EIGHTY YEARS IN THE MAKING

By Kendall MorganEIGHTY YEARS IN THE MAKINGThe life of a genetics pioneerOLIVER SMITHIES JASON VARNEY | VARNEYPHOTO.COM As a child in England in the 1930s, Oliver Smithies found his path before he knew that "science" was its name. "I remember, as a six- or seven-year-old, fairly clearly, that I wanted to be an inventor," says Smithies, who is Excellence Professor of Pathology at the University of North Carolina at Chapel Hill. "In a sense, that's what I've been ever since. I've invented various methods of doing things." In 1950, Smithies invented starch-gel electrophoresis, enabling easy protein separation. Decades later, he accomplished the first gene targeting, allowing the precise insertion of genes into mammalian cells. That contribution, which he shares with Mario Capecchi of the University of Utah, influenced the creation of knockout mouse models of diseases, from cystic fibrosis to atherosclerosis. Now in his early 80s, this man whose efforts twice changed the way that genetics is done, maintains a habit that is virtually unheard of among accomplished scientists: He spends nearly every day at the laboratory bench, tinkering with new ideas and resurrecting old ones. "It's not the achievements," Smithies explains. "It's got more to do with curiosity, trying to solve problems, understand something." He simply enjoys working on something that is completely new, and he craves understanding how things work. "Curiosity is a common feature of all humanity," Smithies notes. "You see it in children. They always want to know why." He adds, "That's what it is, I haven't ever grown up."Perhaps Smithies' collaborator, Thomas Coffman of Duke University Medical Center, sums it up best: "The thing about Oliver," Coffman says, is that "science is his oxygen." A PATH TOWARD DISCOVERY "The thing about Oliver is that science is his oxygen."After graduating from Heath Grammar School, a small, academically rigorous institution in West Yorkshire, UK, Smithies obtained a scholarship at Oxford University and enrolled as a medical student. His interest, though, soon turned from medicine to research. "If you want to find things out, then you want to do research," Smithies says. "It's not something you get convinced of, it's something you just know." He graduated with degrees in physiology and chemistry, a fortunate combination that he says left him "not at all nervous of things that happen in animals or molecular things." Still at Oxford, he began his doctoral work with Alexander "Sandy" G. Ogston on the development of a method for measuring protein interactions based on osmotic pressure. Although Smithies created such an instrument, and an "extraordinarily accurate" one at that, "nobody ever used it, including me," he says. Nonetheless, Smithies credits those early days with Ogston for the patience that would carry him through his later successes.Smithies made his first important scientific contribution while working at the University of Toronto in the 1950s. While looking for a method to differentiate insulin from its precursor, Smithies developed gel electrophoresis, an advance that he, in his typically modest fashion, considers an accidental discovery. Still, gel electrophoresis led Smithies to another finding. After determining what his "molecular sieve" was doing, an unexpected pattern emerged: "Not all people were the same," Smithies says. That normal variation opened a "whole new area of science," turning Smithies into a geneticist.He returned to Wisconsin, where he'd completed postdoctoral work, and began working with DNA. During those years, he came to understand the "rules" of homologous recombination between chromosomes, and how unequal crossing over could lead to certain kinds of genetic alterations. If he could harness that natural process, Smithies thought, perhaps genes responsible for disease could be corrected. "That's what I was trying to do with gene targeting," he says of his discovery, which, after three years of work, was no accident. Although his method's application to gene therapy never came to fruition, it was a triumph that his colleagues refer to as transcendent, and which Smithies, a licensed pilot, calls his "runway moment."Francis Collins, director of the National Human Genome Research Institute, vividly recalls hearing Smithies present the data demonstrating successful homologous recombination in mammalian cells at a Gordon Conference. "I'll not forget his words as he described this, leaving us all gasping: 'It was like coming out of the clouds on a stormy day in your small plane and finding the runway right in front of you.'"A PASSION FOR LIFEWhile his dedication to discovery is absolute, science is not Smithies' sole preoccupation. "Oliver basically has three passions: science, friends, and flying, in no particular order," says Bradley Popovich, president and CEO of Sirius Genomics in Vancouver and a former postdoc in Smithies' lab.Upon their first meeting, Popovich found himself strapped into a small plane with Smithies at the controls, engaging the plane in acrobatic maneuvers. Yet it is Smithies' warmth and genuine concern for others that his colleagues seem to find most defining. "He is a scientist's scientist in every sense," Collins says. "He identifies critically important problems, he approaches them in the laboratory with his own hands, he comes up with creative solutions, and he makes profoundly important discoveries that change the face of science." "On top of all that," Popovich adds, "he is the most gentlemanly, open-minded, non-self-promoting individual you will meet." Despite the competitive spirit that can sometimes color the scientific enterprise, Coffman notes, "Smithies is always very generous and open. He'll talk to anyone." In recent years, Smithies and his wife, Nobuyo Maeda, also a professor at Chapel Hill, focus on more subtle individual variations, particularly those responsible for common diseases including atherosclerosis and hypertension. "My general feeling about looking around at people is that they don't vary qualitatively very much," Smithies says. "They differ quantitatively - with different proportions of nose to face, long and skinny or short and fat. So, many quantitative differences must be made by altering genes not with respect to what they make, but by changing the amount they make." To approach these concepts, Smithies continues to work out new methods for varying the level of a chosen gene's activity. "It's very important to like the process," Smithies says. "If you don't, you will be disappointed because you only get exciting results occasionally. You get the process all the time."

EIGHTY YEARS IN THE MAKING

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