In the Jigsaw World of Human Genetics, UW Professor Mary-Claire King Found a Crucial Piece that Helps Solve the Mystery of Breast Cancer

By Laurie McHale

In a sense, Mary-Claire King began preparing to do battle with cancer when she was just fifteen years old, as she watched her best friend die of a kidney tumor. "We had been friends since age seven," she recalls. "Her death was devastating. I didn't know she had cancer: I just knew she was very ill and in terrible pain, and then she died. It seemed so unfair. It wasn't a conscious decision, but I said to myself, something needs to be done. It's the little pebbles that make a path."

Three decades later, King's youthful resolve led to spectacular results, with her proof in 1990 of the existence of the first gene for hereditary breast cancer, now known as BRCA1.

"She did the seminal work," says Leroy Hood, William Gates professor and chair of molecular biotechnology at the UW, and a major factor in King's decision last year to leave the University of California at Berkeley and accept an appointment at the University of Washington. "It let the world get into the hunt to pinpoint the gene."

"Mary-Claire has made extremely important scientific contributions, beyond the search for a cure for breast cancer," adds Maynard Olson. "She changed the way people think about human genetics." Olson, UW professor of molecular biotechnology and medical genetics, is a prime mover in the Human Genome Project, the huge international effort to map the entire genetic makeup of the human being.

A mutation in a family-inherited variation on the BRCA1 gene is revealed on film. Photo by Dennis Galloway.
Until King's lab mapped BRCA1, the best success in using DNA techniques to study human genetics came in analyzing diseases with simple patterns of inheritance--like Huntington's disease, where those who receive the mutation from one parent inevitably succumb to the disease--or like sickle-cell anemia and cystic fibrosis, where those who inherit recessive genes from both parents get the disease.

"Breast cancer is a more typical disease than those textbook disorders," says Olson. "Genetics is intermingled with environmental and lifestyle factors. Family history is important, but not predictive in the same way." Other diseases in which inheritance and environment are dual influences include heart disease, hypertension, stroke, Alzheimer's disease, and some mental illnesses.

"Before BRCA1, there was a widespread view that diseases like breast cancer were caused by multiple genes that interact with environmental factors. This didn't provide geneticists with a clear road ahead," says Olson. "In the midst of that, Mary-Claire's initial report was a jolt. She told a different story: that in carefully selected families she could find a fairly simple genetic link for breast cancer. It provided us with a powerful path forward. We now know that many important diseases can be attacked in the same way.

"There has been a mythology that breast cancer has been understudied. In actual fact there has been intense research and only slight advances in understanding it. Mary-Claire broke the logjam."

After King's lab showed that BRCA1 existed on chromosome 17 and was responsible for many inherited breast and ovarian cancers, the race was on to clone the gene and pinpoint its exact location. Mark Skolnick of the University of Utah was first to the finish line. "Cloning the gene is not the hardest part of the task," says Olson. "It's labor-intensive, but it happens sooner or later. Within 10 years, that phase will no longer be necessary, because the whole human genome will have been sequenced."

"When Mary-Claire lost the race to clone the gene, everyone expected her to be disappointed," says Piri Welcsh, a post-doctoral fellow in King's lab. "I imagine there was some disappointment, but we all had the same reaction. It meant we could now really start working on the biology of breast cancer. We can now determine how alteration in the gene creates breast cancer."

Last February, King and researchers at Vanderbilt University took the research a step further, reporting they had found the first direct evidence that the same gene can halt--and in some cases reverse--breast and ovarian cancers. Using mice inoculated with human breast cancer cells, they showed that normal BRCA1 secretes a protein that appears to inhibit certain cells from engaging in uncontrolled division and growth.

King's Science Also Serves Human Rights
Berkeley's Loss, UW's Gain
A Eureka Moment ... Someday
The Woman as Scientist

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