
NEW YORK — Oliver Smithies, a British-born biochemist and inveterate tinkerer who shared a Nobel Prize for discovering a powerful tool for identifying the roles of individual genes, died on Tuesday in Chapel Hill, N.C. He was 91.
His death, after a short illness, was announced by the University of North Carolina Chapel Hill, where he was a professor of pathology and laboratory medicine at the medical school.
Dr. Smithies’ discovery, known as gene targeting, allows scientists to disable individual genes in mice to understand what the genes do. The loss of a gene typically brings about changes in the appearance or the behavior of the mouse, providing important clues about the gene’s function. Mice are ideal models because about 90 percent of their genes correspond to human genes.
Scientists have also used gene-targeting technology to create mice that have symptoms of human diseases, including cardiovascular and neurodegenerative diseases, diabetes, and various cancers. These designer mice are widely used in research to understand the genetic causes of diseases and to develop and test potential new therapies.
Dr. Smithies shared the 2007 Nobel Prize in Physiology or Medicine with Mario Capecchi of the University of Utah and Martin J. Evans of Cardiff University in Wales. The scientists worked separately but built on one another’s research.
In addition to gene targeting, Dr. Smithies invented a method of separating proteins with a jelly made from ordinary potato starch, a major advance that was cheaper, easier, and more precise than existing technologies. His invention, called gel electrophoresis, is in wide use today.
Behind Dr. Smithies’ breakthroughs were ingenious homemade contraptions cobbled from everyday objects and junk. He thought of himself as an inventor and toolmaker and acknowledged that he could not pass a rubbish bin without pausing to inspect the contents — a trait he said he shared with his paternal grandfather, who used to pick up nails and straighten them for later use.
His tinkering did not go unnoticed. Colleagues at Oxford University, where Dr. Smithies pursued his graduate studies, set aside their discarded equipment for him, labeling it, “NBGBOKFO,’’ or “No bloody good but OK for Oliver.’’
The research that led to Dr. Smithies’ Nobel grew out of experiments he had been doing in the early 1980s with a family of genes involved in sickle cell disease, an inherited form of anemia characterized by misshapen red blood cells. He had normal genes in his lab, and he thought there might be a way of using genetic material from them to repair the mutation involved in sickle cell disease.
Dr. Smithies spent three years trying to insert bits of genetic material into cells to correct the gene. He turned cafeteria trays into oversize petri dishes and used electrical supplies and an infant washtub to build a device to force genetic material into cells. Most scientists thought gene targeting could not be done; many of his students drifted to other projects.
Then came what Dr. Smithies, an amateur pilot, called his “runway moment.’’ He was alone in a darkroom, developing an X-ray film that would reveal whether gene targeting was possible. As he lifted the film from the fixative solution, he had the same sensation he got whenever he guided his plane through clouds and the landing strip came into view.
The film showed 10 bars in a straight line and an 11th bar that was separate from the others. Each bar was a gene, and the 11th bar was the gene Dr. Smithies had altered. It was exactly where he had predicted it would be.
Capecchi subsequently showed that gene targeting could be used not only to repair genes but also to turn them off. Then Dr. Smithies and Capecchi each showed that genetic changes made in one kind of cell, an embryonic stem cell, could be passed on, a discovery that enabled scientists to breed mice with specific disease conditions. Evans had discovered embryonic stem cells in mice.
Gene-targeting technology was too inefficient to use to treat human diseases. But its wide adoption as a research tool transformed the field of genetics, which had previously relied largely on statistics to connect individual genes with illness or health.
“For the first time in history, genetics has become an experimental science,’’ Dr. Goran K. Hansson, a member of the 2007 Nobel Prize committee, said after the award was announced.
Oliver Smithies was born in Halifax, England. His father, William, was an insurance salesman; his mother, the former Doris Sykes, was a teacher in a technical college. A heart murmur prevented him from playing sports, so he amused himself by making things. He built a loudspeaker by stretching a pig’s bladder across a wooden frame and made a radio-controlled boat by using an ignition coil from a Ford Model T as a transmitter.
He earned bachelor’s degrees in physiology and chemistry and a doctorate in biochemistry from Oxford University.
He moved to the University of Toronto, where he found work as a research chemist, then joined a genetics research group at the University of Wisconsin in 1960. He moved to the University of North Carolina in 1988. He received the Albert Lasker Basic Medical Research Award, often a forerunner to the Nobel, in 2001. In his later years, he created designer mice to study the complex genetics of hypertension.
To Dr. Smithies, the process of invention was straightforward. “You use whatever is lying around, and you see something that needs to be done, and you try to do it,’’ he said. “I think it is making things work, you know, somehow.’’