2014 Lasker~Koshland Special Achievement Award in Medical Science

Breast cancer genetics and human rights

The 2014 Lasker~Koshland Award for Special Achievement in Medical Science honors a scientist who has made bold, imaginative, and diverse contributions to medical science and human rights. Mary-Claire King (University of Washington, Seattle) discovered the BRCA1 gene locus that causes hereditary breast cancer and deployed DNA strategies that reunite missing persons or their remains with their families. Her work has touched families around the world.

As a statistics graduate student in the late 1960s, King took the late Curt Stern's genetics course just for fun. The puzzles she encountered there — problems posed by Stern — enchanted her. She was delighted to learn that people could be paid to solve such problems, and that mathematics holds their key. She decided to study genetics and never looked back.

During her PhD work with the late Allan Wilson (University of California, Berkeley), King discovered that the sequences of human and chimpanzee proteins are, on average, more than 99 percent identical; DNA sequences that do not code for proteins differ only a little more. The two primates therefore are much closer cousins than suggested by fossil studies of the time. The genetic resemblance seemed to contradict obvious distinctions: Human brains outsize those of chimps; their limbs dwarf ours; and modes of communication, food gathering, and other lifestyle features diverge dramatically. King and Wilson proposed that these contrasts arise not from disparities in DNA sequences that encode proteins, but from a small number of differences in DNA sequences that turn the protein-coding genes on and off.

Just as genetic changes drive species in new directions, they also can propel cells toward malignancy. From an evolutionary perspective, the topic of breast cancer began to intrigue King. The illness runs in families and is clearly inherited, yet many affected women have no close relatives with the disease. It is especially deadly for women whose mothers succumbed to it — and risk increases for those who have a mother or sister with breast cancer, particularly if the cancer struck bilaterally or before menopause. Unlike the situation with lung cancer, no environmental exposure distinguishes sisters who get breast cancer from those who remain disease free.

By studying a rare familial cancer, Alfred Knudsen (Lasker Clinical Medical Research Award, 1998) had shown in the early 1970s how an inherited genetic defect could increase vulnerability to cancer. In the model he advanced, some families harbor a damaged version of a gene that normally encourages proper cellular behavior. Genetic mishaps occur during a person's lifetime, and a second 'hit' in a cell with the first physiological liability nudges the injured cell toward malignancy. A similar story might play out in families with a high incidence of breast cancer, King reasoned. She began to hunt for the theoretical pernicious gene in 1974.

The hunt

Many geneticists doubted that susceptibility to breast cancer would map to a single gene; even if it did, finding the culprit seemed unlikely for numerous reasons. First, most cases are not familial and the disease is common — so common that inherited and non-inherited cases could occur in the same families. Furthermore, the malady might not strike all women who carry a high-risk gene, and different families might carry different high-risk genes. Prevailing views held that the ailment arises from the additive effects of multiple undefined genetic and environmental insults and from complicated interactions among them. No one had previously tacked such complexities, and an attempt to unearth a breast cancer gene seemed woefully naïve.

To test whether she could find evidence that particular genes increase the odds of getting breast cancer, King applied mathematical methods to data from more than 1500 families of women younger than 55 years old with newly diagnosed breast cancer. The analysis, published in 1988, suggested that four percent of the families carry a single gene that predisposes individuals to the illness.

The most convincing way to validate this idea was to track down the gene. Toward this end, King analyzed DNA from 329 participating relatives with 146 cases of invasive breast cancer. In many of the 23 families to which the participants belonged, the scourge struck young women, often in both breasts, and in some families, even men.

In late 1990, King (by then a professor at the University of California, Berkeley) hit her quarry. She had zeroed in on a suspicious section of chromosome 17 that carried particular genetic markers in women with breast cancer in the most severely affected families. Somewhere in that stretch of DNA lay the gene, which she named BRCA1.

This discovery spurred an international race to find the gene. Four years later, scientists at Myriad Genetics, Inc. isolated it. Alterations in either BRCA1 or a second breast-cancer susceptibility gene, BRCA2, found by Michael Stratton and colleagues (Institute of Cancer Research, UK) increase risk of ovarian as well as breast cancer. The proteins encoded by these genes help maintain cellular health by repairing marred DNA. When the BRCA1 or BRCA2 proteins fail to perform their jobs, genetic integrity is compromised, thus setting the stage for cancer.

About 12 percent of women in the general population get breast cancer at some point in their lives. In contrast, 65 percent of women who inherit an abnormal version of BRCA1 and about 45 percent of women who inherit an abnormal version of BRCA2 develop breast cancer by the time they are 70 years old. Individuals with troublesome forms of BRCA1 and BRCA2 can now be identified, monitored, counseled, and treated appropriately.

Harmful versions of other genes also predispose women to breast cancer, ovarian cancer, or both. Several years ago, King devised a scheme to screen for all of these genetic miscreants. This strategy allows genetic testing and risk determination for breast and ovarian cancer; it is already in clinical practice.

Genetic tools, human rights

King has applied her expertise to aid people who suffer from ills perpetrated by humans as well as genes. She helped find the "lost children" of Argentina — those who had been kidnapped as infants or born while their mothers were in prison during the military regime of the late 1970s and early 1980s. Some of these youngsters had been illegally adopted, many by military families. In 1983, King began identifying individuals, first with a technique that was originally designed to match potential organ transplant donors and recipients. She then developed an approach that relies on analysis of DNA from mitochondria — a cellular component that passes specifically from mother to child, and is powerful for connecting people to their female forebears. King helped prove genetic relationships and thus facilitated the reunion of more than 100 of the children with their families.

Later, the Argentinian government asked if she could help identify dead bodies of individuals thought to have been murdered. King harnessed the same method to figure out who had been buried in mass graves. She established that teeth, whose enamel coating protects DNA in the dental pulp from degradation, offer a valuable resource when attempting to trace remains in situations where long periods have elapsed since the time of death.

This and related approaches have been used to identify soldiers who went missing in action, including the remains of an American serviceman who was buried beneath the Tomb of the Unknowns in Arlington National Cemetery for 14 years, as well as victims of natural disasters and man-made tragedies such as 9/11.

Mary-Claire King has employed her intellect, dedication, and ethical sensibilities to generate knowledge that has catalyzed profound changes in health care, and she has applied her expertise to promote justice where nefarious governments have terrorized their citizens.

by Evelyn Strauss

Key publications of Mary-Claire King

King, M.-C. and Wilson, A.C. (1975). Evolution at two levels in humans and chimpanzees. Science. 188,107-116.

Hall, J.M., Lee, M.K., Morrow, J., Newman, B., Anderson, L.A., Huey, B., and King, M.-C. (1990). Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 250,1684-1689.

King, M.-C. (1991). An application of DNA sequencing to a human rights problem. Mol. Genet. Med. 1, 117-131.

Ginther, C., Issel-Tarver, L., and King, M.-C. (1992). Identifying individuals by sequencing mitochondrial DNA from teeth. Nature Genet. 2,135-138.

Friedman, L.S., Ostermeyer, E.A., Szabo, C.I., Dowd, P., Lynch, E.D., Rowell, S.E., and King, M.-C. (1994). Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nature Genet. 8, 399-404.

King, M.-C. (2014). "The race" to clone BRCA1. Science. 343, 1462-1465.

Award presentation by Marc Tessier-Lavigne

Pioneering scientist, social activist, humanitarian — Mary-Claire King is also foremost a free spirit who for over four decades has marched to the beat of her own drummer, animated by the impulse to solve iconic scientific puzzles, a passion for victims of disease and social injustice, and a warm humility that belies her profound impacts on science, on medicine, and on society.

Perhaps because I'm from Canada, when I think of Mary-Claire, the person who comes to mind is Wayne Gretzky, the hockey great with the most career assists and goals, who was a master of the hat trick — scoring three or more goals in 50 games. Now, all scientists strive to contribute lasting findings to our body of scientific knowledge — important assists, if you will. Most also aspire to make at least one discovery that changes the way we think or that has a direct tangible effect on their fellow humans — to score a goal. Few succeed, of course, in these loftier aims, and even fewer score more than one goal. Mary-Claire is the rare scientist to have scored a hat trick, with major impacts in at least three fields — evolutionary genetics, medical genetics, and molecular forensics. Like the Great One himself, Mary-Claire is in a league of her own.

Trained in mathematics, Mary-Claire began her unconventional trajectory through biological science as a graduate student in statistics at Berkeley in the early '70s. There, realizing that statistics could help solve problems in genetics, she switched fields, joining the laboratory of Allan Wilson. With a flair for tackling the biggest, most foundational problems, she sought to determine the degree of identity between the genes of humans and chimpanzees. This was long before direct sequencing of DNA made it possible to compare genomes in detail.

Even so, she applied statistical analysis to what data she and others could generate on proteins and DNA molecules from the two species and made the startling discovery that they are more than 99% identical — much closer than previously thought. The genetic similarity seemed to contradict anatomical and behavioral distinctions, leading her and Wilson to propose that the marked divergence arose not from markedly divergent DNA sequences, but rather from a small number of mutations affecting gene regulation — a theory at the center of current evolutionary thinking. The ramifications of her findings for how we think about ourselves were so profound that the two ended up celebrities, on the cover of Science magazine.

It's hard to believe that this discovery could be topped, yet that's exactly what she achieved. Returning from teaching abroad — more on this later  Mary-Claire accepted a research position to study breast cancer and proceeded to do what she does best: she thought hard and unconventionally about how to make a contribution. Thus began a seventeen-year odyssey that led her to discover the first gene defect that predisposes to breast cancer. What was revolutionary about her finding is that breast cancer is a common complex disease, and the prevailing view was that such diseases arise from interactions among multiple genetic and environmental factors. But Mary-Claire was intrigued by hints that there might be inherited forms of the disease and tested this head-on by studying over 1500 families in which multiple members were affected by breast cancer. She showed mathematically that clustering of cases could be best explained by the presence of a disease gene in a very small fraction of families. Yet the field remained skeptical, so to convince skeptics, she set out to determine where the hypothetical gene resides in our DNA, working at the cutting edge to apply tools for gene mapping that were just being developed.

The work culminated in 1990 in her demonstration that in selected families in which breast cancer appeared to strike early, inheritance of a small stretch of DNA conferred a hundred-fold greater risk of breast cancer, leading her to predict existence of a susceptibility gene in that region, which she named BRCA1. Her announcement electrified the community, converted even the most hardened skeptics, and set off a race to isolate the affected gene. The isolation of BRCA1 — and its close relative BRCA2 —made it possible to diagnose whether a woman in an affected family is at high risk of developing breast cancer and for her to seek prophylactic treatment, as recently highlighted by Angelina Jolie.

Just as important, the innovative approach Mary-Claire took — that is, to focus on specific families with striking inheritance patterns of particular forms of a common disease — was a methodological breakthrough that has provided a roadmap for isolating genetic forms of other common diseases.

Mary-Claire also had her third big win in that same period. She always possessed a strong sense of social justice and had embraced activism, for example in protesting the war in Vietnam. She had also developed an affinity for Latin America, spending time teaching in Chile after her PhD. There she witnessed the 1973 coup that overthrew the Allende government and led to incarceration or death of many government supporters, including some of her acquaintances. It's perhaps no coincidence, then, that when approached later, she was moved to help address the problem of identifying the families of young children in Argentina who had been kidnapped and given to military families during the dictatorship there.

In 1984 she reported a first method to help match children with surviving relatives based on a blood test. In doing so, she was a forerunner in the nascent field of molecular forensics. She soon conceived an even more powerful test, based on mitochondrial DNA, that has been used in matching many more children to relatives and is widely used for identification of human remains, including the previously 'unknown soldier' entombed at Arlington, as well as other soldiers and victims of executions around the world.

What made it possible for Mary-Claire to score so big in three fields? Wayne Gretzky famously said that his success was due to his ability to skate to where the puck is going to be, not where it has been. Mary-Claire's farsightedness in entering new fields where she sees big opportunities likewise seems to be her secret weapon. Gretzky was also fond of saying that you miss 100% of the shots you don't take. Mary Claire's drive to keep taking shots on goal — her relentless probing and her fearlessness in entering new fields — also helps explain both her past successes and her staying power, as she continues to make fundamental contributions to both science and to society, including on the genetics of deafness and schizophrenia, and in fostering interactions between Israeli and Palestinian scientists.

Mary-Claire King is a role model for how a brilliant scientist who remains curious, courageous, driven, and compassionate, can multiply her impact in a truly magnificent way. Science and society are the great beneficiaries of Mary-Claire's passion, for which we are all most grateful.

Mary-Claire King

Acceptance remarks, 2014 Lasker Awards ceremony

Nature Medicine Interview


One of the many pleasures of being chosen for the Lasker~Koshland Award is the realization that I am part of a culture of science and that the community that makes up this culture considers me a part of it. It may be that some scientists come to this realization very young; it has taken me far longer. So as a result, I've been musing about this culture, what it means to us, and what we've gotten ourselves into.

The central feature of life in science is that we want to be here. We enjoy this life. Science is fun. Genetics is enormous fun. It allows us to be imaginative and creative in an elegant way. It is work for a greater good, yet appeals to our curiosity and to our pleasure with puzzles solved. The work is useful and valued by society. What more could we ask?

In genetics, each new discovery is opening a gift box from Nature. We can understand the pleasure that discovery holds for other geneticists, even those we never met. My work draws directly on results from Gregor Mendel, Charles Darwin, and Paul Broca. I can see exactly what excited them about patterns: revealed to Mendel by shapes and colors of peas, to Darwin by shapes of bills and feathers of finches, and to Broca by shapes of the brain and clustering of breast cancers in families of his patients. I wish for them only that they had known each other. From the 1840s through the 1870s, Mendel was working in Brno, Darwin in Kent, and Broca in Paris. Broca was an admirer or Darwin's work and a member of a society of free thinkers devoted to the study of evolution. But none of the three met each other. Imagine if they had had Skype.

150 years later, it is our extraordinary luck to be working in a revolutionary period in genetics. It's irresistible not to succumb to a sense of unlimited horizons. Every result, regardless of gene, pathway, or organism is part of a whole story that will eventually make sense to us. The lesson of evolution is that the natural world is ordered and that people can figure it out.

Sometimes students ask whether genomics hasn't replaced genetics — whether genetics isn't old hat, displaced by spiffy new technology. It hasn't and it isn't. Genetics is a way of thinking; genomics is a set of tools. The questions geneticists ask now are the same as those asked by Mendel, Darwin, and Broca. The questions go to the nature of life and the meaning of being human. What has changed is our capacity to answer them. In genetics, there are difficult questions and incredibly difficult questions, but we do not acknowledge any unanswerable problems. Genetics as a way of thinking enables us to frame questions in a testable way, while genomics offers a means to carry out the tests.

To me the greatest challenge of new discovery is framing questions in ways that are meaningful both to the scientist and to the larger community. In my efforts to do this, I am guided by three principles first suggested to me almost 40 years ago by Zena Stein:
The most important questions come from people on the frontlines.
The most righteous projects demand the most rigorous science.
No question is too big to ask.
Thank you very much.

Key publications of Mary-Claire King

King, M.-C. and Wilson, A.C. (1975). Evolution at two levels in humans and chimpanzees. Science. 188,107-116.

Hall, J.M., Lee, M.K., Morrow, J., Newman, B., Anderson, L.A., Huey, B., and King, M.-C. (1990). Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 250,1684-1689.

King, M.-C. (1991). An application of DNA sequencing to a human rights problem. Mol. Genet. Med. 1, 117-131.

Ginther, C., Issel-Tarver, L., and King, M.-C. (1992). Identifying individuals by sequencing mitochondrial DNA from teeth. Nature Genet. 2,135-138.

Friedman, L.S., Ostermeyer, E.A., Szabo, C.I., Dowd, P., Lynch, E.D., Rowell, S.E., and King, M.-C. (1994). Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nature Genet. 8, 399-404.

King, M.-C. (2014). "The race" to clone BRCA1. Science. 343, 1462-1465.

 

Interview with Mary-Claire King

Image Credit: Susan Hadary