the rarity of chloroquine resistance compared to other malaria resistances. The best explanation for that is that it is a more complex mutation, requiring "at least" two independent, selectable mutations. That explanation, and White's calculations, all fit very well the data. The objections of JAM (I am sorry that he is no more here, even if I agree that his attitude was very destructive, to the point of disrespect for others) and of other darwinist are, it seems, of two kinds: 1) White's (and Behe's) statement that CQR happens so rarely (1 in 10^20 individuals) is wrong. Maybe CQR happens much more frequently. I think this objection is unsubstantiated and doesn't fit the data. CQR could happen more frequently if it were a single mutation, which it is not, or if it were the result of two independent, sequential, selectable mutations, which is not in accord with the data. JAM, I think, tried to support both these views (which is contradictory). The first point is simply not true, at least if we refer to clinically significant resistance, whcih is the only one which, in the real world, has produce a true fixed mutant. In all isolated CQR forms, if I understand well, we find at least two mutations, sometimes more. Besides, if CQR were the product, at least in some cases, of a single mutation, that mutation should absolutely be found much more frequently than all others, and I really believe that any contribution of other factors (immune system of the host, reversal of mutation for fitnell loss, etc.) cannot explain the great difference in orders of magnitude between observed CQR and other observed resistances. 2) But, even if one of the alternative views were partially true, Behe's thesis is more than valid. The fact remains that, in the real world, an organism (malaria plasmodium) in the presence of a very strong fitness landscape constraint (chloroquine generalized use, or if you want S hemoglobin), and with a huge probability resource available (a very high number of replications) has developed nothing more than "burning the bridge" adaptations, all of them molecularly very simple (one or a few more "destructive" mutations), none of them building true new information. That's a fact, and it is not really important if White's calculations be one or two orders of magnitude wrong. The malaria plasmode, in all that time, with all those replications, and using all possible tools of randomness and selection, including both asexual and sexual reproduction, has manages just that. Darwinian evolution has managed just that. Now, maybe malaria plasmodium, or HIV, or E. coli, are not loved by darwinian evolution, and so they are purposely kept out of its best resources. The fact is that humans, with infinitely less resources, are supposed to have developed in a short time all the adaptations which explain the difference with chimps, however big you think they are. I just want to answer here to another objection that I have read, that the plasmodium could only adapt to chloroquine with those "simple" mutations, while humans could have benefited of much more complex mutaations for their evolutionary goals. That's not true. If plasmodium evolved that way it was not because it was the only way, it was the only "simple" way. It coul, alternatively, have developed a metabolic way of destroying the drug (a "chloroquinase", or something like that). Bacteria have penicillinases, but they have not evolved by random mutation. They are simply exchanged by horizontal gene transfer. Or the plasmodium could have developed a new pump system, out of the blue, with the only function of getting rid of the drug. Or it could have adapted its own metabolism (not only the drug target) so that the drug could no more affect it, for instance developing a new pathway to get rid of the heme molecule. Or it could have become a completely different organism, a new species, more efficient as a parasite, to avoid the S hemoglobin menace. Or it could have become a multicellular organism, or an independent, non parasitic organism, or just a parasite of something else. Or... Just mention what you want. After all, with lower evolutional resources, chimps are supposed to have become men. And many other magic adaptations are supposed to have taken place. And, if CQR can happen with only one mutation, which is not true, Behe's thesis stays valid: why only so simple mutations have taken place? Why nothing more complex, more elegant, more efficient? Why is the blind watchmaker so blind that he cannot produce any watch? And if the CQR mutation happens more frequently, the same questions apply. Why so poor results? If mutation reversal is so powerful a force, isn't that a further proof of how darwinian mutations are almost always negative, or neutral at best, even when they bring some advantage? In the end, the only truth is this: Behe is right, completely right.gpuccio
July 14, 2007
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Magnan, The number White gives is "less than 10" for de novo CQR events. As of 2002 only 4 de novo CQR events were known. It appears that another was discoverd in the Philipines. That makes 5. So "less than 10" is twice as many as were actually discovered. You say White put the odds of selection at 2-3%? If White really believed that he should have estimated the number of de novo CQR events at 250 instead of "less than 10." I think the odds of selection in a sick person is about 50%, which fits with White's calculation.Jehu
July 14, 2007
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In his 2004 paper White estimates the effect of specific immune response. It boils down to there being a 2-3% chance that the mutant parasite will evade the host's specific immune response and expand in population to "transmissable densities". So my guess of 1% is very conservative at 1/2 - 1/3 the expert estimate of the factor, making it unlikely to be relevant.magnan
July 14, 2007
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Jehu: "You really have to allow very slim chances of selection to dent those numbers. Since we are only talking about sick people, that criticism doesn’t really hold water." The point is that this estimate is technically for the number of CQR genetic events in parasites that survived past host immune response and differential fitness selection. I just wanted to verify that this factor really was irrelevant. I think you are right, but I just wanted to look at some numbers. For this issue the crucial parameter in the calculation is the number of occurrences of CQR reported worldwide. If there were no such selection factors killing off some occurrences of CQR in individual parasites during the period leading up to actual clinical detection of patient CQR, how many reports of CQR in patients would there have been? With 10 reports actually and if the "die-off" factor is 99 out of a hundred (1% survive), with no die off there would have been 10 x 10^2 = 10^3 = 1000 reports. Then instead of 1 in 10^20 - 10^21 the estimate would be 1 in 10^18 - 10^19. Still very low and leaving Behe's argument essentially untouched. This "CQR parasite die off factor" must be limited (and is probably less than the 99% assumed in the above calculation), because during the sickness the immune system is compromised so immune system attack is not a large factor killing off CQR parasites, and during much of the course of the disease chloroquine is being administered, so selection is definitely for the CQR strain and not being periodically reversed to favor the non-CQR strains. So it seems to me this is a technical objection that is not germain to the validity of Behe's thesis. Any critic would have to show these effects to be many orders of magnitude greater to make the objection credible.magnan
July 14, 2007
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PaV
The calculation I made is from memory and comes from numbers in another paper by White. The 10^12 number of parasites is true ONLY for those who become seriously ill with malaria—and probably end up dying. That represents just a percentage of all those who are infected. That’s why for (b) I used the figure of 4 to 5% of the world-wide number infected.
Let's see if we can tighten the numbers up a bit. The number of sick people each year is about 4.25 x 10^8. (WHO report) The median number of parasites in a symptomatic person at any given time is 2.5 x 10^11 (Dondorp 2005) Over 50 years CQR has occured de novo less than 10 times. So our calculation is [(4.25*5*2.5)*(10^8*10^11*10^1)]/10. So that gives us a per parasite probability of 1 in 5.31 x 10^20. That is over five times lower than the probability White and Behe give. However, I think the actual probability is even lower than that . The number I used for the parasite population of sick people is the biomass on any given day. The actual number in question is the number of reproductive events over the term of the sickness. Remember, we are looking for opportunities to mutate to CQR. I invite you to challenge my math. I'm no William Dembski you know.
As I also pointed out, though, this number becomes around 10^19 parasites in the whole world in any one calendar year—-which is in contradiction of White’s number of 10^17 for the total number of parasites. So, there’s a discrepancy. And, Behe’s number could possibly be criticized for being too high.
You might be confusing the total number in a year with the total number on any given day. White gives the number of between 10^16 and 10^18 as the population in sick people in any two-day period, not over the course of a year.Jehu
July 13, 2007
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Looks like I made an error, the population of sick people is 4.25 x 10^8. So, according to my calculations, that would put the de novo CQR probability at 1 in 2.125 x 10^22. or 212.5 times higher than White gives. Jehu The calculation I made is from memory and comes from numbers in another paper by White. The 10^12 number of parasites is true ONLY for those who become seriously ill with malaria---and probably end up dying. That represents just a percentage of all those who are infected. That's why for (b) I used the figure of 4 to 5% of the world-wide number infected. As I also pointed out, though, this number becomes around 10^19 parasites in the whole world in any one calendar year----which is in contradiction of White's number of 10^17 for the total number of parasites. So, there's a discrepancy. And, Behe's number could possibly be criticized for being too high. But let's note two things: first, the number is still extremely high, and, second, the 1 in 10^20 is a number that White comes up with, NOT calculating "probabilities", but just a "statistical fact" regarding CQR. Behe's response to Coyne at his Amazon.com blog fully states his argument. And fully illustrates the dilemna that fair-minded Darwinists face. Fred Hoyle, in "Mathematics of Evolution", using a type of path-integral formula right out of quantum mechanics, calculated that the most that evolution could do in sexual species is to move one or two steps in one direction or other. Snoke and Behe, using a computer model, calculate that the population size, and the time period needed, to bring about a double a.a. switch in coding DNA are both extremely high. Now, per White and his malarial statistics, a CCC is 1 in 10^20, leading to the mathematical conclusion that about the most that RM+NS can do is bring about two a.a. changes. As they say: Strike Three! You're Out!!!PaV
July 12, 2007
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Looks like I made an error, the population of sick people is 4.25 x 10^8. So, according to my calculations, that would put the de novo CQR probability at 1 in 2.125 x 10^22. or 212.5 times higher than White gives.Jehu
July 12, 2007
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PaV: “Then, per White, (a) is 10^12; (b) world-wide 350-500 x 10^6 people have malaria each year; but of those a small percentage get seriously ill. If we assume four to five percent of those with malaria are seriously ill, that gives 2 x 10^7; (c ) is 5 years (ten developments of CQR in 50 years): Thus, (10^12) x (2 x 10^7) x 5 = (approx) 10^20.” According to the World Health Organization, 350 to 500 million people became ill with Malaria in 2003. So 425 million is a good estimate for the number of people who get sick with Malaria each year. That is 4.25 x 10^7 sick people, with a population of 10^12 each, per year for 50 years. With those numbers, I calculate a total population of 2.125 x 10^22. If we allow CQR has occurred de novo 10 times (it has actually only been discovered 4 or 5 times I believe) then the probability of CQR occuring de novo 1 in 2.125 x 10^21. That is 21.25 times higher than the number that White gives. You really have to allow very slim chances of selection to dent those numbers. Since we are only talking about sick people, that criticism doesn't really hold water.Jehu
July 12, 2007
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magnan,
Each case is the result following a long process of immune system attack of any clones of parasites that happened to acquire CQR, and differential fitness selection (at least prior to administration of the drug). So it seems the actual rate of parasites developing CQR must be higher than the 1 in 10^20 figure, if White derived the 10^20 number the way suggested by PaV.
I don't think White used the same numbers as PaV. One thing is clear, with his over 400 publications on the topic, White clearly understands that odds against a de novo occurance being selected and that consideration taken into his calculation. Just read some of White other papers that have been linked to in this thread if you are interested. You also have to consider the population that the figure is calculated from. Sick people. It is not calculated from the population of all malaria in the world. Sick people have compromised immune systems. I pointed this out in post #71. In the 2004 paper, White states, "Taken together, the balance of evidence strongly favors acute symptomatic infection as the source of de novo antimalarial resistance.” Additionally, White calculates the number of times CQR has arisen at "less than 10" not "5". As I previously pointed out in post #102, a massive NIH study found only four historic instances of CQR occuring de novo. This would mean that White allowed for roughly double the number of de novo instances than have actually been found. From what I have read, this is consistent with population genetics probabilities of a trait being selected under strong selective pressure. In stating the estimated number of times CQR has occurred de novo, White cites to, Su, X., Kirkman, L.A., Fujioka, H., and Wellems, T.E. 1997. Complex polymorphisms in an approximately 330 kDa protein are linked to chloroquine-resistant P. falciparum in Southeast Asia and Africa. Cell. 91:593-603. Unfortunately, I don't have access to that article. It would be important to see how the "less than 10" number is justified. So if anbody can post the referenced portion of the article it would be appreciated.Jehu
July 12, 2007
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PaV: "Then, per White, (a) is 10^12; (b) world-wide 350-500 x 10^6 people have malaria each year; but of those a small percentage get seriously ill. If we assume four to five percent of those with malaria are seriously ill, that gives 2 x 10^7; (c ) is 5 years (ten developments of CQR in 50 years): Thus, (10^12) x (2 x 10^7) x 5 = (approx) 10^20." I have been trying to understand this issue despite JAM's distasteful and unclear posts. This may get me banned from this blog, but I just have a need to understand the truth of these issues, whatever it is and regardless of the consequences. I say this as an ID advocate. (c) above is the rate of observed clinical resistance developing somewhere in the world. Each case is the result following a long process of immune system attack of any clones of parasites that happened to acquire CQR, and differential fitness selection (at least prior to administration of the drug). So it seems the actual rate of parasites developing CQR must be higher than the 1 in 10^20 figure, if White derived the 10^20 number the way suggested by PaV. White's statement in his 2004 paper in which he furnished the 10^20 figure: "...This suggests that the per-parasite probability of developing resistance de novo is on the order of 1 in 10^20 parasite multiplications." The critic was claiming that White's statement was poorly written, and that it should have been as follows: "...This suggests that the probability of a parasite both developing resistance and passing on this resistance to produce clinically observed resistance is on the order of 1 in 10^20 multiplications." If this interpretation is correct, then White's figure of 1 in 10^12 for development of "one mutation" resistance (based on atovaquone) was also poorly stated in the paper and would be rewritten in the same way, so the actual per-parasite probability for atovaquone resistance must be much larger. I really want to discover why this reasoning is incorrect. At the same time I have already posted on how this issue needs to be put in perspective.magnan
July 12, 2007
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JAM: You have invoked recombination as a mechanism that increases the probability of getting two mutations simultaneously. However, malarial parasites, though eukaryotic, when reproducing in humans, do so asexually, thus eliminating the possibility of recombination except for a few meiotic cycles in the mosquito. As to "simultanaeity": White published in another paper a number for the world-wide number of malarial parasites for any given year. His number, i.e., the total number of malarial cells in any one given year, is 10^17. If a simultaneous mutation involving two a.a.s is 10^20, then this would be expected once in every thousand years. This strongly suggests that the mutations occur sequentially, and not simultaneously. Now, having said that, I think if we follow what Behe writes on p. 57: "Nicholas White of Mahidol University in Thailand points out that if you mulitply the number of parasites in a person who is very ill with malaria (a) times the number of people who get malaria per year (b) times the number of years since the introduction of chloroquine (c ), then you can estimate that the odds of a parasite developing resistance to chloroquine is roughly one in ahuncred billion billion." Then, per White, (a) is 10^12; (b) world-wide 350-500 x 10^6 people have malaria each year; but of those a small percentage get seriously ill. If we assume four to five percent of those with malaria are seriously ill, that gives 2 x 10^7; (c ) is 5 years (ten developments of CQR in 50 years): Thus, (10^12) x (2 x 10^7) x 5 = (approx) 10^20. But I have to remark that (a) x (b) is greater than 10^17; which gives me pause. Anyway, however nature wanted to work it, it took a hundred billion billion (per White) malarial cells (=organisms) to come up with two mutations that developed resistance to chloroquine. It seems to me Behe's argument still stands.PaV
July 12, 2007
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JAM argued a strawman: Behe was very clear in specifying a single mutation shifting two amino acids that is required to BECOME (not to simply BE clinically) resistant.
Baloney. At some point people run out of patience having to deal with a participant who argues his case by willfully attributing things to ID proponents which they did not say. JAM showed incompetence in interpreting Fidock, but still did not relent. He made a rather ridiculous interpretation of that paper, and when I called him on it he finally relented. That didn't stop him from spewing out more garbage that I just wasn't willing to deal with. Many thanks the admins for dispensing with jam.scordova
July 11, 2007
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JAM: thank you for your comments. I'll try to answer some of your points: 1) Why should Behe discuss the origin of the Vpu protein any more than the origin of any other functional protein in HIV or in any other living system? It's you who have cited the Vpu in the discussion. As far as I know, there is no reason that this particular protein is not designed, like, in my opinion, any complex functional protein in any living system. It's darwinian theory which, without any evidence, declares that all of them have evolved by mechanical, step by step, RM + NS. So, I ask again: are you aware of a detailed, step by step molecular path of evolution for that protein (or for any other) by darwinian means? I think I have answered your question, will you please answer mine? 2) You say: "I’m sorry, but teaching a basic genetics course is beyond the scope of a blog comment". ButI have not asked a course. I only ask that you clarify, as briefly and clearly as possible, your statement that: due to recombination, “the probability of getting two independent mutations together is many orders of magnitude higher”. I just miss the explanation of your quantitative statement. Would you be so kind as to say something more? After all, even if this is only a blog, everyone here is trying to make his points clear to others. Except you, maybe. 3) I appreciate your clarifications about resistance not being binary, and I agree with you on that point. I don't think that changes very much the problem, as you seem to affirm. The fact remains that you cited an article which is only about in vitro manipulations, and has probably scarce connections with what happens in vivo. I would like you to specify better your thoughts. You criticize Behe for having made assumptions you don't agree with. Behe thinks, deriving that from White, that the much lower incidence of CQR compared with other resistances is due to the fact that at least two aminoacid mutations are needed to confer a true "in vivo" selection of the mutant. You say, if I understand well, that that's not true, or at least is not supported enough by facts. Your explanation seems to be that one mutation is enough for CQR, and that its lower incidence (extremely lower) is due to reversal for loss of fitness. Have I understood well? In that case, even if your objections to Behe should have some basis (which I don't agree), I don't see how your hypothesis is more supported by facts. It seems to me at least as speculative as Behe's. So, unless you have stronger evidence that your explanation is right, I think we can discuss both explanations, and decide for ourselves which one fits data better. In any case, I don't understand how your alternative explanation could in any way undermine the general thesis of Behe's book: if the parasite, in all that time, has not even been able to generate a mutation for which at least two substitutions are necessary before getting an advantage, but has only managed single point selectable mutations of the "burning the bridge" type, then Behe's thesis is stronger than ever. I would like to restate that Behe's point is that no new true biochemichal machine, no new protein interaction, has been developed by the parasite to adapt to the strong constraints of S hemoglobin and/or of drugs. Against that thesis, you have cited an article about point mutations, "CTL Escape Mutations", which are exactly of the "burning the bridge" type, and you have not answered my previous note about that, and you have also cited, out of the blue, the Vpu protein, whose pertinence I still miss. Again, with Behe, I affirm that anything too complex to have evolved by step by step darwinian mechanisms is best explained by design. Unless, obviously, you can show us the detailed molecular path through which it should have reasonably evolved. Again: the problem is not if CQR mutation is simpler than Behe assumes. Anyway, Behe believes that CQR has been achieved by darwinian mechanisms. The problem is that CQR, and similar, perhaps simpler, mutations, are the best thing that malaria parasite could generate, under strong darwinian constraints, by darwinian mechanisms. Nothing of the kind of a flagellum, to be clear, or of a complex new enzyme, protein cascade, or molecular machine. That is Behe's thesis, and to that you should give a reasonable answer.gpuccio
July 11, 2007
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JAM is no longer with us. Patrick Caldon is no longer with us. DaveScot
July 11, 2007
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Jehu: Given the large populations of malaria in sick people, that doesn’t help you make much headway against Behe’s arugment, you still need two mutations to get CQR.
Behe's argument has zero evidence to support it. There is substantial evidence against it. It's telling that you misrepresent a hypothesis as a fact. Science isn't about arguments, it's about evidence derived by testing hypotheses. It's especially important to produce new evidence, something that Behe doesn't do.JAM
July 11, 2007
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Jehu: What is claimed by Behe is that two mutations are required to confer CQR.
How do you derive "two mutations" from "single mutation," Jehu?
...there is no significant positive selection until both are present.
There's zero evidence to support that claim. There is substantial evidence against it, which I cited.
White already factored in the various reasons while CQR will not be selected every time it emerges, including the role of the immune system.
White clearly did, but Behe doesn't. He attributes it all to mutation rates. That's the difference. Which one is the expert?
As for your polio argument, some experiments can be performed in vitro and do not need to be in vivo. It all depends on the context of what you are attempting to determine. So I cannot respond to your polio argument.
You're not even close. Of course you cannot respond, because doing so would open your eyes to how you've been fooled by Behe!
I said your cystic fibrosis argument was laughable because you are comparing an allele that is under negative selection with an allele that is under positive selection.
1) The CFTR mutant allele is under BOTH positive selection (in heterozygotes in Second and Third World nations, who are more resistant to diarrhea) and negative selection (in homozygotes worldwide). 2) The CQR alleles are under BOTH positive selection (in treated humans) as well as negative selection (in mosquitoes and untreated humans). 3) In both cases, sexual reproduction acts as a buffer, maintaining polymorphism in the population and "resisting" selection in both directions. 4) The Plasmodium case is much more fluid, because of shorter generation times and more variance in selection pressures.JAM
July 11, 2007
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JAM,
The initial CQR mutations (the first is most likely K76T) have a bigger fitness cost in the absence of drug than the atovaquanone ones do.
Given the large populations of malaria in sick people, that doesn't help you make much headway against Behe's arugment, you still need two mutations to get CQR.
As a scientist, I make predictions. This hypothesis predicts that most, possibly all, of the other 3-7 substitutions in the CQR haplotypes, when isolated in yeast (the method you blow off), will be compensatory and will NOT increase fitness in the presence of CQ, but will instead increase fitness of K76T in the absence of CQ.
Before you get CQR you need a mutation at 76 and 220 or 76, 144, and 160. The other mutations, as has been previously stated, probably confer fitness on the CQR haplotype.Jehu
July 11, 2007
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gpuccio: First of all, I would appreciate if you were so kind to express more clearly and motivate for us ignorant your concept that, due to recombination, “the probability of getting two independent mutations together is many orders of magnitude higher”,
I'm sorry, but teaching a basic genetics course is beyond the scope of a blog comment.
1) You end one of your posts with the following: “Does Behe discuss the evolution of the HIV Vpu protein, or does he conclude that it was added by a designer?
So why not answer my question?
I don’t understand. Are you suggesting that you know a step by step darwinian evolution of the Vpu protein?
Why? Are you suggesting that God designed it in the last century or so? Behe says that his alleged limits require the intervention of a designer. I'm merely asking you, as someone who apparently takes Behe seriously, to tell me which side of that limit Vpu falls on. You can't discuss HIV evolution in any meaningful way without going into detail on Vpu, which does amazing things despite its small size and recent origin, which is true whether it was designed or evolved.
I want to say that I don’t understand your problem with distinguishing between “selective advantage” and “clinically significant CQR”.
It's orders of magnitude, measured both in vitro and in vivo. The concept of differing curves, along with Emax and EC50 is explained very well in the White & Pongtavornpinyo review. You're going to get selective advantages at doses far below the EC50, and plenty of patients will have serum levels below the EC50. Even the patients who follow instructions will at the beginning and end of treatment.
While the two concepts are certainly not the same thing in general, here we are talking of resistance to CQ in an individual infected.
It's a continuum, not a binary characteristic.
The only significant “fitness constraint”, in this context, is resistance to CQ, and it is an advantage only if it is enough to allow infection of the host who is receiving CQ,
It's not binary at all. Go back to my math challenge, an do the math in the presence of CQ dose so small that the relative fitness of the initial CQR mutant is only 1.02. What will be the ratio of mutant to wild-type after 2-3 weeks?
and myultiplication of the parasite in “that” host.
So, in this context, the only true selective advantage is clinically significant resistance to CQ. That's not what White says.
Indeed, if the parasite is resistant enough, it can multiply in the treated host, otherwise it dies.
Its fate depends on two continuous, nonlinear variables: its level of resistance and the concentration of CQ. Sublethal concentrations of CQ are still going to select against wild-type organisms even when they don't kill them. In mosquitoes and untreated patients, the selection is not merely absent, but reversed. For your model to be correct, the fitnesses could never be fractional. You are assuming that the fitness of the mutant is 1 and the wild-type fitness is 0. It just ain't that simple.JAM
July 11, 2007
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Sal: The mistake you made was to assume K76I is sufficient to confer CQR.
No, that wasn't my mistake. The question is whether either K76T or K76I is sufficient to confer ANY selective advantage in the presence of CQ. This is the converse of the math challenge I issued, but which only Patrick had the courage to take up.
But that was not the mutation Behe was speaking of.
Behe was very clear in specifying a single mutation shifting two amino acids that is required to BECOME (not to simply BE clinically) resistant. He explicitly states that "a shift of two amino acids" in a "single mutation" is the stumbling block: “...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–..."
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.
Sal, your attempt to trivialize it through strategic omissions is ludicrous. The paper shows that mutating K76 to either I or T AND NOTHING ELSE, results in a substantial increase in CQ transporter activity, the most likely mechanism underlying CQR. This is the only presently available way to test the contribution of each individual change. It is a coisogenic experiment, the best kind.
The issue is whether K76* mutations by themselves are sufficient, and it appears they are not.
No, from these well-controlled experiments, it appears that they are more than sufficient to get the process started by themselves. ------
Behe: 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...
Sal: Was he saying the only abosolute possible route to CQR is via 2 mutations,...
He wrote that a single mutation shifting two amino acids is required.
... or was he referring to the two most important mutations in the primary form of CQR observed and studied so far?
How could he possibly have been referring to TWO mutations if he wrote "SINGLE mutation"?
If you don’t know, say so.
I can say with complete confidence that the phrases "two most important mutations" and "single mutation" cannot possibly be referring to the same things or events.
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:
No amount of charity can equivocate between "two most important mutations" and "single mutation," Sal.
Behe: ...different mutations have been found in PfCRT from different regions of the globe…
It does nothing to negate his claim that a single mutation shifting two amino acids is required.
The mutant PfCRTs exhibit a range of changes, affecting as few as four amino acids to as many as eight.
The presence of other changes does nothing to contradict a claim that two changes are required as a single mutation.
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,
Nope. Behe specified a "single mutation" and "a shift of two amino acids," and he used the verb "become," reflecting the process, not the end result. Furthermore, clinical CQ resistance is orders of magnitude more than that required to gain a selective advantage in the presence of CQ.
... not that 2 mutations are the only absolute possible route..
He described it as a "single mutation," Sal, that caused "a shift of two amino acids." Why do you put words in Behe's mouth?
JAM, I’m afraid, you’re unwilling to see what Behe is trying to communicate.
Behe is trying to communicate that the rarity of emergence of CQR is primarily the result of a low mutation rate, when in fact, all the experts agree that it is the result of conflicting selection pressures complicated by sexual reproduction and inability to maintain selective pressure in real-world clinical situations.
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.
No, Sal, the number 2 did not refer to the minimum of 2 mutations needed. It referred to the number of amino-acid shifts in a single mutation that Behe claims is required. Behe: "single mutation" "required" "a shift of two amino acids"
Well then, how do you account for the fact CQR too longer to evolve than other forms atovaquone.
The initial CQR mutations (the first is most likely K76T) have a bigger fitness cost in the absence of drug than the atovaquanone ones do. As a scientist, I make predictions. This hypothesis predicts that most, possibly all, of the other 3-7 substitutions in the CQR haplotypes, when isolated in yeast (the method you blow off), will be compensatory and will NOT increase fitness in the presence of CQ, but will instead increase fitness of K76T in the absence of CQ. Now, why don't you answer my questions, Sal. 1) If the rarity of emergence of CQR represents a failure of Darwinian evolution, instead of an illustration of MET and population genetics applied to a fitness landscape that not only changes, but reverses, over time, how do you explain the fact that CQR emerges more frequently in regions of low-intensity transmission than in regions of high intensity? 2) Do you see the mechanism of deception in my totally dishonest polio argument? 3) Why don't you do the math to see if a relative fitness of 0.86 in Plasmodium is small or huge? 4) Why don't you do the same problem, assuming only K76T with a fitness of 1.02 in a human who has a low serum concentration (clinically ineffective) of CQ?
You’re persistent, JAM, and dialogue with you has been good practice at rhetoric, but I think you’re not persuading the ID side,
Is that even possible? How can I convince anyone who claims that "two mutations" and "single mutation" refer to the same thing? How can I convince anyone who can't identify the deception in an argument that I specify is deliberately deceptive?
... and I’m not so sure your side is believing what you have to say.
Well, Patrick did the math, and you didn't.
The bottom line is that Darwinism, in light of the very large number trials, was relatively slow to evolve resistance to CQ.
The bottom line is that Behe is trying to misrepresent the delay as being caused by mutation rates, when in fact, it is caused by conflicting selection pressures, which obviously are going to slow Darwinian evolution down. Darwinism doesn't evolve anything; organisms evolve.JAM
July 11, 2007
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JAM, What is claimed by Behe is that two mutations are required to confer CQR. After these two mutations are achieved they are positively selected and subsequent mutations can be sequentially added to improve the fitness of the CQR haplotype. The first two mutations can be sequential or the result of the recombination of two different mutant haplotypes but there is no significant positive selection until both are present. White's estimate of 1 in 10^20 as the per-parasite probability of CQR arising de novo is properly cited by Behe and it is the correct number. White already factored in the various reasons while CQR will not be selected every time it emerges, including the role of the immune system. As for your polio argument, some experiments can be performed in vitro and do not need to be in vivo. It all depends on the context of what you are attempting to determine. So I cannot respond to your polio argument. I said your cystic fibrosis argument was laughable because you are comparing an allele that is under negative selection with an allele that is under positive selection.Jehu
July 11, 2007
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JAM: sincerely, I can't follow the rythm of all your discussions. First of all, I would appreciate if you were so kind to express more clearly and motivate for us ignorant your concept that, due to recombination, "the probability of getting two independent mutations together is many orders of magnitude higher", and the important role of the haplotype concept for that, instead of generivally suggesting that we read genetic textbooks. After all, this is a blog, and for the sake of discussion, you should elucidate explicitly your arguments, so that we can either be convinced and happy, or answer them. For the moment, I will answer a couple of things that you have said explicitly: 1) You end one of your posts with the following: "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." I don't understand. Are you suggesting that you know a step by step darwinian evolution of the Vpu protein? And what is the meaning of the article you cite? I have checked, and I would definitely say that the escape mutations of HIV which are treated in it, and in several similar articles, are just a perfect example of what Behe extensively discusses, that is point mutations which, by changing an epitope of an existing structure, do provide an advantage towards an aggressor (CTLs). Exactly as in antibiotic resistance. Exactly what Behe very correctly defines "burning bridges", and very clearly states is inthe normal range of what darwinian evolution can do. Have you read TEOE? Besides, some of these point mutations happen with loss of fitness, and reverse after the removal of the constraint (see: HIV Evolution: CTL Escape Mutation and Reversion After Transmission, at the following URL: www.medscape.com/viewarticle/471679_2). Therefore, I don't understand what is the point you are trying to make. 2) I paste here a couple of your comments to my post: My post: "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." Your comment: "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." My post: "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,…" Your comment: "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?" I want to say that I don't understand your problem with distinguishing between "selective advantage" and "clinically significant CQR". While the two concepts are certainly not the same thing in general, here we are talking of resistance to CQ in an individual infected. The only significant "fitness constraint", in this context, is resistance to CQ, and it is an advantage only if it is enough to allow infection of the host who is receiving CQ, and myultiplication of the parasite in "that" host. So, in this context, the only true selective advantage is clinically significant resistance to CQ. Indeed, if the parasite is resistant enough, it can multiply in the treated host, otherwise it dies. And believe me, if the parasite multiplies, the host is clinically affected. After all, this is my field...gpuccio
July 11, 2007
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