What drinking beer can lead to

Ian Wilmut disentangles the history of DNA 50 years after the 'double helix'

The scientific understanding of life provided by molecular biology and the opportunities to manipulate life through genetics are among the most important developments of the past half-century. They depend on the insight of Francis Crick and James Watson, whose suggestion that the structure of chromosomal DNA (deoxyribonucleic acid) is a double helix was first announced 50 years ago today in their joint 1953 publication in Nature and later described in Watson's well-known book The Double Helix (1968). This new book by Watson, DNA: The Secret of Life , explores the story and significance of DNA from its first isolation in 1869 until now. The second book, Watson and DNA , by Victor McElheny, is a biography of Watson.

The importance of a series of lectures by the theoretical physicist Erwin Schrodinger, published in 1944 under the title What is Life? , has long been recognised by the biologists who played central roles in the DNA story, including both Crick and Watson. Among other things, Schrodinger analysed the essential characteristics of the molecular mechanisms of inheritance and predicted that a "hereditary code-script" must be contained within the chromosomes.

Both these books describe the sequence of critical experiments that provided a detailed description of the mechanisms of inheritance. But although the logic of the sequence is clearly visible to us with the advantage of hindsight, this was not the case at the time. In the first half of the 20th century, and beyond, many researchers considered that proteins, not chromosomes, were likely to constitute the means of inheritance.

In 1945, Oswald Avery and colleagues in New York demonstrated that bacterial characteristics can be altered by the introduction of DNA. They discovered this startling fact as a result of observations made by Fred Griffith, working in Britain at the Department of Health's laboratories, that bacteria could exchange characteristics. Griffith injected mice with two closely related strains of the bacterial cause of pneumonia: one with a rough cell coat known to be harmless, another with a smooth cell coat known to be harmful. When only live rough-coated bacterial cells were injected, the mice lived, ditto with only heat-killed smooth-coated bacterial cells.

Whereas when both types of cell were injected together - the one live but harmless, the other dead but harmful - the mice died. Therefore the dead smooth-coated cells had transformed the live rough-coated cells and made them harmful. Avery's group showed that it was the transfer of DNA between the two strains that brought about the change, although many distinguished biologists were sceptical. It might be argued that it was really Avery who discovered the "secret of life".

Chemical analysis by Erwin Chargaff (like Schrödinger a refugee from Austria) was the first scientific work to identify a consistency in the composition of DNA, by showing that it contains four paired nucleotides. There is always the same amount of adenine and thymine in DNA, likewise cytosine and guanine. This led Crick to develop the idea of complementary strands of DNA. Then X-ray crystallography, notably by Rosalind Franklin, proved the existence of a double helix: the crux of the story told in Watson's first book and more recently in Rosalind Franklin: The Dark Lady of DNA by Brenda Maddox.

However, there was still much to learn. How did the DNA nucleotide sequence direct the activities of the cell? What was the code foreseen by Schrodinger? This involves RNA (ribonucleic acid), which controls the sequence of amino acids in proteins. In the 1950s, most of the active researchers were members of the "RNA tie club", limited to 20 members (20 was the number of amino acids considered important). Sydney Brenner had a leading role in describing the code. In 1956, in a paper circulated among tie-club members, Brenner reasoned that three letters was the minimum number required in the "word" used to select an amino acid. Later, he and Crick confirmed by experiment that three nucleotides are used: they showed by changing bases in the RNA sequence using chemical agents that one or two changes in a base are always damaging but three changes are not. To discover the meaning of each DNA triplet, a series of ingenious means were then used by US groups at the National Institutes of Health and the University of Wisconsin to synthesise different RNA sequences; research that led to Marshall Nirenberg and Har Gobind Khorana receiving a Nobel prize for physiology or medicine (one of the numerous DNA-related Nobels). Not until late in the 1960s was there a clearly understood mechanism for how DNA directs synthesis of RNA and hence the synthesis of proteins.

The impression is sometimes given, not least by Watson in The Double Helix , that scientific progress is linear. The reality is far more complex and chaotic, as is shown in both of these books. Research projects head off on many different lines of investigation, only some of which prove relevant to solving the original problem, while others are unexpectedly fruitful in solving other problems.

Furthermore, the variation in the personalities among scientists is clear. Crick and Watson made a habit of sitting ostentatiously near the front of scientific meetings reading a newspaper, while Griffith was so reserved that he apparently had almost to be forced to give a presentation of his work on the transformation of bacteria.

It takes only a brief acquaintance with Watson to recognise that he is a highly intelligent, extremely energetic and independent thinker, while also someone who is opinionated, unconcerned about the feelings of others and almost uncouth. Watson and DNA reveals how each of these characteristics has contributed to its subject's revolutionary career.

Watson's life can be considered in four phases. His education and training ended spectacularly with the discovery of the structure of DNA in 1953. Then he had a period at Harvard University. After that he moved to the laboratory at Cold Spring Harbor as its director. Finally, he became the first leader of the Human Genome Project. Major scientific contributions were made by him at all four stages.

He was born in a Catholic family in Chicago. His father was a bill collector, and during the Depression his mother did office work to help make ends meet. It was a warm and supportive family, and Jim remained close to his parents and his sister. His parents loved learning and always supported their son's education.

At school Watson describes himself as being small, extremely shy and bookish, with an ambition to study the migration of birds. But judging by his school examination results, he was not outstanding. However, he was always curious, read widely and soaked up knowledge, including the facts in a World Almanac , which stood him in good stead in a radio quiz. He was much influenced by Arrowsmith , a Pulitzer prize-winning account of the life of a scientist, in which the main character trains as a physician yet is attracted by the intellectual freedom and truth-seeking of basic scientific research.

Nevertheless, at the age of only 15, Watson entered the University of Chicago under a policy championed by the university's president, who believed that the later years in school stunted the ability to think by teaching students to assimilate large numbers of facts (a view that seems increasingly plausible today). Again, his examination grades were not outstanding, nor was he personally happy. But he started his habit of never taking notes in lectures and instead concentrating on extracting underlying principles. His reading of Schrödinger's What is Life? was a major factor in his deciding not to become an ornithologist. At Indiana University, where he went for postgraduate work, he directed more and more effort towards understanding the nature of the gene.

I imagine most of us have mentors who are particularly influential. For Watson one of them was Max Delbrück, a hero of Schrodinger's book, who trained at Niels Bohr's Institute for Theoretical Physics and later moved to Cold Spring Harbor. Watson took part in a summer of experiments there on phages with Delbruck and Salva Luria, his mentor in Indiana. Another strong influence was Crick. Their partnership is described by McElheny as "a nagging yet productive symbiosis". Certainly, few partnerships in science have been more productive, as a result, it would seem, of each feeling free to challenge the ideas of the other and having the intellectual confidence to do so. This direct and questioning approach, often bordering on the offensive, continued with others after the two of them split up. At Harvard, the biologist E. O. Wilson remembered that Watson "radiated contempt in all directions". It is a manner that must suit and stimulate some colleagues, while destroying others, especially junior ones.

Over time, Watson became increasingly interested in research relevant to human diseases. Simultaneously, he was less directly involved in research and assumed more of a leadership role. As director at Cold Spring Harbor, he transformed a run-down and neglected research facility into a thriving powerhouse of new ideas. The summer schools became renowned for their penetrating questions and discussions, and for the opportunity to carry on the debate outdoors on the lawns while drinking beer. Watson developed leading programmes in cancer research by recruiting talented young biologists. In bringing together basic research and clinical applications, he has lived out the scientific career portrayed in Arrowsmith . Another invaluable contribution to molecular biology that should not be overlooked was the publication of his textbook, Molecular Biology of the Gene , in 1965, which has gone into four editions.

Watson proved adept at raising funds from government agencies: a talent that was invaluable as the Human Genome Project grew into the largest biological project ever attempted. He was not the first to develop the idea of mapping the human genome, but he seemed the obvious person to lead the project, and many people think its rapid progress reflected his influence in its early phases. His combination of intellectual prestige and experience in building a large scientific programme with star appeal, impatience and political sensitivity was unique.

McElheny provides a very full account of Watson's life and scientific contributions, with perhaps more detail than will be required by the general reader. Watson's own book can be recommended without reservation to anyone wishing to understand the story of DNA and its importance in all our lives. Non-scientists will require a technical dictionary, but the writing is easy to read, full of fascinating details, ideas and opinions that are certain to make one think. I am certain that any reader will share some of Watson's evident continuing excitement.

Ian Wilmut is head of the department of gene expression and development, Roslin Institute.