Uncommon Descent

29 November 2007

Close Up at the Newseum

Michael J Behe

Dear Readers,

Case Western Reserve University Professor Patricia Princehouse and I recently taped an episode of the program “Close Up at the Newseum”, where we discussed intelligent design, Darwinism, The Edge of Evolution, and other topics with an audience of about 40 high school students. The purpose of Close Up is to get students interested in issues of the day, and to become active participants in our democracy. The show will air this Friday, November 30th, at 7:00 p.m. Eastern time, on C-SPAN 2.

16 November 2007

Response to Ian Musgrave’s “Open Letter to Dr. Michael Behe,” Part 5

Michael J Behe

This is the fifth of five posts in which I reply to Dr. Ian Musgrave’s “Open Letter to Dr. Michael Behe” on the Panda’s Thumb blog.

Finally, Dr. Musgrave objects to my placing viral protein – cellular protein interactions in a separate category from cellular protein-cellular protein interactions. In Chapter 8 of The Edge of Evolution I had written:

Another, more important point to note is that I’m considering just cellular proteins binding to other cellular proteins, not to foreign proteins. Foreign proteins injected into a cell by an invading virus or bacterium make up a different category. The foreign proteins of pathogens almost always are intended to cripple a cell in any way possible. Since there are so many more ways to break a machine than to improve it, this is the kind of task at which Darwinism excels. Like throwing a wad of chewing gum into a finely tuned machine, it’s relatively easy to clog a system — much easier than making the system in the first place. Destructive protein-protein binding is much easier to achieve by chance. (pp. 148-149)

Musgrave protests:

This is simply not true, either generally or in the particular case of Vpu. Importantly, your statement shows that you do not understand what Vpu does. Vpu down regulates the surface protein CD4 (the Viroporin activity is something separate related to viral release). It does not “gum-up” CD4, it specifically binds to it….

Dr. Musgrave misunderstands my point. I did not say that Vpu acted as a nonspecific wad of chewing gum. Rather, my point is a general one, that, initially, when during the course of evolution a viral or bacterial protein is injected for the first time into a cell, it is encountering a new environment, one it hasn’t adapted to before, and which hasn’t adapted to it. In that case there are many “targets of opportunity” for the foreign protein. If by serendipity it sticks to some cellular protein to a certain degree, and that association interferes to a degree with the function of the cellular protein, then that will likely benefit the virus, and the association can be strengthened by mutations to the viral protein over time. After a while the association can become very specific, as Vpu’s has.

On the other hand, consider cellular proteins. Cellular proteins must continually exist in a confined space, dense with many other cellular proteins, and so they are normally selected to not bind to most other cellular proteins. In other words, for eons the surfaces of cellular proteins have been honed so as to not interact with almost any other protein in a very concentrated cellular milieu. (Work has shown protein surfaces also adapt to particular sub-cellular compartments.) (6) As the textbook Biochemistryby Voet and Voet puts it: (7)

Proteins, because of their multiple polar and nonpolar groups, stick to almost anything; anything, that is, but other proteins. This is because the forces of evolution have arranged the surface groups of proteins so as to prevent their association under physiological conditions. If this were not the case, their resulting nonspecific aggregation would render proteins functionally useless.

How does this affect the situation when, in some future environment, it might be beneficial for two cellular proteins that had worked separately, to associate, to develop a new protein-protein binding site? From considerations of shape space (8), it seems in general it would be very difficult. Work on antibodies and other proteins shows that a protein which is “tolerant” of a second protein (that is, does not bind it) will be tolerant of mutants of that protein, until a relatively large number of amino acids have changed. (9,10) It seems likely that this will be the case for cellular proteins too. (11) If so, that means that two proteins which had previously tolerated each other over eons in a cell would have to undergo multiple mutations to acquire the ability to specifically bind to each other.

That’s why I put cellular protein-protein interactions in a different category from foreign protein-cellular protein interactions.


1. Gomez,L.M., Pacyniak,E., Flick,M., Hout,D.R., Gomez,M.L., Nerrienet,E., Ayouba,A., Santiago,M.L., Hahn,B.H., and Stephens,E.B. 2005. Vpu-mediated CD4 down-regulation and degradation is conserved among highly divergent SIV(cpz) strains.Virology 335:46-60.

2. Hout,D.R., Mulcahy,E.R., Pacyniak,E., Gomez,L.M., Gomez,M.L., and Stephens,E.B. 2004. Vpu: a multifunctional protein that enhances the pathogenesis of human immunodeficiency virus type 1. Curr. HIV. Res. 2:255-270.

3. Butler,I.F., Pandrea,I., Marx,P.A., and Apetrei,C. 2007. HIV genetic diversity: biological and public health consequences.Curr. HIV. Res. 5:23-45.

4. Gonzalez,M.E. and Carrasco,L. 2003. Viroporins. FEBS Lett. 552:28-34.

5. Mehnert T, et al., Biophysical characterization of Vpu from HIV-1 suggests a channel-pore dualism. Proteins. 2007 Oct 1; doi: 10.1002/prot.21642.

6. Andrade,M.A., O’Donoghue,S.I., and Rost,B. 1998. Adaptation of protein surfaces to subcellular location. J. Mol. Biol.276:517-525.

7. Voet,D. and Voet,J.G. 2004. Biochemistry, 3rd ed. J. Wiley & Sons: New York, p. 265.

8. Smith,D.J., Forrest,S., Hightower,R.R., and Perelson,A.S. 1997. Deriving shape space parameters from immunological data. J. Theor. Biol. 189:141-150.

9. Champion,A.B., Soderberg,K.L., and Wilson,A.C. 1975. Immunological comparison of azurins of known amino acid sequence. Dependence of cross-reactivity upon sequence resemblance. J. Mol. Evol. 5:291-305.

10. Nossal,G.J. 1993. Tolerance and ways to break it. Ann. N. Y. Acad. Sci. 690:34-41.

11. Guo,Z.Y., Shen,L., Gu,W., Wu,A.Z., Ma,J.G., and Feng,Y.M. 2002. In vitro evolution of amphioxus insulin-like peptide to mammalian insulin. Biochemistry41:10603-10607.

16 November 2007

Listen to me on Point of Inquiry

Michael J Behe

Dear Readers,

Recently I was interviewed for the skeptic program Point of Inquiry. You can listen to the interview here.

15 November 2007

Response to Ian Musgrave’s “Open Letter to Dr. Michael Behe,” Part 4

Michael J Behe

This is the fourth of five posts in which I reply to Dr. Ian Musgrave’s “Open Letter to Dr. Michael Behe” on the Panda’s Thumb blog.

And now let’s talk about Dr. Musgrave’s “core argument,” that subsequent to the virus leaping to humans from chimps Vpu developed the ability to act as a viroporin, allowing the leakage of cations which helps release the virus from the cell membrane. Yes, I’m perfectly willing to concede that this does appear to be the development of a new viral protein-viral protein binding site, one which I overlooked when writing about HIV. So the square point in Figure 7.4 representing HIV should be placed on the Y axis at a value of one, instead of zero, and Table 7.1 should list one protein-binding site developed by HIV instead of zero.

One should, however, also make some distinctions with this example. First, although there apparently are five or so copies of Vpu in the viroporin complex, that does not mean that five binding sites developed. Only one new binding site need develop for one area of a protein which binds to a different area of the same protein, to form a homogeneous complex with, say, C5 symmetry. That is all that is required for a circularly symmetric structure to form. Second, the viroporin is not some new molecular machine. There is no evidence that it exerts its effect in, say, an ATP- or energy-dependent manner. Rather, similar to other viroporins, the protein simply forms a passive leaky pore or weak channel. (4,5) This situation is probably best viewed as a foreign protein degrading the integrity of a membrane, rather than performing some positive function.

And third, I explicitly pointed out in Chapter 8 of The Edge of Evolution that HIV had undergone enough mutating in past decades to form all possible viral-viral binding sites, but commented that apparently none of them had been helpful (now I know that one of them helped). This I discussed as the “principle of restricted choice”:

A third reason for doubt is the overlooked problem of restricted choice. That is, not only do new protein interactions have to develop, there has to be some protein available that would actually do some good. Malaria makes about 5,300 kinds of proteins. Of those only a very few help in its fight against antibiotics, and just two are effective against chloroquine. If those two proteins weren’t available or weren’t helpful, then, much to the joy of humanity, the malarial parasite might have no effective evolutionary response to chloroquine. Similarly, in its frantic mutating, HIV has almost certainly altered its proteins at one point or another in the past few decades enough to cover all of shape space. So new surfaces on HIV proteins would have been made that could bind to any other viral protein in every orientation. [Emphasis added here.] Yet of all the many molecules its mutated proteins must have bound, none seem to have helped it; no new protein-protein interactions have been reported. Apparently the choice of proteins to bind is restricted only to unhelpful ones. (pp. 157-158)

So Dr. Musgrave’s “core argument” turns out to be a decidedly double-edged sword. Yes, one overlooked protein-protein interaction developed, leading to a leaky cell membrane. However, in the past fifty years many, many more potential viral protein-viral protein interactions must have also developed but not been selected because they did the virus little good. That, dear readers, is “restricted choice,” a very large contributor to the edge of evolution.

14 November 2007

Response to Ian Musgrave’s “Open Letter to Dr. Michael Behe,” Part 3

Michael J Behe

This is the third of five posts in which I reply to Dr. Ian Musgrave’s “Open Letter to Dr. Michael Behe” on the Panda’s Thumb blog.

In my reply to Smith I quoted from a review (3) which asked the question why, with so much genetic variation, do we just see “interesting variations” in biological properties. Smith, replying to me on her blog in high dudgeon, quotes the next paragraph of the review which details some of those interesting variations:

The long terminal repeat region (LTR) of the HIV genome regulates transcription and viral replication, acting as a promoter responsive to the viral Tat protein. Although all subtypes share the same LTR function, they differ with respect to LTR sequence structure, basal activity and response to cytokines and transcription factors [95]. The majority of HIV-1 group M subtypes contain two nuclear factor binding sites (NF-kB). A minority of subtype C contain an extra NF-kB that may promote replication in the presence of TNF-and chronic immune activation [135]….

Smith remarks, “You know, that kinda looks like my essay, except looking at LTRs instead of Vpu.” She means that she views these as significant as the changes in Vpu she pointed out in her original essay. I agree with her, but think that biochemicallynone of them are all that significant. (One possible point of miscommunication is that I’m concentrating on the biochemical machinery of the virus, while Smith is more concerned with epidemiological factors. As she writes: “Im trying to figure out thephysiological and epidemiological impact of the changes. Im hoping that I can figure out a genetic determinate of transmission, narrowing down the epitopes a potential vaccine would need to contain. Everybody is trying to figure this kind of thing out now in the HIV research world.” That focus is certainly critically important for public health, but it’s not the same question as how do complex biochemical systems arise.)

One must remember that because of HIV’s mutation rate of 10-4, and because of its large population size (109-1010 per individual), multiple mutations in a single virus will occur much more frequently than for cells. For example, in general, all possible double point mutations will occur in a single virus in a single individual every day. All possible triple point mutations will occur in a population of a hundred individuals every month or so. All possible quadruple point mutations will occur in a population of a million individuals every month. All this means that multiple amino acid mutations or nucleotide changes in signaling sequences are easily achieved in HIV. Because of their much lower mutation rate, however, cells cannot match those numbers.

In the paragraph she quotes above from the review, since the transcription factor binding sites are rather short, since HIV has such a large mutation rate, and since duplicating a binding site is certainly not an unusual feat, all of these are what I would call “genome drift” — minor variations on a theme, not something to crow about after 1020 replications and a greatly enhanced mutation rate. In my view Smith and other Darwinists are much too easily impressed. As the review mentions after enumerating these changes: (3)

Although there are clear differences in LTR sequences and basal replication capacity among subtypes, the influence of these molecular level changes on specific subtype epidemics and the global spread of the virus remain uncertain.

In other words, even though it may affect epidemiological properties unpredictably, the frantic variation of HIV seems to occur within a very restricted envelope of biochemical possibilities.

In her original post Smith writes further:

It turns out that one of the biochemical differences is that Subtype B Vps have a Golgi retention signal in the second alpha-helix of the cytoplasmic domain.

Ian Musgrave mentions this too:

HIV-1 Vpu has a new binding site, YRKL in the cytoplasmic alpha helical section, not present in SIVcpz Vpu, which efficiently targets Vpu to the Gogli complex, making the degradation process more efficient. Can you please explain why the appearance of a new targeting motif in HIV-1 Vpu is NOT an example of a new binding site.

But, although not identical, SIV variants have similar sequences at the same location (2): YKRN; WKRN; WRQI; etc. Given the mutation rate of HIV of 10-4, and the fact that an infected individual carries 108-109 viral copies, the conversion of an SIV variant into the Golgi retention signal YRKL could take place with relative ease: perhaps one such de novo mutant per year in a population of ten thousand organisms. If it gave a selective advantage, there would be no problem for this arising by Darwinian means.

At this point I should perhaps remind Dr. Musgrave that the title of my book is The Edge of Evolution. In it I explain that Darwinian processes can do some things, but not others, and I try to find a rough dividing line. As I emphasize, that means one has to makedistinctions between categories. A virus like HIV, with its small genome size and much greater mutation rate, has to be considered differently from cells with their larger genome sizes and lower mutation rates. As a rule of thumb, HIV can acquire two specific point mutations as easily as a cell can acquire one. And with its great population size, it would be child’s play for HIV to alter many signaling sequences. To answer Dr. Musgrave’s question, I wouldn’t list this as a new binding site, not because it doesn’t bind a cellular protein, but because, as I explicitly state in the book, I place viral protein-cellular protein interactions in a separate category. My book concerns cellular protein-protein binding sites (or new viral-viral sites).

13 November 2007

Response to Ian Musgrave’s “Open Letter to Dr. Michael Behe,” Part 2

Michael J Behe

This is the second of five posts in which I reply to Dr. Ian Musgrave’s “Open Letter to Dr. Michael Behe” on the Panda’s Thumb blog.


But by far the worst, you ignored her core argument. That in the space of a decade HIV-1 Vpu developed a series of binding sites that made it a viroporin, a multisubunit structure with a function previously absent from HIV-1.


It is not clear to me why you call that Smith’s “core argument.” In her post, her writing meanders quite a bit; it’s hard for me to glean what she thinks is most important. After sneering a bit at me, Smith began her post by asserting that vpu is a “new” gene (even though it is found in SIVcpz across several primate families, as her own citations show.) (1) She then spent several paragraphs making the point that Vpu’s from chimps and humans share only 37% sequence identity. That was followed by the declaration, “Turns out a LOT of evolution has been going on in HIV-1 since it was transferred to humans 50-60 years ago.” So, rather naturally I think, I concluded that she thought the simple fact of 37% sequence identity was compelling evidence for the power of Darwinian evolution. In reply, I pointed out that proteins with similar structures and functions have such sequence identity (trypsin and chymotrypsin are ~40% identical), so mere degree of sequence identity means little.

After that point she went on to speak of the function of Vpu to assist in degrading CD4 (again, not the “core argument” you assert). She claimed that this involved the evolution of two protein-protein binding sites. In my reply to her, I pointed out that in my book I placed viral protein – cellular proteins binding in a different category (more about that later), so I didn’t reply further to that. However, I now think that reply wasn’t the best one. Rather, I should have simply pointed out that Smith’s references themselves show that “Vpu-mediated CD4 down-regulation and degradation is conserved among highly divergent SIVcpz strains.” (1) Now, why are we even talking about the evolution of a process which has been conserved from chimps and other primates to humans? Where was it shown that the Vpu-CD4 degradation process evolved two protein binding sites? We have primate viral ancestors that have that function and human viruses that have that function. What was the point here again?

She then has two paragraphs on what you call the “core” argument. I’ll get back to those, because right after those paragraphs she reverts to discussing CD4 degradation. She writes:

HIV-1 Vpu requires two casein kinase II sites. … Yet some SIVcpz Vpus have only one CKII site, and instead utilize a simple string of negatively charged amino acids in place of the second site. Different ways of performing similar tricks with totally different amino acids. I think that’s biochemically significant as well.

I disagree with her assessment; I think this is a trivial biochemical change given HIV’s mutation rate. Casein Kinase II sites have the consensus sequence (S/T-X-X-D/E). (2) (Notice one of the consensus amino acids is already acidic.) Now, since the mutation rate of HIV is about 10-4, and since there are 109-1010 viruses in an infected individual, that means any particular double mutation would happen in every individual with AIDS every day. Thus in every hundred persons with HIV, every day there would occur at least one virus with that consensus sequence mutated to, say D-D-X-E. (That would allow for three nucleotide changes, since two are needed to go from S/T to D/E.) If all that was necessary at the site was a blob of negative charge to replace the phosphate negative charge, you’d get that every day in a group of a hundred infected individuals. Smith thinks “that’s biochemically significant.” I think she hasn’t done her math. I view that as sequence drift — the feature stays the same (negatively charged residues), but the sequence drifts within limits.

The same goes for the handful of other changes that impress her.

For instance, Subtype C Vpus are characteristically longer than the others, have key phosphorylation sites shifted, have an extra CKII site, and its tertiary structure is totally different (Subtype B Vpus have an Mr of 43,000 in an SDS-PAGE gel, while Subtype C is 34,000).

Since casein kinase II sites consist of just two specific amino acid residues (separated by any two residues), phosphorylation sites can be shifted, created, or destroyed daily as easily as the calculations from the last paragraph show. By themselves they are no more significant than the simple drift in the sequence of proteins. The fact that the Vpu-fusion proteins molecular weight shifts from 43,000 to 34,000 in SDS-PAGE is difficult to interpret. It may or may not mean anything significant about the protein’s native structure.

12 November 2007

Response to Ian Musgrave’s “Open Letter to Dr. Michael Behe,” Part 1

Michael J Behe

This is the first of five posts in which I reply to Professor Ian Musgrave’s “Open Letter to Dr. Michael Behe” on the Panda’s Thumb blog.


Dear Dr. Behe

I have recently read your response to Abbie Smith’s article on the HIV-1 protein VPU. Ms Smith showed how Vpu’s recently evolved viroporin activity directly contradicts your statement that HIV has evolved no new biding sites since it entered humans (Edge of Evolution, page 143 and figure 7.4, page 144 ). I was greatly disappointed in your response. I must admit to having a special involvement in this case. Firstly, I drew the illustrations for Ms Smith’s article, and its follow up. But secondly, as a member of my professional association’s education committee, I am directly concerned with the support and nurturing of the new generations of enquiring minds, those that we will pass the torch of enquiry on to when we retire. It is in this regard that your response very disturbing. It is almost the exact opposite of what a concerned scientist and science communicator should have done.

It was bad enough that you chose to ignore her for over two months and then did not do her the courtesy of replying on her blog (1). It was bad enough that you chose to start by belittling her and playing the “I’m a Professor and she is a mere student” card (conveniently ignoring the fact that she actually works on HIV). `This is particularly egregious in science, where we pay attention to the evidence and logic of an argument, rather than the letters after an author’s name. Doubly so if we wish to guide young scientists into a demanding profession.


Dear Dr. Musgrave,

I find your letter disingenuous. The tone of Abbie Smith’s post was insulting, jut-jawed, and puerile:

C “I’m ERV. This is my dog, Arnold Schwarzenegger. And this is my friend, Vpu. I presume you and Vpu haven’t met, as you recently repeated in an interview with World magazine the same sentiment you gurgled ad nauseam in ‘Edge of Evolution’”

C “Ah, Michael Behe, you might try to talk your way around Vpu now … Sorry, you’ll find no escape with that limp-wristed, ad hoc parry.”

C “Ah, Michael Behe, you might try to talk your way around Vpu NOW by saying, “Vpu might be *new* new in HIV-1, but its not *NEW* *new* new.”

C “This is just one of a billion plus examples of lazy Creationists taking advantage of the ignorance of their followers.”

As far as I’m concerned, if a complete stranger sends me a message with a sneering tone like that, she can go soak her head. I had no intention of replying to Smith’s post at all; I did so only after I received requests from other folks who wanted me to reply.

At no point in my reply did I “belittl[e] her and play[…] the “I’m a Professor and she is a mere student card” as you allege. The only reference to Smith’s tone I made was the following sentence: “Although she calls herself a “pre-grad student” the tone of the post is decidedly junior high school, of someone who is trying hard to compete with all the other Mean Girls on that unpleasant website.” I think a re-reading of her post shows that my evaluation was quite judicious. After that passage I addressed only the science, not her sneering tone.

Frankly, Professor Musgrave, I find your concern “as a member of my professional association’s education committee” for “the support and nurturing of the new generations of enquiring minds” to be unconvincing. One of the very basic prerequisites for education is to be able to engage in civil discourse, especially with people whose views are different from your own. It is clear to me that Smith has not yet mastered that skill. To the extent that you consider yourself one of her professional mentors, you have failed in your responsibilities.

9 November 2007

Next Week: Responding to Ian Musgrave’s “Open Letter to Dr. Michael Behe”

Michael J Behe

Dear Readers,

Usually I use this space to address reviews of The Edge of Evolution that have appeared in print in journals, newspapers, or magazines. The reason is that usually print media recruit leading figures in evolutionary biology to write a review, and so those reviews represent the thoughts of some of the best minds in the field. Examining their thoughts, then, can quickly give us a good understanding of whether there are ready answers to the challenges and arguments posed by The Edge. After all, if reviews by the likes of Richard Dawkins or Jerry Coyne fail to engage the arguments of the book, and instead rely mainly on bluster and non sequiturs, then that’s solid evidence that no good replies exist.

This series of posts (besides this intro, there will be five posts over the next week) will be different. Here I will address a post on the blog The Panda’s Thumb by a man named Ian Musgrave. Musgrave, a professor at the University of Adelaide, wrote “An Open Letter to Dr. Michael Behe”, in which he questioned my earlier reply to a woman named Abbie Smith, who is a graduate student working on HIV. Musgrave asserts that my response to her was scientifically inadequate and uncivil. I disagree strongly on both counts. Next week I explain why. (I will quote portions of Musgrave and Smith’s posts. The posts can be read in their entirety onThe Panda’s Thumbblog. All references will appear with the final post.)

6 November 2007

Trends in Ecology and Evolution follows the trend, Part III

Michael J Behe

Dear Readers,

The latest issue of the journal Trends in Ecology and Evolution (TREE) carries a tediously disdainful review (1) of The Edge which revisits the blunders of previous reviews while adding new ones. This is the third of a three part series concerning the review.

At the end of his essay our reviewer suddenly reveals his skill at mind reading: “It is clear that Behe is driven not by a truly scientific investigation, but instead metaphysics.” And this: “He is obsessed with ‘randomness,’ which he incorrigibly associates with ‘Darwinism’ and cosmic purposelessness.” Now, wait a darn second. Wasn’t it Darwin himself, we are constantly assured, who based his theory on “random” variation? So it’s “incorrigible” to associate with Darwin’s theory something which Darwin himself associated with it? And isn’t there a rather well-known evolutionary biologist with the initials Richard Dawkins currently traveling the world to tell us exactly that Darwinism means purposelessness?

Don’t ask for consistency or fairness here; the reviewer is just setting the stage for the de rigeur condemnation of “blindly held assumptions common with creationists.”

National Center for Monopolizing Reviews

The reviewer of The Edge of Evolution for TREE is a man named Nicholas Matzke, until recently employed as a staff member of the National Center for Science Education. As its website proclaims, the NCSE “is a not-for-profit, membership organization … working to keep evolution in public school science education.” In other words, the NCSE is an organization dedicated to actively fighting concepts like ID. Folks who associate with the Center, both staff and volunteers, are self-selected to be antagonistic toward those who challenge evolutionary theory. Listed on its website as official “supporters” of the NCSE are Sean Carroll, who reviewedThe Edgefor Science; Kenneth Miller, who reviewed the book for Nature; and Michael Ruse, who reviewed it for the Globe and Mail. About the only reviewer for a major publication who isn’t associated with the NCSE is Richard Dawkins!

So, dear reader, a closing point for this post. Out in the real world there are actually many scientists who think deeply about evolutionary theory, who are dissatisfied with the current state of affairs, and who think neo-Darwinian explanations are missing quite a bit. (I discuss several of these folks in the book.) For example, bioinformatician Eugene Koonin recently proposed that the origin of life might be explained by appeal to the multiverse hypothesis (10) and has compared events in evolution to the Big Bang (11). When warned by reviewers of his paper that he might be giving aid and comfort to ID proponents, Koonin (no well-wisher of ID) in effect remarked, who cares? He is after the truth and won’t tiptoe around worrying about what someone else will say about his ideas.

Good for him! I wish that reviewers of The Edge were like Koonin. Many of them could have engaged the arguments of The Edge of Evolution critically but constructively, and discussion would have been the richer for it. Instead, in my estimation, the NCSE reviewers, true to the organization’s aims of battling evolutionary unorthodoxy wherever it may be found, wrote hatchet jobs. Rather than engaging the book, they wanted it to just go away as quickly as possible. That’s an intellectual shame, but doesn’t affect the reality of life and the universe, both of which, we increasingly realize, are much more finely-tuned and much more elegantly arranged than previous generations of scientists ever knew.

References for Parts I-III

1. Matzke N. J., The edge of creationism, Trends Ecol. Evol. (2007), doi:10.1016/ j.tree.2007.09.004

2. Council of Europe votes against creationist teaching, 10 October 2007, Nature449, 649 (2007), doi:10.1038/449649c

3. Carter,R. and Mendis,K.N. 2002. Evolutionary and historical aspects of the burden of malaria. Clin. Microbiol. Rev. 15:564-594.

4. Mittra, P. et al. (2006) Progressive increase in point mutations associated with chloroquine resistance in Plasmodium falciparum isolates from India. J. Infect. Dis. 193, 1304–1312.

5. Lim,P., et al. 2003. pfcrt polymorphism and chloroquine resistance inPlasmodium falciparum strains isolated in Cambodia.Antimicrob. Agents Chemother. 47:87-94.

6. Volkman,S.K., et al. 2007. A genome-wide map of diversity in Plasmodium falciparumNat. Genet. 39:113-119.

7. Wootton,J.C., et al. 2002. Genetic diversity and chloroquine selective sweeps inPlasmodium falciparumNature 418:320-323.

8. White NJ. 2004. Antimalarial drug resistance. J Clin Invest 113:1084-1092.

9. Roper,C., et al. 2004. Intercontinental spread of pyrimethamine-resistant malaria.Science 305:1124.

10. Koonin,E.V. 2007. The cosmological model of eternal inflation and the transition from chance to biological evolution in the history of life. Biol. Direct. 2:15.

11. Koonin,E.V. 2007. The Biological Big Bang model for the major transitions in evolution. Biol. Direct. 2 :21.

5 November 2007

Trends in Ecology and Evolution follows the trend, Part II

Michael J Behe

Dear Readers,

The latest issue of the journal Trends in Ecology and Evolution (TREE) carries a tediously disdainful review (1) of The Edge which revisits the blunders of previous reviews while adding new ones. This is the second of a three part series concerning the review.

Like other Darwinian reviewers, the one for TREE questions the number I specify of 1 in 1020 for the origin of chloroquine resistance, citing a recent interesting paper on the development of CQR in India, which showed different strains of malaria with various numbers of mutations in their pfcrt genes. (4) Yet such field studies, while very valuable, can be fraught with uncertainty. For example, another recent paper (cited by the first) on CQR in Cambodia (5) reported data showing that the mutations K76T and A220S were not necessarily associated with CQR, which is inconsistent with the great majority of other reports. The most reliable data we have on the independent occurrence of resistance is that which surveys not just the mutations in the pfcrt resistance gene itself, but looks at surrounding DNA sequences for sequence heterogeneity. If drug resistance arose many times, easily and frequently, DNA surrounding the resistance gene would be expected to be as heterogeneous as other DNA regions in the genome. On the other hand, if resistance arose rarely with difficulty, heterogeneity would be suppressed around the resistance gene because of something called “hitchhiking” with the selected DNA. In several thorough studies, DNA heterogeneity was seen to be quite suppressed around pfcrt(6,7) (the chloroquine resistance gene), meaning that the resistance gene arose rarely and swept through a population. Thus since a person sick with malaria can carry 1012 parasites, and since resistance arises rarely, perhaps once for every tens of millions of persons, the number for resistance events of 1 in 1020 seems to be a very good approximation, as the renowned malaria researcher Nicholas White wrote. (8)

(The same sort of data is available for the pyrimethamine resistance gene. (9) The authors of that paper were puzzled: “Why did the triple-mutant allele not arise independently in Africa? Assuming a mutation rate of 10-9 per base per generation, we would expect 10 to 1000 independent origins of triple-mutant parasites in every infection (1010-12 parasites) containing double-mutantdhfr alleles. The implication is that complex compensatory mutations are required to restore parasite fitness.”)

Perhaps even more remarkable than the rarity of malaria resistance to chloroquine — and even more of an indication of the weakness of Darwinian forces — is the puny final result. Truly in this instance the Darwinian elephant labored mightily and brought forth a gnat. After a hundred billion billion chances, we end up with a few measly point mutations in pfcrt. These results from malaria are our best evidence by far of what Darwinian processes can accomplish when given a huge number of chances and strong selective pressure. Behold the result.

The TREE reviewer goes on to complain about my noting that no protein-protein binding sites evolved in malaria in an astronomical number of opportunities: “He apparently thinks that evolutionary theory says anything should evolve a new binding site in response to any arbitrary situation.” (1) The reviewer’s complaint begs a large question, however: when does evolutionary theory say that a protein-protein binding site should evolve? What non-arbitrary situation would cause that? In fact, evolutionary theory says nothing about specifics of what should or shouldn’t evolve. Therefore, we need to get our ideas about what should or shouldn’t evolve not from evolutionary theory, but from evolutionary data. And what we see in our best set of data from malaria is that no such protein sites evolved by Darwinian means in an astronomical number of opportunities. Furthermore, mutations in only one protein,pfcrt, were really able to do much in the face of chloroquine, showing that the number of proteins that it may be helpful to evolve in any given situation might be extremely small: one, maybe none. Ditto for pyrimethamine resistance.

If only one protein could evolve to help malaria avoid chloroquine poisoning, why should we think that a cell will luckily have a dozen or score of proteins that happen to be able to evolve to make a molecular machine?