The Misunderstood Gene. Michel Morange, trans. Matthew Cobb. Harvard University Press, Cambridge, MA, 2001. 222 pp., $24.95 (ISBN 0674003365 cloth).
Misunderstood, maligned, malicious, mutant, mistranslated, and demystified, genes have been central to biology for over a century. Morange joins the notable company of Evelyn Fox Keller (2002), Richard Lewontin (2000), Celeste Michelle Condit (1999), and Jose Van Dijck (1998) in questioning the current excitement over the complete sequencing of the human genome and in providing a complex perspective on intricacies of the relationship between genotype and phenotype. What informs all five of these critics is a deep appreciation for the science of genetics and a desire to instantiate our comprehension in a way that is as free as possible from the eugenicist heritage of human genetics. Thus, Morange is especially concerned with reductionistic interpretations of knockout experiments (“targeted gene inactivation”) and asserts that we must “face the problem of determinism squarely…to go beyond it” (p. 7).
As a biologist and a historian of science, Morange seamlessly navigates both experimental detail and social history with a careful retelling. His analysis invokes plurality, complexity, and diversity, and he cautions us to “be wary of hasty explanations and simplistic schemas” (p. 61). In fact, he labels many popular understandings and newspaper coverage as promoting “dangerous fantasies” and as being “mistaken.”
While converting La Part des Génes to The Misunderstood Gene is not equivalent to translating Proust, Cobb has maintained some syntactical features of the original French that make it somewhat difficult for American readers. Numbered lists abound throughout the book, and often one has to follow three or four subpoints within a particular paragraph that elaborates just one item in a series. On the other hand, Morange frequently gives more attention to European intellectuals (including references to original works in French and German) than do most American molecular biologists, which is often refreshing and illuminating. Nonetheless, most American biologists will find the material familiar and the analysis interrogative rather than authoritarian.
Morange covers an impressive amount of detail on experiments meant to elucidate the genetic basis of behavior, mental illness, development, aging, disease association, and cancer. While his own research is on embryonic heat shock transcription factors, among other topics, he is not prone to self-promotion or self-citation; instead he draws on the work of many laboratories. Furthermore, this is a fresh analysis that is not derivative of his previous book, A History of Molecular Biology (Morange 2000a), although he did publish a review article on gene function (Morange 2000b) that made the same basic argument presented here. In The Misunderstood Gene, he elaborates significant details of conflicting reports in the primary literature on the interpretation of gene function from molecular, cellular, and organismal studies.
The book has 10 chapters, with most of the detailed analysis presented in chapters 4 through 8. Chapter 4 focuses on diseases originally thought to be caused by single genes, such as sickle cell anemia, Williams syndrome (a neuropathology), and Alzheimer's disease. Chapter 5 describes in vivo versus in vitro experiments on genes involved in detoxification of dioxin in the liver, in Lesch-Nyhan disease, in cytoarchitecture (but not tensegrity), and in signaling networks. Chapter 6 explores long-term potentiation of synapses in the brain, Benzer's temporal mutants in Drosophila, and a critique of “cognitive kinases” (p. 90). Chapter 7 looks at oncogenes and cancer, several Nobel Prize–winning discoveries on the relationship of genetic regulation and development, the role of telomerases in life span and aging, and apoptosis and the existence of “death genes” (p. 122). Finally, chapter 8 focuses on behavior through circadian “rhythm genes” such as period, timeless, and clock; on the relationship of sexuality and personality to general mutations “that primarily affect vision, olfaction, or the emission or detection of auditory signals” (p. 131); on transcription factors involved in sexual differentiation; and on a critique of the “gay brain” hypothesis (p. 134), genomic imprinting, heritability and IQ, and altruistic behaviors.
Throughout, Morange imputes to researchers self-preserving scientific behavior, errors of inference, and neglect of work by opponents or investigators with radically different approaches. While his critiques are not gossipy, they do have the effect of suggesting a certain authorial omniscience that can become wearing, especially because of an underlying flag-waving for logical positivism.
Morange emphasizes the biological sources of many of these difficulties in inference-making—intergenic redundancy, multiple pathways and compensation, feedback loops, and the differences between susceptibility and realization in a particular context—while taking on Weissman's heritage of somatic and germ-line dichotomy: “Thus, the strict division between maternal and genetic factors, beloved of certain biologists, is clearly artificial” (p. 73). He concludes chapter 8 with homage to Waddington's “metaphor of a landscape to describe gene action during development” (p. 152).
Some of his observations seem insightful and sound: “A genetic diagnosis not only affects one person, it affects several” (p. 166). But shortly thereafter, his conclusion that “this link between genes and proteins is not primordial, it is not consubstantial with life” (p. 168) and that “we can regret the passing of the RNA world in which two fundamental characteristics of life—self-replication and the organization of complex molecular structures—were expressed by a single type of macromolecule” (p. 169) seems to be merely political rhetoric. Morange here ignores the intertwined evolutionary history of the relevant “eusemantic molecules,” to use Zuckerkandl and Pauling's (1965) language, and 35 years of careful phylogenetic analyses of nucleic acids and proteins. He instead confers ultimate status on speculations about the RNA world. These are not the only examples of omissions; while Morange gives great attention to in vitro and in vivo experiments, he virtually ignores the insights of population and quantitative geneticists. He gives passing lip service to multifactorial and multigenic (p. 50) models of the inheritance of complex traits as well as to the concept of penetrance (p. 75) but never invokes epistasis, pleiotropy, or polygeny explicitly. Furthermore, his apposition of population and molecular genetics screens off readers from extremely fruitful work in molecular population genetics, QTL (quantitative trait locus) analysis by molecular quantitative geneticists, and molecular phylogenetic systematics.
Morange cites the “rediscovery of the cell…[as] a major level in the integration of biological processes (and thus in their explanation)” and declares that it “was probably the most important change that has taken place in molecular biology since its rise in the 1950s” (p. 160). While I applaud this holistic move to combine structure and function in context, I would argue that Morange, like many other molecular biologists, inadequately discusses the primary integrative theory for the past 150 years, namely evolution. Homology of sequences has afforded us the opportunity to systematically test hypotheses such as endosymbiosis (with major ramifications for the whole internal organization and compartmentalization of cells), orthologous versus paralogous functioning of isoenzymes or protein subunits, and whether function is primitive or derived. Morange largely ignores the bioinformatic revolution, which is based on inferences drawn from sequence evolution. He might have heeded his own words: “As with virtually all conceptual changes, most people did not even notice” (p. 160). However, he does cite some of the conclusions of this work throughout the book. For example, on page 98 he states, “Moreover, evolution has not conserved isolated genes but rather pathways and entire networks of developmental genes—functional modules,” and on page 99, “These organisms use the same molecular mechanisms to construct themselves as did their long-dead common ancestor. The resemblance of genes is a mark of a homology in the construction of organisms.”
Nonetheless, I wholeheartedly agree with Morange's conclusion that “we should abandon the naïve idea of a single one mutation, one disease relation” (p. 52). And besides recommending his book The Misunderstood Gene, and other recent books by Richard Lewontin, Evelyn Fox Keller, Jose Van Dijck, and Celeste Michelle Condit, to general readers, I would strongly recommend that students in standard genetics classes read at least one of these informative critiques of the excesses of geneticists' claims.