Half a Century of DNA—James Watson's Life in the Molecular Genetics Revolution

A Passion for DNA: Genes, Genomes, and Society By Watson James D. Plainview NY: Cold Spring Harbor Laboratory Press (2000). 250 pp. $25.00No Nobel Prize is better merited than that awarded to James Watson and Francis Crick for their discovery in 1952 of the double-helix structure of DNA. That structure represented the culmination of half a century of prior work on genetics, a decisive shift in the balance of structural research from data collection to model building, and—above all—introduced a new agenda for the whole of biology. In this collection of essay Watson describes how he got there and what happened next. It answers, as Walter Gratzer here points out, the question asked by one Neanderthaler of another: “So he invented fire and the wheel, but what has he done since?”Watson always writes well. He is at his most moving—indeed inspiring—when describing his upbringing in Chicago and his first flights in research at Indiana University. There Dean Payne had assembled a galaxy of stars that included Herman Muller, Tracy Sonneborn and Salvatore Luria. Presciently Watson avoided the Sonneborn lab, which was then devoted to cytoplasmic inheritance, a concept that did not survive the double helix. Instead he chose to join Luria's laboratory, then an outpost of the phage group (bacteriophages are viruses that attack bacteria), which under the leadership of Max Delbruck had chosen to study the simplest form of genetics then available. There he enjoyed the privilege of belonging to a small but widespread group, which had the clear aim of discovering the phages' genetic mechanism and had built the technology needed to do so. The group met frequently in a critical but encouraging atmosphere. How better to grow up? And how fortunate to do so in the Mid-West where the scientific community placed a higher value on innovation than on past achievements, unlike the East Coast and the Europe of that era. In the spirit of the phage group, Watson was determined summarily to reject anything that stood in the way: the demand of a cosupervising Professor that he study histology received short shrift. The ethos of the phage group, tempered by his experience in Cambridge while working with Crick, is summarized here in his “Rules of Thumb” for young scientists written forty years later. His rules include such sage advice as “Learn from winners” and “Have fun and stay connected.”The definitive description of the work in Cambridge appeared, of course, in Watson's The Double Helix, a wonderfully dramatic account from which the author famously emerges as an unscrupulous comic. Crick's account can be found in his autobiography What Mad Pursuit, and Horace Judson's The Eighth Day of Creation provides a less personal account that Watson here endorses. An addition here is the touching account of how much Watson valued the preface to his book written by Lawrence Bragg, the eminent crystallographer. Bragg was the Director of the MRC Unit where Crick and Watson had worked, and his preface at last gave his authoritative approval of their use of modeling.Molecular biology expanded rapidly during the decade following the discovery of the double helix. The challenge was to sort out the role of RNA, and eventually to establish the “Central Dogma” of DNA→RNA→protein. Watson moved to Harvard, where he endearingly got off on the wrong foot by searching for a double-helical structure for RNA. By the end of the decade RNA had gotten sorted out, with Crick's “adaptors” confirmed as tRNA. The discovery of mRNA was published back-to-back in 1961 in papers from the Watson and Meselson groups. This sparkling account, written thirty years later and now published for the first time, is the scientific core of the volume. What fun the “in” group had with its RNA-club tie and the warm personal and scientific welcome in Paris from Francois Gross and Jacques Monod, the pioneers of bacterial genetics. And how easy Watson finds it to poke fun at the older generation that had the audacity to undervalue DNA: Cyril Hinshelwood, Cyril Darlington, Ronald Fisher, Conrad Waddington. He gives no inkling here of Waddington's contributions to animal breeding, reproductive biology, and developmental decanalization (the latter now vindicated, see Trends Genet. 15, 169, 1999). His attitude did not endear him to his colleagues in the Harvard Biology Department, and he became a subject of innumerable anecdotes. His proposal that embryology should be put in the deep freeze was not well received, nor was one that the samples of pond water in the museum should be removed to make room for Walter Gilbert's lab.Meanwhile, Watson had invented a new style of textbook that was to make him not only famous but also financially independent. The Molecular Biology of the Gene in 1966 played a crucial role in defining the new subject of molecular biology, and was succeeded by the even more definitive The Molecular Biology of the Cell. Successive editions of the latter mark the spread of molecular biology into immunology, reproductive biology, and neurobiology, as well as development, now out of the freezer at last.In 1967 Watson became Director of the Cold Spring Harbor Laboratory, with the aim of tackling cancer. Viruses had begun to contribute to the progress of molecular biology: for instance tobacco mosaic virus had provided the classical example of mRNA incorporated into the structure of a virus. Work was just beginning on the small DNA viruses that could make cells cancerous and which therefore stood a fair chance of emulating the maximum-simplicity role that phages had earlier played. Watson here describes how Lionel Crawford from Glasgow and then ICRF helped him design the tumor virus laboratory, and how the former Director John Cairns advised him that the virologist to go after was Joe Sambrook. What he doesn't mention is his later struggle to prevent Sambrook returning to ICRF and the UK. Cold Spring Harbor did succeed in establishing a dominant position in SV40 research, in parallel with similar research on polyoma virus at ICRF. Over the next decade the extraordinarily compact nature of these viral genomes emerged, with large-T as the dominant oncogene product. The final story has yet to be told, and will certainly turn out more complex than had been hoped. Nevertheless, the interaction of large-T with p53 is now known not only to play a crucial role in SV40-mediated oncogenesis, but also to provide a model for oncogenesis at large. As Watson points out, Hanahan's transgenic mice (made at Cold Spring Harbor) expressing large-T off the insulin promoter demonstrate how much more there is to carcinogenesis: the mice develop benign growths in the pancreas that seldom turn into true tumors.Directors are notoriously unable to evaluate their own Institute objectively, in public at least. We can hardly complain if the account here of cancer research centers on Cold Spring Harbor. For a more balanced account, read the last chapter of The Molecular Biology of the Cell.In the final sections of this book, we see Watson as both sage and gadfly applying himself to the public issues raised by DNA. On the war against cancer: more resources should be put into academic centers so as to attract bright students, on the MIT pattern. On apprehensions voiced at the famous Asilomar Conference concerning the hazards of recombinant DNA: they were maybe right about large-scale handling of oncogenes, but went too far. On unquantifiable risks: these should not be allowed to hold up science. On the human genome project: it should receive full support, and it is high time the Germans joined in. On genetically modified food: this is not a valid category, considering what orthodox plant-breeders get up to. These are sensible views with which most of us would now agree, and it has surely helped to have them put so forcibly by a scientist of such prestige. The problem is that Watson's impatience with the slow-witted works well in science, but can be counterproductive in the outside world of politicians, the media, and eco-publicists. Yet in spite of all, science surely need its Watson.