The First Nobel: Oliver Smithies' Work Pays Off

Posted on Oct. 25, 2007

The quiet talk in the halls of UNC’s genetics labs that’s been going on for years turned out to be accurate. Oliver Smithies, who has labored at the tedious task of genetics research for more than 50 years, was honored Monday with the 2007 Nobel Prize in medicine — the first Nobel for a Carolina faculty member.

Smithies will receive his Nobel Prize in a ceremony Monday, Dec. 10, in Stockholm, Sweden. The ceremony begins at 4:30 p.m. in Stockholm, which correlates to 10:30 a.m. in Chapel Hill. The webcast of the ceremony can be watched here. (Windows Media Player is needed to view the webcast.)

The Nobel Prize award ceremony takes place at the Stockholm Concert Hall, Sweden, on Dec. 10 every year, the anniversary of Alfred Nobel’s death. At the ceremony, the Nobel Prize in physics, chemistry, physiology or medicine, literature and the prize in economics are awarded to the Nobel laureates.

Smithies, who is Excellence Professor of pathology and laboratory medicine in the School of Medicine, shares the prize with Mario R. Capecchi of the University of Utah’s Howard Hughes Medical Institute and Sir Martin J. Evans of the United Kingdom.

Specifically, the Nobel is for their work in creating animal models of human disease. It marks one of the seminal accomplishments in genetics research, a process known as gene targeting, which has been credited to Smithies. The three have been honored together previously.

The achievement marks the pinnacle of a scientific career for Smithies, a UNC faculty member for 19 years, containing numerous honors and two major innovations that have fundamentally changed the science of genetic medicine and laid the foundation for today’s research into gene therapy.

Smithies’ presence at UNC has been credited with attracting other prominent genetics and genomics researchers, including Terry Magnuson, Sarah Graham Kenan Professor and chair of the department of genetics.

About seven years ago, the medical school started building what it intends to be one of the University’s signature programs: a genetics department built around mouse research and, in the larger sense, a push into genomics research that will involve all of the health sciences on campus. Early in his chancellorship, James Moeser listed genomics as one of Carolina’s top priorities for fundraising and building of an elite faculty.

Smithies told The Associated Press that getting award was “very gratifying.” After working on the research for more than 20 years, he said it’s “rather enjoyable being recognized at this level.” Later Monday, he spoke to a gathering on campus. (See related story, “A Humble Scientist Gets the Proverbial Phone Call.”)

He told The AP that he hopes winning the prize will make it easier to secure funding for other work. Early Monday, he told The News & Observer  that he had no immediate plans to celebrate the award.

Magnuson said Smithies had “revolutionized biomedical research. He’s done this in a way that is allowing biomedical scientists to look at the role and function of genes.”

“I think the bottom line is, he and Mario Capecchi and Martin Evans really changed how research into disease susceptibility is being done,” Magnuson said. Virtually every lab in the world working on disease susceptibility is using Smithies’ methods, he added.

In the mid-1980s, while at the University of Wisconsin at Madison, Smithies co-discovered a technique to introduce DNA material in cells, replicated a natural process called homologous DNA recombination. He thought that genetic disorders could be treated by correcting mutations in bone marrow cells, or stem cells. This “gene targeting” led to the creation of transgenic mice, or “designer mice,” that replicated human disease. Smithies’ lab produced the first animal model of cystic fibrosis, a disease caused by one defective gene, and also studied high blood pressure, atherosclerosis and other diseases.

This method also enabled scientists to study specific genes by creating “knock-out mice.” By targeting and removing, or knocking out, a specific gene, researchers can find out what happens when it’s missing. Smithies has used the analogy of removing a steering wheel from a car; without it, you soon find out why it has a steering wheel. Now this research method is commonplace in biomedical research and has been the basis for thousands of published papers.

According to the Nobel committee, “gene targeting in mice has pervaded all fields of biomedicine. Its impact on the understanding of gene function and its benefits to mankind will continue to increase over many years to come.”

It was in Chapel Hill that Smithies first made a mouse. In this process, the researcher takes embryonic stem cells and grows cells in culture from them. The cultures enable the scientist to make changes, or mutations, in the cells. The cells then are placed in the embryo of a mouse and, when all goes well, the mouse that develops from that embryo has the desired mutation.

This making of a mouse is sort of a microcosm of the necessarily slow pace of genetics research; it takes at least six months, on average a year, and as much as two years to make a mouse.

The first breakthrough at UNC came in Smithies’ lab when an associate of his created the first animal model for cystic fibrosis. The gene related to the disease in humans had been found; now, that same gene in the mouse could be altered and the results studied. The goal is effective therapies for humans.

But only some 50,000 people are affected by cystic fibrosis. Some years ago, a colleague urged Smithies to take a look at hypertension, which affects millions.

“I decided to look for evidence that hypertension might be due to small variations in more than one gene,” he said in 2000. “I’ve been at this almost nine years now. It’s going quite well.”

At that time, 10 genes had been identified in mice that, if altered quantitatively, have an effect on blood pressure.

“It’s hard to find a good drug for hypertension that works for everybody,” Smithies said. “A lot of times there are bad side effects; some drugs work for some, not for others. People have to mess around with a lot of drugs and side effects to try to control blood pressure.

“I think it’s fair to say we’re the people who have pursued this line of research the most.”

In the 1950s, while at Connaught Medical Research Laboratory in Toronto, Smithies greatly improved gel electrophoresis, a process of separating proteins to identify genes, using starch. The innovation simplified the procedure and became standard in laboratories.

“Oliver Smithies’ innovations have revolutionized genetic research and advanced the effective treatment of many diseases, and millions of people worldwide have better and longer lives because of the talent and determination he has brought to his work,” said UNC Chancellor James Moeser. “For decades, he has embodied the very best of academic research and humanity through his modesty, good humor, creativity and love of invention. Through his example, hundreds of students and colleagues have learned how to help the world through research.

“We are honored to have him as an anchor for the UNC community and grateful that his many contributions have been recognized with a Nobel Prize.”

“Scientist, scholar, mentor – Oliver Smithies adds Nobel Laureate to a long and glorious career,” said Dr. William L. Roper, dean of the UNC School of Medicine, vice chancellor for medical affairs and chief executive officer of the UNC Health Care System. “It gives us great pleasure to say congratulations on achieving this wonderful honor.”

Two UNC alumni have won a Nobel:

• In 1998, Robert Furchgott, who did his undergraduate work in Chapel Hill and graduated in 1937, shared the prize in the physiology or medicine category with two other scientists for the discovery of how the natural production of nitric oxide works in the body. Furchgott was a Distinguished Professor of pharmacology at the State University of New York Science Center at the time. The discovery figured in the development of impotence drugs such as Viagra.
• In 1947, Mary Lindsay Elmendorf ’37 was part of a group of Quakers who sent food to Europe during World War II that was awarded the Nobel Peace Prize for their efforts.

The University also has had brushes with the prize before: Rudolph Marcus, who won the Nobel for chemistry in 1992, was a post-doctoral student at UNC. Gertrude Elion and George Hitchings, Research Triangle Park scientists who won the prize for medicine in 1988, both were adjunct professors in medicine at UNC. Both were awarded honorary degrees from the University. In 1994, Martin Rodbell, also an adjunct professor in biochemistry at UNC while working at RTP, won for medicine.

Smithies was born in 1925 in Yorkshire, England, where as a young child was drawn to the idea of invention and enjoyed building telescopes and radios. He attended a high school for bright students and won a scholarship to Oxford University. He earned a bachelor of arts degree (first-class honors) in physiology from Oxford in 1946, and he went on to earn his master’s degree and doctorate in biochemistry from Oxford in 1951.

In an interview with the Lasker Foundation, which honored him in 2001, Smithies credited his inspiration for science to a comic strip he read as a boy. The strip had an inventor, and, Smithies said, that’s what he wanted to be, and that’s what he always has been.

He also said scientists should have three things in their lives: their work, a hobby and a family. Smithies is married to UNC colleague Nobuyo Maeda, Robert H. Wagner Distinguished Professor of pathology and laboratory medicine. He also is a licensed airplane pilot and is especially fond of gliding.

Smithies came to UNC in 1988. His lab focuses on developing animal models for studying gene therapy in hypertension and other genetic disorders, including sickle cell disease. He is a member of UNC’s Lineberger Comprehensive Cancer Center.

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Related coverage is available online:

• A Humble Scientist Gets the Proverbial Phone Call
  News report from October 2007
• Of Mice and Man: The human genome is complete. Now medical schools will subdivide the vast field of genetics research. Carolina is making a major investment to strengthen its specialty in genetic engineering.
  Cover story from the November/December 2000 issue of the Carolina Alumni Review, available online to Carolina Alumni members.
• Accompanying profile, detailing Smithies’ work, also in the November/December 2000 issue of the Carolina Alumni Review.

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