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University Gazette

The University of North Carolina at Chapel Hill

The legacy of Oliver Smithies

The great man left behind valuable research tools, meticulous records and an inspirational way of life.

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Smithies was rewarded for his work in gene targeting with a Nobel Prize in 2007, given to him in Stockholm by the King of Sweden. Photo by Pascal Le Segretain.

 

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Smithies emerged from his beloved lab for a press conference on the day his Nobel Prize was announced in 2007. Photo by Dan Sears.

Nobel laureate Oliver Smithies passed away Jan. 10, but he leaves behind a tremendous legacy in laboratories around the world and in the hearts of the many scientists who shared in his work. Here are just a few reasons Smithies will always be remembered.

The knockout mouse

An inveterate tinkerer, Smithies understood the importance of tools. And his dogged tinkering led to one of the most important tools in the research laboratory: the knockout mouse. This is the achievement for which he shared the 2007 Nobel Prize in Physiology or Medicine with Mario R. Capecchi of the University of Utah and Martin J. Evans of Cardiff University in Wales.

Smithies’ contribution to the work was gene targeting, a tool that allowed scientists to create two kinds of laboratory mice: the knockout mouse, in which a certain gene is removed to be able to determine what the gene controls, and the genetically engineered or designer mouse, in which a certain gene is added to create mice with the symptoms of gene-related human diseases, so that researchers can understand and try to cure these diseases.

How widely used are these tools? If you search for “knockout mice” in the online U.S. National Library of Medicine, more than 130,000 entries come up.

Smithies also invented starch-gel electrophoresis, a method of separating proteins in blood samples. Other researchers were using starch grains, which was like working with “a tray of wet sand,” Smithies said in a 2007 interview. Remembering how his mother made starch when she did the laundry, he cooked up a batch in the lab. He stained the proteins with dye and could easily see them in the starch slurry, impossible to do with the grains. Scientists still use a modified version of this process (acrylamide gel electrophoresis) today.

Dr. Oliver Smithies, Excellence Professor of Pathology and Laboratory Medicine and 2007 Nobel Laureate, at the University of North Carolina at Chapel Hill (Melanie Busbee/UNC-Chapel Hill)

Smithies spent long hours working side-by-side with researchers in his lab. Photo by Melanie Busbee.

Oliver Smithies Research Archive

Smithies starting keeping notes on his research – and his life – as a graduate student in the 1940s by writing them by hand in a laboratory notebook. Technology introduced other means of keeping track of research, but Smithies never saw the need to change. From 1943 through 2016, he filled more than 150 notebooks with his observations.

Just a few months ago, this incredible window on how a scientist thinks was thrown open online as the Oliver Smithies Research Archive (smithies.lib.unc.edu/).  Anyone in the world with Internet access can now page through his discoveries, disappointments and questions, even listen to his soft-voiced British accent as he explains research points in online audio. The archive is an unprecedented sharing of a great mind.

“When you are doing science, you have to keep a good record of what you do, and I suppose I’m a person that saves things,” said Smithies, Weatherspoon Eminent Distinguished Professor at the School of Medicine, in an interview following the November 2016 launch. “They accumulated without any particular thought about them being kept for anybody except for me. I think the reason to digitize them was not for any personal vanity or anything, but because they have a record of what an everyday scientist is doing for a lifetime.”

OLIVER SMITHIES, PATHOLOGY

Smithies spent long hours working side-by-side with researchers in his lab. Photo by Dan Sears.

Influence on the people in his lab

Being a principal investigator is a tricky job. The lab is yours. Most of the funding is yours. But much of the work of experimenting and testing is done by other people in your lab – from postdocs and research assistants to graduate and undergraduate students – often with little official acknowledgment.

Smithies never forgot that. He kept a quote from his Oxford University mentor, Sandy Ogston, on a piece of paper in his wallet: “For science is more than the search for truth, more than a challenging game, more than a profession. It is a life that a diversity of people lead together, in the closest proximity, a school for social living. We are members one of another.”

After Smithies won the Nobel Prize, a former member of his lab recalled what the atmosphere was like. “Characterizing the knockout took years of work and endless days and nights in the laboratory,” said Linda Hammond, who went on to become a postdoctoral fellow in the department of molecular biology and biochemistry at University of California, Irvine.

On the wall outside his office door, Smithies posted a map with tiny flags pinned on it to show where his former graduate students work.

Each year, the lab would have a holiday party at the end of the year, and Smithies always brought his home-cooked cranberry pudding and made sure everyone got a taste, said Jenny Holt, longtime administrative assistant to Smithies and his wife, researcher Nobuyo Maeda, in the School of Medicine. Smithies served up his cranberry pudding at the end of      2016, too.

“He always gave so much of himself to people, and I appreciate that,” Holt said.

OLIVER SMITHIES, PATHOLOGY

Smithies said he was happiest at the bench. Photo by Dan Sears.

An incredible work ethic

Smithies was as excited to come into the lab at age 91 as he was when he was a graduate student. As he said after winning a Lasker Award in 2001, “What people need to understand about scientists is that their work is their reward. If you enjoy the science, you have something to look forward to every day.”

Smithies was persistent. He never gave up on a problem. Sometimes it took him years to prove one of his hypotheses. He conceived the idea of gene targeting in about 10 days, but it was three years before he actually made it happen in the lab.

But he kept plugging away, experimenting at the bench, writing his notes and referring back to them for clues. That persistence against the odds cost him graduate student helpers early in his career, but led to important discoveries.

Hammond said, “Day or night working in the laboratory, I was never alone. Other graduate students and postdoctoral fellows were always there working, which is what is expected. However, what was really amazing was that Oliver Smithies was also in the lab doing experiments. It is pretty much unheard of for a full professor, especially one with such a huge reputation in the scientific field, to still be working in  the laboratory.”

The lab was his favorite place to be.

“If I die somewhere — which I’m sure will happen,” he said in an Endeavors interview in 2008, “it might as well be at the bench, because that’s where I’m happiest.”