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BOOK REVIEW

Genes in Context

William Summers

The Misunderstood Gene. Michel Morange. Translated by Matthew Cobb. xii + 222 pp. Harvard University Press, 2001 (originally published as La Part des Gènes by Editions Odile Jacob, 1998). $24.95.

The Impact of the Gene: From Mendel's Peas to Designer Babies. Colin Tudge. viii + 375 pp. Hill and Wang, first American edition (originally published in the United Kingdom in 2000 by Jonathan Cape as In Mendel's Footnotes). $27.

The Cooperative Gene: How Mendel's Demon Explains the Evolution of Complex Beings. Mark Ridley. xii + 324 pp. The Free Press, 2001. $26.

Books about genes seem to have joined the ranks of cookbooks and doctor books in that there appears to be an insatiable market for them. But then, we live in the era of genes—genes for happiness, genes for sadness, genes that can make us monsters, genes that shape our very culture. There is no shortage of authors anxious to explain, illuminate and guide us in our thinking about genes. Unfortunately, just as many new cookbooks offer only rewarmed fare (old recipes in new combinations), many books about genes offer a flood of recycled stories, metaphors and explanations, with very little fresh information. The books under review offer up both old and new insights and will be of interest to readers with diverse points of view and varying levels of background knowledge of genetics.

The concept of the gene is usefully vague, and as some thoughtful scientists and a few philosophers have observed, such vagueness can be of heuristic value in scientific work, even though scientists often pretend that they deal only in clarity and precision. What is a gene? Is it a chemical? A "determinant"? A unit of "information"? Do genes exist? If so, in what sense? At one time, genes were fundamentally mental constructions helpful in explaining the phenomenology of breeding of animals and plants. Later, a physical interpretation was sought, and more recently, concepts based on information theory have become popular. In everyday usage, geneticists effortlessly slide from one concept to another, with the usage almost universally and unconsciously understood from the context. Nonspecialists often overlook or fail to adequately appreciate this context-embeddedness. To some extent each of the three books under review attempts to contextualize the concept of the gene.

The most successful and most balanced account is given by Michel Morange in The Misunderstood Gene. Morange is a biochemist and geneticist who also directs the Center for the Study of the History of Science at the École normale supérieure in Paris. He lays out a clear view of the gene as the way to understand how cellular processes are controlled and regulated. This approach, often called "physiological genetics," has Continental origins in the early work on embryology, cell growth and differentiation. The view of genes as the regulators of life processes, from embryonic development, to enzyme regulation and control of metabolism, to cancer, is now often conceived in terms of genetic "programs." The operon model for gene expression is the classic example of this "physiological" conception of the gene. On the other hand, genes can be thought of as the agents ensuring generation-to-generation continuity of being—that is, the agents of heredity. This "transmission genetics" was the strong suit of American geneticists from the time of Thomas H. Morgan. These two views of genes (some scholars have characterized them as nuclear versus cytoplasmic) were often at odds until the 1950s and 1960s, when the underlying chemical basis of gene structure and function provided unifying explanations for them.

In The Misunderstood Gene, Morange gives examples of the ways in which genes are related to physiological processes. His examples emphasize the diversity and complexity of these relationships. He particularly focuses on the nature of the evidence used in thinking about these relationships, evidence that is most often derived from genetic manipulations that alter or replace a gene so that the corresponding protein is missing or inactive. The fruits of these genetic manipulations, which have been exploited by geneticists at least since the 1930s and are now known by the trendy name of "knockout mutants," allow one to test whether, and in what way, a gene product matters to the functioning of an organism, cell or particular subcellular reaction. The early biochemists, to learn how things work, used specific chemical inhibitors (poisons and their analogs) to intervene in cellular processes; these blunt tools have been replaced by the geneticist's mutations, which often offer more specific, more complete and more reproducible ways to alter or delete some cellular function. As Morange shows quite convincingly, we are constantly being surprised by the results of such experiments. He argues that these surprises often result from our rather crude understanding of the nature and function of genes. In rather old-fashioned terms, he is concerned with the causal relationship between genotype and phenotype: How do genes play out in the organism?

This question of genetic determinism may explain a lot of the interest in books about genes. What does it mean to say a person has the "gene for x"? As Morange explains, it all depends. If you have the "gene for blood group A," every single one of your red blood cells will have a certain antigen on its surface; you will unambiguously have "type A" blood. If, however, you have the "gene for phenylketonuria" (PKU), what does that mean? PKU is a state of excess urinary excretion of phenylketones. This state occurs if two conditions are met simultaneously: You fail to oxidize phenylalanine to tyrosine, and you eat sufficient phenylalanine to cause a buildup of unconverted phenylalanine into the phenylketones that appear in the urine. Further, it appears only in early life; as individuals with the "PKU gene" mature, they can consume normal quantities of phenylalanine with no apparent harm. What then is the meaning of the "gene for PKU"? Although medical geneticists understand the contextual meaning to imply that an individual has the DNA sequence that encodes phenylalanine hydroxylase with perhaps "sluggish" kinetics, the nonspecialist certainly has a fuzzier notion of the "gene for PKU." Morange suggests that PKU might better be thought of as an environmental rather than a genetic disease.

Even more problematic (misunderstood, in Morange's terminology) are concepts such as the "gene for breast cancer," the "gene for altruism" and the "gene for sexual orientation." All of these aspects of the human condition seem to have some genetic basis—that is, there are reasons to believe that one's genetic background matters and that these aspects are the end product of some complex interaction between the physical organism and its environment. But just how we should interpret the "gene for x" is not at all clear. The causal connection between the occurrence of a certain run of DNA bases and what it is that we identify as a "trait" ranges from clear, in the case of blood groups and hemoglobinopathies, to vague and uncertain, in the case of behavioral traits. In keeping with the cosmic perversity principle, it is the hardest cases that we find most interesting.

In Colin Tudge's The Impact of the Gene, we are given the standard account of Mendel's work on peas, its loss and rediscovery in 1900, various challenges to Mendel's methodologies, and the reconciliation between Mendelian genetics and Darwinian evolution that took place in the 1930s under the name "the Modern Synthesis." Tudge trudges through conventional history, relying mostly on standard sources; there are no surprises here.

Halfway through his story, however, he branches out and introduces some recent thinking in evolutionary psychology as a way to approach what he sees as ethical problems of modern genetic technologies. This latter half of the book provides some fresh insights. Specifically, Tudge is particularly clear in his attempt to develop a metaphysical approach to thinking about genetic experimentation. By abstracting what he sees as the common principles of the "prophets" (religious and secular), he adopts three tests by which we might judge the "rightness" of genetic experimentation: personal humility, respect for other sentient beings and reverence for the universe as a whole. Interestingly, these very principles may have a genetic basis, arrived at through Darwinian selection for particularly successful human beings. Although this approach is not original with Tudge, his arguments are clear, well-considered and forceful. Once we have come to understand a gene with Morange's aid, Tudge helps to clarify our "attitude" toward genes.

To explain a crucial step in the evolution of life, Mark Ridley in The Cooperative Gene offers an account of how the genetic complexity explained by Morange could have arisen. The basic problem is that multicellular "higher" organisms have a great many more genes than do single-cell organisms; this seems to allow them to do more things, but it also poses severe evolutionary problems. One problem is simply the error rate of replication: If each organism is to reproduce more or less faithfully (as is necessary for Darwinian evolution), its genome size is inherently limited by the fundamental error rate per base pair replicated. It is easy to copy a small nucleic acid sequence without error; it is hard (maybe impossible) to copy a long sequence without error. The problem of the stability of genes and the accuracy of their transmission has puzzled geneticists almost from the beginning. Ridley reviews this problem at a conceptual level without much technical explanation. Evolution has solved the error problem in several ways: with redundancy of information through the use of double-helical DNA rather than single-strand RNA; through error checking (editing) by the DNA polymerase in replication; and through excision and recombinational repair pathways.

Once evolution devised ways to overcome errors so that a large genome became possible, there was still a problem of sorting genes in replication and maintaining related genes in the same cell. Ridley explains that sex is not an unalloyed good: Biparental inheritance helps provide genetic diversity and gives a survival advantage, but in the case of duplicate copies of genes, there is a selection against the "less fit" of the two copies, and probably even selection against having two copies at all. Concomitant with the evolution of sexual reproduction, some mechanism was needed to force genes to be cooperative, in Ridley's terminology. This step in evolution—the acquisition of stable diploidy—was the second prerequisite for evolution of organismic complexity.

Ridley has thought seriously and deeply about the evolutionary problems about which he writes. He realizes their complexity, and in trying to explain and illuminate them, he employs everyday metaphors, similes and analogies. Therein lies the problem with his book: By avoiding anything slightly technical (for example, nucleotides, bond energies, enzymes), he almost completely obscures his message. We hardly ever read about DNA replication; instead, he tells us about communication errors in the children's whispering game of "telephone." The analogy he draws between the economics of corporate mergers and sexual mating or mitochondrial symbiosis will, I suspect, leave nonspecialist readers more bewildered than enlightened. This reviewer has more than the usual familiarity with mutagenesis and repair phenomena, yet still some of the analogies and metaphors seemed obscure to me. Ridley's erudition, for me, often muddles his message. For example, when he tries to explain "Mendelian justice" by comparing it with John Rawls's ideas on justice, the role of chance in genetics is obscured.

These three books present differing perspectives, yet each author, in his own way, is seeking to explain genetics in realistic terms and aiming to provide a basis for informed judgment about human activities in the "postgenomic world." The concept of total inclusive fitness, although it is not as clearly articulated as it deserves to be in this context, clearly undermines traditional, simplistic Darwinian explanations. Each author also argues against the traditional reductionistic view of genetic determinism. The "gene for" concept, which seems to threaten free will and human autonomy, is shown to be a misunderstanding of the concepts and workings of "the gene."


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