Oliver Smithies (1925–2017)

Oliver SmithiesView Large Image | View Hi-Res Image | Download PowerPoint SlideThough some 25 years have passed, I can still recall the comfortable predictability of arriving at the lab on a weekend morning and finding Oliver Smithies at work, perhaps at his lab bench setting up a restriction digest in a 5 mL tube or in his office poring over a manuscript. Throughout most of Oliver’s scientific career, one could expect to find him in the lab most evenings and many weekends. The exceptions during my tenure in his lab were weekends when there was a breeze in the air and the sky was a bright Carolina blue. On days like that, Oliver could often be found soaring in his glider thousands of feet above the town, in search of the next updraft he needed to stay aloft.In many ways, Oliver’s approach to aviation mirrored his approach to science. In both pursuits, he strove to push past existing limits and open new personal frontiers, and he often mentioned in talks and interviews the need in both flying and science to push past fear to reach new heights. While his scientific achievements are well known in the research community, few are aware of Oliver’s flying accomplishments. For instance, in September of 1980, Oliver, along with fellow aviator Field Morey, flew across the Atlantic and back in a Cessna 210 single-engine high-wing; and, during the leg of the flight from Goose Bay, Labrador to Reykjavik, Iceland, they set a speed record for that class of aircraft that lasted for 20 years. In his science, as well as his flying, Oliver often stressed the importance to clear thinking of a quiet mind. Oliver’s preference for a quiet work environment was evident in the fact that, while working at his lab bench, he often wore the type of hearing protectors one might see on an airport runway. Similarly, when preparing for a flight, he insisted on a moment of silence while performing his final systems check. Oliver also insisted that an open mind is a prerequisite to the type of insight upon which scientific discoveries depend, and he compared such insight to the sensation of flying into open sky upon exiting a bank of clouds. Oliver’s openness to small clues provided by the natural world extended to his gliding, where he often relied on a circling hawk to point him toward the next updraft.Another metaphor that Oliver drew on in discussing his approach to science involved collecting sea shells. Years ago, after returning from a trip to the Outer Banks, he related that his walks along desolate winter beaches reminded him of his life in science. During these walks, he would fill his pockets with interesting shells that he came across along the tideline. Although many of these would become dry and dull over time, occasionally, one would maintain its luster, drawing him back to it again and again. In science, he noted, we are similarly surrounded by mysteries that beckon to be investigated. Many of these lead us down dull, frustrating paths, and our interest eventually fades. However, with persistence and a little luck, we may on occasion happen upon a line of inquiry that maintains its luster, draws us in, and, over time, alters our lives as scientists. For Oliver, one of these lines led to the introduction of starch gel electrophoresis in the 1950s, while a second in the 1980s led to homologous recombination in mammalian cells, a pursuit that would intertwine our paths for many years and that would lead to his sharing of the 2007 Noble Prize in Physiology or Medicine with Mario Capecchi and Martin Evans.Sadly, at the beginning of this year, Oliver took his last step during one of his traditional New Year’s walks on the beaches of the Outer Banks. Having entered his tenth decade, one might reasonably assume that he had reached a point where he was content to enjoy a well-deserved retirement spent reflecting on a long and fruitful scientific career. However, remarkably, at the time of his death, Oliver was actively engaged in research, still working at the bench and looking forward to starting a new project with the coming year. His enthusiasm for science had not dimmed after a career spanning seven decades that touched the lives of innumerable researchers, including myself.Oliver’s work on homologous recombination was first brought to my attention by Lap-Chee Tsui, who together with Jack Riordan and Francis Collins would later clone and identify the cystic fibrosis gene. He told me about a talk by Oliver at a meeting he attended, detailing the first recombination between a mammalian genome and exogenous DNA. Lap-Chee related that the talk had been met with cheers and applause. As a graduate student, my interest was piqued by the report of such an emotional display by a group of scientists. Further investigation into the technique on my part eventually led to me joining Oliver’s lab in Wisconsin to explore the possibility of using homologous recombination to interrogate gene function.Oliver’s lab in Wisconsin was full of what—to me, as an incoming post doc—seemed, at first, like endless piles of outdated junk. To make things worse, a thin film of petroleum jelly, originating in the “grease gels” that were a hallmark of the lab, had crept over time across benchtops and many other lab surfaces. Oliver had come up with the idea that gels run hot were superior to submerged gels. To accomplish this, the gel was covered in a quarter inch of Vaseline, which melted as the resistance heated the gel, protecting the gel and samples. Also, to my initial dismay, much of the lab equipment was handmade, although remarkably effective; and, although the tradition of requiring each new lab member to purify a stock of restriction enzyme for lab use had ended just prior to my arrival, many of the restriction enzymes in the freezer still bore the names of the lab members who had made them. I heard several stories about how Oliver, spanner and screwdriver in hand, was known to chase down service personnel who were in the process of removing ancient lab equipment from the lab, hoping to salvage components for future projects. Long before it became a cool catchphrase in an increasingly environmentally conscious society, “repurposing” had been standard practice in the Smithies lab for decades.It didn’t take me long to learn that one of the basic maxims of Oliver’s life was that if you need it and it doesn’t exist, build it. Whether it was an electroporation device for more efficiently introducing targeting constructs into cells for homologous recombination, a machine for screening recombination events by polymerase chain reaction before commercial PCR machines were available, or a device for measuring blood pressure in mice, Oliver and his collaborators found a way to design it, assemble it, and make it work. As contradictory as it may sound, Oliver’s approach to running his lab managed to be at once frugal, antiquated, and leading edge.When I joined his lab, Oliver was a seasoned scientist in his sixties, an age when most investigators begin to leverage their years of research to obtain positions such as chairmanships or vice chancellorships, trading the first-hand excitement of discovery at the bench for security, stability, and prestige. Oliver was certainly in a position to do this, as by the time I began working with him, he was well recognized by the scientific community for his work in protein isolation and gel electrophoresis and had been elected to the National Academy of Sciences. It was only years later, while raising my own children, that I came to completely understand why such positions were of no interest to Oliver. I realized that Oliver had managed to retain into adulthood that same sense of wonder and inquisitiveness that I observed in my children as they explored the world around them. An example that comes to mind involves an occasion when Oliver had just returned to the lab after a cardiovascular test that he needed to maintain his pilot’s license. Rather than fretting about the dose of radioactive tracer still circulating through his bloodstream, Oliver struck on the idea of fashioning his initials out of strips of lead, placing them in his shirt pocket, exposing his chest to a piece of X-ray film, and then hanging up the developed piece of film, blackened except for the “OS” silhouette where the lead had blocked the radiation. On another occasion, a postdoc from a neighboring lab had a water bomb disguised as a package containing a biological sample delivered to a member of the Smithies lab. After the package was opened, dousing the recipient, Oliver was much more interested in the trigger mechanism of the device than in any impropriety that may have been committed. I believe it is an appreciation of this childlike sense of wonder that tethered so many of us to him long after we had left his lab.Oliver would often tell us that to have a truly full life required three things: a job you love, a hobby you love, and a person to love. The triad was completed for Oliver when he met his future wife, Nobuyo Maeda. Nobuyo’s research focused on the genetics of atherosclerosis, and when she was successfully recruited by the University of North Carolina into a tenure track position, Oliver followed, relocating his lab from Madison to Chapel Hill, where they shared lab space on the seventh floor of the Brinkhous-Bullitt Building for over 25 years.When celebrating Oliver’s incredible life, I believe that we mourn not only the loss of a friend and mentor, but also of an ideal. In our hearts, we know that what Oliver represented was larger than a single life. It represented the freedom to be an explorer, to enjoy a lifetime of discovery, to continually ask why, and to continually challenge the consensus. He lived the “why I want to go into science” narrative described in many of the PhD applications we read. We mourn, perhaps, also that the scientific landscape now seems to support fewer such individual adventures into the unknown.