Author's final comments.

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.

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).

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.

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.

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.

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.

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.

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."

{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.

Copyright © 1994, 1997 Foundation for Thought and Ethics.

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