Michael Smith: The Scientist

By: Howard Akler

Photo credit: Dina Goldstein.

Michael Smith made one microscopic alteration and in doing so, he leapfrogged hundreds of thousands of years of evolution. It was his own evolution as a scientist, however, that readied him for this momentous hurdle.

In 1956, when Smith completed his PhD at the University of Manchester, his field was organic chemistry, which is the study of the synthesis of carbon-compound molecules, such as those found in drugs, food additives, and cosmetics. HIs arrival at UBC, under the supervision of Har Gobind Khorana, necessitated a move to biochemistry, a discipline that explores the molecular processes of all living things. Smith himself admitted that biochemistry was a more difficult field of study. 

His first task at the Khorana lab was to develop a procedure for the chemical synthesis for nucleoside triphosphates, which are subunits of the nucleic acid known as DNA. After four years of molecular investigation, Smith followed Khorana to the Institute for Enzyme Research at the University of Wisconsin. He lasted a year there, then moved back to Vancouver and took a position with the Fisheries Research Board of Canada, studying the feeding habits of salmon along the Fraser River. 

He was also able to continue his work on nucleic acids, thanks to a grant from the U.S National Institutes of Health. Smith was given use of a lab on the UBC campus and the title of associate professor in the Department of Biochemistry, a part-time, unpaid position. He plugged away in both roles until the Medical Research Council of Canada named him a Research Associate, a salaried job that allowed him to become a full faculty member at UBC. The Department of Biochemistry would be his primary academic home for the rest of his life.

In 1976, Smith took a sabbatical. He spent one year at the University of Cambridge, working with Fred Sanger, winner of the 1958 Nobel for his discovery of the molecular structure of proteins. Smith was there to study DNA sequencing, which is the method of determining the order of the four chemical building blocks that make up a DNA molecule. 

One of his colleagues, an American biochemist named Clyde Hutchison III, was also at Cambridge doing similar research. They loved to talk shop. Hutchison’s recent work involved mutating a virus and having it infect and replicate inside bacteria. Smith theorized something similar: he could alter the sequence of a DNA fragment and insert it into a host organism. This re-programmed genetic information would be used in the creation of new proteins, which, in turn, would be passed on as those proteins built the body’s muscles, bones, organs, teeth, hair, and nails. 

When Smith returned to Vancouver the following year, he put this theory to the test. He pushed himself hard, sometimes spending as much as 18 hours a day at the bench. By the early 1980s, his lab was producing large quantities of genetically-altered proteins. Evolution on its own needed hundreds of thousands, or even millions, of years to modify inherited traits. Scientists through the 20th century had been trying to use radiation to alter genes. Their successes were few and completely random, the results far from exact. Smith’s breakthrough allowed scientists to alter any specific gene at any specific site. His site-specific “mutagenesis” process created the possibility of fixing genes that were malfunctioning. 

In his later years, Smith summed up his career this way: “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.”

Courtesy of BC Cancer