- N. G. Coley
Smith, Michael (1932–2000), biochemist, was born at 65 St Heliers Road, South Shore, Blackpool, on 26 April 1932, the son of Rowland Smith, a market gardener, and his wife, Mary Agnes (née Armstead), who worked in the family boarding-house. Educated at Arnold School, Blackpool, he entered the chemistry honours course at Manchester University in 1950. Having graduated in 1953 he proceeded to research on cyclohexane diols and gained a PhD degree in 1956. Like many others at that time he applied for postdoctoral research fellowships in North American universities; he was at length invited to Canada to work with Gobind Khorana, a young biochemist who had recently discovered a method of synthesizing deoxyribo-oligonucleotides at the University of Vancouver, British Columbia.
Synthesis of nucleic acids
Smith realized that nucleic acid chemistry was far more complex than anything he had so far tackled, but he was impressed by Khorana's use of chemical or enzymatic methods as appropriate. His first project was to develop a general procedure for the chemical synthesis of molecules belonging to the biologically important organophosphate groups. This led him to investigate the reactions of carbodiimides with phosphoric acid esters, and to a general procedure for the preparation of nucleoside-3ʹ, 5ʹ cyclic phosphates whose biological significance had only recently been recognized. In the course of this work he discovered methoxyl-trityl protecting groups for nucleoside-5ʹ hydroxyl groups, which are still used in automated syntheses of DNA and RNA fragments.
In 1960 Smith married Helen Wood; they had three children, two boys and a girl. In the same year Khorana's group moved to the Institute for Enzyme Research at the University of Wisconsin. Here Smith worked on the synthesis of ribo-oligonucleotides, a challenging problem in nucleic acid chemistry. After a year, wishing to return to the west coast of North America, Smith joined the Fisheries Research Board of Canada in its laboratory at Vancouver. Here he learned about marine biology while sustaining his interest in nucleic acid chemistry with a grant from the US National Institutes of Health. He discovered a new synthetic method for preparing complex phosphates, though the laboratory was not intended for academic research. In 1966 Smith was nominated for the post of medical research associate at the Medical Research Council of Canada. This allowed him to become a faculty member of the department of biochemistry in the University of British Columbia, where he remained during the rest of his career.
The pioneering work which led to site-directed mutagenesis began in the 1970s, when Smith learned how to synthesize oligonucleotides, short single-strand DNA fragments. He also studied how these synthetic fragments could bind to the DNA of a virus, and discovered that even if one of the small molecules in the synthetic DNA fragment was incorrect it could still bind in the correct position in the virus DNA. The idea of getting a reprogrammed synthetic oligonucleotide to bind to a DNA molecule and then having it replicate in a suitable host organism occurred to Smith in 1975–6, during a sabbatical at Frederick Sanger's laboratory of the Medical Research Council in Cambridge. He learned Sanger's ‘plus–minus’ method of sequencing as a member of a team studying the amino-acid sequence of the E. coli phage ΦX174.
Having returned to Vancouver in 1978 Smith used this virus as a model for site-directed mutagenesis using a synthetic oligonucleotide. With his co-workers he succeeded in inducing a mutation in the virus and also in correcting a mutation so that the virus regained its natural properties. Reprogramming the genetic code allowed gene sequences to be altered in designated ways, and it became possible to change any amino acid in a polypeptide sequence that made up the backbone of a protein or enzyme. Thus, by changing the nucleotides in a gene encoding a protein or enzyme of medical or industrial importance, a modified product of predetermined structure could be obtained that was not only more stable than the natural protein or enzyme but also perhaps more active. In 1982 Smith and his colleagues were able for the first time to produce and isolate large quantities of an enzyme in which one amino acid had been exchanged for another. This opened up a new approach to the study of the relationships between structure and function in enzymes, and provided a clearer understanding of how biological systems operate.
As a consequence of these discoveries the concept of ‘protein design’, the construction of proteins with predetermined properties, was introduced. Later applications of this concept have shown, for example, that the stability of an enzyme used in detergents can be improved so that it will withstand the chemicals and high temperatures used in laundry work. Smith's discovery also paved the way for gene therapy, by which hereditary diseases might be cured by correcting mutations in the genetic material. A mutated haemoglobin might provide a new way of replacing blood, while mutated proteins in immune system antibodies might be constructed to neutralize cancer cells. In plants, too, there was the possibility of producing disease-resistant crops that could make more efficient use of atmospheric carbon dioxide during photosynthesis.
Such commercial possibilities led Ben Hall and Earl Davie of the University of Washington to invite Smith to join them in founding a new biotechnology company, Zymos. Funded by the Seattle venture capital group Cable and Howse, this company developed a process for producing human insulin in yeast for the Danish pharmaceutical company Novo. This was successfully accomplished in 1988, and afterwards the Danish company, now Novo-Nordisk, purchased Zymos outright. Renamed ZymoGenetics, the company engaged in research on a wide range of potential protein pharmaceuticals, though Smith's connections with the company ceased with the take-over.
In 1986 Smith was asked by the dean of science at the University of British Columbia to establish a new interdisciplinary institute, the biotechnology laboratory, and he set about recruiting people with expertise in physics, chemistry, botany, zoology, and biology. In 1990 he was also founding director of the Network of Centres of Excellence in Protein Engineering, in which established scientists in the various subdisciplines of biochemistry work together on important problems in protein structure–function analysis. At the same time co-operation with Canadian industry improved technology transfer. In 1991 Smith became acting director of the Biomedical Research Centre, a privately funded research institute operating on the campus of the University of British Columbia. Its source of funding having disappeared, Smith had the unenviable task of managing the centre on a tight budget, negotiating future funding from the provincial government, and helping to ensure the transfer of ownership to the university. As many of the staff had been led to believe that Smith was trying to take over and subvert the activities of the centre, the issue became a ‘political football’ in an election year. However, he succeeded in negotiating funding, the university took over the ownership, and, after a fraught year, he was able to step down, leaving the centre and its work intact.
In 1993, the year in which he received the Nobel chemistry prize jointly with Kary Mullins, inventor of another technique in genetic engineering, Smith began to anticipate retirement and was looking forward to the chance to return to the laboratory work which was his first scientific love. Instead he found himself suddenly world-famous as his field of expertise in genetic engineering hit the headlines internationally. Fully aware of public concern about genetic engineering, Smith nevertheless believed that biotechnology was essential for the future welfare of humanity. In 1997 he retired from the university to become director of a new Genome Sequencing Centre at the British Columbian Cancer Agency in Vancouver, a post he held until his death. Convinced of the need to educate the public so that people could better understand the issues, he began to travel the world to promote the ideals of improved general education, especially a better understanding of science. His final illness cut short this aspect of his work.
Smith's many academic honours included election as fellow of the Royal Society of Canada in 1981 and of the Royal Society of London in 1986. Yet Smith never forgot his roots. He visited Blackpool as often as possible and was a lifelong supporter of Blackpool United Football Club. He loved the Pennines and moorland country, and thought that this accounted for his pleasure in the rugged outdoors and natural beauty of British Columbia. Smith, who died in Vancouver on 5 October 2000, separated from his wife, Helen, in 1983; he was survived by his partner, Elizabeth Raines, and by his daughter and two sons.
- B. G. Malmström, ed., Nobel lectures: chemistry, 1991–95 (1997), 114–36
- P. Wright, ‘Michael Smith’, The Guardian (10 Oct 2000)
- K. S. Shenton, ‘Professor Michael Smith’, The Independent (24 Oct 2000)
WW (1998); (1999)
- Nature, 408 (2000), 786
- b. cert.