Geneticist Mary-Claire King, Ph.D., talks about discovering the BRCA1 gene and advances in medical science research
December 05, 2017
By Greg Peters
Over the years, Mary-Claire King, Ph.D., has been a mother, a geneticist, a teacher and an activist, but when it comes to the story of breast cancer research, the 71-year-old American Cancer Society Professor in the departments of Genome Sciences and Medicine at the University of Washington is a rock star.
While most researchers would be happy to have just one of what King describes as "once-in-a-blue-moon" discoveries, she has had four such moments during her 40-plus year career - most notably the landmark discovery of the breast cancer gene, BRCA1, in 1990, which opened the door for many major breakthroughs in the treatment and research of breast and ovarian cancers. King was in Kansas City recently to speak at The University of Kansas Cancer Center's 2017 Research Symposium.
"When a woman comes up to you and says 'I want you to meet my kids, and these are kids I wouldn't have because I wouldn't be alive if it weren't for knowing I had genetics that I needed to address and deal with," said King, whose quick wit and razor-sharp mind were on display during her hour-long presentation before a packed house at Regnier Hall Auditorium on the University of Kansas-Edwards campus. "That's tremendous. Having them tell me their stories and about their successes is enormously moving and tremendously gratifying."
Born in suburban Chicago, King began her academic path in mathematics, but a course in genetics early on in her doctoral studies at the University of California-Berkeley led to a change of plans and a blue-moon moment that landed her on the cover of Science magazine in April 1975. Her dissertation detailed how 99 percent of the amino acid sequences are identical in chimpanzees and humans. That work was the basis for the cover article.
The anti-war protests and civil unrest in Berkeley in the '60s proved to be a breeding ground of sorts for King, who has always been a strong human rights advocate. In 1984, she was able to combine her knowledge of genetics and evolutionary biology with her passion for human rights to formulate a way to use mitochondrial DNA to prove connections between grandmothers and their grandchildren who had been kidnapped during Argentina's "Dirty War" of the late 1970s. This finding led to many children being reunited with their families - blue-moon moment No.2.
The discovery of BRCA1 was blue moon No. 3 and interestingly, she identified the gene before the Human Genome Project was completed. More recently, she has found a link between genetic mutations and schizophrenia - blue moon No.4.
"Partly it's because I've had a long career," said King, explaining her four blue-moon discoveries. "I've had probably one lightning strike a decade. I've been very fortunate to be working in genetics at exactly a time when genetics has come into its own. Genetics has in the course of my career made the transition from being purely a descriptive science to being fully analytical and having technologies that allow us to ask questions about ourselves.
"The capacity to understand the genetics of people by understanding genomic sequences is brand new. We can now understand so much more about humans and human genetics that we couldn't just a few years ago, let alone 40 years ago."
Path to BRCA1
King's path to discovering BRCA1 began in earnest in the early-1970s in the lab of Dr. Nick Petrakis at the University of California-San Francisco where she focused on breast cancer research with the belief that the disease was genetic, which ran contrary to the popular notion of the day that the disease was viral. Adding to her difficulties was the fact that she was one of the few women working in research at the time, so King often found herself at odds in a male-dominated field.
In 1976, King was hired for a tenure-track assistant professorship in the School of Public Health at Berkeley. Ultimately, King and her team tested their theories for 17 years, base pair by base pair, looking for familial genetic connections before their breakthrough moment in 1990. Much of the work was done before the advent of today's technology, which obviously could have made the process much easier. In addition, a lot of the information they gathered came directly from talking to cancer patients and their families.
King credits her Heartland roots with giving her the mettle to persevere through the years as her team toiled in the wilderness of the unknown looking for the breast cancer gene. "I'm a Midwesterner, and in the Midwest you're expected to be self-reliant and think for yourself," she said. "One factor is that it is a really important problem, so it's worth the investment of time. If I failed, I knew I wouldn't have failed for want of trying.
"Second was that I had several other things going on at the same time, so it wasn't that if I got discouraged on a Thursday morning I could for that day do something else and then come back to it on Friday.
"The third reason I could stay with it - and I didn't realize it at the time but in retrospect - distinctive to my cohort of young women in science, nobody paid any attention to us. There weren't very many of us who were working and had NIH money, so there was an enormous freedom in being ignored.
"I was doing good work and careful work, and there were enough people who believed in it that when I would get reviewed, I'd get good reviews. But there wasn't the expectation to produce results quickly like the young people frequently confront now."
In 1990, King's lab published its landmark paper in Science, identifying BRCA1 on chromosome 17 as a breast cancer gene. It was a bold pronouncement, but one that King was confident in making.
"We thought, 'well, maybe,'" she recalled, thinking back about the finding. "I think scientists usually think 'well maybe' until somebody else produces your result. The relief that I was right - and I knew we were right based on our evidence - and that it was a general result and not just a fluke that applied just by chance to the subset of families we were looking at, came when a group in France working with the same reagents we were working with but with different families got exactly the same results."
The Jensen connection
Just months after King's paper was published, Roy Jensen, M.D., director of The University of Kansas Cancer Center, who was working with Jeff Holt at the Vanderbilt-Ingram Cancer Center at the time, invited her to Nashville so they could share their BRCA1 findings. "We had worked really, really hard for a few months and had some data we were excited about. She came to Vanderbilt, and we had the opportunity to present to her some of the first data that demonstrated the first direct in vitro evidence that BRCA1 acts exactly as she had predicted as a tumor suppressor. It was an exhilarating experience to have someone who I considered to be one of the greatest minds to come out of the 20th Century to be excited about my work."
Since their initial meeting, Jensen and King have been collaborators and, more importantly, family friends. "Shortly after I met Roy, his oldest son, Andrew, who is currently a fourth-year resident in urology at the University of Oklahoma, made me a terrific drawing of his dad wearing a white lab coat and holding a test tube that says 'DNA Scientist.'"
It's been more than 25 years since the paper mapping the BRCA1 sequence has been published, and King continues to be amazed how much has been learned about cancer and genetics. For example, the ability to both examine and edit genes are enormously powerful tools that King says are moving science forward at a rapid pace. She is astonished about how much can be done with the technology that has evolved since her discovery, and she looks forward to what's ahead in genomic research.
"What excites me for the future is the continued exploitation of genomics for the benefit of patients, which I think happens in several ways," said King. "I think it happens at the level of understanding tumors, so that once a woman is diagnosed with breast cancer or ovarian cancer we're able to understand the genetics of the tumor in such detail that in many cases if the tumor has BRCA1 or BRCA2 mutations - either inherited or tumor-specific - there are chemotherapies that can be used specifically for those tumors.
"Additional chemotherapies of those sorts, called synthetic lethals, are being developed. That will expand the range of very effective therapies against very aggressive tumors.
"Another area is being able to identify women who are at extremely high risk of cancer for genetic reasons before any cancer is diagnosed," continued King, who strongly urges all woman older than 30 to have their BRCA1 and BRCA2 tested for genetic mutations. "Therefore we can focus very early on detection schemes for those women, and also offer those women preventive medical treatments and interventions, and that could involve the removal of the fallopian tubes and ovaries by age 40 or so."
In addition to her four blue-moon moments, 14 honorary doctoral degrees and countless accolades, including the Lasker-Koshland Award for Special Achievement in Medical Science in 2014 and the National Medal of Science in 2016, King has been portrayed by actress Helen Hunt in the movie "Decoding Annie Parker." She also was a featured storyteller in a June 2014 edition of The Moth Radio Hour at the World Science Festival.
During her Moth presentation, King notes how out of necessity she was forced to leave her 6-year-old daughter with a stranger named Joe DiMaggio for a short time at the San Francisco airport in 1981. When asked which of today's celebrities she would entrust her child to King says without hesitation, "Barack Obama." And then, after a few minutes of thought, "Roy Jensen and his family."