Michael Smith, who shared the 1993 Nobel Prize for chemistry, died on October 5th aged 68. He developed one of the fundamental techniques used in genetic engineering that allows scientists to reprogramme the genetic code.
By rearranging the small molecules - nucleotides - from which they are formed, he found out how to alter genes. The invention was the biochemical equivalent of using a pair of tweezers to rearrange the chemical building blocks that make up the genes contained in DNA.
The name of the discovery was oligonucleotide-based, site-directed mutagenesis. His co-prizewinner was Kary Mullis, an American chemist who developed another advance in genetic engineering, the polymerase chain reaction.
Michael Smith's technique opened a route to combating certain inborn diseases through gene therapy, correcting the mutations that caused disease by rearranging an abnormal sequence of molecules in DNA sequences to the normal one.
Michael Smith was born in Blackpool, where his father worked on the family market garden. At 11, he won a scholarship to the independent Arnold School, where he was inspired by Sidney Law, his chemistry teacher.
He went to Manchester University in 1950 to study chemistry. In 1956, he got a Ph.D and applied for a vacancy as research assistant to the brilliant young scientist at the British Columbia Research Council, in Vancouver, Gobind Khorana. The job was to develop ways of synthesising molecules that belonged to the biologically important organophosphate groups.
He got the job. The chemistry was far more difficult than the research into the classes of compounds on which he had been trained for his Ph.D, but it led him to carry out research on substances whose existence and biological significance had only recently been discovered.
He stayed with Khorana's group when it moved in 1960 to the Institute for Enzyme Research at the University of Wisconsin, where he worked on what he described as the most challenging of problems for a nucleic acid chemist - the synthesis of ribo-oligonucleotides.
In 1961, he returned to Vancouver to a job with the Fisheries Research Board of the Canada Laboratory. It gave him a chance to learn about marine biology and continue work in nucleic acid chemistry, and to develop a new method for synthesising complex phosphates.
He became a research associate of the Medical Research Council of Canada in 1966 with a salary which allowed him join the faculty at the University of British Columbia, where his Nobel prizewinning work was done. In 1986, he created a new interdisciplinary institute, the Biotechnology Laboratory, which remained his academic home, punctuated by sabbaticals at Rockefeller University, New York; the Laboratory of Molecular Biology of the Medical Research Council, in Cambridge; and Yale University.
He had not set out to solve the particular question that his discovery so importantly answered. It was one scientists had been toying with since the discovery that the flow of genetic information went from genes contained in DNA via the translator molecule RNA as coded instructions to the protein-manufacturing part of cells in the body. Many wondered if re-programming the code of a DNA molecule was possible - to manipulate the production of protein molecules.
His oligonucleotide-based site-directed mutagenesis turned it into a reality. It emerged from work in the 1970s in which he learned how to synthesise oligonucleotides - short, single-strand DNA fragments. He also studied how these synthetic fragments could bind a virus to DNA. To his surprise, he discovered that even if one of the small molecules of the synthetic DNA fragment was incorrect, it could still bind at the correct position in the virus DNA and be used when new DNA was being synthesised.
The story goes that while at Cambridge, during a coffee-break discussion, the idea arose of getting a reprogrammed synthetic oligonucleotide to bind to a DNA molecule and then having it replicate in a suitable host organism. This would give a mutation, which, in turn, would be able to produce a modified protein.
In 1978, Michael Smith and his co-workers made this idea work. They succeeded both in inducing a mutation in a virus, and in "curing" a natural mutant of this virus so that it regained its natural properties. Four years later they were able, for the first time, to produce and isolate large quantities of a mutated enzyme in which a pre-determined amino acid had been exchanged for another.
In 1997, he retired from the university to become director of a new Genome Sequencing Centre at the Cancer Agency, Vancouver, a post he held until his death.
He was separated from his wife, Helen, in 1983. His partner, Elizabeth Raines, two sons and a daughter survive him.
Michael Smith: born 1932; died, October 2000