Oliver Smithies, who passed away in January 2017 at 91 years of age, was a highly accomplished scientist, Nobel Laureate, and Member of the National Academy of Sciences. However, for those who had the opportunity to know him, collaborate with him, or attend one of his lectures, he was also an endearing, inspirational, and entertaining figure, with a deep love for science and a complete lack of pretension. Oliver had a profound curiosity and an inventor’s spirit.
During his long career, Oliver made several contributions to science, 2 of which particularly stand out. The first was the development of starch gel electrophoresis as a simple and reliable method for separating proteins by molecular size. Oliver’s invention of this technique, which was a precursor to modern polyacrylamide gel separation, was inspired by his recollections of his mother using starch as she was doing laundry at home, remembering that starch dissolved in water and heated, developed a jelly-like consistency. After perfecting this technique, Oliver defined common inherited polymorphisms of haptoglobin and other human plasma proteins. This work was his gateway into genetics, which would become a lifelong passion, and he was an active participant in the revolution of molecular biology and genetics in the 1950s and 1960s.
Oliver’s second major contribution was the development of an approach for specifically modifying the mammalian genome using homologous recombination in embryonic stem cells, commonly referred to as gene targeting, for which he was awarded the Nobel Prize in Physiology or Medicine in 2007 along with Mario Capecchi and Martin Evans. This discovery had broad impact on biological research, making it possible to induce precise alterations in a specific gene, starting with cloned DNA in a microcentrifuge tube on a laboratory bench to produce permanent modifications in the genome of a living animal. It proved to be powerful avenue for understanding the function of genes and has been broadly and productively used in almost every field of biological sciences, including hypertension research.
I first met Oliver in 1990. At the time, I was a newly minted junior faculty member, and my department chair had suggested that I seek out a good laboratory where I could spend time putting sorely needed new skills into my research tool box. This was ≈2 years after Oliver had relocated his laboratory from University of Wisconsin to the University of North Carolina (UNC) in Chapel Hill. UNC had offered a position to Oliver’s wife, Nobuyo Maeda, a talented scientist in her own right, and Oliver followed along. I was aware that this interesting new team has moved into the neighborhood and was drawn to the potential power of these pioneering techniques. Accordingly, I cold-called Oliver and was invited to visit the laboratory and give a seminar. After a bit of cajoling, Oliver and Nobuyo agreed to take me on, beginning a collaboration and friendship that lasted more than 25 years.
The Smithies-Maeda laboratory was a large, window-lined facility encompassing the entire seventh floor of the Brinkhouse-Bullitt Building at UNC, with beautiful views of the green Carolina landscape. But more compelling than the view was the work being performed by the team of talented faculty, post-docs, students, and technicians. There was a palpable feeling of shared adventure and excitement as the initial applications of this novel and disruptive technology were being explored. Oliver presided over the group with an intellectually rigorous but fun-loving, nonauthoritarian style. The group spent long hours in the laboratory, punctuated by humor, camaraderie, and frequent ice cream parties (Oliver loved ice cream).
Oliver was also a fastidious editor, and before the era of tracked changes, would notoriously return draft manuscripts to laboratory members with copious notes and corrections penciled into the margins on almost every page. All who spent time in Oliver’s laboratory emerged with an appreciation for the importance of precise written communication in science. Oliver’s approach to writing grants was similarly fastidious. Invariably, he would generate complete, polished drafts of his grant proposals many weeks ahead of deadlines, circulating them to colleagues for critique before submitting to the funding agency.
Oliver loved doing experiments and constantly worked at the bench up until the end of his life. During the time I was in the laboratory, Oliver’s personal scientific projects were primarily focused on understanding the mechanisms of homologous recombination, with an eye toward optimizing gene targeting efficiency and achieving more complex genetic alterations beyond knockouts. One of his long-term aims was to use these approaches for gene therapy to correct genetic errors in human disorders, such as the sickle cell mutation. Thus, Oliver did not really become interested in hypertension research until a few years after I left the laboratory, spurred on by a young internal medicine resident named John Krege.
When Oliver called me out of the blue one day to ask if I would be interested in working with him on a project aimed at understanding genetic mechanisms of hypertension, of course I jumped at the chance. At the time, he was following the example of his wife Nobuyo’s successful studies using gene targeting to understand the pathogenesis of atherosclerosis. He thought that hypertension, another common cardiovascular disorder with obscure pathophysiology, would be similarly amenable to this approach. Oliver had at least one other motivation behind his studies of hypertension. Namely, he himself had hypertension and had taken a angiotensin-converting enzyme (ACE) inhibitor for many years to control his blood pressure. During a plenary talk at an American Heart Association meeting, Oliver confessed to a rapt audience that he was particularly interested in the ACE pathway and ACE inhibitors “…because I’m a user.”
As he contemplated entering the field of hypertension research, Oliver recognized the need to develop new tools for carrying out precise assessments of blood pressure and other relevant physiological functions in mice because at that point, the rat was the animal model of choice for hypertension studies. These efforts resulted in the first tail cuff manometry unit designed specifically for mice, which is still on the market and widely used today. This reflected his long-standing philosophy that if you need equipment that is not available to get to the next stage of your experiments, build it yourself! In fact, there are many well-documented examples of Oliver scrounging spare parts and discarded pieces of equipment to build highly functional contraptions to support his research. He was fond of sharing the story of his time at Oxford, where his fellow students, on decommissioning laboratory equipment, would affix the label NBGBOKFO (“No Bloody Good, But OK For Oliver”).
Oliver’s impact on hypertension research reached beyond simply introducing the use of gene targeting as a powerful experimental approach for dissecting blood pressure control. He approached the problem of hypertension with creativity and skepticism of the status quo that characterized all of his work in science. In looking at our field through new eyes, he brought energy and novel perspectives, questioning paradigms in an area that had largely been dominated by physiologists, challenging, and sometimes irritating established investigators. Oliver’s contributions to hypertension research were formally recognized when he received the Novartis Award for Excellence in Hypertension Research in 1996. Notably, he shared this award with Bob Lefkowitz, who also went on to win a Nobel Prize in Chemistry in 2012.
Oliver especially enjoyed interacting with young scientists and famously addressed his Nobel lecture specifically to the graduate students in the audience at the Karolinska Institute. He was able to break down complex scientific principles into comprehensible bits and weave them together into entertaining story lines (see Figure), allowing him to inspire senior scientists and trainees alike. Perhaps, most compelling was his ability to transmit his love and enjoyment of science to those around him. And this was not limited to the rush of an exciting major discovery but was rooted in the joy and satisfaction derived from carrying out a successful experiment and summarizing a day’s work in his laboratory notebook. Oliver loved his life in science…and it was contagious.
Thomas M. Coffman
Cardiovascular and Metabolic Disorders Signature Research Program
Duke-NUS Medical School
Division of Nephrology
Department of Medicine
Duke University Medical Center
- © 2017 American Heart Association, Inc.