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The Cheshire Cat’s DNA

1.

In 1900, three biologists independently rediscovered Mendel’s laws, according to which the characteristics of organisms are determined by hereditary units, each kind being present once in a gamete, sperm or egg, and hence twice in the fertilized egg. In effect, it was an atomic theory of heredity. The term “genetics” was introduced by William Bateson in 1906, and, for the hereditary units themselves, the word “gene” by Wilhelm Johannsen in 1909. By 1930, Thomas Hunt Morgan and his colleagues, working with the fruit fly Drosophila, had shown that genes are arranged linearly along chromosomes.

In 1953, James Watson and Francis Crick elucidated the structure of DNA, the material of which genes are made, and by so doing suggested a mechanism whereby genes could carry genetic information, and could replicate. There followed in rapid succession the discovery that genes produce their effects by determining the sequence of amino acids in proteins, that they do so by means of a “code” in which a triplet of bases in the DNA specifies an amino acid, and that there is a process whereby one gene can regulate the activity of another. During the last twenty years there has been an explosion in our knowledge of how genes influence the development of animals and plants. Finally, in the year 2000, we await the publication of the complete sequence of the human genome.

It is this history that Evelyn Fox Keller celebrates, and criticizes, in her book. A professor of the history and philosophy of science at MIT, she is at the same time enthusiastic about the light that has been shed on the nature of life and critical of the oversimplifications that she feels have been made. Later in this review I shall argue with some of her conclusions, so I must start by emphasizing that she is well qualified to draw them. She has an admirable grasp of recent research in molecular genetics—certainly wider and more detailed than my own—and has read widely in the history of genetics. I was delighted to meet again in her pages biologists who influenced me when I was starting in research, but whose work I imagined had been forgotten. She has also thought hard about both the history and the current state of the subject. Our disagreements are not of the kind that can be settled by specific experiments or observations; they concern differences about the best strategy to pursue when faced by the complexities of living organisms. I know that the world is complicated, but always seek for simple explanations of the complexity. For Keller, living organisms only work because they are complex; to simplify them is to leave out their essence.

The book can be read by those without previous knowledge of molecular genetics. However, it is not the kind of account I would write if I was aiming at a nonprofessional readership; I would leave out a lot of the complications. Clearly, this is not an option for Keller, because for her the complications are crucial. This means that reading the book is hard work in places, but it is worth it. It is commendably short, but if you understand it you will have learned a lot about contemporary biology.

I will illustrate the nature of my disagreement with Keller by discussing how genes are replicated. I remarked earlier that the structure of DNA as revealed by Watson and Crick already suggested how it might replicate; in fact, their paper ends with the memorable last sentence, “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” As is well known, they showed that DNA consists of two complementary strands, each a string of four kinds of chemical units, or bases: adenine, cytosine, guanine, and thymidine, or A, C, G, and T for short. In the double-stranded helix, a C in one strand is always paired with a G in the other, and an A is paired with a T. This structure at once suggests a mechanism of replication. The two strands separate, and each acts as a template for the synthesis of a new complementary strand. The sequence, and hence the information, is preserved by the pairing of complementary bases. For reasons of chemical affinity, C pairs with G, and A with T. And, in a simple account, that is all there is to it.

Sadly, real life is more complicated. If matters were left just to the chemical affinity of C for G, and A for T, a “wrong” base would frequently be inserted; the error frequency would be at least 1 in 100. There would therefore be no way in which a large genome, with some 1,000 million bases, could be reproduced; errors would accumulate at an enormous rate. In practice, the process is executed by enzymes, that is, by proteins that make chemical reactions more rapid and more precise. Indeed, matters are more complex still. After the first enzyme-mediated pairing, the error rate is still about 1 in 1,000. There are then two further steps of checking and error correction, called, appropriately enough, proof-reading and mismatch-repair.

Keller describes this three-stage process in detail. She points out that the notion that DNA “replicates itself” is nonsense; it is replicated by a battery of enzymes. But if DNA cannot replicate without enzymes, it is equally true that enzymes would not exist without DNA, or without the whole machinery of protein synthesis, which starts with DNA. Thus heredity, the property that like begets like, depends not only on complementary base pairing, but on a complex dynamical system, involving both DNA and proteins. In this context she quotes with approval a remark by Max Delbrück, an ex-physicist and early molecular biologist. He pointed out that a system of cross-reacting and inhibiting chemical reactions can lead not just to one steady state, but to multiple steady states.

Delbruck himself did not see this “multiple steady states” model as a general explanation of heredity, but rather as an explanation of “cell heredity”; that is, of the fact that cells of a given type—fibroblasts or lymphocytes, for example—give rise when they divide to more cells of the same type. Keller’s own position is not fully clear to me. However, she is attracted to the idea that heredity depends not just on the copying of genes, but also on the stability of dynamic systems. Discussing the origin of life, she suggests, following the physicist Freeman Dyson, that self-maintaining metabolic systems, initially lacking any replicating molecules, may have played an essential role.

The idea that stable dynamic systems play a role in heredity is one that recurs; I remember being puzzled by it when I was a student. For evolution to be possible, a hereditary system is needed that permits the stable reproduction of an indefinitely large number of different structures; I do not think that a system relying on the alternative steady states of a dynam-ical system could permit this. I would draw quite a different moral from our present knowledge of DNA replication. It is one that Francis Crick famously called “the central dogma of molecular biology”—that information can pass from nucleic acid (DNA and RNA) to nucleic acid, and from nucleic acid to proteins, but not from proteins to nucleic acids. What he meant was this. If, in a lineage of reproducing cells, a single nucleotide—i.e., an individual component of nucleic acid—in a DNA molecule is altered, that alteration will be transmitted to the DNA in future generations, and may alter an amino acid in a protein; but if an amino acid is altered in a protein, that might interfere with DNA replication, but would not result in proteins appearing in future generations with the same altered amino acid. Changes in DNA are inherited, but changes in proteins (specifically, in their amino acid sequence) are not. Although Crick named this a “dogma,” it does appear to be true, perhaps the only universal truth we biologists have. It explains why geneticists take DNA seriously. Its significance for evolution is obvious.

One thing, however, is clear. The present process whereby DNA is replicated is far too complicated to have been a feature of the first living things. What, then, were the first living things like? In particular, how did it come about that like begot like? Without such heredity, there could be no evolution. Keller prefers Freeman Dyson’s suggestion that life originated as a symbiosis between a self-maintaining metabolic system involving proteins and a population of inaccurately rep-licating molecules, probably nucleic acids. I prefer the idea that the first living things—that is, the first entities with heredity and so able to evolve—were molecules, perhaps RNA (a molecule resembling DNA but single-stranded), which acted both as inac-curate replicators and as primitive enzymes; the suggestion is supported by the fact that there are RNA catalysts, analogous to enzymes, in existing organisms. My colleague Eörs Szathmáry and I have discussed elsewhere how this primitive RNA system might have evolved gradually into a DNA-protein system, with a genetic code.* The ideas are necessarily speculative, but I think they make more sense than a system of heredity based on alternative steady states of a dynamical system.

The fundamental difference between Keller and myself is that, for her, dynamic complexity is fundamental. For me, the crucial idea is the one first suggested by the Watson-Crick structure of DNA—that heredity depends on the chemical affinity of G for C and A for T. As Leslie Orgel remarked, as one traces life back to its origins, features are lost one by one, until one is left just with homologous base pairing, like the smile on the face of the Cheshire Cat.

Another situation in which it seems to me that Keller needlessly complicates things concerns the question, what do genes do? The simple answer, foreshadowed by the slogan “one gene, one enzyme” proposed by Beadle and Tatum in 1941, is that a gene codes for a protein. By a well-understood mechanism, different triplets of bases in the DNA specify different amino acids. The DNA that carries the information also has sequences meaning “start translating here” and “end of protein.” Sadly, for me but not for Keller, there are many complications. I have space to discuss only two. First, between the “proper” genes there are long stretches of DNA that are not translated into protein. A small fraction of this DNA has known regulatory functions, but most of it does not. Most of us tend to regard this DNA as “junk,” but it may have functions we do not know about. Second, within the coding genes there are “introns”—intervening sequences—which are spliced out before the gene is translated.

Obviously, anyone working with DNA must be aware of these complications. There are also fascinating questions about how this extra DNA came to be there in the first place. But in practice, given the sequenced genome of a simple animal such as a fruit fly or a nematode worm, it is possible to identify most of the “genes” that code for proteins, and to deduce the amino acid sequence of the proteins coded for. It is harder to identify all the protein-coding genes in the human genome because of the larger proportion of DNA that codes for nothing. But most biologists would accept that the meaningful part of the human genome consists largely of protein-coding genes. Yet Keller thinks that there is a difficulty in defining a gene functionally as a length of DNA that codes for a protein. I can see that there is a real difficulty in providing a philosopher’s definition that is true of all genes (for example, there are genes which code for functional RNA molecules, but not for proteins), but I don’t think this need worry biologists. After reading what Keller has to say in the last chapter about the way biologists use words, I think she might agree.

  1. *

    See our The Major Transitions in Evolution (Freeman, 1997).

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