Oliver Smithies (1925–2017) Nobel-Winning Inventor of Ways to Modify Genes

COMMENT OBITUARY Oliver Smithies (1925–2017) Nobel-winning inventor of ways to modify genes.

liver Smithies had a habit of filter paper, which made the job easier and individual genes has proved powerful in inventing ways to do the experi- more precise. This first application of gel deciphering gene function, including in ments he wanted to do, and electrophoresis found widespread use in human health and disease. Smithies con- Ocrafted tools that are now used widely in separating proteins and other biomolecules tributed to these efforts by creating the first biology. He won the Nobel Prize in Physi- of different sizes. Smithies used it to reveal animal model for cystic fibrosis. ology or Medicine in 2007 for developing variation in a group of blood proteins Smithies was a problem solver. His lab methods to genetically modify individual called haptoglobins. bench was his office. He loved physically mammalian genes. When DNA-cloning technologies doing science: designing his experiments, His work provided mixing his own rea- the means to modify any gents and building new gene in mouse embry- equipment when what onic stem cells. This he wanted was not com- approach, known as mercially available. He gene targeting, has been was working in the lab used to create thousands until a few days before of lines of mice carrying the end of his life. desired genetic muta- Besides his passion tions. It transformed our for science, Oliver loved MELANIE BUSBEE/UNC-CHAPEL HILL knowledge about the flying single-engine aer- roles that many genes oplanes and gliders. In have in human health 1980, he was a co-pilot and disease. Few areas on a record-breaking of mammalian physiol- crossing of the Atlantic ogy were not touched by Ocean in a single-engine these methods. plane. The speed record Smithies died on 10 held for 20 years. I flew January, aged 91. He and with him in a small plane his twin brother were in 1984 from Chicago, born in Halifax in York- Illinois, to Cold Spring shire, UK, on 23 June Harbor, New York, where 1925. His mother intro- we missed the runway at duced him to literature, the small local airport on his father to mathematics. His grandfather became available, Smithies studied some our first approach, because of low cloud, taught him how to make useful things from of the human genes for haptoglobin and and had to circle around. On the second junk, a talent that served him throughout haemoglobin. Some are present in two approach, we were thrilled to see the run- his career. Smithies attended the University copies, near one another, on the same chro- way and land safely. Oliver referred to this of Oxford. He worked with chemist A. G. mosome. Smithies discovered that genetic frequently in his later lectures. The thrill of ‘Sandy’ Ogston and received his under- material was exchanged between duplicated discovery was like finding the runway. graduate degree in animal physiology in genes. That sparked his interest in a natu- Oliver never sought fame and lived 1946, and his PhD in biochemistry in 1951. rally occurring process called homologous a simple life. He was always in the lab Smithies came to the University of Wis- recombination, in which genetic material or — when the weather was fine — in the consin–Madison, for a postdoc and later is swapped between paired chromosomes air. Throughout his career he made sig- worked at the Connaught laboratories, part during the production of gametes. nificant contributions to the many aspects of the University of Toronto in Canada. He Smithies’ Nobel-prizewinning work of science that fascinated him. He used to moved back to Madison in 1960 and stayed came from his desire to replace the gene boast that he was over 60 years old when there until he moved to the University of responsible for sickle-cell disease with a he did his Nobel-prizewinning work. His North Carolina at Chapel Hill in 1988, normal gene. Through a series of experi- career demonstrates that one is never too where he remained for the rest of his career. ments in the early 1980s, he harnessed old to advance — or enjoy — science. ■ Smithies’ first major contribution came homologous recombination to insert a gene when he was working in Toronto trying to into a specific location in the mammalian Raju Kucherlapati is professor of genetics find the precursor to insulin. The separa- genome. He went on to use this technique and medicine at Harvard Medical tion of proteins at that time depended on to modify a gene in a mouse embryonic School and Brigham and Women’s how quickly they moved through a matrix stem cell and produce mice carrying that Hospital, Boston, Massachusetts, USA. of filter paper. Frustrated with the short- mutation. For this pioneering work Smith- He collaborated with Oliver Smithies on comings of this method, Smithies devel- ies shared the prize with Mario Capecchi homologous recombination and other work oped an alternative. He used common and Martin Evans. in the 1970s and 1980s. starch to make a gel that could replace the The ability to target and modify e-mail: [email protected]