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Irreducible Complexity and the Evolutionary Literature: A Response to Critics

Michael Behe


Editor’s note: In celebration of the 20th anniversary of biochemist Michael Behe’s pathbreaking book Darwin’s Black Box and the release of the new documentary Revolutionary: Michael Behe and the Mystery of Molecular Machines, we are highlighting some of Behe’s “greatest hits.” The following was published by Discovery Institute on July 31, 2000. Remember to get your copy of Revolutionary now! See the trailer here.

I. Summary

Although several persons have cited numerous references from the scientific literature purporting to show that the problem of irreducible complexity I pointed out in Darwin’s Black Box is being seriously addressed, the references show no such thing. Invariably the cited papers or books either deal with non-irreducibly complex biochemical systems, or do not deal with them in enough detail for critical evaluation. I strongly emphasize, however, that I do not prefer it that way. I would sincerely welcome much more serious, sustained research in the area of irreducible complexity. I fully expect such research would heighten awareness of the difficulties of Darwinian evolution.

II. Web Spinners

The necessary starting point of Darwin’s Black Box was the contention that, despite the common assumption that natural selection accounts for adaptive complexity, the origins of many intricate cellular systems have not yet been explained in Darwinian terms. After all, if the systems have already been explained, then there’s no need to write. While most scientist-reviewers disagreed (often emphatically) with my proposal of intelligent design, most also admitted to a lack of Darwinian explanations. For example, microbiologist James Shapiro of the University of Chicago declared in National Review that “There are no detailed Darwinian accounts for the evolution of any fundamental biochemical or cellular system, only a variety of wishful speculations.” (Shapiro 1996) In Nature University of Chicago evolutionary biologist Jerry Coyne stated, “There is no doubt that the pathways described by Behe are dauntingly complex, and their evolution will be hard to unravel. . . . [W]e may forever be unable to envisage the first proto-pathways.” (Coyne 1996)

In a particularly scathing review in Trends in Ecology and Evolution Tom Cavalier-Smith, an evolutionary biologist at the University of British Columbia, nonetheless wrote, “For none of the cases mentioned by Behe is there yet a comprehensive and detailed explanation of the probable steps in the evolution of the observed complexity. The problems have indeed been sorely neglected — though Behe repeatedly exaggerates this neglect with such hyperboles as ‘an eerie and complete silence.'” (Cavalier-Smith 1997) Evolutionary biologist Andrew Pomiankowski agreed in New Scientist, “Pick up any biochemistry textbook, and you will find perhaps two or three references to evolution. Turn to one of these and you will be lucky to find anything better than ‘evolution selects the fittest molecules for their biological function.'” (Pomiankowski 1996) In American Scientist Yale molecular biologist Robert Dorit averred, “In a narrow sense, Behe is correct when he argues that we do not yet fully understand the evolution of the flagellar motor or the blood clotting cascade.” (Dorit 1997)

A prominent claim I made in Darwin’s Black Box is that, not only are irreducibly complex biochemical systems unexplained, there have been very few published attempts even to try to explain them. This contention has been vigorously disputed not so much by scientists in the relevant fields as by Darwinian enthusiasts on the Internet. Several web-savvy fans of natural selection have set up extensive, sophisticated sites that appear to receive a significant amount of notice. They influence college students, reporters, and, sometimes, academic reviewers of my book such as Cal State-Fullerton biochemist Bruce Weber, who lists the addresses of the websites in his review in Biology and Philosophy as “summaries of the current research that Behe either missed or misrepresented” (Weber 1999), and Oxford physical chemist Peter Atkins, who writes:

Dr. Behe claims that science is largely silent on the details of molecular evolution, the emergence of complex biochemical pathways and processes that underlie the more traditional manifestations of evolution at the level of organisms. Tosh! There are hundreds, possibly thousands, of scientific papers that deal with this very subject. For an entry into this important and flourishing field, and an idea of the intense scientific effort that it represents (see the first link above) [sic]. (Atkins 1998)

The link Atkins refers to is a website called “Behe’s Empty Box” that has been set up by a man named John Catalano, an admirer of Oxford biologist Richard Dawkins (his larger site is devoted to Dawkins’ work, schedule, etc.). The Empty Box site is, I think, actually a valuable resource, containing links to many reviews, comments and other material, both critical and favorable, related to my book. One subsection of the site is entitled “Alive and Published,” and contains citations to a large number of papers and books which Catalano believes belie my claim that “There has never been a meeting, or a book, or a paper on details of the evolution of complex biochemical systems.” (Behe 1996) (p. 179) The citations were solicited on the web from anyone who had a suggestion, and then compiled by Catalano.

Something, however, seems to be amiss. The assertion here that very many papers have been published clashes with statements of the reviews I quoted earlier which say, for example, that “The problems have indeed been sorely neglected.” (Cavalier-Smith 1997) Would reviewers such as Jerry Coyne and Tom Cavalier-Smith — both antagonistic to my proposal of intelligent design — be unaware of the “hundreds, possibly thousands, of scientific papers that deal with this very subject”? Both claims — that the problems have been neglected and that the problems are being actively investigated — cannot be correct. Either one set of reviewers is wrong, or there is some confusion about which publications to count. Which is it?

In the context of my book it is easy to realize that I meant there has been little work on the details of the evolution of irreducibly complex biochemical systems by Darwinian means. I had clearly noted that of course a large amount of work in many books and journals was done under the general topic of “molecular evolution,” but that, overwhelmingly, it was either limited to comparing sequences (which, again, does not concern the mechanism of evolution) or did not propose sufficiently detailed routes to justify a Darwinian conclusion. Yet the Catalano site lists virtually any work on evolution, whether it pertains to irreducible complexity or not. For example it lists semi-popular books such as Patterns in Evolution: The New Molecular View by Roger Lewin, and general textbooks on molecular evolution such as Molecular Evolution by Wen-Hsiung Li.

Such books simply don’t address the problems I raise. Molecular Evolution by Wen-Hsiung Li (Li 1997) is a fine textbook which does an admirable job of explicating current knowledge of how genes change with time. That knowledge, however, does not include how specific, irreducibly-complex biochemical systems were built. The text contains chapters on the molecular clock, molecular phylogenetics, and other topics which essentially are studies in comparing gene sequences. As I explained in Darwin’s Black Box, comparing sequences is interesting but cannot explain how molecular machines arose. Li’s book also contains chapters on the mechanisms (such as gene duplication, domain shuffling, and concerted evolution of multigene families) that are thought to be involved in evolution at the molecular level. Again, however, no specific system is justified in Darwinian terms.

Here is an illustration of the problem. Li spends several pages discussing domain shuffling in the proteins of the blood-clotting cascade (Li 1997). However, Li himself has not done work on understanding how the obstacles to the evolution of the clotting cascade may have been circumvented. Since those investigators who do work in that area have not yet published a detailed Darwinian pathway in the primary literature1, we can conclude that the answer will not be found in a more general text. We can further assume that the processes that text describes (gene duplication, etc.), although very significant, are not by themselves sufficient to understand how clotting, or by extension any complex biochemical system, may have arisen by Darwinian means.

Catalano’s site lists other books that I specifically discussed in Darwin’s Black Box, where I noted that, while they present mathematical models or brief general descriptions, they do not present detailed biochemical studies of specific irreducibly complex systems. (Gillespie 1991; Selander et al. 1991) There is no explanation on Catalano’s website of why he thinks they address the questions I raised. The site also points to papers with intriguing titles, but which are studies in sequence analysis, such as “Molecular evolution of the vertebrate immune system” (Hughes and Yeager 1997) and “Evolution of chordate actin genes: evidence from genomic organization and amino acid sequences.” (Kusakabe et al. 1997) As I explained in Darwin’s Black Box, sequence studies by themselves can’t answer the question of what the mechanism of evolution is. Catalano’s compendium also contains citations to papers concerning the evolution of non-irreducibly complex systems, such as hemoglobin and metabolic pathways, which I specifically said may have evolved by natural selection. (Behe 1996) (pp. 150-151; 206-207)

III. Equivocal Terms

Another website that has drawn attention (as evidenced from the inquiries I receive soliciting my reaction to it) is authored by David Ussery (Ussery 1999), associate research professor of biotechnology at The Technical University of Denmark. One of his main goals is to refute my claim concerning the dearth of literature investigating the evolution of irreducibly complex systems. For example, in a section on intracellular vesicular transport he notes that I stated in Darwin’s Black Box that a search of a computer database “to see what titles have both evolution and vesicle in them comes up completely empty.” (Behe 1996) (p. 114) My search criterion, of having both words in the title, was meant to be a rough way to show that nothing much has been published on the subject. Ussery, however, writes that, on the contrary, a search of the PubMed database using the words evolution and vesicle identifies well over a hundred papers. Confident of his position, he urges his audience, “But, please, don’t just take my word for it — have a look for yourself!” (Ussery 1999)

The problem is that, as I stated in the book, I had restricted my search to the titles of papers, where occurrence of both words would probably mean they concerned the same subject. Ussery’s search used the default PubMed setting, which also looks in abstracts.2 By doing so he picked up papers such as “Outbreak of nosocomial diarrhea by Clostridium difficile in a department of internal medicine.” (Ramos et al. 1998) This paper discusses the “clinical evolution” (i.e., course of development) of diarrhea in hospitalized patients, who also had “vesicle catherization.” Not only do the words evolution and vesicle in this paper not refer to each other, the paper does not even use the words evolution and vesicle in the same sense as I did. Since the word evolution has many meanings, and since the word vesicle can mean just a container (like the word “box”), Ussery picked up equivocal meanings.

The paper cited above shows Ussery’s misstep in an obvious way. However, there are other papers resulting from an Ussery-style search where, although they do not address the question I raised, the unrelatedness is not so obvious to someone outside the field. An example of a paper that is harder for someone outside the field to evaluate is “Evolution of the trappin multigene family in the Suidae.” (Furutani et al. 1998) The authors examine the protein and gene sequences for a group of secretory proteins (the trappin family) which “have undergone rapid evolution” and are similar to “seminal vesicle clotting proteins.” The results may be interesting, but the seminal vesicle is a pouch in the male reproductive tract for storing semen — not at all the same thing as the vesicle in which intracellular transport occurs. And trappins are not involved in intracellular transport.

A second example is “Syntaxin-16, a putative Golgi t-SNARE.” (Simonsen et al. 1998) This paper actually does concern a protein involved in intracellular vesicular transport. However, as the abstract states, “Database searches identified putative yeast, plant and nematode homologues of syntaxin-16, indicating that this protein is conserved through evolution.” The database searches are sequence comparisons. Once again I reiterate, sequence comparisons by themselves cannot tell us how a complex system might have arisen by Darwinian means.

Instead of listing further examples let me just say that I have not seen a paper using Ussery’s search criteria that addresses the Darwinian evolution of intracellular vesicular transport in a detailed manner, as I had originally asserted in my book.

It is impossible for me to individually address the “hundreds, possibly thousands” of papers listed in these websites. But perhaps I don’t have to. If competent scientists who are not friendly to the idea of intelligent design nonetheless say that “There are no detailed Darwinian accounts for the evolution of any fundamental biochemical or cellular system, only a variety of wishful speculations,” (Shapiro 1996) and that “We may forever be unable to envisage the first proto-pathways” (Coyne 1996), then it is unlikely that much literature exists on these problems. So after considering the contents of the websites, we can reconcile the review of Peter Atkins with those of other reviewers. Yes, there are a lot of papers published on “molecular evolution,” as I had clearly acknowledged in Darwin’s Black Box. But very few of them concern Darwinian details of irreducibly complex systems, which is exactly the point I was making.

IV. Kenneth Miller

In Finding Darwin’s God (Miller 1999) Kenneth Miller is also anxious to show my claims about the literature are not true (or at least are not true now, since the handful of papers he cites in his section “The Sound of Silence” were published after my book appeared). Yet none of the papers he cites deals with irreducibly complex systems.

The first paper Miller discusses concerns two structurally-similar enzymes, both called isocitrate dehydrogenase. The main difference between the two is simply that one uses the organic cofactor NAD while the other uses NADP. The two cofactors are very similar, differing only in the presence or absence of a phosphate group. The authors of the study show that by mutating several residues in either enzyme, they can change the specificity for NAD or NADP. (Dean and Golding 1997) Although the study is very interesting, at the very best it is microevolution of a single protein, not an irreducibly complex system.

The next paper Miller cites concerns “antifreeze” proteins. (Logsdon and Doolittle 1997) Again, these are single proteins that do not interact with other components; they are not irreducibly complex. In fact, they are great examples of what I agree evolution can indeed do — start with a protein that accidentally binds something (ice nuclei in this case, maybe antibiotics in another case) and select for mutations that improve that property. But they don’t shed light on irreducibly complex systems.

Another paper Miller cites concerns the cytochrome c oxidase proton pump (Musser and Chan 1998), which is involved in electron transfer. In humans six proteins take part in the function; in some bacteria fewer proteins are involved. While quite interesting, the mechanism of the system is not known in enough detail to understand what’s going on; it remains in large part a black box. Further, the function of electron transfer does not necessarily require multiple protein components, so it is not necessarily irreducibly complex. Finally, the study is not detailed enough to criticize, saying things such as “It makes evolutionary sense that the cytochrome bc1and cytochrome c oxidase complexes arose from a primitive quinol terminal oxidase complex via a series of beneficial mutations.” In order to judge whether natural selection could do the job, we have to know what the “series of beneficial mutations” is. Otherwise it’s like saying that a five-part mousetrap arose from a one-part mousetrap by a series of beneficial mutations.3

Finally Miller discusses a paper which works out a scheme for how the organic-chemical components of the tricarboxylic acid (TCA) cycle, a central metabolic pathway, may have arisen gradually. (Melendez-Hevia et al. 1996) There are several points to make about it. First, the paper deals with the chemical interconversion of organic molecules, not the enzymes of the pathway or their regulation. As an analogy, suppose someone described how petroleum is refined step by step, beginning with crude oil, passing through intermediate grades, and ending with, say, gasoline. He shows that the chemistry of the processes is smooth and continuous, yet says nothing about the actual machinery of the refinery or its regulation, nothing about valves or switches. Clearly that is inadequate to show refining of petroleum developed step by step. Analogously, someone who is seriously interested in showing that a metabolic pathway could evolve by Darwinian means has to deal with the enzymic machinery and its regulation.

The second and more important point is that, while the paper is very interesting, it doesn’t address irreducible complexity. Either Miller hasn’t read what I said in my book about metabolic pathways, or he is deliberately ignoring it. I clearly stated in Darwin’s Black Box metabolic pathways are not irreducibly complex (Behe 1996) (pp. 141-142; 150-151), because components can be gradually added to a previous pathway. Thus metabolic pathways simply aren’t in the same category as the blood clotting cascade or the bacterial flagellum. Although Miller somehow misses the distinction, other scientists do not. In a recent paper Thornhill and Ussery write that something they call serial-direct-Darwinian-evolution “cannot generate irreducibly complex structures.” But they think it may be able to generate a reducible structure, “such as the TCA cycle (Behe, 1996 a, b).” (Thornhill and Ussery 2000) In other words Thornhill and Ussery acknowledge the TCA cycle is not irreducibly complex, as I wrote in my book. Miller seems unable or unwilling to grasp that point.

V. A Plea for More Research

In pointing out that not much research has been done on the Darwinian evolution of irreducibly complex biochemical systems I should emphasize that I do not prefer it that way. I would sincerely welcome more research (especially experimental research, such as done by Barry Hall — see my discussion of Hall’s work in the essay on the “acid test” at this website) into the supposed Darwinian origins of the complex systems I described in my book. I fully expect that, as in the field of origin-of-life studies, the more we know, the more difficult the problem will be recognized to be.


Atkins, P. W. (1998). Review of Michael Behe, Darwin’s Black Box. http://www.infidels.org/library/modern/peter_atkins/behe.html.

Behe, M. J. (1996). Darwin’s black box: the biochemical challenge to evolution. (The Free Press: New York.)

Cavalier-Smith, T. (1997). The blind biochemist. Trends in Ecology and Evolution 12, 162-163.

Coyne, J. A. (1996). God in the details. Nature 383, 227-228.

Dean, A. M. and Golding, G. B. (1997). Protein engineering reveals ancient adaptive replacements in isocitrate dehydrogenase. Proc.Natl.Acad.Sci.U.S.A 94, 3104-3109.

Dorit, R. (1997). Molecular evolution and scientific inquiry, misperceived. American Scientist 85, 474-475.

Furutani, Y., Kato, A., Yasue, H., Alexander, L. J., Beattie, C. W., and Hirose, S. (1998). Evolution of the trappin multigene family in the Suidae. J.Biochem. (Tokyo) 124, 491-502.

Gillespie, J. H. (1991). The causes of molecular evolution. (Oxford University Press: New York.)

Hughes, A. L. and Yeager, M. (1997). Molecular evolution of the vertebrate immune system. Bioessays 19, 777-786.

Kusakabe, T., Araki, I., Satoh, N., and Jeffery, W. R. (1997). Evolution of chordate actin genes: evidence from genomic organization and amino acid sequences. Journal of Molecular Evolution 44, 289-298.

Li, W. H. (1997). Molecular evolution. (Sinauer Associates: Sunderland, Mass.)

Logsdon, J. M., Jr. and Doolittle, W. F. (1997). Origin of antifreeze protein genes: a cool tale in molecular evolution. Proc.Natl.Acad.Sci.U.S.A 94, 3485-3487.

Melendez-Hevia, E., Waddell, T. G., and Cascante, M. (1996). The puzzle of the Krebs citric acid cycle: assembling the pieces of chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution. Journal of Molecular Evolution 43 , 293-303.

Miller, K. R. (1999). Finding Darwin’s God: a scientist’s search for common ground between God and evolution. (Cliff Street Books: New York.)

Musser, S. M. and Chan, S. I. (1998). Evolution of the cytochrome c oxidase proton pump. Journal of Molecular Evolution 46, 508-520.

Pomiankowski, A. The God of the tiny gaps. New Scientist. 9-14-1996.

Ramos, A., Gazapo, T., Murillas, J., Portero, J. L., Valle, A., and Martin, F. (1998). Outbreak of nosocomial diarrhea by Clostridium difficile in a department of internal medicine. Enfermedades Infecciosas Y Microbiologia Clinica 16, 66-69.

Selander, R. K., Clark, A. G., and Whittam, T. S. (1991). Evolution at the molecular level. (Sinauer Associates: Sunderland, Mass.)

Shapiro, J. In the details . . . what? National Review, 62-65. 9-16-1996.

Simonsen, A., Bremnes, B., Ronning, E., Aasland, R., and Stenmark, H. (1998). Syntaxin-16, a putative Golgi t-SNARE. European Journal of Cell Biology 75, 223-231.

Thornhill, R. H. and Ussery, D. W. (2000). A classification of possible routes of Darwinian evolution. Journal of Theoretical Biology 203, 111-116.

Ussery, David (1999). A biochemist’s response to “The Biochemical Challenge to Evolution”. http://www.indiana.edu/~ensiweb/behe.rev.html.

Weber, Bruce (1999). Irreducible complexity and the problem of biochemical emergence. Biology & Philosophy 14, 593-605.


(1) See my essay on blood clotting on this website.

(2) In a later version of his review (the website has been updated several times, making it a moving target that is hard to pin down precisely), Ussery did note explicitly that one needed to search abstracts as well as titles to come up with the total of 130 papers. He then noted that a total of just four papers have both words in the title. These papers were not picked up in my search because they either were published after my search was completed in 1995, or because the papers were published before the mid 1980s (which is outside the scope of a CARL search). None of the papers affects the questions discussed in this manuscript.

(3) See my discussion of “mousetrap evolution” on this website.

Photo credit: TGoeller (Own work) [Public domain], via Wikimedia Commons.