SMITH, Michael




Michael Smith was a philanthropic atheist who was fond of Sibelius' music and reading the Manchester Guardian. He was also a chemist and molecular biologist who shared the Nobel Prize for Chemistry with Kary B. Mullis in 1993 "for his fundamental contributions to the establishment of oligonucleiotide-based, site-directed mutagenesis and its development for protein studies."

Born in 1932 in Lancashire, the have-not region of England, Michael Smith grew up in a working class world populated largely by coal miners and factory workers with rough manners and a dialect considered comical and uncouth. By passing an examination at the age of eleven he qualified for a grammar school that would prepare him for university entrance. As the son of a market gardener, Smith was keenly aware of his lower social status when he entered an elite school. He emerged from his seven-year ordeal with a deep-rooted social insecurity and a first-rate education. Smith’s writing skills made him an expert in drawing up grant proposals—an invaluable asset in the operation of a science laboratory. Smith’s ability in the sciences qualified him for Cambridge, but he did not have the required Latin credit. He went instead to nearby Manchester where his work was less than brilliant. With a second-class degree, he was admitted into the doctoral program and completed the degree with the all-too-familiar agony caused by an absentee and otherwise uncooperative dissertation supervisor. Possibly that experience accounted for his conscientiousness when he became a supervisor to others.

Aided by years of publicly-funded education in Britain, Smith became part of the brain drain from England when he was recruited to UBC at the urging of Har Gobind Khorana in 1956. Khorana was a Nobel Prize-winning chemist who taught him the organic chemistry of biological molecules which make up DNA. Smith planned a year’s stay in Canada but fell in love with Vancouver and stayed there for the rest of his life, except for a brief period when he followed Khorana to Wisconsin after UBC wouldn't accept Khorana's research. Smith launched UBC’s internationally acclaimed Biotechnology Laboratory and became a powerful advocate for science, influencing national policy and helping to establish Canada’s Genome Sciences Centre; and he became responsible for training future scientists.

At age 61, with typical generosity, Michael Smith invited some of his UBC colleagues as his guests for the Nobel Prize awards ceremony in Sweden, paying their expenses. One half of Smith’s Nobel Prize money went to support post-doctoral fellowships in schizophrenia research; the other half went to the Vancouver Foundation to fund public science education through Science World and the Society for Canadian Women in Science and Technology. Several of his doctoral students and some of his most important collaborators had been women, and he recognized that as scientists they faced many obstacles not encountered by men. Smith had only seven years in which to relish his status as a Nobel laureate and to use its prestige to further scientific education and his favourite causes. A month after he died in 2000, some 1,000 people from Canada, England and the United States gathered to honour his memory. He left big Birkenstocks to fill.

EDUCATION:

BSc (Honours Chemistry), University of Manchester, England, 1953
PhD (Chemistry), University of Manchester, England 1956

OTHER AWARDS:

Jacob Biely Faculty Research Prize, UBC, 1977
Fellow, Royal Society of Canada, 1981
Boehringer Mannheim Prize of the Canadian Biochemical Society, 1981
Gold Medal, Science Council of BC, 1984
Fellow, Royal Society (London), 1986
Gairdner Foundation International Award, 1986
Killam Research Prize, UBC, 1986
Award of Excellence, Genetics Society of Canada, 1988
G. Malcolm Brown Award, Canadian Federation of Biological Societies, 1989
Flavelle Medal, Royal Society of Canada, 1992
Manning Award, 1995
Laureate of the Canadian Medical Hall of Fame

[BCBW 2003] "Science" "Nobel"

Nobel Prize autobiography
personal essay



I was born on April 26th, 1932 at 65 St. Heliers Road, South Shore, Blackpool, England in the house of my maternal grandmother, Mary Martha Armstead, having been delivered by the District Nurse, Ms. Parkinson, a lady who I can remember from my infant and juvenile days in her uniform and navy blue raincoat on her bicycle doing her rounds and visiting schools for health inspections. My parents, Mary Agnes Smith and Rowland Smith, both had to work since their early teens, she in the holiday boarding house of her mother and he in his father's market garden in Marton Moss, a village on the south side of Blackpool, just north of Saint Anne's-on-Sea. I went to the local school, Marton Moss Church of England School for 6 years from the age of 5. My mother attended the local church, Saint Nicolas, and consequently I attended that church and its Sunday School. My only prizes from the Sunday School were "for attendance", so I presume my atheism, which developed when I left home to attend university, although latent, was discernible.

During my last year at elementary school, 1943, I sat for the "Elevenplus" examination which was used in the English schools in those days. In principle, of course, it was an invidious system designed to identify the approximately 20% of the school population that would be offered an academic education and the 80% who would be obligated to take a secondary education that terminated with no further academic options at age 15 (of course, there was the alternative of private schooling, but that was not an option if you were the child of poor parents, as was I). I was lucky enough to obtain a scholarship to the local private school, Arnold School. I did not, at the time, consider this to be luck. I did not want to go to Arnold School because the pupils were considered to be snobs and I thought that I would be ostracized by my friends in Marton Moss. Luckily, my mother insisted, and I went to Arnold School. I cannot say it was the happiest time in my life (I was no good at sports, and proficiency in sport is important in private school life. And I hated the war-time meals that were provided at lunch, as well as the prefect who insisted that I eat the awful food). But the schooling was first-rate, and in this I flourished, although not equally well in all subjects. Clearly, science was my metier, and I was lucky to have a chemistry teacher, Sidney Law, who stimulated my interest in chemistry and who took a personal interest in me (he told me I should read a better newspaper than the one to which my parents subscribed and, as a consequence, I became a life-long reader of the Manchester Guardian. That, in turn, stimulated me to become a reader of the New Yorker as soon as I came to North America, another life-long addiction).

The seven years from 1943 to 1950 were also a time when I became a boy scout. That was a piece of luck. The headmaster at Arnold School, Mr. Holdgate, at the end of my first term, sent me to a dentist, Mr. Paterson, in the hope that he could correct my protruding front teeth, about which I had been teased by my schoolmates. Mr. Paterson did not correct the problem with my teeth but he did introduce me to a wonderful scoutmaster, Mr. Barnes, who inducted me into the happy world of camping and outdoorsmanship which provided me with enjoyment and vacations throughout my secondary school years and right up to the present. An enjoyment that explains why I have a particular delight in living amid the rugged outdoors and beauty of British Columbia.

The second World War impinged on the lives of many of us who were alive at the time. Blackpool, as it turned out, was a very safe place, being in the northwest of England and distant from the targets for German bombing. The large number of hotels and boarding houses in this seaside resort were used to house military trainees, mainly for the airforce. And my father, working his father's market garden, grew primarily food crops rather than his preference, chrysanthemums. Occasionally, bombers, presumably diverted from their primary targets of Manchester and Liverpool, would try to bomb the new factory behind our house that produced Wellington bombers. Usually, they hit the market gardeners' greenhouses which showed up better at night. And I remember one night, alone in the house with my baby brother Robin, when a stick of bombs fell on either side of the house.

I was not proficient in Latin and so was not able to go to Oxford or Cambridge. However, I did enter the first-rate chemistry honours program at the University of Manchester in 1950, where the professors were E.R.H. Jones and M.G. Evans, and graduated in 1953, with the financial support of a Blackpool Education Committee Scholarship. I had hoped to get a firstclass degree, but only got a 2(i)! I was very disappointed. However, I still was able to obtain a State Scholarship which supported me throughout my graduate studies until I finished my Ph.D. degree in 1956. My supervisor was H.B. Henbest. He was an outstanding young organic chemist, and I was glad to have him as a supervisor of my work on cyclohexane diols. However, we did not have a particularly warm relationship. I was socially shy and moody and was probably quite hard to understand.

The last year of our graduate studies saw me and my classmates writing to various American professors seeking post-doctoral fellowships. I had no luck in obtaining my desire of a fellowship on the west coast of the United States, but I heard, in the summer of 1956, that a young scientist in Vancouver, Canada, Gobind Khorana, might have a fellowship to work on the synthesis of biologically important organo-phosphates. While I knew this kind of chemistry was much more difficult than the cyclohexane stereochemistry in which I was trained, I wrote to him and was awarded a fellowship after an interview in London with the Director of the British Columbia Research Council, Dr. G.M. Shrum.

I arrived in Vancouver in September 1956. My first project was to develop a general, efficient procedure for the chemical synthesis of nucleoside-5' triphosphates based on the synthesis of ATP by Khorana in 1954. This study led to more extensive investigations of the reactions of carbodumides with acids, including phosphoric acid esters and to a general procedure for the preparation of nucleoside-3',5' cyclic phosphates, a class of compounds whose existence and great biological significance had only recently been discovered. One particular pleasure of that period was the development of the methoxyl-trityl family of protecting groups for nucleoside-5'-hydroxyl groups (one synthesis of trimethoxytritanol erupted and left a large orange stain on the laboratory ceiling); this class of protecting group is still in use in modern automated syntheses of DNA and RNA fragments.

In 1960, the Khorana group, including myself, newly married (I have three children, Tom, Ian and Wendy. My wife Helen and I separated in early 1983), moved to the Institute for Enzyme Research at the University of Wisconsin. There I worked on the synthesis of ribo-oligonucleotides, that most challenging of chemical problems for a nucleic acid chemist. Early in 1961, I began to realize that it was time to move on. Helen and I wanted to return to the West Coast of North America, and I accepted a position with the Fisheries Research Board of Canada Laboratory in Vancouver. I enjoyed my time there because of the opportunity it presented to learn about marine biology and I was able to sustain my interest in nucleic acid chemistry because of the award of a U.S. National Institutes of Health Grant, which led to a new synthetic method for nucleoside-3',5' cyclic phosphates. However, the atmosphere of the laboratory, although based on the campus of the University of British Columbia, was not really conducive to, or supportive of, academic research. Hence, in 1966, I was very glad that Dr. Marvin Darrach, then Head of the Department of Biochemistry, offered to nominate me for the position of Medical Research Associate of the Medical Research Council of Canada. This award, which provided salary support, allowed me to become a faculty member of the Department, my academic home ever since, except for sabbaticals at Rockefeller University, the Laboratory of Molecular Biology of the Medical Research Council in Cambridge and Yale University. The Council also has provided research grant support throughout my academic career.

In 1981, Ben Hall and Earl Davie, of the University of Washington, invited me to be a scientific cofounder of a new biotechnology company, Zymos, which was funded by the Seattle venture capital group, Cable and Howse. One of the first contractors was the Danish pharmaceutical company, Novo, who asked Zymos to develop a process for producing human insulin in yeast. After a considerable cooperative effort by Zymos and Novo researchers a successful process was developed. In 1988, the pharmaccutical company, now Novo-Nordisk, purchased outright the biotechnology company, now named ZymoGenetics. I am pleased that, although I no longer have any involvement, ZymoGenetics has subsequently expanded and has continued research on a wide variety of potential protein pharmaceuticals.

In 1986, I was asked by the then Dean of Science at the University of British Columbia, Dr. R.C. Miller, Jr., to establish a new interdisciplinary institute, the Biotechnology Laboratory. I decided that it was time for me to start paying back for the thirty years of fun that I had been able to have in research. I have very much enjoyed recruiting and helping to get established the group of young faculty members that constitute the core of the Biotechnology Laboratory. I also have enjoyed being Scientific Leader of the National Network of Centres of Excellence in Protein Engineering that was funded in 1990. It has been very satisfying, in this case, to see established scientists, working in the various subdisciplines of biochemistry, come together in nation-wide collaborations to solve important problems in protein structure-function analysis and to work with Canadian industry in improving technology transfer which has been less than optimal in the past.

One difflcult chore was presented to me in 1991 when I became Acting Director of the Biomedical Research Centre, a privately funded research institute on the Campus of the University of British Columbia. Its source of funding disappeared; therefore I had the responsibilities 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. This task was made difficult because many of the staff had been led to believe that I was trying to take over and subvert the activities of the Centre. This misguided belief helped the problems of the Centre to become a public political football in an election year. However, funding was negotiated, the University took over the ownership and I was able to step down after 12 months with the Centre and its mission intact.

I look forward to shedding all my administrative responsibilities in another couple of years and returning to my first scientific love, working at the bench and having more time for sailing and for skiing.



Nobel Prize summary
presentation speech



In the 1970s, Michael Smith developed a general method for producing mutations in a gene, not in a random fashion but at specific positions determined in advance from the sequence of the nucleotides in the gene. This method of site-directed mutagenesis has created completely new opportunities to study the properties of protein molecules: how they function as catalysts or as signal transmitters through membranes, which factors determine how they fold into specific three-dimensional structures and how they interact with other molecules in the cell. Such protein engineering is also of importance in modern biotechnology and drug design. Novel antibodies have been created that can kill certain cancer cells. Plants that produce proteins enriched in essential amino acids are being field tested and in the future this method might produce engineered wheat and corn flour that has the same nutritional value as meat.

Isolation and amplification of a specific gene was one of the outstanding problems in DNA technology, including site-directed mutagenesis, until 1985 when Kary Mullis presented the Polymerase Chain Reaction, now commonly known as PCR. Using this method it is possible to amplify and isolate in a test tube a specific DNA segment within a background of a complex gene pool. In this repetitive process the number of copies of the specific DNA segment doubles during each cycle. In a few hours it is possible to achieve more than 20 cycles, which produces over a million copies.

The PCR method has already had a profound influence on basic research in biology. Cloning and sequencing of genes as well as site-directed mutagenesis have been facilitated and made more efficient. Genetic and evolutionary relationships are easily studied by the PCR method even from ancient fossils containing only fragments of DNA. Biotechnology applications of PCR are numerous. In addition to being an indispensable research tool in drug design, the PCR method is now used in diagnosis of viral and bacterial infections including HIV. The method is so sensitive that it is used in forensic medicine to analyze the DNA content of a drop of blood or a strand of hair.


Michael Smith's speech at the Nobel Banquet, December 10, 1993
Nobel Prize press release



Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,

On behalf of Dr. Kary Mullis and myself, I would like to express our deep gratitude to the Royal Swedish Academy of Sciences and to the Nobel Foundation for the honour that has been bestowed on us today.

Dr. Georges Charpak, in his speech of 1992 in acknowledgment of his prize in Physics, conjured up, with elegant Gallic flair, an image involving the number 137, the ancient Nordic gods Odin and Freja, and his work on subatomic particles. Not being French, such imagery is not within my compass. However, others, most specifically Michael Crichton and Stephen Spielberg in the novel and subsequent film Jurassic Park, have conjured with dramatic impact, an image of the use of the polymerase chain reaction (PCR) to recreate the dinosaurs.

One could imagine a less dramatic reincarnation that is more relevant to this uniquely special occasion. Suppose that one could use PCR to resuscitate Alfred Nobel and that one could use site-directed mutagenesis to cure the heart disease to which he and his brother fell victims. What would he, a vigorous 160 year old, have to say as he contemplated the approaching 100th anniversary of the commencement of the awarding of Nobel Prizes. I hope that he would have enormous satisfaction in the honour and prestige that his bequest has brought to his memory, to the Nobel Foundation, to the two Swedish Academies, to the Karolinska Institute, to the Norwegian Nobel Committee and to the Swedish and Norwegian people. I hope that he would be both surprised and pleased to see that this year molecular biologists have won the Prizes in Chemistry and in Physiology or Medicine, which speaks to the adaptability of the Prize selection process in the face of the unpredictable dynamics of scientific discovery. And he would be pleased, I'm sure, by the action of the Bank of Sweden in instituting a new prize in 1968, the Alfred Nobel Memorial Prize in Economic Sciences.

I believe that Alfred Nobel, in contemplating this munificent act of the Bank and in contemplating what might happen in the next 100 years, would be concerned about the problems of that next century. And, of course, there is one problem that would attract his attention beyond all others. That is the impact of the uncontrolled growth and demands of the human population on the finite capacity of planet Earth. We, Homo sapiens, destroyed the majority of the large mammalian species in North America and Australasia just over 10,000 years ago. We, Homo sapiens, now are destroying the other species that presently exist on this planet at a rate of about 15,000 to 20,000 per year. Given that the current estimate of the total number of species on the planet is about 2 million, this rate, by the end of the next century, will be equivalent in biological effect to the catastrophic event(s) of 65 million years ago that eliminated not only the dinosaurs but also the ammonoid cephalopods, many echinoids, and many genera of foraminifera and of calcareous phytoplankton, the kind of mass extinction that previously in the earth's history has required 5 million years for recovery, such recovery resulting in a completely different biota from that preceeding it.

I believe that Alfred Nobel, being aware of the unique and enormous impacts of his prizes on world thought and opinion, would wish to see a new prize or new prizes instituted to commemorate the 100th anniversary, perhaps related to studies on the control of human population, perhaps on biodiversity, perhaps on the environment, perhaps on sustainability.

I, thus, want to express my deep-felt gratitude for the award of the prize in Chemistry in the form of a wish on behalf of Alfred Nobel. This wish is intended only as the greatest of compliments to those who value and support the Nobel Prizes, because of the enormous power for good that the Prizes represent. I hope that the 100th anniversary can be celebrated by the endowment of a new prize that addresses these problems of the next century as I think Alfred Nobel would see them, if only we could have worked magic with the polymerase chain reaction and with site-directed mutagenesis.

[From Les Prix Nobel 1993.]



No Ordinary Mike: Michael Smith, Nobel Laureate (Ronsdale, 2004)
Review (Summer 2004)



When Mike Smith was leading three carloads of his University of British Columbia colleagues and students to hear a prominent biologist speak in Seattle, a bemused American border guard asked the driver of the third car, “Just what in the hell is an allosteric enzyme?” Although the science-challenged reader of No Ordinary Mike: Michael Smith, Nobel Laureate (Ronsdale $24.95) sometimes shares that border guard’s bemusement, this biography has an appeal that goes beyond the mysteries of the gene.

Eric Damer & Caroline Astell’s No Ordinary Mike is an uplifting story of extraordinary achievement, hard work, an ability to overcome setbacks, and a passionate dedication to science. Michael Smith did it the hard way. The biography also offers ample documentation of Smith’s effectiveness as a teacher and colleague. Both Smith and David Suzuki were Ph.D. supervisors to one of its authors, Caroline Astell, who became one of Smith’s colleagues. Since Caroline Astell was among those invited to Sweden for the Nobel Prize ceremony, she includes a first-hand behind-the-scenes account of the events in Stockholm. Smith, who could hardly conceal his pleasure, conducted himself with great dignity, unlike his co-recipient who climbed on the table at one party and mocked the Royal Family.

Generations of university graduates have paid tribute to Smith as a clear, organized lecturer and were grateful that he instilled in them the intellectual tools needed to solve problems rather than requiring them to memorize and regurgitate information. But these very qualities alienated some students, and he was constantly pained by the stream of negative evaluations of his teaching by undergraduates in the Faculty of Medicine. Like many of his colleagues in biochemistry, he felt that medical students were too anxious to become physicians, and failed to appreciate the value of the basic sciences.

1-55380-014-1

—Joan Givner