Smith, Michael

▪ 2001

      British-born Canadian biochemist (b. April 26, 1932, Blackpool, Lancashire, Eng.—d. Oct. 5, 2000, Vancouver, B.C.), won the 1993 Nobel Prize for Chemistry for the development of oligonucleotide-based site-directed mutagenesis, a technique for introducing precise changes (mutations) into genes through the hybridization of chemically synthesized sequences of DNA. The technique involved the preparation of a short piece of single-stranded DNA (an oligonucleotide) containing the desired alteration in the base sequence of the gene of interest, and it took advantage of Smith's discovery that the altered oligonucleotide, when mixed with the complementary strand of the gene, would still bind to, or hybridize with, the strand at the proper location, forming a short stretch of double-stranded DNA. When the hybridized DNA was placed in a suitable host organism, the bound oligonucleotide served as a primer for new DNA replication, using the complementary strand as a template. The result was a complete gene containing the altered sequence. The procedure, which allowed scientists to modify as well as study DNA and the proteins that they encode, was considered to hold enormous practical implications, including the development of new treatments for diseases through gene therapy and the production of bioengineered food. Smith shared the Nobel Prize with Kary B. Mullis, an American chemist who developed the polymerase chain reaction, another tool of genetic engineering. Smith entered the University of Manchester (England) in 1950 and earned a Ph.D. in 1956. In the same year he moved to Canada to work for the British Columbia Research Council. In 1966 he began teaching at the University of British Columbia, an affiliation that lasted more than 30 years. In 1987 Smith founded and became director of the university's biotechnology laboratory, and he also helped found Zymos (later ZymoGenetics Inc.), a biotechnology company. On his retirement in 1997 he became director of the Genome Sequence Centre at the Cancer Agency. He gave half of his Nobel Prize money to support research in schizophrenia and the rest to support science education for women and for elementary schoolteachers.

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▪ Canadian chemist

born April 26, 1932, Blackpool, England

died October 4, 2000, Vancouver, British Columbia, Canada

      British-born Canadian biochemist who won (with Kary B. Mullis (Mullis, Kary B.)) the 1993 Nobel Prize for Chemistry for his development of a technique called oligonucleotide-based site-directed mutagenesis, which enabled researchers to introduce specific mutations into genes and, thus, to the proteins (protein) that they encode. Using site-directed mutagenesis, scientists have been able to dissect the structure and 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 the viral proteins involved in immunodeficiency disease; and improve the properties of industrial enzymes used in food science and technology.

      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.

      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. A protein is a compound made up of strings of amino acids (amino acid) that fold into a three-dimensional structure, and the protein's structure determines its function. Instructions for the amino-acid sequence of a protein are contained in its gene, namely, in the sequence of DNA subunits, called nucleotides (nucleotide), that make up that gene. 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, a technique that can be used to modify nucleotide sequences at specific, desired locations within a gene. This has made it possible for researchers to determine the role each amino acid plays in protein structure and function. Aside from its value to basic research, site-directed mutagenesis has many applications in medicine, agriculture, and industry. For example, it can be used to produce a protein variant that is more stable, active, or useful than its natural counterpart.

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