Women in Science: Mary-Claire King

This month I am covering the life and career of Dr. Mary-Claire King, a distinguished scientist who has applied her talents to the good of humanity, and provides a clear ideal of what it means to truly impact society through research. She is fearless, tenacious, and logical, and I couldn’t imagine a better woman to write about in the current political climate.

Dr. Mary-Claire King was born February 27, 1946, in Evanston, Ill., a suburb of Chicago. She studied mathematics at Carleton College in Northfield, Minn., graduating in 1966 at the age of 20. King then went to University of California, Berkeley to pursue a doctorate in statistics. An early course in genetics changed the entire course of her career, and she fell in love with the application of mathematics and statistics to solving genetic problems. She transferred to the genetics PhD program in 1967, and for the first time began doing experimental biology.

It was not an easy transition. Compounded with the growing anti-war movement on the Berkeley campus, in which King was actively involved and incredibly passionate, she considered dropping out of the PhD program all together. Throughout 1968 she worked for political activist and consumer advocate Ralph Nader, researching the effects of pesticides on farmers and helping to write a report on the environmental conditions in California. When Nader offered King a job in Washington, D.C., to help found the Public Interest Research Group (PIRG), she was tempted. She spoke with Dr. Allan Wilson, a UC Berkeley genetics professor and one of King’s mentors, about her frustrations with experimental science and the possibility of moving to D.C. Wilson told King that, “If all the people for whom nothing ever worked dropped out of science, there'd be nobody left.” King joined Wilson’s lab, and together they created a project that combined her talent and love of statistics with evolutionary biology research.

Her project analyzed the molecular similarities between humans and chimpanzees, with an emphasis on protein coding genes. Genes are composed of DNA sequences, which provide the blueprint for protein. She analyzed both the DNA sequence of protein coding genes and the resulting amino-acid sequences, and found that the evolutionary distance between the two species is quite small. King’s thesis work culminated in a 1975 Science cover article, which reported that 99% of amino acid sequences in humans and chimpanzees are identical. In fact, sibling species of mice harbor more genetic differences in protein coding regions than humans and chimps!

Marie-Claire King Science coverDue to the obvious physical and anatomical differences between humans and chimpanzees, it was rather confusing that the DNA and protein sequences were so similar. King suggested that her results pointed to a role for transcriptional regulation of protein coding genes in driving evolutionary changes, and that many of these mutations may have been missed by this study, since they were focused solely on protein-coding DNA. In fact, this has proven to be the case, as many non-protein coding regions have high mutation rates and are more variable between humans and closely related species. It was a daring hypothesis, against current genetic dogma of the time, and gave a subtle hint to the exciting science she would discover in the future.

After earning her PhD in 1973, King moved with her husband and young daughter to Chile to teach at the University of Chile. The Chilean military coup of 1973 and the overthrow of President Salvador Allende created a dangerous environment for social and political activists. Many of her students did not survive, and thousands of political leftists were killed or imprisoned in the coup aftermath. King’s family returned to Berkeley, where she was offered a postdoctoral fellowship with Dr. Nick Petrakis at University of California, San Francisco, in cancer epidemiology and genetics. 

King focused specifically on breast cancer, as previous studies had shown an increased risk of breast cancer in families with a documented history of the disease. King was able to approach this problem differently due to her strong background in mathematics and evolutionary biology, demonstrating a keen intellect and ability to analyze the evidence and come to a logical conclusion. She soon became convinced that these familial links were due to inherited genetic mutations that predisposed women to develop breast cancer; no other hypothesis made sense. It is important to put King’s theory in context, because although at present cancer is overwhelmingly considered a genetic disease, in the early 1970s cancer research mainly focused on viruses, such as Epstein-Barr and Hepatitis B. In addition, techniques that we take for granted today in molecular biology, such as PCR (polymerase chain reaction), were not even invented yet. Thus, King’s insistence that breast cancer could be caused by inherited mutations was a fairly novel idea in the field of cancer research.

In 1976 King applied for a tenure-track assistant professorship School of Public Health at UC Berkeley. Although universities were making a concerted effort to hire more women, there was still push-back from those unaccustomed to women running their own research labs and being in a position of authority. She has expressed in several interviews that, “I am absolutely a child of affirmative action. After I had accepted the job, the division head said to me, ‘I just want you to know that you are only here because of all these new regulations, and we are really scraping the bottom of the barrel in hiring you.” King’s response? “We’ll see how long you feel that way!”

In the early 1980s, the National Cancer Institute (NCI) was surveying women across the United States as part of a large study to determine the effects of birth control pills in the development of breast, ovarian, and uterine cancer. King convinced the NCI to add several questions regarding family history of these cancers, asking about cases of breast cancer in immediate and extended family members. In parallel, the King lab built mathematical models using complex segregation analysis, to search for a variable that would explain the patterns of breast cancer in affected families. King’s group tested genetic and non-genetic models of cancer inheritance, and compared the predictions from their models with the data collected by the NCI. The results were striking: models with the assumption of an autosomal-dominant breast cancer trait explained all cases of heritable breast cancer.

Although only 4% of the families in this study were considered carriers of such a trait, the results still had broad implications for breast cancer research as a whole. As in the case of retinoblastoma and many other types of cancer, both inherited and non-inherited forms of cancer are caused by mutations in the same genes. At this point, King knew there was a breast cancer gene, “But the gene was hypothetical. The best way to prove that it existed was to find it.” 

So that is exactly what she did.

King’s group mapped the breast cancer gene using linkage disequilibrium analysis, which involves isolating polymorphisms in DNA sequences that are shared among individuals with the same phenotype. They built on the data collected by the NCI used in their previous study. Already painstaking work, this research was further complicated by the devastation of breast cancer throughout these families. In the case that a patient in a given pedigree had succumbed to breast cancer, King’s lab collected DNA from siblings, parents, and children, and reconstructed genome maps of breast cancer patients.

It took 17 years, but they located the gene. In 1990 King’s lab published the landmark paper in Science, which identified the breast cancer gene BRCA1 on chromosome 17. This article initiated a race to clone and sequence the BRCA1 gene, which King ultimately lost to Mark Skolnick’s lab and Myriad Genetics in 1994.* King continued to study BRCA1, describing multiple mutations in BRCA1 that occur in breast cancer, and has worked to develop inexpensive screening tools to detect breast-cancer associated mutations.

In 2014 King received the Lasker Award, one of the highest honors given to researchers in the medical sciences. This award coincided with a short viewpoint article by King in The Journal of the American Medical Association (JAMA), supporting genetic screening of all women over the age of 30 for BRCA1 variants and other common mutations associated with breast cancer. The penetrance of BRCA1 mutations is extensive, with 83% of women carrying BRCA1 mutations developing breast or ovarian cancer by the age of 80, compared to an 8% lifetime risk in a control population. Importantly, King’s research found that half of women that have inherited BRCA1/BRCA2 gene mutations have no family history of breast or ovarian cancer. Screening at an early age is therefore essential to prevention, early treatment, and survival.

Last year Dr. King was awarded the National Medal of Science, recognizing not only her work on BRCA1 and breast cancer, but also her commitment to applying her skills to humanitarian efforts around the world. In 1983 she began a decades-long collaboration with Abuelas de Plaza de Mayo (Grandmothers of Plaza de Mayo), a human rights group that aimed to reunite children kidnapped during the eight-year “Dirty War” in Argentina. During this war, thousands of political activists and revolutionists were killed, but the whereabouts of their children were unknown. King developed the first PCR sequencing assays using mitochondrial DNA, helping identify and reunite over 100 Argentinian children with their biological families. King has also published novel forensic methods to harvest mitochondrial DNA from teeth, helping to identify remains of soldiers in Vietnam, and Korea, and WWII. The King lab continues to work with The United Nations Forensic Anthropology Team in investigating cases of human rights abuse, and their research has helped establish the field of forensic science. 

Dr. King moved her lab to the University of Washington in 1995, where she is a Professor of Genome Sciences and Medicine. Her research aims to apply epidemiology, sequencing, and genomics to identify novel disease-causing mutations and improve human health. What is most remarkable to me is that, throughout her career, King has consistently applied logic to make prescient hypotheses regarding the nascent fields of evolutionary biology, cancer genetics, and forensic science. When technology, such as PCR and genome-wide sequencing, finally became available to prove these hypotheses, she built on these advancements to benefit those most in need.

In addition to her scientific research and humanitarian efforts, King is a strong advocate for the citizen scientist. “The most daunting task for us is not tackling new discovery but rather integrating discovery into a meaningful social context.” Dr. Mary-Claire King’s life and work serves as an ideal for scientific investigation and using our knowledge to empower communities. I’ll conclude with another word of advice from Dr. King: “the most important questions come from people on the frontlines, the most righteous projects demand the most rigorous science, and no question is too big to ask.”

* Following their discovery of BRCA1 cDNA sequence, Myriad Genetics fought for exclusive rights to research and develop products using BRCA1. This lawsuit was ultimately taken to the Supreme Court in 2013, which voted unanimously that, “’naturally occurring’ human genes cannot be patented.”