John Smith

Cambridge molecular biologist who made outstanding contributions to the early work on nucleic acids

John Derek Smith, molecular biologist: born Southampton 8 December 1924; scientific staff, Agricultural Research Council Virus Research Unit, Cambridge 1945-59; Research Fellow, Clare College, Cambridge 1949-52; Rockefeller Foundation Fellow, University of California, Berkeley 1955-57; Senior Research Fellow, California Institute of Technology 1959-62, Sherman Fairchild Scholar 1974-75; Member of Scientific Staff, Medical Research Council Laboratory of Molecular Biology, Cambridge 1962-88, Head, Subdivision of Biochemistry, Cell Biology Division 1976-88; FRS 1976; married 1955 Ruth Aney (marriage dissolved 1968); died Cambridge 22 November 2003.

John Smith participated in many of the major discoveries that underpin modern molecular biology. He was one of only a handful of scientists who understood the importance of nucleic acids before 1953, the year Watson and Crick uncovered the structure of DNA.

John Derek Smith was born in 1924; his father was an insurance inspector. At five years old, and as an only child, he lost both parents in a flu epidemic. The next 12 years were unhappy, dominated by his two aunts. He lived mostly with one whom he loathed in Wetherby, Yorkshire, attending Knaresborough Grammar School, where he eventually became head boy. These dark times - when he was forced to walk two miles to church with his aunt each Sunday - were interspersed with holidays in Worthing with his other aunt, Aunt Iris, a dashing lady whom he adored. It may be that his shattered childhood led him to seek the security of an academic life. In any event, he entered Clare College, Cambridge in 1942, gaining a degree in botany.

His research career started as a student with Roy Markham and David Keilin at the Molteno Institute in Cambridge. Here he became interested in RNA (ribonucleic acid molecules), the genetic material of many plant and animal viruses, and developed paper chromatographic methods for analysing nucleosides and their relatives - these are the building blocks from which RNA is constructed. This, together with studies of how the enzyme pancreatic ribonuclease (which digests the RNA molecules in food you eat) carries out its chemical action, helped elucidate the backbone structure of all RNA molecules.

He then used the same chromatographic techniques to analyse the units of which DNA is built. It was well known at that time that the major components are A, C, T and G but Smith discovered, with David Dunn, rare and unexpected modifications of the DNA bases in bacterial genomes. These modifications are often just an extra methyl group on an A, G or C and seemed just curiosities at the time. However, we now know that they constitute a major bacterial defence against foreign DNA: the bacterium modifies its own DNA so any invading DNA molecules, lacking these very specific modifications, is cut and destroyed by enzymes made by the bacterium. In this way it can protect itself against attack by DNA viruses, for example.

These enzymes are the "restriction" enzymes which are now used to manipulate all kinds of DNA: they are at the heart of modern genetic engineering. In the latter 1950s Smith went to Caltech (the California Institute of Technology) where he collaborated with Renato Dulbecco and Giuseppe Attardi. Amongst other things, he showed that polyoma, a member of the virus family responsible for human warts, is a DNA virus.

By 1962, Smith was recognised as one of the leading nucleic acid chemists and in that year accepted an invitation to return to Cambridge as a permanent member of staff in the newly formed Medical Research Council Laboratory of Molecular Biology (LMB). Together with Francis Crick and Sydney Brenner, he formed the core of the Division of Molecular Genetics and remained there until his retirement in 1988.

In the early 1960s it was known that the sequence of bases in DNA - the genetic information - is used to determine the amino acid sequence of proteins, those molecules which execute all our bodily functions. But the mechanism by which this translation, from a DNA sequence to a protein sequence, is achieved was a dominating theme of molecular biology. At its centre lay the genetic code: which particular triplet of bases, or codon, encodes a particular amino acid. It was in this field that Smith made his most outstanding contributions.

As the bases in DNA are chemically quite different from the amino acids which constitute proteins, it was suggested by Crick in 1957 that the translation machinery contains a family of small RNA "adaptors" which would mediate the translation process. Each adaptor would first have a particular amino acid attached to it and would then bring it to the template where it would be assembled into a protein. The template, messenger RNA (itself a copy of the DNA), would be responsible for arranging all the adaptors in order by standard Watson-Crick base pairing (as in DNA) and so bring the encoded amino acids into order to assemble the protein.

These putative adaptor RNA molecules were subsequently discovered in America and called "transfer RNAs" - they transfer amino acids onto the template for protein synthesis. Each is about 100 bases long. By 1964 it was known that "nonsense" codons exist - codons which cannot normally be read as an amino acid by any transfer RNA. If such a codon arises by mutation in a gene, the encoded protein will be stunted and almost certainly will not function.

Working with bacteria, Sydney Brenner discovered in 1964 that a mutation in one particular transfer RNA could counteract nonsense mutations in messenger RNAs. It appeared that altering a particular transfer RNA could change the genetic code of that organism. The work of Smith and his colleagues showed that this is exactly what happens: each transfer RNA has a region in it - the anti-codon - which pairs with the codon in the template. They found that mutations in the anti-codon of a particular transfer RNA changed its codon-reading properties so that it could read an otherwise unreadable codon.

Following this line further, they made many other mutations in the 85-odd bases of this transfer RNA to understand how different parts of it are required for its function: we would now say they carried out a "structure-function" study. This revealed much about how these adaptor molecules act and helped understand why they are so large.

Quite separately he discovered, with Sid Altman, one of many American post-doctoral visitors working with him, that the transfer RNA they were studying is initially made as a larger precursor RNA. Furthermore, they discovered a specific enzyme, now known as RNAaseP, which processes the precursor by cutting a chunk off it to reduce it to its correct length. Further study of this enzyme by Altman and his colleagues led to the discovery of catalytic RNA for which Altman shared the 1989 Nobel Prize for Chemistry with Tom Cech.

Throughout his scientific career, Smith worked at the bench, showing a dedication to experimental science which is increasingly unusual for a person of his eminence. He presented a relaxed exterior, usually through a haze of cigarette smoke. He was extremely approachable, generous with his time and thoughts and much admired by his colleagues. He extended this generosity to students and post-docs, allowing them to take full credit for the work done in his lab even though it sometimes meant that his own contribution was overshadowed.

He loved talking, especially over a glass of beer, about anything and his excellent memory provided a source of anecdotes of his early years at Caltech and later at LMB. These stories might recall some unfortunate misstep by a student or member of staff but were always told with a delicacy and a wistful smile that disarmed any potential embarrassment. In short, John Smith was a most generous scientist who possessed a strong sense of fairness.

He was elected to the Royal Society in 1976 and his retirement in 1988 was marked by a fine party at the Golden Helix, Francis Crick's former house, in Portugal Place, Cambridge.

Mark S. Bretscher and Andrew A. Travers