Pandora's DNA: Tracing the Breast Cancer Genes Through History, Science, and One Family Tree

by Lizzie Stark

  I paged through a bunch of things that didn’t interest me—medical papers detailing my mother’s treatments and family trees—until I lit on a piece of personal correspondence she’d written to one of her friends in Texas. We’d lived in Dallas until I was five, and my mother had run in the very first Susan G. Komen Race for the Cure there in 1983, only months after finishing breast cancer treatment. As she wrote to me years later, since then “I have been able to do all the things I love—hug my daughter, play tennis, garden, shake my fist at injustice—all sorts of things.” We’d moved to Washington, DC, in 1986, though of course my mom still had friends back in Texas. In 1991, when I was ten, she’d written a letter to one, a politician who briefly sat on one of the Susan G. Komen boards. My mother begged the woman to vote to fund research into the new so-called breast cancer genes, not on behalf of herself but on behalf of her ten-year-old daughter—me. Reading this letter nine or ten years later scared me. I’d stumbled onto something unexpectedly personal and intimate, proof of my mother’s love and of her fear. She must have been so scared for me. I cried over the note but put it carefully back in the file and said nothing.

  While my mother wondered what might be in our genes, an extraordinary scientist and human being had already made possible this search for the specific BRCA mutations. So let us sing the praises of Mary-Claire King, scientist and citizen, whose humanity and goodwill toward others is well known, whose deep engagement in the world has reunited families and revolutionized genetics, a remarkable woman of uncommon scientific stamina and ambition.

  I’ve never spoken with Mary-Claire King, but as you might have guessed, I’m a bit in love with her from afar, sort of in the same way I’m in love with Dorothy Parker and Susan B. Anthony, a distant lady crush sparked by reading her words and about her work. Mary-Claire King is the Eleanor Roosevelt of science—an advocate for social justice and human rights, a prolific contributor to her chosen field of genetics, and an inspiring feminist. Mary-Claire King once turned down a shot at the directorship of the National Institutes of Health (NIH) because she thought it would take her away from her addiction, the daily practice of science! Mary-Claire King puts a premium on hiring women and ethnic minorities and supports the new mothers who work for her by providing pumping space in the lab! Mary-Claire King is fostering a rare scientific collaboration between Israeli and Palestinian scientists seeking a gene for inherited deafness! Mary-Claire King once single-handedly wrestled a newborn rabbit away from a gorilla! OK. So maybe that last one isn’t true. Although her résumé is full of accolades and impressive finds, she’s best known for three scientific feats.

  She performed the first one in the 1960s and 1970s while still in graduate school at Berkeley, where she initially studied mathematics. While there, she met anthropological geneticist Allan C. Wilson, a renowned scientist who would later become famous for his work on mitochondrial Eve—the hypothesis that all humanity descended from a single woman, “Eve,” who lived more than a hundred thousand years ago. Mitochondria live inside all of our cells and are responsible for creating the energy that each cell uses. They also have their own DNA that is distinct from the DNA in the cell nucleus. And we inherit our mitochondrial DNA from our mothers only—sperm do not contain mitochondria, but eggs do. In this way, matrilineal lines may be traced by examining this unique form of DNA, a fact King would later put to good use. Wilson’s theoretical and experimental discovery of mitochondrial Eve earned him worldwide recognition in the late 1980s. But back in the late 1960s and early 1970s, he convinced the young King to enter the bourgeoning field of genetics, and he advised her dissertation, which tackled another aspect of evolutionary genetics, namely, the similarity of human and chimpanzee DNA. Her doctoral research proved that the two species are 99 percent genetically identical, leading to the conclusion that it is not merely genetics that shapes our biological processes but a complicated system of timing, with cells turning proteins on and off at particular moments. King and Wilson published their results in Science in 1975 and earned worldwide recognition for the discovery.

  At the same time, working in the Wilson lab taught King many attitudes that would shape her practice of science for decades to come. Wilson taught her to be “very methodical and very self-critical” but to trust absolutely in the data unless someone else had better data that proved her wrong; he also taught her to never let anyone intimidate her. As she told an interviewer years later, “You did not grow up in the Wilson lab thinking that you were right! We were extremely critical of ourselves and of each other. Persistence was also part of the culture of the Wilson lab and it is part of me.” Working with Wilson taught her to become comfortable living with years of uncertainty—to me it sounds a bit like living with a BRCA mutation.

  At the same time, King was also deeply politically engaged as an activist agitating against the Vietnam War. As she told an interviewer more than four decades later, “I don’t indulge in nostalgia about that period because it was a terrible time for our country. It’s very American: When you see something wrong, you try to fix it.” The best thing the activists King worked with did, she said, was put on their professional clothes the day after the United States invaded Cambodia, “not clothes that any of us had worn since coming to Berkeley,” she noted. They marched down to synagogues and churches. “By the end of Sunday we had 30,000 letters opposing the action. It made it longer to get a dissertation done, but it was an interesting, intense time,” she said. At one point, she even dropped out of school briefly to work on an environmental project with consumer activist and later Green Party presidential candidate Ralph Nader. But in the end, research reeled her back in, and as it turned out, her political sensibility was eminently compatible with her scientific ambition.

  King once told an interviewer, “I’ve learned not to question the motives of bastards. They just do what they do, and you try to stop it.” And as it turns out, she can stop bastards—with science. The second major accomplishment in her lifetime achievement hat trick combines genetics with justice. After finishing her dissertation, King moved to Chile to teach genetics, a stint cut short when a military coup deposed the government of President Salvador Allende and killed him. Although King and her then husband, a zoologist, moved back to the States, the episode left her with an understanding of the political situation in parts of South America. Her genetic expertise and political sympathies soon converged with the needs of a civilian activist group in Argentina, the Abuelas de Plaza de Mayo, a group of grandmothers seeking their lost grandchildren.

  During the Dirty War of the 1970s, Argentina’s government—a dictatorship supported by the United States—“disappeared” thousands of so-called dissidents, including whole families with children. In some cases, the victims were pregnant women who were tortured and killed and who may have given birth in prison. Many of these taken or prison-born children—who would be about the same age as King’s own daughter—had been sold to or illegally adopted by junta supporters. In 1977 the Abuelas de Plaza de Mayo, the grandmothers of these children, banded together to find them; the group drew its name from the plaza where they protested in front of the junta’s headquarters in Buenos Aires. They began gathering data about children who might have been illegally adopted, and they searched for a geneticist, settling finally on Mary-Claire King. She was an ideal choice both because she had a connection to the region and because she had done work on human DNA. They asked her to produce a test that could prove a genetic connection between these kids and their grandparents. First, King developed a test using blood proteins to prove grandparentage, and later she worked on mitochondrial DNA testing, which could prove matrilineal descent. In 1984, the Argentinian Supreme Court ruled that a child identified by King’s test had to be returned to relatives, setting precedent for later reunions. In early 2014, the Abuelas found their 110th missing grandchild, though her grandmother had already died, according to the Abuelas’ press release. The identity of many of these children was confirmed through DNA testing
.

  King went on to develop a process to extract mitochondrial DNA from teeth, a useful tool for identifying bodies—many aged human remains don’t have enough skin or hair remaining to make DNA extraction possible, and DNA from bones is easily damaged. Watch out, murderous dictator bastards: her lab has helped UN war crimes tribunals identify remains of victims of violence in Cambodia, Guatemala, El Salvador, Rwanda, Ethiopia, and Bosnia. Though her lab operated for a time as the forensic lab for these tribunals, now that the science of forensic genetics has improved across the board, the King lab is mainly consulted for special cases. It has helped identify the remains of the Romanovs, the last czars of Russia, as well as MIA US soldiers from WWII, Korea, and Vietnam.

  When King undertook this forensic science project of social justice she was already deep into her research on genetics and cancer risk. The link between certain families and cancer had been known for more than a century. In 1866 Parisian surgeon Paul Broca—known primarily for his discovery of one of the brain’s language centers—had published a pedigree of one such family tree, going back four generations; the family was his wife’s. Of the twenty-six relatives she had over age thirty, fifteen of them—all women save one—had developed or died of cancer, a staggering 74 percent of the women and 14 percent of the men. In contrast, the rate of cancer in the general population at the time was about 3 percent. These numbers convinced Broca that cancer could be inherited, although the mechanisms of inheritance would remain opaque for a long time.

  An early study on hereditary breast cancer published in Denmark eighty years later would establish the process for studying cancer families. The study examined two hundred families and used the national cancer registry to help generate pedigrees—researchers tracked down relatives of those who suffered cancer. Finding patients, questioning them about their own cancer, seeking out distant relatives with disease, and finding their pathology or autopsy reports to verify the presence of cancer was time-consuming but necessary work. The study showed that women with a first-degree relative—parent, sibling, child—with breast cancer were at a higher risk of developing the disease, a conclusion that a similar 1948 British study confirmed.

  Yet hereditary breast cancer proved difficult to study. For starters, many scientists still doubted that cancer had any hereditary component. After all, families share much more than just DNA. A family of smokers might all develop lung cancer, but that wouldn’t necessarily make their disease hereditary—it could be that the parents passed on their pack-a-day habit to their kids. Or maybe they all lived on top of a landfill full of nuclear waste. Environmental and cultural causes made looking for hereditary disease tricky. So did the fact that most cancer is sporadic. Today, about one in three women and one in two men will develop some sort of cancer in their lifetimes, according to the American Cancer Society (ACS), so it makes sense that most families will have more than one case of cancer in them. But that doesn’t mean that these cancers are necessarily inherited—even cancer families have some cases of sporadic cancer. I have inherited breast and ovarian cancer syndrome in my family, but not all of the cancer in my family is linked to our BRCA mutation. My mother’s thyroid cancer, her father’s colon cancer, and on my dad’s side of the family, relatives with prostate, stomach, ovarian, and lung cancer all occurred independent of the Muehleisen curse. Those cancers are just the roll of the dice we all make by living. Inherited breast cancer was particularly confusing to study. Because breast cancer is one of the most common cancers in women, there are many families with multiple cases. And finally, as Ilana Löwy, senior researcher at the French National Institute of Health and Medical Research, reports, “Researchers initially confused two distinct phenomena—a relatively moderate (two-to threefold) increase of incidence of breast cancer in daughters or sisters of women diagnosed with this disease, and the existence of ‘breast cancer families’ with an exceptionally high frequency of this pathology.” For all these reasons—the commonness of sporadic cancer in general and the frequency of breast cancer in particular, the possibility that familial cancer might be caused by lifestyle or environmental factors, and the presence of two similar cancer syndromes—the whole issue was hard to study.

  Therefore, scientists needed large families because large sample sizes give more accurate predictions than small ones. If you do a poll at my house about the color of human hair, you’ll conclude that humans have dark hair, because that’s what my husband and I have. Poll my entire neighborhood, and you’ll have a much better idea. Hereditary cancer is relatively rare—searching for it meant looking for the proverbial needle in a haystack, or more accurately, the proverbial needle in a field of haystacks. Looking at large families gave researchers a better shot at examining the syndrome. If a couple has eight kids and seven of them end up with breast cancer, that family is probably better to study than a family with four kids and two cases of breast cancer. Sure, it’s possible that both families simply suffer from an unlucky bout of sporadic cancer, but if you’re looking for a familial link, it makes sense to study the ones that seem stronger first. The larger the family, the better, which meant painstaking research to trace familial cancer in large families over many generations, even before the human genome had been sequenced.

  Omaha physician Henry Lynch began collecting such pedigrees in the 1960s for colon and endometrial cancer. Colleagues in the field would dismiss and ignore his work for decades, until science’s growing knowledge of genetic sequencing improved and other theories of cancer transmission—such as the idea that it was caused by viruses—fell by the wayside. Lynch insisted that some cancers were hereditary and argued for preventive surgery as a treatment; eventually he became interested in breast cancer. By that time, in the 1970s, geneticists had already figured out that women from breast cancer families often developed the disease at unusually young ages and frequently suffered cancer in both breasts.

  Mary-Claire King joined the search for hereditary breast cancer in the mid-1970s and would spend most of the next two decades exercising the persistence she’d acquired in Wilson’s lab. She had a personal connection to cancer. Her best friend since the age of four had died from kidney cancer, when the girls were both fifteen, after a long painful battle with the disease, an unjust, too-young death that made a deep impression on King. Although she doesn’t have breast cancer in her own family, in 2004 she told the Chicago Tribune, “I was interested in it because it was a disease of women. I was interested in the familial form because it seemed to strike young women disproportionately.” And as she began her research, “it’s been very much a story about people I’ve come to care about enormously. The participants in this kind of work are very sophisticated about there being no quick answers.” An unabashed feminist, King speculates that the public feels so keenly about breast cancer because “almost uniquely among cancers, breast cancer is a cancer of women who are successful. The longer the interval between one’s first menstruation and first birth, the higher the subsequent breast cancer risk. It’s a cancer of women who are educated, who have children later in life. Whereas many illnesses are the consequence of poverty, breast cancer is closely tied to success.”

  While working on a project at the University of California, San Francisco, searching for risk factors linked to breast cancer, King had a eureka moment. She had pored over thousands of questionnaires filled in by breast cancer patients, trying to categorize all the different risk factors, when “I was struck by something that others had seen before and that seemed so obvious I couldn’t think of anything else,” she told author Michael Waldholz. Many of the women stricken also had a close relative with the disease. “Given my background [in genetics], it’s understandable that I homed in on inheritance.”

  In 1975 she landed a job at the University of California at Berkeley, thanks to the presence of the only woman on the hiring committee and to the new policies 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 becaus
e of all these new regulations, and we are really scraping the bottom of the barrel in hiring you.’ And I said, ‘We’ll see how long you feel that way!’ ” she told PLOS Genetics. Mostly, as she has told numerous interviewers, being a woman in a male-dominated profession helped her because other researchers didn’t see her as a threat. On top of this she was working in the unfashionable field of inherited cancer, which ran contrary to the current hot theory of viruses. As she told the Washington Post years later, “In retrospect, there was something liberating about being of no interest to the leaders of my field. If one is ignored, there are no expectations to meet. There was great freedom in being invisible.”

  King’s goal was to get enough good data about cancer families to build a testable mathematical model. So she found her way onto a National Cancer Institute study investigating whether birth control changed a woman’s risk for breast, ovarian, or uterine cancer and persuaded them to add a couple of questions about family history. “It wasn’t too long before the family history questions threatened to overwhelm the project! The interviews were fabulous, and we ended up with 1,500 pedigrees based on reports of cases and another 1,500 based on reports of controls,” she told an interviewer years later.

  King worked the case the old-fashioned way: with lots and lots of tedious work. Though we now know that humans have around twenty thousand genes, at the time King began her research we didn’t know what the upper ceiling was. Only a few hundred genes had been located on chromosomes, and only a fraction of those had been sequenced at all. So in order to prove that breast cancer risk could be genetic, King had to sequence an unknown gene on an unknown chromosome that was maybe or maybe not shared by members of large cancer families. First things first, though—she needed a bunch of huge cancer families to begin her research. Suddenly, Henry Lynch’s work in Omaha became a treasure mine.