Uncommon Descent Serving The Intelligent Design Community

Ken Miller, the honest Darwinist

Salvador Cordova
June 27, 2007
Intelligent Design
Share
Facebook
Twitter
LinkedIn
Flipboard
Print
Email

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
JAM: Their lack of randomness is largely predicted by genetics, chemistry and biochemistry. Is that similar to how the lack of randomness in coin flips and die rolls is largely predicted by physics? So then, what would count as a random process once we've set the standard for randomness so high? Or was that the point? Phinehas: Can you please explain the difference in these spontaneous resistance rates? JAM: Easily. Substitutions that confer some degree of CQR decrease fitness in the absence of CQ much more than the substitutions that confer atovaquone decrease fitness in the absence of atovaquone. 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." So, what is the relative fitness of atovaquone resistant strains? 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. In addition, the population in a human victim is vastly greater than in the mosquitoes. 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. So an alternating fitness landscape doesn’t explain the rarity of CQR." 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. That sounds like wishful thinking to me.Phinehas
July 8, 2007
July
07
Jul
8
08
2007
04:32 PM
4
04
32
PM
PDT
CJYman, Their lack of randomness is largely predicted by genetics, chemistry and biochemistry. For example, tandem repeats expand and contract at incredibly high frequencies (10E-5) by recombination. The sequences between tandem repeats are lost by recombination. Triplet CAG repeats (for example, those that cause Huntington's disease) expand by polymerase "stuttering." Transitions occur more frequently than transitions. Chromosomes break more frequently at some places than others, giving translocations. Does that answer your question?JAM
July 8, 2007
July
07
Jul
8
08
2007
09:45 AM
9
09
45
AM
PDT
Hello JAM, Just for the sake of educating myself, if mutations are not purely random, which natural law or pattern do they follow?CJYman
July 8, 2007
July
07
Jul
8
08
2007
07:44 AM
7
07
44
AM
PDT
Phinehas: Can you please explain the difference in these spontaneous resistance rates?
Easily. Substitutions that confer some degree of CQR decrease fitness in the absence of CQ much more than the substitutions that confer atovaquone decrease fitness in the absence of atovaquone. The most likely scenario is that for CQR, some of the substitutions merely "correct" some of the structural distortions caused by the CQR-conferring substitutions (both K->T and K->I are huge changes). This makes very clear experimental predictions: when the substitutions in resistant haplotypes are mixed and matched in all possible combinations in experimental systems, some will increase CQR while some will increase fitness of the resistance haplotype in the absence of CQR. Now, since I answered your question, how about answering mine: 1) If terminology is more important than data, why is the term "haplotype" used instead of "allele"? 2) Why are there papers on linkage disequilibrium? Does Behe offer a clue? 3) Why choose Plasmodium to extrapolate to human mutation rates instead of using actual human mutation rates?
Are not both arising from the same reversing fitness landscapes?
Yes, but they differ in degree--more accurately, the ratio of fitness relative to wild-type with the drug to without the drug.
Wow. Way to keep your eye on the science and the data. :rolleyes:
Keeping our eyes on the science, Behe's hypothesis (which he misrepresents as fact) suggests radically different strategies for both drug choice and design than does sequential acquisition (particularly including recombination). If he really believes that two substitutions must occur simultaneously, he should be working in his lab instead of doing book tours.
…it seems to me that assuming two SIMULTANEOUS mutations are needed instead of just two SEQUENTIAL mutations puts the accomplishments of random mutation in a better light given the White quote.
It's not about putting things in a better light in the context of a quote from someone who doesn't use accurate genetics terminology. It's about figuring out what happened and how we might be able to save millions of lives, most of them belonging to children.
In other words, if only two SEQUETIAL mutations are needed to confer CQR, and yet it has only arisen spontaneously less that ten times in the last fifty years, doesn’t that say even less about what purely random forces are capable of accomplishing?
There's nothing in evolutionary theory that's "purely random," remember? Mutations are only random with respect to fitness, not "purely random." Selection isn't random at all. If this were "purely random," how is it that we see may of the same substitutions arising independently? Isn't that the antithesis of randomness, much less pure randomness?
Look, I can see that you really want the dispute to be about sequential vs. simultaneous,...
The post was about Miller. That was the precise nature of his criticism of Behe, wasn't it?
...but for me, the ten successes in fifty years is the real point, and those numbers don’t change no matter how much smoke is blown to cloud the issue.
Behe is blowing the smoke here.
I find it extremely refreshing to see evolutionary biology discussing real-world data like this representing what evolutionary processes are actually able to accomplish over a large number of generations in a purely natural setting and not one subject to intelligently designed lab experiments and wishful thinking.
In my real scientific world, the ecological and experimental data complement each other. Neither replaces the other. We won't know which substitutions in CQR haplotypes do what until someone does the experiments in the lab. Would you like to bet some money on what will be found?
I can see how it would be extremely frustrating for Darwinists to have to deal with this sort of real-world data without being able to bring their refined speculative powers to bear.
Maybe you can offer a useful definition of "Darwinist" in this context. Are you suggesting that the authors of these malaria papers are ID proponents, or agnostic about evolutionary theory? Are you suggesting that I am an evolutionary biologist? That Miller is? That we follow a man instead of the evidence? Think about it.
Evolution happens.
So does denial.
And when we look at the evolution that happens in the real world, it turns out that it is very different to the evolution that happens in the imaginations of Darwinists.
In what way is it different? Since you invoked the "purely random" straw man twice, I'd like to see some evidence that you've made an effort to look at the scientific output of scientists like Miller and me.
To me, this is the real take-away from the discussion.
God forbid you might abandon the "purely random" canard. That would represent real intellectual progress.JAM
July 7, 2007
July
07
Jul
7
07
2007
11:02 PM
11
11
02
PM
PDT
Phinehas: Perhaps I am just not understanding the argument here, but it seems to me that assuming two mutations are needed instead of just one… JAM: You are completely misunderstanding the dispute here. The question is not whether two mutations are needed, the dispute is whether they must occur SIMULTANEOUSLY and not SEQUENTIALLY. OK. Let me rephrase. ...it seems to me that assuming two SIMULTANEOUS mutations are needed instead of just two SEQUENTIAL mutations puts the accomplishments of random mutation in a better light given the White quote. In other words, if only two SEQUETIAL mutations are needed to confer CQR, and yet it has only arisen spontaneously less that ten times in the last fifty years, doesn’t that say even less about what purely random forces are capable of accomplishing? Look, I can see that you really want the dispute to be about sequential vs. simultaneous, but for me, the ten successes in fifty years is the real point, and those numbers don't change no matter how much smoke is blown to cloud the issue. I find it extremely refreshing to see evolutionary biology discussing real-world data like this representing what evolutionary processes are actually able to accomplish over a large number of generations in a purely natural setting and not one subject to intelligently designed lab experiments and wishful thinking. I can see how it would be extremely frustrating for Darwinists to have to deal with this sort of real-world data without being able to bring their refined speculative powers to bear. Evolution happens. And when we look at the evolution that happens in the real world, it turns out that it is very different to the evolution that happens in the imaginations of Darwinists. To me, this is the real take-away from the discussion.Phinehas
July 7, 2007
July
07
Jul
7
07
2007
09:10 PM
9
09
10
PM
PDT
JAM, I note that you keep passing by this: magnan: Spontaneous resistance to atovaquone occurs to about every third sick person. Spontaneous resistance to CQ has only appeared about ten times total in the last 50 years. Can you please explain the difference in these spontaneous resistance rates? Are not both arising from the same reversing fitness landscapes? JAM: The papers you and Jehu are quote-mining were written by people who are trying to save millions of human lives, something that Behe will never attempt. Wow. Way to keep your eye on the science and the data. :rolleyes:Phinehas
July 7, 2007
July
07
Jul
7
07
2007
08:51 PM
8
08
51
PM
PDT
Jehu: This in vitro study of CQR found that,”The association of the K76T mutation with chloroquine resistance was not clear. The mutation was detected in resistant and susceptible samples, suggesting that additional factors are involved in chloroquine resistance."
There's no doubt that additional ones are involved. The issue is Behe's assumption that two must occur simultaneously. There's no evidence supporting it.
The researchers further stated,...
What they stated is not the issue. What they showed is the issue. In the real world, many people don't take their medicine often enough or long enough. If you're trying to determine whether a change at K76 has to occur simultaneously with a second change, you have to look at low CQ concentrations. Of course, these researchers weren't trying to address Behe's unsupported assumption that two substitutions had to occur as a single event. They didn't do a dose-response curve.
"...the K76T mutation was also detected in 15 of 17 samples classified as susceptible to chloroquine in vitro.”
What was the classification criterion used?
This is consistent with a mutation at 76 and at least one other position being required for CQR.
That depends on how you define it, which is why quote-mining is so misleading. The issues here are: 1) whether Behe's assumption that two substitutions must occur simultaneously is supported by the evidence, and 2) Whether looking at genotypes after literally billions of generations of on/off selection represents the mutation rate. Whether two changes are REQUIRED for clinically-defined CQR is irrelevant to #1, as single changes would need to be tested for resistance to low concentrations of CQ. If both substitutions HAD to occur to get to resistance, neither can confer ANY resistance to CQ at even the lowest doses.
In fact, White specifies...
In fact, what White specifies or labels doesn't matter. What matters is that to measure mutation rates, you need an absolute, black/white selection. If you want to go with authority (always fallacious in science), BEHE HIMSELF states that the CQR mutants are less fit than wild-type in the absence of CQ, so selection is reversed in the mosquito and in humans not taking CQ. Reversing selection is the antithesis of the simple, absolute selection (like sporadic mutations to dominant lethal alleles in humans) required to infer mutation rates. Think about it: why would Behe choose to extrapolate from Plasmodium to human mutation rates instead of going with measured mutation rates in real humans?
...White very clearly estimated the “per-parasite resistance mutation frequency” of CQR at a very similar 10^19.
Then he was simply wrong in using that term.
In calculating his estimate, White cites to a 1997 paper for the figure of CQR arising 10 times in the last 50 years.
Yes, but it is clear that selection for CQR is intermittent and very complex when it is present. You can't look through the funhouse lens of that kind of selection and claim to be looking directly at mutation rates.
In contrast, a significant 2002 study by the NIH identified only four de novo points of origin for CQR. So there is reason actual rate is even lower. However, as Behe pointed out, it is probably “roughly” 1 in 10^20.
That's not the mutation rate.
Phinehas: Perhaps I am just not understanding the argument here, but it seems to me that assuming two mutations are needed instead of just one...
You are completely misunderstanding the dispute here. The question is not whether two mutations are needed, the dispute is whether they must occur SIMULTANEOUSLY and not SEQUENTIALLY.
...puts the accomplishments of random mutation in a better light given the quote above.
Unfortunately, the job of a scientist is to see if her hypothesis holds up in the worst light by actively testing its predictions, not to cherry-pick observations to support it. The papers you and Jehu are quote-mining were written by people who are trying to save millions of human lives, something that Behe will never attempt.
In other words, if only one mutation is needed to confer CQR, and yet it has only arisen spontaneously less that ten times in the last fifty years, doesn’t that say even less about what purely random forces are capable of accomplishing?
It clearly says that the completely NONrandom forces of selection account for the rarity. Also, please remember that nothing is purely random in evolutionary theory. The mutations are only random in a single way: with respect to fitness.
Given the data, I would think that NDE would come off much better if a rather large number of mutations were required simultaneously for CQR.
Why? The frequency with which it arises is far too HIGH to be accounted for by more than two simultaneous mutations. Did you not notice that up to eight substitutions are found in CQR haplotypes? Say, since specifications seem to be so important to you folks, would you mind explaining why the experts call these "haplotypes" instead of "alleles"? You might try searching for papers that include "linkage disequilibrium" in the title/abstract.
I’m a little stumped about how arguing for fewer mutations is supposed to help NDE’s case.
That's understandable. Miller and I are arguing for sequential mutations, not fewer. Behe is assuming that two must occur simultaneously, with no evidence to support his assumption.
Jehu: If CQR can be achieved by a single step...
Jehu, it's not about whether clinically-defined CQR can be achieved by a single step. It's about whether any of the 4-8 substitutions found in CQR haplotypes (why do they use that word?) had to occur simultaneously.
... and yet has only been selected less than 10 times in 50 years of intense selective pressure in an astronomical number of organisms,
What you're not seeing is that the selection isn't very intense. In fact, Behe himself acknowledges that it gets reversed in the absence of CQ, which happens very often.
then what does that say about the power of natural selection?
What does the power of recombination during sexual reproduction suggest to you?
Mangan: This confirms Behe’s conclusion from the clinically determined resistance in victims and the genetic mutation evidence that CQR requires more than one (at least two) mutations.
The issue, as Miller noted, is whether those mutations occurred simultaneously or sequentially. If they occurred sequentially, given the existence of sexual reproduction in Plasmodium, would the second mutation have had to occur in the initial mutant allele?
JAM: No, because you missed the unsupported assumption that two were required simultaneously. I have shown that the conclusion that at least two were required is well established from research studies. Whether the mutations for CQ resistance were simultaneous or happened sequentially, the clinical rates of appearance of resistance, and White’s estimates of de novo rates clearly indicate the approaching of a limit to NDE as Behe contends.
I suggest that you read the book. Behe is claiming that mutation fails to supply sufficient variation for NS to act upon. The problem with the centerpiece of the book is that his probability has nothing to do with mutation frequencies, and everything to do with reversing selection layered over sequential mutations and recombination during the sexual phase of reproduction (always in the absence of CQ).
...Notice the phrase “lead to the emergence”.
I notice the data more than the phrases. But since you place so much stock in semantics, please explain the use of the term "haplotype" in these papers.
This obviously refers to the probability of the mutation(s) spontaneously occurring in a parasite prior to subsequent selection and expansion of the parasite population in the victim’s body.
Since the detection of it is only possible after many life cycles of selection for alternating with selection against this, your inference is fatally flawed. What does "linkage disequilibrium" obviously refer to?JAM
July 7, 2007
July
07
Jul
7
07
2007
06:12 PM
6
06
12
PM
PDT
JAM: "The problem with his conclusion (1 in 10^20) is that it is based on an assumption that two (mutations for CQR) are required, for which he has no evidence." No. This was based first on the clinical data (occurrence of spontaneous resistance in victims) and then supported by the gene mutation data. Spontaneous resistance to atovaquone occurs to about every third sick person. Spontaneous resistance to CQ has only appeared about ten times total in the last 50 years. The 2005 Bray, Martin et. al. (including Fidock) study Behe refers to (page 50) clearly states that K76T is common between the two types of CQR, with the predominant type of CQR being also always accompanied by the position 220 mutation. The other (Philippine) strain has K76T plus two different additional mutations. From the paper: "Note that the critical Lys76 Thr mutation is accompanied by an Arg220 Ser mutation in all CQR lines except for some (the P2a/P2b types) from the Philippines, where this mutation appears to be replaced by the paired Ala144 Thr and Leu160 Tyr mutations..." It would be predicted that the Philippine type of CQR would have a much lower frequency of occurrence, based on there being three rather than two mutations required. The evidence bears that out. The clinical data is that atovaquone resistance (one mutation) is acquired by about one in three victims, and by about one in a billion for CQ (all known occurrences with at least two mutations). If these differences in clinical rates aren't due to numbers of mutations, then what is the factor? If CQR really only requires one mutation, why have no occurrences of this been found? Viana, Machado, Calvosa and Povoa confirm this in their paper "Mutations in the pfmdr1, cg2, and pfcrt genes in Plasmodium Falciparum samples from endemic malaria areas in Rondonia and Para State, Brazilian Amazon Region", at http://www.scielo.br/pdf/csp/v22n12/18.pdf . They state: "There is evidence that chloroquine resistance is a multigenic phenomenon and that the K76T mutation in the pfcrt gene is necessary, but not sufficient, to confer resistance." This confirms Behe's conclusion from the clinically determined resistance in victims and the genetic mutation evidence that CQR requires more than one (at least two) mutations. Magnan: This is because Behe’s estimate is based on the difference between the two numbers (acquisition of atovaquone and CQ resistance), and both numbers have the same bias. The implications of this reasoning for NDE are untouched. JAM: No, because you missed the unsupported assumption that two were required simultaneously. I have shown that the conclusion that at least two were required is well established from research studies. Whether the mutations for CQ resistance were simultaneous or happened sequentially, the clinical rates of appearance of resistance, and White's estimates of de novo rates clearly indicate the approaching of a limit to NDE as Behe contends. I already pointed out that White in the paper cited by Behe clearly states that the estimate of one in 10^20 multiplications is for a new occurrence at random in one parasite in one multiplication, period. Not per parasite just for populations after extensive selection. Thanks Jehu for finding White's later paper "The de novo selection of drug-resistant malaria parasites" (2002) (at http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1691263&blobtype=pdf ) in which he even more clearly derived a per parasite de novo probability just a little greater than in the 1999 paper (1 in 10^19 multiplications). This figure is described as "per parasite resistance mutation frequency" and is in Table 1, which he describes as "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." Notice the phrase "lead to the emergence". This obviously refers to the probability of the mutation(s) spontaneously occurring in a parasite prior to subsequent selection and expansion of the parasite population in the victim's body. The 1 in 10^12 estimate for atovaquone was also given by White in the same table in the 2002 paper, and has the same definition.magnan
July 7, 2007
July
07
Jul
7
07
2007
04:36 AM
4
04
36
AM
PDT
Phinehas, You are exactly right. It appears to be an article of faith amongst Darwinists that everything can be achieved by single step wise mutations. If CQR can be achieved by a single step and yet has only been selected less than 10 times in 50 years of intense selective pressure in an astronomical number of organisms, then what does that say about the power of natural selection?Jehu
July 6, 2007
July
07
Jul
6
06
2007
11:23 PM
11
11
23
PM
PDT
The title of the Table that Jehu pulls the 10^19 number indicates that White is most definitely not referring to a simultaneous double mutational event. "Table 1. 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." "Mutations" - could be two, could be ten (and the 2003 paper mentions the involvement of multiple genes and epistasis in drug resistance, things not consistent with Behe's overly simplistic portrayal of the situation). It's becoming quite clear that, if Behe is relying on White as an authority, then 10^20 is not even close to being an accurate estimate for the frequency of a simultaneous double mutation. Which brings me back to the question - given this, how does one come close to estimating the "Edge of Evolution" based on chloroquine resistance?Art2
July 6, 2007
July
07
Jul
6
06
2007
09:27 PM
9
09
27
PM
PDT
From the White paper: Resistance to chloroquine in P. falciparum has arisen spontaneously less than ten times in the past fifty years (14). Perhaps I am just not understanding the argument here, but it seems to me that assuming two mutations are needed instead of just one puts the accomplishments of random mutation in a better light given the quote above. In other words, if only one mutation is needed to confer CQR, and yet it has only arisen spontaneously less that ten times in the last fifty years, doesn't that say even less about what purely random forces are capable of accomplishing? Given the data, I would think that NDE would come off much better if a rather large number of mutations were required simultaneously for CQR. I'm a little stumped about how arguing for fewer mutations is supposed to help NDE's case.Phinehas
July 6, 2007
July
07
Jul
6
06
2007
09:04 PM
9
09
04
PM
PDT
It has been suggested that K76T alone can confer CQR. This in vitro study of CQR found that,"The association of the K76T mutation with chloroquine resistance was not clear. The mutation was detected in resistant and susceptible samples, suggesting that additional factors are involved in chloroquine resistance. The researchers further stated, "we found a correlation between the in vitro response to chloroquine and the mutated sequence at codon 76, which was present in all resistant isolates examined. However, this correlation was far from perfect, as the K76T mutation was also detected in 15 of 17 samples classified as susceptible to chloroquine in vitro." This is consistent with a mutation at 76 and at least one other position being required for CQR. It has also been claimed that Whites figure of 1 in 10^20 is the probability of selection of CQR rather than the probability of a CQR mutation occuring. In fact, White specifies that the figure is a per-parasite figure, stating,"the per-parasite probability of developing resistance de novo is on the order of 1 in 10^20 parasite multiplications." In a paper by White two years earlier titled The de novo selection of drug resistant malaria parasites White very clearly estimated the "per-parasite resistance mutation frequency" of CQR at a very similar 10^19. (Apparently White upped his estimate two years later.) In calculating his estimate, White cites to a 1997 paper for the figure of CQR arising 10 times in the last 50 years. In contrast, a significant 2002 study by the NIH identified only four de novo points of origin for CQR. So there is reason actual rate is even lower. However, as Behe pointed out, it is probably "roughly" 1 in 10^20.Jehu
July 6, 2007
July
07
Jul
6
06
2007
07:54 PM
7
07
54
PM
PDT
Sal, My mistake. I missed that they had put K76I it into the Dd2 context. I must have been confusing it with this one, in which either K76T or K76I confer resistance alone: 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. Would you like a PDF? Also, I'm confused by your embrace of a negative result in cultured Plasmodium in culture at #96, while expressing complete disdain for results from culture in #100. The only difference seems to be whether you like the result or not. Is that accurate? BTW, "in vivo" does not mean "in the real world," and "in vitro" does not mean "in laboratory." An experiment done on a mouse in a laboratory is an in vivo experiment.JAM
July 6, 2007
July
07
Jul
6
06
2007
08:56 AM
8
08
56
AM
PDT
Why are you playing a semantic game in pretending that when I wrote “only one change to K76,” that I was necessarily referring to K76T?
No need to play semantic games because the refutation of K76T as being a sole source CQ resistance, as you suggested, is shown to be suspect if not completely wrong. Furthermore, in the 2005 paper I cited is co-authored by Fidock. The K76I mutation is not listed in Table 1 of Fidock's earlier paper Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance Finally, the 2005 paper assert K76T is the critical mutation in-vivo (in the real world), not K76I which appears apparently only in-vitro (in laboratory ) so far. Further, in the 2000 Fidock paper, the K76I line presumed 7 other mutation were in place (the 106/1 Sudan clone).scordova
July 5, 2007
July
07
Jul
5
05
2007
04:18 PM
4
04
18
PM
PDT
Sal, I do know what you're asking. That's why I don't simply say #3.JAM
July 5, 2007
July
07
Jul
5
05
2007
03:41 PM
3
03
41
PM
PDT
Sal, Semantic game is right! Why are you playing a semantic game in pretending that when I wrote "only one change to K76," that I was necessarily referring to K76T?JAM
July 5, 2007
July
07
Jul
5
05
2007
03:39 PM
3
03
39
PM
PDT
JAM says: So since Behe offers the number of 10E-20, it is closer to #1 than #2.
JAM, You did try to answer the question with that respone, but for the sake of the readers, so that they totally know what you mean. Answer the question simply, not for my sake, but for theirs. You asserted:
what matters is that Behe claims that two changes are required simultaneously.
Does that mean two mutaions are required for: 1. one particular kind of CQR malarial strain 2. ANY conceivable CQR malarial strain. 3. You don’t know how to answer I don't know why it's hard to say #1, #2, or #3? If you don't know what I'm asking, simply say #3. Ok?scordova
July 5, 2007
July
07
Jul
5
05
2007
03:36 PM
3
03
36
PM
PDT
JAM confidently asserted at TelicThoughts: Only one change to K76 is required. This has been shown experimentally.
I see some semantic games are being played. In theory K76 might in and of itself do the trick, but because of other factors, it is unlikely. Behe cited the 2000 study by Fidock. Did he cite the study, only then to close his eyes to the data, as JAM insinuates? Consider this 2005 study on the question of the sufficiency of K76T alone: A critical role for PfCRT K76T in Plasmodium falciparum verapamil-reversible chloroquine resistance
While our data indicate a key role for K76T in CQR, it is notable that no fewer than four pfcrt mutations have ever been found in a CQ-resistant isolate (Chen et al, 2003). These other mutations may have been selected to compensate for loss/alteration of endogenous function associated with acquisition of K76T, or may themselves directly contribute to resistance to CQ or other antimalarial drugs. To test whether K76T might itself be sufficient to confer VP-reversible CQR in vitro (which presumably is more favorable than in vivo semi-immune conditions), we employed allelic exchange to introduce solely this mutation into wild-type pfcrt (in GC03). From multiple episomally transfected lines, one showed evidence of K76T substitution in the recombinant, full-length pfcrt locus (data not shown). However, these mutant parasites failed to expand in the bulk culture and could not be cloned, despite numerous attempts. These results suggest reduced parasite viability resulting from K76T in the absence of other pfcrt mutations. This situation is not reciprocal however, in that parasites harboring all the other mutations except for K76T (illustrated by our back-mutants) show no signs of reduced viability in culture.
scordova
July 5, 2007
July
07
Jul
5
05
2007
03:28 PM
3
03
28
PM
PDT
Sal: This was referring to a deduction of the approximate likelihood, not an a priori absolute assumption that this is the absolutely the likelihood.
Likelihood of what, exactly? Behe claims that two aa changes are required (even though the data say that only one is) in a single mutation to get resistance. If we apply it to your #1, the probability is 10E-18. If we apply it to your #2, the probability is N x 10E-18, where N is the number of different CQR haplotypes requiring two aa changes in a single mutational event ("malarial strain" is meaningless in this context). So since Behe offers the number of 10E-20, it is closer to #1 than #2. I've responded several times to your question, Sal, and you've falsely accused me of avoiding it. I've also politely asked you to use accurate, unambiguous terms, and you've refused to do so. The bottom line is that Behe claims that two changes are required in a single mutation for resistance, and the experimental data say that only one is required. Behe also cites only ecological data obtained after extensive filtering by selection to draw conclusions about what happens before selection, which is simply indefensible. Please note that there's a huge difference between citing a paper and citing the data in the paper.JAM
July 5, 2007
July
07
Jul
5
05
2007
03:22 PM
3
03
22
PM
PDT
JAM quotemines 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
This was referring to a deduction of the approximate likelihood, not an a priori absolute assumption that this is the absolutely the likelihood. JAM fails to cite the passages which I have cited that would put the appropriate qualifiers on Behe's statement, giving the impression Behe outrightly presumed this was the case from the start. Answer the question JAM. You said:
what matters is that Behe claims that two changes are required simultaneously.
As in: 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.scordova
July 5, 2007
July
07
Jul
5
05
2007
02:57 PM
2
02
57
PM
PDT
Therefore, if Behe's position is that two specific substitutions are required simultaneously, his number 10E-20 points more to your #1. As I said before, he is ambiguous. If you're going to play NIGYYSOB, I'd appreciate it if you'd use standard genetic terms like "haplotype" and "substitution" and "allele" instead of ambiguous ones like "kind" and "form."JAM
July 5, 2007
July
07
Jul
5
05
2007
02:22 PM
2
02
22
PM
PDT
Sal, here are Behe's own words: “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?JAM
July 5, 2007
July
07
Jul
5
05
2007
02:16 PM
2
02
16
PM
PDT
JAM misrepresents again: what matters is that Behe claims that two changes are required simultaneously.
As in: 1. one particular kind of CQR malarial strain 2. ANY conceivable CQR malarial strain. 3. You don't know how to answer You're obfuscating a simple question, so I'll pose it to you again. Is it #1 or #2 or #3. If you say, #3, then I'll ask "why do you keep asserting #2 and speaking out of both side of your mouth."scordova
July 5, 2007
July
07
Jul
5
05
2007
02:04 PM
2
02
04
PM
PDT
"I know that Behe claims that two are required simultaneously. I know that only one is required. I also know that I never evaded your question." JAM. Where is your proof that only one mutation is needed? Are you making this stuff up??DarwininianIgnorance
July 5, 2007
July
07
Jul
5
05
2007
02:03 PM
2
02
03
PM
PDT
Sal: In that case, you have proven by your own words you have no grounds for insisting that Behe argues a malarial strain will have CQ resistance if and only if it has the 76 and 220 mutations (and by way of extenstion, ONLY 2 mutation combinations).
It doesn't matter which two they are, what matters is that Behe claims that two changes are required simultaneously.
So if you don’t know, it would be advisable to say you don’t know, rather than asserting what you don’t know as a refutation of Behe’s claims.
Behe claims that two are required simultaneously. He doesn't tell his audience that only one is required experimentally. He draws conclusions about mutation rates by looking at what is observed in populations after thousands of generations of both positive and negative selection.
In that case, until you believe you know, kindly refrain from making pronouncemnts that you believe something to be true, when in fact you don’t know.
I know that Behe claims that two are required simultaneously. I know that only one is required. I also know that I never evaded your question.
There are possibly several forms of CQR (Chloroquine Resistant)malarial strains.
If by "forms" you mean "haplotypes," there definitely are several.
One of the most prominent is PfCRT [P. falciparum chloroquine resistance trait].
Indeed, a single substitution in PfCRT is sufficient to confer resistance.
But even with respect to PfCRT resitance alone, not to mention other forms of CQR, Behe writes: 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.
Which is misleading, because a single change of K76 is sufficient.
Later Behe uses the phrase, “almost always”, he doesn’t insist, NEVER.
So where does Behe cite the evidence that demonstrates that two are required?
You just admitted you don’t know this is Behe’s position.
Behe's position is that two changes are required simultaneously. The evidence does not support this assumption. The difference between one and two represents a billion-fold difference in probability, so it matters a lot.JAM
July 5, 2007
July
07
Jul
5
05
2007
01:55 PM
1
01
55
PM
PDT
"Do you realize that your assumptions would make the well-studied spontaneous genetic events that occur during human carcinogenesis impossible? You might want to tell friends in Stockholm about this before they give Bert Vogelstein a Nobel Prize." - JAM Hi JAM, I just wanted to point out one or two falsities in your comment above. First of all, there are no well-studied spontaneous genetic events that have beneficent results for the organism. The only time a mutation works to the advantage of a particular organism is if the designer is directing that adaption. Second, your attacks on Behe are sloppy.DarwininianIgnorance
July 5, 2007
July
07
Jul
5
05
2007
01:24 PM
1
01
24
PM
PDT
JAM wrote: Then you disagree with Behe, too.
You just admitted you don't know this is Behe's position. You're saying one thing in one post, and then suggesting otherwise in another post. If you don't know for sure what Behe said, then you're in no position to adjudicate whether someone agrees with Behe or not.scordova
July 5, 2007
July
07
Jul
5
05
2007
01:10 PM
1
01
10
PM
PDT
In response to my question JAM said: It’s ambiguous, Sal.
Thank you for responding. In that case, you have proven by your own words you have no grounds for insisting that Behe argues a malarial strain will have CQ resistance if and only if it has the 76 and 220 mutations (and by way of extenstion, ONLY 2 mutation combinations). So if you don't know, it would be advisable to say you don't know, rather than asserting what you don't know as a refutation of Behe's claims. In that case, until you believe you know, kindly refrain from making pronouncemnts that you believe something to be true, when in fact you don't know. There are possibly several forms of CQR (Chloroquine Resistant)malarial strains. One of the most prominent is PfCRT [P. falciparum chloroquine resistance trait]. But even with respect to PfCRT resitance alone, not to mention other forms of CQR, Behe writes:
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.
Later Behe uses the phrase, "almost always", he doesn't insist, NEVER.scordova
July 5, 2007
July
07
Jul
5
05
2007
01:07 PM
1
01
07
PM
PDT
mangan: The objection has been made that the clinically derived probabilities of 10^20 and 10^12 from scientific studies are not spontaneous mutation rates, but really reflect probabilities of CQR after periodically varying selection due to body environmental attack and transition outside the body to the mosquito life cycle.
Correct.
This objection does not affect Behe’s conclusion that a slightly more elaborate combination of two primary required specific mutations has only one hundred millionth the chance of spontaneously occurring in a single plasmodium than a single mutation.
The problem with his conclusion is that it is based on an assumption that two are required, for which he has no evidence.
This is because Behe’s estimate is based on the difference between the two numbers, and both numbers have the same bias. The implications of this reasoning for NDE are untouched.
No, because you missed the unsupported assumption that two were required simultaneously.
...Say P. falciparum actually has a spontaneous mutation rate for CQR one billion (10^9) times the 10^20 figure in White’s paper. This would be 1 in 10^(20-9) = 1 in 10^11 multiplications.
Except that we've measured the spontaneous mutation rate directly in many systems (including human cells), and it is consistently 10E-9, 100x higher than your revised estimate. Observed rates from ecological studies are 1-2.5 x 10E-8: Genetics, Vol. 156, 297-304, 2000 Estimate of the Mutation Rate per Nucleotide in Humans Michael W. Nachmana and Susan L. Crowell
...The random mutations or other genetic changes required to build Homo Sapiens from a primitive prehominid would be vastly, astronomically greater than a few single point mutations, so this makes human evolution by a NDE process ridiculous.
On what basis do you assume that the number would be vastly, astronomically greater? For example, are our nervous system connections specified or do they occur by promiscuous connection pruned by selection?
For the same reasons, quibbling over whether two or three mutations are required for CQR, or whether they need to be simultaneous or sequential, is also irrelevant to Behe’s argument.
Then you disagree with Behe, too.
On top of this, Behe didn’t even bother to point out that his extrapolated estimate is based on the P. falciparum genome size of about one hundred million, much less than that of humans. The human genome is about 3 billion nucleotides, making the probability of specific mutational changes by random mutation much less.
No, larger genomes have more mutations, not less. The base frequency is per nucleotide, per replication. Do you realize that your assumptions would make the well-studied spontaneous genetic events that occur during human carcinogenesis impossible? You might want to tell friends in Stockholm about this before they give Bert Vogelstein a Nobel Prize.JAM
July 5, 2007
July
07
Jul
5
05
2007
12:38 PM
12
12
38
PM
PDT
scordova: So let me try to rephrase the question. Did Behe argue that a malarial strain will have CQ resistance if and only if it has the 76 and 220 mutations that confer resistance? If you answer #3, then explain why you don’t know how to answer.
It's ambiguous, Sal. He clearly derives his 10E20 from requiring two simultaneous mutations. Whether the second one is in codon 220 or somewhere else doesn't matter. He offers no evidence even suggesting that two simultaneous mutations are required, and doesn't cite the evidence showing that a change in K76 is sufficient to confer resistance in culture: Fidock et al. Mutations in the P. falciparum Digestive Vacuole Transmembrane Protein PfCRT and Evidence for Their Role in Chloroquine Resistance Molecular Cell, Vol. 6, 861–871
jerry: JAM is desperately trying to find some minutae wrong with Behe’s book.
If these are minutae, why does Behe himself write about "the book’s centerpiece example of chloroquine resistance"?JAM
July 5, 2007
July
07
Jul
5
05
2007
11:53 AM
11
11
53
AM
PDT
1 2 3 4 5 6

Leave a Reply