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Oliver Smithies
Oliver Smithies, a British-born biochemist and inveterate tinkerer whoshared a Nobel Prize for discovering a powerful tool for identifying the roles of individual genes in health and disease, 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 at Chapel Hill, where he was a Weatherspoon eminent distinguished professor of pathology and laboratory medicine at the medical school.
Dr. Smithies’s 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 mice, providing important clues about the gene’s function. Mice are ideal models for people because about 90 percent of mouse 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 R. Capecchi of the University of Utah and Sir 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’s 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 O.K. for Oliver.”
The research that led to Dr. Smithies’s 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 some 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.
Dr. Capecchi subsequently showed that gene targeting could be used not only to repair genes but also to turn them off. Then Dr. Smithies and Dr. 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. Dr. Evans 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 ofgenetics, 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 Prizecommittee, said after the award was announced.
Oliver Smithies was born on June 23, 1925, 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 attended Heath Grammar School, a competitive high school that selected students based on standardized tests. He excelled in mathematics and received a scholarship to Oxford University, where he earned bachelor’s degrees in physiology and chemistry and a doctorate in biochemistry.
After a fellowship at the University of Wisconsin, he moved to the University of Toronto, where he found work as a research chemist.
His lab chief, an expert on insulin, told Dr. Smithies that he could do whatever he wanted, as long as it was related to insulin. In the 1950s, insulin was derived from the pancreases of cows and pigs and was thought to be contaminated with another protein, which today is known as proinsulin. Dr. Smithies set out to find it.
He turned to a method that uses electricity to separate proteins on filter paper. The electrical current typically causes proteins to migrate across the paper; the proteins separate as they move. But when Dr. Smithies ran the experiment, the insulin stuck to the paper. His search for something else to use summoned memories of the gooey liquid his mother had used to starch the collars of his father’s shirts. The liquid, he recalled, set into a gel when it cooled. Would insulin move through the gel in the same way other proteins migrated across filter paper?
Dr. Smithies found a bottle of starch in a chemical storeroom. He cooked the starch, cooled it, and waited as insulin, spurred by electricity, traveled through the goo. Over the next few months, Dr. Smithies worked at improving his method, using it to separate cabbage enzymes and, eventually, the proteins in blood plasma.
He detected proteins in plasma that had not been seen by other researchers who had used the filter-paper method, establishing the superiority of his technology. He went on to discover inherited differences in one of the proteins, a finding that shifted his research toward genetics. (He never completed his insulin study.)
Today, protein separation is typically conducted using gel made of polyacrylamide instead of potato starch.
Dr. Smithies returned to the University of Wisconsin in 1960, joining its genetics research group. He moved to the University of North Carolina in 1988. He was elected to the National Academy of Sciences in 1971 and 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.
Dr. Smithies’s first marriage ended in divorce. He is survived by his wife,Nobuyo Maeda, a professor at the University of North Carolina, and he lived in Chapel Hill.
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.”
SOURCE - NEW YORK TIMES.
Excellent work. Well done. RIP.
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