Monday, March 25, 2013
Oliver Smithies did not set out to become one of the world’s foremost pioneers in cancer research. He merely had a question that needed answering.
The path to that answer led to one of the greatest advances in modern biomedical research, a Nobel Prize and now recognition as a member of the first class of Fellows of the American Association for Cancer Research Academy. On April 5, Smithies, DPhil, Weatherspoon Eminent Distinguished Professor in the Department of Pathology and Laboratory Medicine and member of the UNC Lineberger Comprehensive Cancer Center, will join 106 other of the nation’s most accomplished cancer researchers as the first group to receive the honor.
Smithies shares his 2007 Nobel Prize with Mario Capecchi of the University of Utah and Martin Evans of University College London for their work in developing the technique of gene targeting. Gene targeting has become a cornerstone of modern genetics and pharmaceutical research, allowing for the breeding of research animals that have specific genes turned on and off to allow researchers to investigate the function of genes and assist in developing treatments for a variety of genetically based disorders, including cancer.
“It is possible to modify a gene in a living cell in a planned way. That’s gene targeting, and that was the first time anyone had been able to demonstrate that that was possible,” said Smithies.
In 1982, Smithies’ work as a geneticist revolved around finding a cure for sickle cell anemia. A decade earlier, researchers had developed the first genetic engineering techniques to allow molecular cloning, the modifying of an organism’s genome by introducing DNA fragments from another organism. After reading an article from a cancer researcher who had changed the behavior of a petri dish full of cells using genetic engineering techniques, Smithies wondered if he could use the same techniques to make a targeted modification to a gene.
“The initial experiments that I did at that time were trying to find a way to correct a genetic abnormality. I thought that what I would like to do is find a way of using the DNA from a normal individual to change the mutated gene in the person that had sickle cell anemia. In that way, I’d help that person live a normal life,” said Smithies.
It took Smithies three years to devise a working method. Unfortunately, the frequency of success was not high enough for clinical use, so Smithies began to look for another uses for gene targeting.
“It was too inefficient. It worked, but it worked very rarely,” said Smithies.
His search led him to the work of two researchers with whom he shared the Nobel Prize – Martin Evans and Mario Capecchi. Evans had isolated embryonic stem cells and shown that inserting those stem cells into a developing mouse egg would lead to them being incorporated into the developed mouse. Using this technique, now known as homologous recombination, Smithies was able to correct a faulty gene in a mouse.
“I thought that if I can modify the embryonic stem cell in a planned way, I could add changes in different genes. And that would be very valuable, even if it would be difficult to do,” said Smithies.
At the same time, Capecchi proved that gene targeting could be used to “knock out” genes from a mouse, effectively inactivating the genes. This improved the efficiency of the methods, creating a set of tools that have benefited researchers across the world and led to the development of the knockout mouse model of biological research. Both Evans and Capecchi have also been named to the AACR Academy.
“That’s why the three of us together were important in that work. First of all showing that it was possible, that was my work. Showing that you could do experiments with mice in tissue culture, that was Martin Evans’s work. Showing that you could get much better results and do important knock out experiments, that was Mario Capecchi’s work,” said Smithies.
The knockout mouse has become a central tool in the study of genetics. They have served as models for research into disorders such as cancer, aging, obesity, heart disease, diabetes, arthritis, anxiety and substance abuse.
“Smithies quickly recognized the potential for applying the gene targeting technology to creating preclinical animal models of complex diseases in humans such as cancer. He noted that the mouse system is particularly valuable because the effects of combinations of genetic changes can be studied, and because environmental influences can be varied in a controlled fashion. His work led to the ability to systematically study endogenous mouse models for cancer,” said Terry Magnuson, chair of the UNC Department of Genetics.
The inaugural class of Fellows will be inducted into the AACR Academy on April 5, 2013 at the National Museum of Women in the Arts in Washington, D.C. The induction ceremony will be followed by a meeting of the Academy on April 6, and special recognition of the inaugural Fellows during the opening plenary session on April 7. The AACR plans to induct new members annually at this event, with future classes consisting of no more than 11 fellows.