Genes at work

Gene Action: A Historical Accountedited by Werner Karl Maas Oxford University Press, 2001 $35.00 (161 pages) ISBN 0195141318Geneticists have been well served by histories of their subject. There were three early classics: Alfred Sturtevant's A History of Genetics and Leslie Dunn's A Short History of Genetics, both published in 1965, and Elof Carlson's The Gene: A Critical History, published in 1966. DNA was covered in detail by Robert Olby (Path to the Double Helix), and Jack Cohen and Franklin H. Portugal (A Century of DNA), and Horace Judson went beyond the DNA story in The Eighth Day of Creation to describe the modern experimental work on protein synthesis and the determination of protein structure.Werner Maas’ title, Gene Action, led me to expect a more detailed treatment of part of the territory covered by Judson, namely research on the regulation of gene action and expression. This work had its roots in biochemical genetics, beginning with the studies of Boris Ephrussi and George Beadle, and continuing when Beadle joined Ed Tatum to work with Neurospora. Escherichia coli then became the organism of choice, and Bernard Davis, Maas and Norman Horowitz investigated the biosynthetic pathways of the bacteria using temperature-sensitive mutants.By the early 1950s, biosynthetic pathways had become a rather unfashionable area of research, overshadowed by the double helix and the search for the genetic code. However, even then some notable scientists, including Jacques Monod, Arthur Pardee, Milislav Demerec and Philip Hartman, were determining how cellular biosynthetic activities were adjusted to meet the needs of the moment. These studies of feedback control of biosynthetic pathways came together with the more fashionable molecular world in a talk given by Francois Jacob and Monod at the 1961 Cold Spring Harbor Symposium. They combined the biochemical findings on gene regulation with detailed genetic analyses of the lac region of E. coli and the regulation of lysogeny in λ phage, and set out an explicit model for gene regulation involving control regions, inducers and repressors. (This was later published as one of the great papers of molecular biology [1xGenetic regulatory mechanisms in the synthesis of proteins. Jacob, F. et al. J. Mol. Biol. 1961; 3: 318–356CrossRef | PubMedSee all References][1].)Although this makes an exciting story, its impact in Gene Action is muted because Maas has chosen to treat ‘gene action’ in the widest possible sense, including material that detracts somewhat from what I perceived as the central theme. Instead of beginning with the origins of biochemical genetics, Maas’ first two chapters are devoted to Gregor Mendel and Thomas Hunt Morgan. The story is again disrupted by chapters on Oswald Avery, the double helix, transfer RNA and the genetic code and, although Maas provides a succinct rendition of these topics, he adds nothing new to existing accounts. This is unfortunate given that the book is rather short; the pages could instead have been used for topics of which Maas has direct experience.There are also inaccuracies. Some are trivial – the RNA Tie Club tie was ordered by Jim Watson from a haberdasher in Pasadena, and not by George Gamow from one in Oxford – but others are serious. For example, Maas writes that Watson and Francis Crick were told of Chargaff's rules (that C=G and A=T) by Erwin Chargaff himself, and that they were ‘…overjoyed by the unexpected support for their model’. However, they met Chargaff in May 1952, some ten months before elucidation of the double helix. At this time, Watson and Crick had speculated that some form of base pairing might hold the chains together and a colleague, John Griffith, did a calculation suggesting that A might pair with T, and G with C. However, they were thinking of pairings between the flat surfaces of interleaved bases, arranged rather like the cards in a pack of playing cards. As Griffith's was a ‘back of the envelope’ calculation, Crick was not impressed enough to pursue its implications. It was not until Chargaff told Watson and Crick of his results that Crick attempted to detect base–base interactions. These failed and Watson and Crick did not return to the problem of the bases until Watson began building models in February of 1953.Maas also writes that it was Crick who coined the name ‘messenger RNA’. This is not correct. Even before the double helix, Watson had written ‘DNA makes RNA makes Protein’, and it was generally assumed that, because DNA was in the nucleus and protein synthesis took place in the cytoplasm, something had to be a messenger between these two compartments. This RNA was not ‘messenger RNA’; rather it was thought to be ribosomal RNA. Evidence gradually accumulated suggesting that the latter did not have the characteristics of the postulated message. The definitive experiment was carried out by Pardee, Jacob and Monod (‘PaJaMo’) in 1959 and showed that the kinetics of protein synthesis following the introduction of genes into a cell did not fit with ribosomal RNA being the messenger. It was Jacob and Monod who first named ‘messenger RNA’ in their 1961 paper [1xGenetic regulatory mechanisms in the synthesis of proteins. Jacob, F. et al. J. Mol. Biol. 1961; 3: 318–356CrossRef | PubMedSee all References][1], and its existence was demonstrated by Sydney Brenner, Jacob and Matt Meselson at CalTech, and by Francois Gros and colleagues at Harvard.The development of genetics from the early years of the 20th century through the closing years of the same century is one of the greatest of intellectual achievements. It is an epic story of heroes and ‘villains’, of seized moments and missed opportunities, and of beautiful theories, some slain by cruel but no less beautiful facts. Maas’ book is a satisfactory if rather brief account of an intriguing part of this story.