Won the Nobel Prize in chemistry in 1993 for discovering site-directed mutagenesis: that is, how to make a genetic mutation precisely at any spot in a dna molecule.
"In research you really have to love and be committed to your work because things have more of a chance of going wrong than right. But when things go right, there is nothing more exciting."
Michael Smith arrives in his office wearing his usual shabby old sweater and trousers that long ago should have been sent to a charity like the Salvation Army. You would never guess that just a few days before he had been awarded half a million dollars, his share of the 1993 Nobel Prize in chemistry. Smith passes by a wall of shallow shelves jammed full of medals, awards and plaques for prizes he has won. The office is modestly furnished, with a cluttered, lived-in look. A beautiful picture window looks out onto the treed University of British Columbia campus with the Coast Mountains in the distance. Smith picks up the telegram from Sweden to take another look at the Nobel announcement.
“Darlene?” he calls out the door to his administrator, Darlene Crowe, who is sitting at her desk.
“Yes, Mike,” she calls back, cheerily. Everyone’s in a good mood because of the prize.
“If you ever see my behaviour start to change and I get a swelled head with all this attention, I want you to give me a good, swift kick,” says Smith.
Crowe remembers only one occasion on which she had to “kick” him. Mostly, he behaved himself. Smith relied heavily on people like Crowe. “He was a bit like the rabbit in Alice in Wonderland,” she says fondly of her boss, who like the rabbit often ran late. Smith rewarded his co-workers generously. He took 12 colleagues to Stockholm with him, mostly graduate students and research assistants, all expenses paid, to share in the glory of the Nobel awards ceremony.
Smith didn’t keep the Nobel Prize money. He gave half of it to researchers working on the genetics of schizophrenia, a widespread mental disorder for which research money is scarce. The other half he shared between Science World BC and the Society for Canadian Women in Science and Technology.
Certainly Smith could afford it. He had made a small fortune in 1988 when he sold his share of Zymogenetics Incorporated, a Seattle-based biotechnology company that he co-founded in 1981. Even before he won the Nobel Prize, his genetic engineering techniques were used by Zymogenetics to develop a strain of yeast implanted with the human gene for insulin. With the drug company Novo-Nordisk, Zymogenetics commercialized a process that used yeast to produce human insulin.
The original idea for his award-winning discovery, site-directed mutagenesis, came to Smith while talking with an American scientist named Clyde Hutchison over coffee in an English research institute. Every seven years, university professors get one year off, with pay, to travel anywhere in the world to do research; the break is called a sabbatical. It was 1976 and Smith was spending a sabbatical year in Fred Sanger’s lab, part of the famous institute in Cambridge, England, where DNA was first explained by James Watson and Francis Crick. Smith was there to learn how to sequence genes — how to determine the order of the thousands of links that make up a chain of DNA.
He was in the cafeteria explaining to Hutchison how he was making short chains of nucleotides — the chain links in DNA — for use in the separation and purification of DNA fragments. His technique was based on the natural affinity of one DNA chain to link up with its mirror image. It didn’t take much of a leap to realize that the same method might be used to induce mutations — new qualities or traits in offspring not found in their parents — but it meant changing directions again, and not for the first time. It took Smith and his team several more years to perfect the method. At first it didn’t work at all, but he kept at it. Eventually the technique became so well known and useful that it ended up winning the Nobel Prize.
Smith didn’t become successful by accident. He was a very hard worker, some say a workaholic. Things were not always easy for him. When he submitted his first article on site-directed mutagenesis for publication in Cell, a leading academic journal, it was rejected; the editors said it was not of general interest. But Smith never stopped working on it. Above all, he was always prepared to do what he called “follow-your-nose research” — repeatedly changing directions to explore new ideas even if it meant learning entirely different processes and techniques.
Michael Smith was born into a working-class family in Blackpool, England. He was seven when World War II broke out. Though his family lived in northern England and was quite far away from London, he does remember one time when his mom and dad were not home and German bombs fell on either side of their house, barely missing him and his brother, Robin.
In those days, English working-class children had to take an exam called the Eleven-Plus when they were 11 to see if they would go on to a private school or continue in the public school system, where they would learn a trade and finish at age 16. Smith did very well in his Eleven-Plus and was offered a scholarship to a local private school called Arnold School, but he didn’t want to go, because the students there were considered snobs and he thought his friends would make fun of him. His mother insisted that he go.
His time there was not a happy period. He lost most of his old friends. He had homework to do every night and they didn’t. He did not like the food. He was not very good at sports, which were very important in English private schools. He had few friends. His schoolmates teased him because of his big front teeth. He was sent to a dentist to see about his overbite and, fortunately, the dentist happened to introduce him to the world of Boy Scouts, where he made friends and learned about camping.
Smith did not go to a prestigious English university, but he did get into the honours chemistry program at Manchester University. He hoped to earn all As, but alas, he was a B student. He was very disappointed, but he still won a state scholarship and managed to complete his doctorate.
Smith wanted to do post-doctoral research on the west coast of the United States and he wrote to many universities, but was rejected by all. Then in 1956 he heard of a young scientist in Vancouver, Gobind Khorana, who had a position available for a biochemist. This was not the chemistry in which Smith had been trained, but he went to Canada anyway. It turned out to be a very good decision, because in Khorana’s lab, Smith began learning the chemistry that would lead to his Nobel Prize. Khorana himself received a Nobel Prize in 1968.
In 1961 Smith took a job as chemist at the Fisheries Research Board of Canada laboratory in Vancouver and published many papers about crabs, salmon and marine molluscs, but he managed to sustain his research in DNA chemistry with grants he obtained on his own, outside his fisheries-related work. The lab was located on the ubc campus and, because he was collaborating so much with professors in biochemistry and medicine, in 1966 he was appointed a ubc professor of biochemistry in the Faculty of Medicine, where he worked until his death.
Molecular biology is the study of biological systems at the level of individual chemicals and molecules. Michael Smith was an expert on the chemistry of DNA — the molecule that makes up genes, the instructions required to create every part of an organism. DNA is a large molecule that is like a twisting chain. Actually it is two chains twisted together. Smith worked on genomics, the sequencing of the DNA of an organism to understand how it works.
Smith won fame and fortune by developing a new way to create mutations in living organisms. Plant and animal breeders rely on naturally occurring beneficial mutations that result in improved plants and animals. Conversely, unwanted natural mutations can cause diseases such as cystic fibrosis or sickle-cell anemia. Smith found a way to create a specific mutation by precisely changing any particular part of the DNA in an organism. This has allowed countless researchers around the world to develop special bacteria, plants and animals with new qualities or abilities that either do not occur naturally or would take years and years of trial and error in breeding to achieve. With further research, his technique might even be used to correct mutations that cause disease.
Before Smith’s technique of site-directed mutagenesis, there was no way to create specific mutations. Geneticists had to expose a bunch of organisms to radiation or chemicals that would result in all sorts of mutants, then select the one they wanted. It was all by chance, and it could take a long time to get exactly the right mutation.
1. A small portion of a long DNA molecule showing the backbone (in light grey) made of deoxyribose, a type of sugar. The backbone sugar segments are all the same, but they can have one of four different basic “connectors” — adenine, thymine, cytosine and guanine (A, T, C and G in the figure) — that couple with complementary connectors on a second sugar chain. An A on one side always matches up with a T on the other. Similarly, C always matches up with G. These couplings are called base pairs. A DNA strand is made up of two chains, one a mirror image of the other (that is, if one side’s sequence goes ATCG, then the other side will be TAGC). In real DNA the chain could continue up for millions of base pairs and down for thousands more. The sugar elements (A, T, G and C) are known as nucleotides and their sequence is what makes up the genes in an organism.
2. The nucleotide guanine. The phosphate sugar is on the left and the basic group is on the right. Note the two hydrogen atoms and one oxygen atom poking out on the extreme right to form the chemical bond with cytosine on the sister chain.
3. Michael Smith’s idea for which he won the Nobel Prize was to slip a synthetic stretch of nucleotides — called an oligonucleotide — into one DNA chain. “Synthetic” means the nucleotide was created in a test tube, not by nature. The synthetic segment is added to normal DNA using standard chemicals for breaking and reforming DNA chains. But there is one thing wrong with this synthetic oligonucleotide: it has an adenine where there should be a guanine. This is done on purpose to create a mutation. (Remember, A normally combines with T, and G goes with C.) The four nucleotides below and above the adenine act as a kind of address that causes this stretch of DNA to match up to the correct place on the other DNA strand. (In humans, it turns out that you need only 17 nucleotides to define a unique match somewhere among the three billion nucleotides of the entire genome.)
4. When this new altered DNA is put back into an organism, say a bacterium, and it divides in the normal process of growth and reproduction, one half of the DNA will recombine normally and will produce a correct copy of the original gene — a normal bacterium. The other side with the synthetic oligonucleotide will create a mutation, because a thymine is sitting where there should be a cytosine. The resulting mutant bacterium might have some new appearance or function that it never had before.
5. With Smith’s technique, geneticists can mutate a gene in three ways: substitution, deletion and addition. Precise substitution of one or more nucleotides in a DNA sequence is shown here. Scientists can also delete nucleotides or add extra nucleotides to the sequence.
In a 1996 interview, Smith predicted a change in the way people do biological research. He was right. With the completion of the human genome project in 2003, the total sequence of the DNA in all the genes for a human being — the human genome — is known. Genomes have now been completely decoded for many plants and animals.
Those genes have the code or “recipe” for the tens of thousands of proteins that make up people, plants, insects or other animals. As time goes by, geneticists are amassing more and more genetic information detailing what the genome encodes. According to Smith, the hard part will be discovering which part of the genome does what, picking out what is crucial, and learning how to recognize the most important bits of DNA.
Eric Damer, No Ordinary Mike: Michael Smith, Nobel Laureate, Ronsdale, 2004.
Gina Smith, The Genomics Age: How DNA Technology Is Transforming the Way We Live and Who We Are, AMACOM, 2004.
Donald Voet and Judith G. Voet, Biochemistry, The Expression and Transmission of Genetic Information, Wiley, 2004.
James D. Watson, The Double Helix: A Personal Account of the Discovery of the Structure of DNA, Touchstone, 2001.
United States National Centre for Biotechnology Information.
United States Department of Energy Human Genome Project.
So You Want to Be a Biochemist
As in any career in which you are investigating the unknown all the time, scientific research often leads to a lot of disappointments. Things go wrong. Smith said, “For kids who have been very bright all the way through school, all the way through undergraduate university, and almost aced all their classes, sometimes getting into research is very traumatic for them, because it doesn’t matter how bright they are, chances are, any experiment they do is not going to work the first time.” For brilliant young people used to succeeding, it can be very upsetting.
Yet the only way to be successful in research is to do experiments, have them go wrong, and then do another experiment, and then another one. So anyone planning a career in scientific research ought to be commited to long-term goals. “Even though you’ll have disappointment in the short term, ultimately discovering new things is so exciting, it’s worth putting up with that for the long-term excitement and pleasure of discovering something new about the biological or the chemical or the physical world in which we live,” said Smith. However, as a biochemist he wanted to do more than just discover new things. “I wanted to do something that was useful experimentally to other people,” he said. Certainly, his technique of site-directed mutagenesis is one of the more useful contributions ever made to the field of biochemistry and genetics. It is used daily by tens of thousands of researchers worldwide.
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