by Michael J. Behe
1994

Response to this paper.

Author's final comments.


IN WRITING ON THE TOPIC of naturalism and evolution the problem arises of what to call the contending camps. The difficulty comes from the fact that
although the term evolutionist is often used to refer to persons who
demand the unrelenting application of physical laws to all phenomena in
the universe, many other persons who are opposed to this view are
perfectly willing to concede that a limited number of phenomena can be
explained by Darwinistic principles. Similarly, although a term like
creationist brings to mind champions of a young-earth theory, it is often
applied to persons who do not defend that thesis but do contend that
natural laws have at some point been superseded by a supernatural agency
Since the focus of this symposium is the sufficiency of natural law, and
in order to avoid the confusing terminology discussed above, in this essay
I will use the term believer for those who believe in the universal
application of natural law and the term skeptic for those who doubt it.
This has the advantage of using terms for each side that the opposite side
generally regards positively. Perhaps this will go a little way toward
promoting the good will that this conference strives for.

Introduction

Several years ago the fossilized remains of an extinct species of whale
were unearthed in the Zeuglodon valley of Egypt. The particular aspect of
the fossil which excited archaeologists and science writers was the fact
that the whale apparently had functional legs and feet From the condition
of the fossilized leg bones it could be discerned by trained eyes that the
legs were well muscled and thus must have been actively used during the
life of the whale. A Washington Post story describing the discovery
included a drawing of both a modern whale and an ancient whale, showing
the differences in their shapes but the similarities in their lengths.

Also included in the illustration, down in the lower righthand corner, was
a drawing of an animal that looked for all the world like a scruffy dog.
Underneath the dog was the caption "Mesonychid, the ancestor of the
whales," in the story it was explained that

Most researchers agree the earliest whales descended from a line of
large carnivorous beasts the size of wolves and bears. These furry land
mammals, known as mesonychids, ran around on four legs. But for unknown
reasons, some mesonychids evolved into forms that returned to the sea,
from which all life originally arose. The legs found on primitive whales
are remnants from their time on land (July 13, 1990).

Even allowing for the enthusiasms of the popular press, the story reflects
the way in which a theory, here evolution, is allowed to supply "facts"
which the evidence in no way justifies. I discussed this article with my
students in a course I teach for freshmen, entitled "Popular Arguments on
Evolution." The course is intended to develop critical reasoning skills,
using popular books that have opposing viewpoints on evolution as the
vehicle. This past semester we read, side by side, Richard Dawkins's The
Blind Watchmaker and Michael Denton's Evolution: A Theory in Crisis. This
forced the students to argue over the meaning of observations, without the
automatic social support that usually goes to proponents of evolution in
academic settings. The students themselves, after reading the Post
article, pointed out that there is no reason to suppose that the ancient
whale appeared on earth before the modern whale, since modem whales have
vestigial legs that could have developed into the functional legs of the
Zeuglodon whale. For the same reason, the students noted, the discovery
does not represent the development of a new trait or even the loss of an
old one. Finally, most glaringly obvious, if random evolution is true,
there must have been a large number of transitional forms between the
Mesonychid and the ancient whale. Where are they? It seems like quite a
coincidence that of all the intermediate species that must have existed
between the Mesonychid and whale, only species that are very similar to
the end species have been found. The students concluded that the fossil
whale, although a fascinating discovery for natural history, was no
evidence for the Post's evolutionary scenario.

I have started my contribution to this symposium with a discussion of the
Zeuglodon whale because it is a paradigmatic example of evolutionary
argumentation: a small change in a preexisting structure is used to argue
to massive changes involving completely new structures or functions. It is
like arguing that because a man can jump over a fissure five-feet wide,
then given enough time he could jump over the Grand Canyon. Now, a
believer in the unabating rule of natural law would argue that the man
could jump over the Grand Canyon if there were ledges and buttes for him
to use as steppingstones. The skeptic would ask to be shown the
steppingstones.

This essay will examine how the search is going for steppingstones in one
area of biochemistry, that of protein structure. We will see that, without
a prior commitment to naturalism, there is little reason to suppose that
steppingstones exist in the canyon separating functional classes of
proteins.

Protein Structure

I ask for the patience of those who already have a working knowledge of
protein structure, but in order to make sure that everyone reading this
essay has the necessary background I will spend a little time discussing
some fundamentals.

Although most people think of proteins as something we eat-one of the
major food groups- when they reside in the body of an uneaten animal or
plant, proteins serve a different purpose. Proteins are the machinery of
living tissue that builds the structures and carries out the chemical
reactions necessary for life. For example, the conversion of foodstuffs to
biologically usable forms of energy is carried out, step by step, by part
of a group of proteins called enzymes. Skin is made in large measure of a
protein called collagen. When light impinges on your retina it interacts
first with a protein called rhodopsin.

As can be seen even by this limited number of examples, proteins carry out
amazingly diverse functions. In general, however, a given protein can
perform only one or a few functions: rhodopsin cannot form skin, and
collagen cannot interact usefully with light. Therefore a typical cell
contains thousands and thousands of different types of proteins to perform
the many tasks necessary for life, much like a carpenter's workshop might
contain many different kinds of tools for various carpentry tasks.
What do these versatile tools look like? The basic structure of proteins
is quite simple: they are formed by hooking together in a chain discrete
subunits called amino acids. Now, although the protein chain can consist
of anywhere from about fifty to about one thousand amino acid links, each
position can contain only one of twenty different amino acids. In this
they are much like words: words can come in various lengths but they are
made up from a discrete set of twenty-six letters. As a matter of fact,
biochemists often refer to each amino acid by a single letter
abbreviation: G for glycine, S for serine, H for histidine, and so forth.

Each different kind of amino acid has a different shape and different
chemical properties; for example, W is large but A is small, R carries a
positive charge but E carries a negative charge, S prefers to be dissolved
in water but I prefers oil, etc. A protein in a cell does not float around
like a floppy chain; rather, it folds up into a precise structure that can
be quite different for different types of proteins. This is done
automatically through interactions such as a positively charged amino acid
trying to get near a negatively charged one, oil-preferring amino acids
trying to huddle together to exclude water, large amino acids being
excluded from small spaces, etc. When all is said and done, two different
amino acid sequences, two different proteins, can be folded to structures
as specific and different from each other as a three-eighths inch wrench
and a jigsaw. Like the household tools, if the shape of the proteins is
significantly warped, they fail to do their jobs.

Proteins and Language

Because amino acid residues are often abbreviated by letters, because
there is a similar number of letters and amino acids (twenty-six vs.
twenty, respectively), and because a small protein consists of about one
hundred amino acids, many commentators have likened a functional protein
(i.e., one that has the correct shape to be able to do a particular job)
to a functional sentence (i.e., one that obeys the rules of English
grammar) of about one hundred letters. My students in "Popular Arguments
on Evolution" found it interesting that both believers and skeptics used
this kind of analogy in their writings, but that their reasonings brought
them to opposite conclusions. The skeptic typically argues that a monkey
banging away at a typewriter (monkeys and typewriters are very popular)
would be unlikely to produce an intelligible, grammatically correct
sentence like "Drop the anchor in one hour" in a reasonable length of
time. Near misses don't count for the skeptic since the change of even one
letter would break a spelling or grammar rule, or change the sense of the
sentence. Needless to say, the hour would most likely pass, and the anchor
remain undropped, before the monkey produced the correct sentence.
Believers in the universal application of physical law take a different
approach with their monkey and typewriter. Their argument generally goes
something like this. Suppose in his first try the monkey typed "bsqm
dshcbbbk,RR .nsurlei aknex." Admittedly this is poor grammar, but it's the
only sentence we've got. Since living systems reproduce, and since there
is Darwinian competition, the bad sentence will be reproduced until a
better one comes along. Now suppose in his second try the monkey typed a p
in the fourth position and a u in the penultimate position. Well, since
these are closer to the target sentence we will throw out the original
sentence and keep "bsqp dshcbbbk.RR .nsurlei aknux." After a few more
rounds perhaps the monkey has gotten a few more letters correct, say, a d
in the first position and a ch in the thirteenth and fourteenth positions.
Now we have "dsqp dshcbbbchRR .nsurlei aknux." Since this has more matches
with the target sentence we'll keep it and throw out the last sentence.
After perhaps fifty rounds we get to "dsop dhe abehRR in uneei hour."
Breed from this. In another fifty rounds or so we arrive triumphantly at
our target "Drop the anchor in one hour."

The above argument in its pure form can be convincing only to persons
already convinced. It asserts a functional difference between two
nonsensical strings of letters. No person, or machine for that matter,
looking for a sentence would notice a difference between "bsqm dshcbbbk,RR
.nsurlei aknex" and "bsqp dshcbbbk,RR .nsurlei aknux." It is only because
the believer has a distant goal in mind that he or she chooses one
nonsense character string over the other. In the believers' argument the
analogy of proteins to language is implicitly abandoned in the first
rounds of the monkey's typing, since the character string does not have to
obey any rules of spelling or grammar. The analogy to language is used
simply to try to impress the unwary with the apparent production of sense
from nonsense. My students in "Popular Arguments on Evolution" were uneasy
with this argument when they read it in Dawkins's book, but they could not
refute it. It is not easy for the casual reader to see that the illusion
of steady, gradual evolution to a functional sentence is produced by an
intellect, either the believer's directly or in some cases a computer
program written by him, guiding the result to a distant goal. This of
course is the antithesis of Darwinian evolution.

But perhaps there is a middle ground between the skeptic's insistence on
absolute grammatical correctness and the believer's abandonment of
grammatical rules. Suppose we allowed the vowels in the sentence to vary
to produce something like "Drep tha enchir on une hoir." Such a sentence
could probably still be recognized by someone, perhaps a sailor, even
though all the words are misspelled. Or, alternatively, suppose we vary
some consonants: "Trof tte ankhow im ode hous. Clearly some misspelled
words would be easier to recognize than others and some letter
substitutions (t for d, k for c) would be easier to follow than others (r
for t, l for g). The ability of a sentence like that to function would
depend a lot on the reader and the context.

To put this back into a protein context, it might be possible for a
protein to tolerate a lot of amino acid substitutions and remain
functional. (Again, when talking about proteins, functional means folded
to a discrete, stable structure.) And in fact it has been known for a long
time that this is true. Analogous proteins from different species- for
example, human hemoglobin and horse hemoglobin-have differences between
their amino acid sequences, yet fold to discrete and closely similar
structures.

But what is the limit to tolerance for amino acid changes? Are proteins
significantly more tolerant to changes in "spelling" than words are? Is
there a point at which, like our sentences above, further changes will
render a protein nonfunctional? What then is the probability of finding
some member of a particular class in a reasonable time in a nondirected
search? These are empirical questions and, although they can be speculated
upon in the absence of relevant data, such speculations must be radically
curtailed when data are available. A direct approach to the question,
''How isolated are functional protein sequences?" would have been
experimentally impossible twenty years ago, before the molecular
biological revolution. But since the development of powerful tools to
probe the molecules of life, an answer to that question appears to be
within reach. Progress in this area is the topic of the following sections.

How Rare are Functional Proteins?

The observation that analogous proteins from different species could
differ from each other, often by quite a bit, and yet retain the same
compact shape led workers in the field to speculate that perhaps the exact
identity of an amino acid at a particular position in a protein was not so
important as its overall chemical properties. So, for example, if one
finds an I at position 10 of hedgehog hemoglobin and an L in position 10
of the analogous protein from skunk, then perhaps the imponant feature is
that both I and L prefer an oily environment, and maybe any other amino
acid, such as W, F, or V, that prefers a similar environment would also be
suitable at that position. This is something like saying that in a
language perhaps all of the vowels are interchangeable. Taking the idea
further, perhaps amino acids, such as S, A, H, and T. that prefer a watery
environment could form an interchangeable group, and perhaps charged amino
acids (E, D, R, and K) another group.

Fifteen years ago a man named Hubert Yockey published an article in the
Jourrnal of Theoretical Biology{1} showing that these considerations could
enormously reduce the odds against finding a functional protein by trial
and error. If we do not insist on the perfect diction of the typical
skeptic, but allow some slurred speech in proteins, then the probability
of finding a small, functional protein of one hundred amino acids in
length is reduced from one in ten to the 130th power to one in ten to the
65th power-a reduction of sixty-five orders of magnitude! Yockey went on
to show in the article that his calculation of one in 1065, which he
obtained from theoretical considerations, fit very closely with the number
that could be calculated from considerations of the known sequence
variability of the protein cytochrome c among many different species,
Now, the problem with Yockey's calculation for a believer in the
sufficiency of natural law is that, although 1065 is enormously smaller
than 10130, it still is quite a large number. It has been calculated that
there are about 1065 atoms in a galaxy. Thus, if Yockey was correct, the
odds of finding a functional protein are about the same as finding one
particular atom in the Milky Way. Not too likely. Well, if you were a
believer, how might you answer this challenge? One way is through
obfuscation, like the production of sentences from nonsense character
strings, as was discussed above. A second way is by claiming that Yockey's
calculation is inaccurate and that the known sequences of cytochrome c
that he used to buttress his work do not reflect all the possible
sequences that could produce a folded protein. The best way, though, in
the absence of relevant data, is to produce your own calculation, starting
from a separate set of independent principles, and show that the odds are
not quite so long as Yockey thought. This is what has been done in an
elegant series of calculations from the laboratory of Ken Dill{2} {3}at
the University of California at San Francisco.

Dill's laboratory asked a question that can be paraphrased as follows.
Given a ten-by-ten square matrix (like a big checkerboard) and a string of
pearls containing both black beads and white beads, in how many ways can a
string of one hundred pearls be laid on the checkerboard so that each
square contains one and only one pearl, and most of the black pearls are
in the middle spaces of the board? This analogy is intended to represent a
folding protein comprised of two types of amino acids, ones that prefer
watery surroundings and ones that do not. After feeding this scenario into
a computer, Dill's group obtained the surprising result that it wasn't
that hard to fit the pearl necklace on the checkerboard in the right way.
They then mathematically extrapolated from the two dimensional
checkerboard to three dimensional space, and finally arrived at the
conclusion that about one in 1010 amino acid sequences would yield a
folded protein That is a much smaller number than Yockey's (the federal
government spends 1010 dollars, ten billion dollars, every three days) and
brings the spontaneous generation of functional proteins into the realm of
the credible.

The problem for a skeptic is how to refute Dill's calculation. It isn't
easy, since few people are as mathematically talented as he and since it's
hard to disprove the simplifying assumptions his model contains. Skeptics
are free to criticize the assumptions, but there is enough uncertainty in
such things to allow believers to tout Dill's calculation credibly over
Yockey's. To resolve this dilemma, to gain firm ground to stand on, hard
experimental results are required. Fortunately in the past several years
such results have been forthcoming from the laboratory of Robert Sauer{4}
{5} {6} in the department of biology at the Massachusetts Institute of
Technology. We now turn to those crucial experiments.

Functional Proteins Are Very Rare

In the past twenty years the science of molecular biology has made
enormous strides. It is now possible, in laboratories with such expertise,
to cut up a gene, rearrange it to suit yourself, and place it back in a
functioning biological system. Since genes code for proteins, one can also
produce proteins made-to-order in this manner. Sauer's laboratory, in
order to answer questions about protein structure that interested them,
took the genes for several viral proteins, systematically took out small
pieces of them (corresponding to instructions for three amino acids at a
time), and inserted altered pieces back in the genes. They did this, three
amino acids "codons" at a time, for the whole length of the gene. By
clever manipulation of the altered pieces they were able to screen codons
for all twenty amino acids at each position of the protein. This is like
trying all twenty-six letters of the alphabet in turn at each position of
a word. The altered genes were then placed in bacteria, which read the DNA
code and produced chains of amino acids from them. It turns out that
bacteria quickly destroy proteins that are not folded, so Sauer's group
looked for the altered proteins that were not destroyed. By determining
their sequences they could tell which amino acids in a given position were
compatible with producing a folded, functional protein.

What did they see? In some positions of the protein, Sauer's group saw
that a great deal of amino acid diversity could be tolerated. Up to
fifteen of the twenty amino acids could occur at some positions and still
yield a functional, folded protein. At other positions in the amino acid
sequence, however, very little diversity could be tolerated. Many
positions could accommodate only three or four different amino acids.
Other positions had an absolute requirement for a particular amino acid;
this means that if, say, a P does not appear at position 78 of a given
protein, the protein will not fold regardless of the proxirnity of the
rest of the sequence to the natural protein. In terms of our sentence
analogy, this is like saying that, yes, all vowels are interchangeable,
but that if the last r is changed to any other letter, such as s ("Drop
the anchor in one hous"), the protein sentence is no longer understandable.
Sauer's results can be used to calculate the probability of finding a
given protein structure.{6} We proceed in the following manner. If any of
ten amino acids can appear in the first position of a given functional
protein sequence, then the odds are one in 2 that a nondirected search
will place one of the allowed group there. If any of four amino acids can
appear in the second position, then the odds are one in 5 of finding one
of that group, and the odds of finding the correct amino acids next to
each other in the first two positions are one-half times one-fifth, which
is one-tenth. Suppose in the third position there is an absolute
requirement for G. Then the odds of getting a G at that position are one
in twenty and the odds of getting the first three amino acids right are
now up to one in two hundred. In this aspect it is like winning a trifecta
in horse racing. Over the course of one hundred amino acids in our small
protein, the odds quickly reach astronomical numbers.

From the actual experimental results of Sauer's group it can easily be
calculated that the odds of finding a folded protein are about one in 10
to the 65th power.{6} To put this fantastic number in perspective, imagine
that someone hid a grain of sand, marked with a tiny X, somewhere in the
Sahara Desert. After wandering blindfolded for several years in the desert
you reach down, pick up a grain of sand, take off your blindfold, and find
it has a tiny X. Suspicious, you give the grain of sand to someone to hide
again, again you wander blindfolded into the desert, bend down, and the
grain you pick up again has an X. A third time you repeat this action and
a third time you find the marked grain. The odds of finding that marked
grain of sand in the Sahara Desert three times in a row are about the same
as finding one new functional protein structure. Rather than accept the
result as a lucky coincidence, most people would be certain that the game
had been fixed.

The number of one in 1065, arrived at by Sauer's experimental route, is
virtually identical to the results obtained by Yockey's theoretical
calculation and his deduction from natural cytochrome c sequences! It
therefore strongly reinforces our confidence that a correct result has
been obtained. Sauer's group obtained closely similar results for two
different proteins: arc repressor{4} and lambda repressor.{5} {6} This
means that all proteins that have been examined to date, either
experimentally or by comparison of analogous sequences from different
species, have been seen to be surrounded by an almost infinitely wide
chasm of unfolded, nonfunctional, useless protein sequences. There are no
ledges, no buttes, no steppingstones to cross the chasm.

The conclusion that a reasonable person draws from this is that the laws
of nature are insufficient to produce functional proteins and, therefore,
functional proteins have not been produced through a nondirected search.
Implications of Protein Sequence isolation
The numerical concreteness of Sauer's and Yockey's results is
breathtaking. When a skeptic sees a drawing of Mesonychid next to the
Zeuglodon whale, he or she intuitively realizes that the transformation is
highly improbable. But how improbable? There is no way to put a
quantitative measure on the difference between a doglike animal and a
whale, and believers in the relentless application of physical law take
advantage of this by verbally minimizing the differences.

The situation is otherwise with proteins. Because there is a discrete set
of amino acids and a finite number of positions in a given protein, the
odds of attaining a folded, functional protein can be calculated quite
closely, but only if the tolerance of proteins to amino acid substitution
is known. Thanks to Sauer and Yockey we now have such quantitative data.
It is important to realize that Sauer's and Yockey's results hold whether
or not the system can replicate and is subject to Darwinian selection. The
odds against finding a new functional protein structure remain
astronomical in either case. This is because Darwinian selection can only
discriminate based on function and, with the exception of those found in
living organisms, virtually all protein sequences are functionless. An
amino acid sequence can be replicated and mutated in living organisms till
the cows come home, and the odds are still one in 1065 that a new
functional protein class will be produced.

The problem of the isolation of functional protein sequences is a vivid
illustration of the truth of the symposium thesis,
Darwinism and neo-Darwinism as generally held and taught in our society
carry with them an a priori commitment to meta-physical naturalism, which
is essential to make a convincing case on their behalf.

The skeptic can accept Sauer's and Yockey's results with equanimity
because his world is not necessarily limited to those phenomena that can
be explained by naturalism. Furthermore, the skeptic can happily concede
that many biological phenomena are explained by natural laws. He can agree
that beak shape and wing color can change under selective pressure, or
that different proteins in the same structural class, such as the alpha
and beta chains of hemoglobin, may have arisen through Darwinistic
mechanisms. But the believer in the universal application of physical law
is stuck. He must maintain, against the evidence, that different protein
classes, like cytochromes and immunoglobulins, found their way by raw luck
through the vast, dark sea of nonfunctional sequences to the tiny islands
of function we observe experimentally. He must maintain, without any
evidence, that Mesonychid gave birth over time to the whale. And why, we
ask, must he maintain these positions against impossible odds and without
supporting evidence? Because, he replies, I can measure only material
phenomena, and therefore nothing else exists.

In closing I would like to paraphrase Hubert Yockey,{7} who in his career
repeatedly pointed out facts that are not supposed to be mentioned in
polite scientific company: "Since science has not the vaguest idea how
[proteins] originated, it would only be honest to admit this to students,
[to] the agencies funding research, and [to] the public."

NOTES

{1} Yockey, H. P. (1978), "A Calculation of the Probability of Spontaneous
Biogenesis by information Theory," Journal of Theoretical Biology
67:377-398.
{2} Lau, K. F., & Dill, K. A. (1989), "A Lattice Statistical Mechanics
Model of the Conformational and Sequence Spaces of Proteins,"
Macromolecules 22:3986-3994.
{3} Chan, H. S., & Dill, K. A. (1990), "Origins of Structure in Globular
Proteins," Proceedings of the Natural Academy of Sciences USA 87:6388-6392.
{4} Bowie, J. U., & Sauer, R. T. (1989), "Identifying Determinants of
Folding and Activity for a Protein of Unknown Structure," Proceedings of
the National Academy of Sciences USA 86:2152-2156.
{5} Bowie, J. U. Reidhaar-Olson, J. F., Lim, W. A., & Sauer, R. T. (1990),
"Deciphering the Message in Protein Sequences: Tolerance to Amino Acid
Substitution," Science 247:1306-1310.
{6} Reidhaar-Olson, J. F., & Sauer, R. T. (1990), "Functionally Acceptable
Substitutions in Two a-Helical Regions of l Repressor," Proteins:
Structure, Function, and Genetics 7:306-316.
{7} Yockcy H. P. (1981), "Self Organization Origin of Life Scenarios and
information Theory," Journal of Theoretical Biology 91:13-31.


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