Response to Critics
By: Michael J. Behe
Discovery Institute
July 31, 2000


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 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 web sites 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 web-site called "Behe's Empty Box"
( http://www.world-of-dawkins.com/box/behe.htm) 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 literature (1), 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 web site 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 web sites. 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 web sites, 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 web site) 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.

References

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.cbs.dtu.dk/dave/Behe.html.

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

Endnotes

1. See my essay on blood clotting on this web site.

2. In a later version of his review (the Web site 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 web site.