Michael Smith (chemist)

2.1. Birth and Childhood

Michael Smith was born on April 26, 1932, in Blackpool, Lancashire, England. He hailed from a working-class family, and his early education took place at St. Nicholas Church of England School, a state-run elementary institution. At that time, it was uncommon for children from state schools in England to pursue higher academic education, but Smith demonstrated exceptional ability by excelling in the eleven plus exam. This achievement allowed him to receive a scholarship to attend the Arnold School for Boys, providing him with a pathway to further his studies.

2.2. Academic Journey

Following his time at Arnold School for Boys, Michael Smith secured another scholarship that enabled him to study chemistry at the University of Manchester. There, he developed a keen interest in industrial chemistry. He earned his Bachelor of Science (BSc) degree and subsequently completed his doctoral studies, receiving a Doctor of Philosophy (PhD) in 1956. His PhD research focused on the stereochemistry of diols.

3.1. Early Research and Postdoctoral Work

After completing his PhD, Smith immigrated to Canada in 1956, becoming a Canadian citizen in 1963. His research career commenced with a postdoctoral fellowship at the British Columbia Research Council in Vancouver, British Columbia, Canada. He worked under the supervision of Har Gobind Khorana, who was himself a future Nobel laureate in Physiology or Medicine (1968) for his work on the genetic code. Khorana's laboratory was at the forefront of developing new techniques for synthesizing nucleotides. This period marked a new era in science, where the principles of physics and chemistry were being applied to living organisms, especially after DNA had been identified as the genetic material of a cell. Researchers like Khorana were actively investigating how DNA encoded the proteins that constitute an organism.

In 1960, Smith briefly moved with Khorana's group to the Institute for Enzyme Research at the University of Wisconsin-Madison in the United States, when Khorana accepted a new university position there. However, Smith returned to Vancouver in 1961, taking on the role of senior scientist and head of the Chemistry Division at the Vancouver Technological Station of the Fisheries Research Board (FRB) of Canada. In this capacity, he conducted studies on the feeding habits and survival of spawning salmon and worked on identifying the olfactory stimuli that guide salmon back to their birth streams. Concurrently, he maintained his primary research interest in nucleic acid synthesis, securing a United States Public Health Service Research Grant for this work. Smith also held positions as an associate professor in the University of British Columbia's (UBC) Department of Biochemistry and an honorary professor in the Department of Zoology. In 1966, he was appointed a research associate of the Medical Research Council of Canada, working within UBC's Department of Biochemistry.

Smith's specific area of interest continued to be the synthesis of oligonucleotides and the characterization of their properties. A sabbatical in 1975-1976 at the MRC Laboratory of Molecular Biology in England, collaborating with Frederick Sanger (a two-time Nobel laureate), placed Smith at the forefront of research into the organization of genes and genomes and methods for sequencing large DNA molecules. Upon his return from England, he was recognized as one of the world's leading molecular biologists. Smith and his team then began to investigate the possibility of creating specific mutations at any site within a viral genome, a process that could serve as an efficient method for engineering heritable changes in genes. This theory was successfully confirmed by his team in 1977.

3.2. Innovation in Site-Directed Mutagenesis

In the late 1970s, Michael Smith intensely focused on molecular biology projects, particularly how genes within the DNA molecule function as reservoirs and transmitters of biological information. In 1978, in collaboration with his former sabbatical colleague from Fred Sanger's lab, Clyde A. Hutchison III, Smith introduced a revolutionary technique to molecular biology: "oligonucleotide-directed site-directed mutagenesis." This method provided a solution to the critical problem of efficiently determining the effect of a single mutant gene. They developed a synthetic DNA technique that allowed for the introduction of site-specific mutations into genes, enabling direct comparison of different protein molecules and revealing the specific role of the initial mutation.

This pioneering technology enabled the rapid identification and deliberate alteration of genes to change the characteristics of an organism. It significantly expanded the possibilities for new diagnostic strategies and treatments for genetic disorders, and even facilitated the creation of novel artificial forms of life. Site-directed mutagenesis is considered the progenitor technique for other fundamental molecular biology methods such as polymerase chain reaction (PCR) and synthetic biology. The profound impact of this technique is evident in its wide-ranging applications:

• Scientists have used site-directed mutagenesis to dissect the structure and function relationships involved in protein plaque formation in the pathophysiology of Alzheimer's disease.
• It has been instrumental in studying the feasibility of gene therapy approaches for conditions like cystic fibrosis, sickle-cell disease, and hemophilia.
• The technique has been crucial in determining the characteristics of protein receptors at neurotransmitter binding sites, leading to the design of analogs with novel pharmaceutical properties.
• It has allowed for the examination of viral proteins involved in immunodeficiency diseases.
• Furthermore, it has been applied to improve the properties of industrial enzymes used in food science and technology.

The team's seminal paper describing site-directed mutagenesis, titled "Mutagenesis at a Specific Position in a DNA Sequence," was published in the *Journal of Biological Chemistry* in 1978. For their groundbreaking work in developing oligonucleotide-directed site-directed mutagenesis, Michael Smith shared the 1993 Nobel Prize in Chemistry with Kary Mullis, who was honored for his independent invention of the polymerase chain reaction.

3.3. Leadership in Biotechnology

Michael Smith's career also included extensive administrative and leadership roles, where he guided the development of significant biotechnology initiatives. In 1981, he was elected as the Faculty of Medicine's representative to the University of British Columbia (UBC) Senate. He served on the advisory committee of the Canadian Institute for Advanced Research's Evolutionary Biology Program and on the Biotechnology Sector Committee of British Columbia, influencing policy and research direction in the province.

In 1982, Smith spearheaded the establishment of the Centre for Molecular Genetics within the UBC Faculty of Medicine, taking on the directorship in 1986. He also served as the interim scientific director of the UBC Biomedical Research Centre in 1991. A major achievement was the establishment of the Biotechnology Laboratory at UBC in 1987, which became one of three provincial "Centres of Excellence." This new facility absorbed the Centre for Molecular Genetics, with Smith as its founding director, a position he held until 1995. He was pivotal in bringing together scientists and in writing the proposal for what would become the "Protein Engineering Network of Centres of Excellence" (PENCE). In recognition of his contributions, he was named Peter Wall Distinguished Professor of Biotechnology in 1996.

Throughout the 1980s, Smith and his colleagues at the Canadian Institute for Advanced Research championed the establishment of a facility that would allow Canada to participate significantly in the burgeoning Human Genome Project. Their advocacy bore fruit when funding was secured from the BC Cancer Agency, leading to the establishment of the Genome Sequencing Centre in 1999. This center, later renamed Canada's Michael Smith Genome Sciences Centre in his honor, was mandated to develop and deploy genomics technologies to support the life sciences, with a particular focus on cancer research. The Genome Sciences Centre also provided essential technological support to Genome Canada and Genome BC projects in critical areas such as human health, environmental science, forestry, agriculture, and aquaculture.

3.4. Commercial Ventures

In 1981, Michael Smith ventured into the business world, becoming a pioneering pharmaceutical entrepreneur. He co-founded ZymoGenetics, a pharmaceutical company based in Seattle, Washington, United States. His co-founders were Professors Earl W. Davie and Benjamin D. Hall from the University of Washington. ZymoGenetics focused on developing recombinant proteins, initiating an international collaboration with Novo Nordisk of Denmark. While recombinant DNA technology is primarily used in basic research, its further applications extend broadly into human and veterinary medicine, agriculture, and bioengineering. ZymoGenetics was later acquired by Bristol-Myers Squibb.

7.1. Charitable Donations

Demonstrating his profound generosity and commitment to scientific advancement and social betterment, Michael Smith made substantial donations of his Nobel Prize money. He donated half of the Nobel Prize winnings to researchers working on the genetics of schizophrenia. The other half was given to Science World BC and to the Society for Canadian Women in Science and Technology, underscoring his dedication to science education and supporting women in STEM fields. Furthermore, when he received the Royal Bank Award in 1999, he promptly donated the accompanying grant to the BC Cancer Foundation.

7.2. Commemoration and Remembrance

Michael Smith's enduring legacy is recognized through various initiatives and institutions established or named in his honor, reflecting his profound impact on health research, genomics, and scientific education.

• In 2001, the Michael Smith Foundation for Health Research was founded, dedicated to supporting health research in British Columbia.
• In 2004, the UBC Biotechnology Laboratories were fittingly renamed the Michael Smith Laboratories, marking his founding directorship and leadership in the field.
• Also in 2004, Canada's Michael Smith Genome Sciences Centre was named in his honor, acknowledging his crucial role in establishing and leading Canada's participation in the Human Genome Project.

• The University of Manchester, his alma mater, named its new biological sciences research center the Michael Smith Building in 2004, a tribute to his academic roots and scientific achievements.
• In 2005, the Smith-Yuen Apartments were opened in Vancouver, further commemorating his name.
• Additionally, the Natural Sciences and Engineering Research Council of Canada established the Michael Smith Award, which recognizes Canadian citizens and organizations for their achievements in promoting science.