Michael Smith

Michael Smith (born April 26, 1932, Blackpool, England—died October 4, 2000, Vancouver, British Columbia, Canada) was a British-born Canadian biochemist who in the 1970s conceived and developed a method by which sequences of DNA can be edited by a technique known as site-directed mutagenesis. The approach was revolutionary because it enabled researchers to introduce specific mutations into genes by simply synthesizing oligonucleotides (short chains of nucleotides, the building blocks of DNA) that are complementary to the target DNA sequence and that include the desired mutation. For his breakthrough, Smith was awarded the 1993 Nobel Prize for Chemistry (shared with Kary B. Mullis).

Education and early career

Smith received a Ph.D. from the University of Manchester, England, in 1956. Later that year he moved to Vancouver and in 1964 became a Canadian citizen. After holding a number of positions in Canada and the United States, he joined the faculty of the University of British Columbia in 1966, becoming director of the university’s biotechnology laboratory in 1987. He was a founder of ZymoGenetics Inc., a biotechnology company.

Development of site-directed mutagenesis

Smith first conceived of site-directed mutagenesis in the early 1970s and devoted several years to working out the details of the technique. The method provided researchers with a new way to study protein function. The amino-acid sequence of a protein, and hence its function, can be modified by inducing mutations in the nucleotide sequence of its gene. Once an altered protein has been produced, its structure and function can be compared to those of the natural protein. Before the advent of Smith’s method, however, the technique biochemical researchers used to create genetic mutations was imprecise, and the haphazard approach made it a difficult and time-consuming task. Smith remedied this situation by developing site-directed mutagenesis,which can be used to modify nucleotide sequences at specific, desired locations within a gene.

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Applications of site-directed mutagenesis

Using site-directed mutagenesis, scientists have been able to dissect the structure–function relationships involved in protein plaque formation in the pathophysiology of Alzheimer disease; study the feasibility of gene therapy approaches for cystic fibrosis, sickle-cell disease, and hemophilia; determine the characteristics of protein receptors at neurotransmitter binding sites and design analogs with novel pharmaceutical properties; examine viral proteins involved in immunodeficiency disease; and improve the properties of industrial enzymes used in food science and technology.