As a first-year graduate student at the University of Wisconsin-Madison, Michelle Bennett was beginning to see the future more clearly. She pictured a fulfilling career in basic research, one that would benefit those who are suffering from illness and disease. And she knew she had the tools to make that dream come alive -- a keen interest in science, a strong work ethic, and the ability to make the most of the opportunities that came her way.
But never in her wildest dreams could she have imagined that just months after receiving her degree, she would be accepted for a postdoctoral position with the NIH's National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, and get the chance to do some cutting-edge biomedical research in molecular genetics. Or that just one year later, she would play a pivotal role in the internationally-acclaimed discovery of BRCA1, the first gene shown to be responsible for inherited breast and ovarian cancer.
But what Bennett finds even more remarkable is that she has just been awarded a three-year, $120,000 medical research grant from the U.S. Army to develop a genetically engineered strain of mice that will have defective copies of a second breast cancer gene, BRCA2, that has been linked to the majority of inherited breast cancers not caused by BRCA1. NIEHS investigators will use the mice to learn more about how hereditary breast cancer develops in humans.
While these accomplishments have validated her career as a scientist, Bennett credits her early years as an undergraduate as having pointed her in the right direction. "During my first couple of years at Kalamazoo College, I spent a quarter doing administrative work for Illinois Senator Charles Percy -- reading mail, answering the phone," says Bennett. "While the experience didn't have a direct impact on my career, it helped me realize I didn't want to go into politics!"
Although Bennett had tentatively set her sights on becoming a doctor, she wanted to find out more about the world of laboratory research. During her senior year, she took a quarter off to do an independent project with Upjohn, a pharmaceutical company in the area. Her mentor was Leonard Post, a molecular biologist who was working on a strain of herpes virus that infects pigs. The virus is very similar to the one that causes cold sores in humans. "That experience was the real turning point for me," recalls Bennett. "The fact that we were working on a vaccination that might protect the pigs from getting this virus was incredibly exciting."
With her goals more clearly mapped out, Bennett enrolled at the University of Wisconsin-Madison for graduate study in cancer genetics and a chance to work with Norman Drinkwater, one of the country's most renowned molecular biologists. Under Drinkwater's tutelage, Bennett learned the intricacies of gene mapping, a powerful gene-finding approach that was being used by the NIEHS scientists in their search for the breast cancer gene. "When I interviewed for a position with NIEHS, I realized my training and experience were ideally suited to the project they were working on," says Bennett.
By the time Bennett joined the NIEHS team in 1993, the effort to pinpoint the location of BRCA1 was already well underway. The gene had been traced to a specific region of chromosome 17, and lead investigators Roger Wiseman and Andrew Futreal were looking at breast tissue samples taken from healthy women in an effort to find a "candidate gene" -- that is, a gene that they suspected might be BRCA1.
The researchers then compared these normal genes with the same genes taken from breast tumor samples of women known to be genetically predisposed to breast cancer. "Analysis of the tumor samples revealed a specific gene that was somehow different from its 'normal' counterpart," says Bennett. "When we found this same pattern of alterations in subsequent samples, we began to feel confident that we had found BRCA1."
Bennett's job was to "organize" the bits and pieces of DNA obtained from pools of DNA sequences into recognizable pictures of potential genes that could be used in the comparisons. "Gene mapping is a bit like fishing from a lake that contains many different species of fish," explains Bennett. "Some of the fish taken from the lake are easily identified, while others are curious specimens that the fisherman has never seen before. The fisherman must then draw upon the information he gets from both kinds of fish in order to find what he is looking for."
Bennett remembers how easy it was to get caught up in the excitement of the gene discovery and its immediate impact -- the possibility of a long-awaited test that could identify those at greatest risk for developing inherited breast cancer, international recognition for her and her colleagues, and unprecedented publicity for NIEHS. But in the years since the breakthrough, some of Bennett's enthusiasm has given way to caution. "I can picture the day when everyone will carry an identification card that lists their genetic history," she says. "The social, legal and ethical ramifications of this would be enormous."
In spite of these recent advances, scientists do not yet understand how a single gene like BRCA1 can influence a process as complex as breast cancer. With the discovery of the second breast cancer gene by Futreal, now with the Duke Comprehensive Cancer Center, and a host of other collaborators, those answers may be close at hand. "We know that women who inherit a defective copy of BRCA2 from one parent have an 80 to 90 percent chance of developing breast cancer during their lifetime," explains Bennett. "Now we want to know what makes this gene so critical."
In order to answer this question, Bennett will attempt to breed a line of genetically engineered mice that are "BRCA2-deficient" -- that is, mice that carry one or two defective copies of their BRCA2 genes. She will then compare their growth and development with that of normal mice, looking for differences that can be attributed to the faulty gene. These differences may help to unlock some of the secrets about how the gene works and what happens when it doesn't. "We should eventually be able to design studies that can identify some of the environmental factors and lifestyle practices that influence breast cancer development in genetically predisposed individuals," says Bennett.
And what kind of future does Bennett picture five years from now? "That's a very difficult question to answer, because cancer research is such a highly competitive field," she admits. "Right now, I have two small boys -- Kyle and Parker - who need a lot of my attention. Once they get a bit older, I would enjoy having a lab of my own. I have also thought a lot about teaching. I think it is important that our young people understand how exciting and fulfilling a science career can be."