*The Queen of DNA*

Prof. Mary-Claire King, one of the world’s leading medical geneticists and a good friend of Israel, has won a prestigious award that often leads to the Nobel.

By JUDY SIEGEL-ITZKOVICH
PROF. MARY-CLAIRE KING (left) and PROF. EPHRAT LEVY-LAHAD (photo credit: JUDY SIEGEL-ITZKOVICH)
PROF. MARY-CLAIRE KING (left) and PROF. EPHRAT LEVY-LAHAD
(photo credit: JUDY SIEGEL-ITZKOVICH)
She concedes that she was pretty good at math but not enough for a career as a theoretician, did not do well in laboratory work and lacked the drive and interest to become a physician. But Prof. Mary-Claire King is one of the leading human geneticists and cancer researchers in the world, having made three breakthrough discoveries that have become axiomatic and changed the world.
An admirer of the State of Israel who has conducted joint research with researchers here for two decades, the eminent geneticist will this week receive the prestigious $250,000 Lasker Foundation’s Lasker-Koshland Special Achievement Award in Medical Science, which is reserved for people of Nobel Prize caliber.
The American Cancer Society Professor in the departments of medicine (medical genetics) and genome sciences at the University of Washington’s School of Medicine, she studies the genetics and interaction with the environment on breast and ovarian cancer, schizophrenia, inherited deafness and other conditions of newborns. Each of her major discoveries would have been enough for any single scientist, but the 68-year-old King managed to make her triple mark: She discovered that man and chimpanzees share 99 percent of their genes; she helped to match up 114 families whose grandchildren were kidnapped by the military during the “Dirty War” between 1978 and 1983; and she discovered the BRCA1 gene that causes inherited breast cancer.
She is even the model for a leading character in a recent Hollywood movie called Decoding Annie Parker – with Helen Hunt playing her role. It relates the story of two women − Annie Parker, who is diagnosed with breast cancer after her mother and sister both succumbed to the disease, and Mary-Claire King. The women’s lives gradually intersect over 15 years. Surprisingly, the scientist was not consulted or even informed about the movie in advance. “I learned about it by accident after it was completed. By law, if they use you as a character, they can do it without permission if they use only public aspects of my life.”
The movie trailer, she recalled, was well photographed. Most of it is about the empowerment of a young, working-class woman. But I worried about the scientific aspect, and indeed, if you’re looking for understanding for the genetics, don’t go to see it. A Washington Post reviewer suggested that I deserved a movie myself,” she recalled with amusement.
After serendipity introduced her to Tel Aviv University geneticist Prof. Karen Avraham and Shaare Zedek Medical Center’s medical genetics institute director Prof. Ephrat Levy-Lahad in 1995, King has visited Israel about once and sometimes even twice a year. “It had never occurred to me to visit Israel, she told The Jerusalem Post in an extensive interview together with Levy-Lahad. “After one visit, I was completely sold.”
After being the star speaker at SZMC’s second annual breast cancer symposium last week, she intended to stay on to attend the wedding of Levy-Lahad’s daughter Karney, but had to return to receive her Lasker award in New York the same day.
BUT PERHAPS the most emotional genetics discovery that King made was her own: While raised as a Christian and not halachically Jewish, she learned by a chance encounter with a dictionary at parents’ home that her maternal grandfather was a Jew, in fact of the priestly tribe, and named Louis Cohen. He was a department store salesman and let go early in the Depression in the 1930s.
“I was on a vacation while studying in graduate school in the mid-60s and visited my parents’ home in Chicago. As I had moved everything to the University of California at Berkeley, I looked for a dictionary on the shelves and came upon a Webster’s from 1934. On the front page, the name ‘Clarice Cohen’ was written. As I had thought my mother’s name was Clarisse Gates, the first thing I thought was that my mother had been married before.”
Questioning her in the kitchen about this, Mary-Claire asked her if she had been named Cohen. “The glass she was holding dropped and shattered.” Her mother insisted: “You must never tell that to anyone!”
King learned that her grandfather Louis married a Christian woman, also named Clarice. “They lived in Tulsa, Oklahoma, and in the 1920s, the Ku Klux Klan was very powerful. There was a nearby segregated town where middle-class blacks lived. When my mother was a girl of six, the Klan burned the homes of their black neighbors; many fled. After her family helped the black neighbors, the racist organization burned crosses on their lawn. She was scarred by this. I asked: ‘Why didn’t you tell me?”
Her mother responded: “They’ll find us. You don’t know how bad it was in the South.”
“But there is no more Ku Klux Klan,” I said.
“Yes, there is, but they don’t wear sheets anymore.”
When her mother applied to Ivy League colleges as a young woman, she was always told: “We have filled our quota for Jewish ladies, so we can’t admit you,” A friend suggested she apply to the University of Chicago, and she was accepted.
King, who got her surname from her father, feels an “emotional and intellectual connection on an intuitive level” to the Jews. “I know some ancient Jewish history from the Bible and, of course, modern Jewish history, but not that of the medieval and Renaissance periods.”
The first member of her family to reach higher education, King as born the Illinois suburb of Wilmette. “My father was born on a farm in Michigan at the end of the 19th century. He was much older than my mother, who was his second wife. King’s younger brother, however, studied math at Princeton and the Massachusetts Institute of Technology. “Paul is very bright. When I took the Putnam Exam in math in my senior year in high school, I was proud of myself for being in the top 10%. But then, he was number 10! He went into business and was very successful. He retired at 50 and is involved in philanthropy, for chamber music and for conservation. He’s also a bird lover, so I hope one day he will come with me to Israel, and we’ll visit the migrating cranes and other species.” King’s daughter Emily works in Berkeley, California for the local humane society and is responsible for the adoption of animals.
ALTHOUGH KING had never thought of going into cancer research, the traumatic death of her best friend, a 15-year-old girl named Debbie, triggered her thinking about it. “We had been together since kindergarten. She had Wilms’ tumor, a rare kidney malignancy that primarily affects children. Today, it’s curable, but she was never told it was cancer, so I didn’t know either. She was in the hospital a lot, and her parents encouraged her to be active. She developed a bone metastasis, and her leg was amputated. Then one day, I cam home from school and my mother told me Debbie had died.” I thought something needed to be done but at that point couldn’t think what to do.
After attending Carleton College, a liberal- arts college in Minnesota, and majoring in math, she went on to study statistics at Berkeley. “It was years before I saw a connection between math and cancer,” she recalled. Taking a genetic course from Curt Stern inspired her to transfer into genetics. “I had never studied biology, but genetics as fascinating. I thought to myself – it’s fabulous that people do this for a living.” Her doctoral studies with Allan Wilcon were the discovery that human and chimpanzee genes are 99% the same. King’s work supported Wilson’s view that the two primates diverged only five million years ago. The physical and other differences, suggested Wilson and King, was due to gene regulation; they made chimps’ arms longer and human brains more developed. “A relatively small number of changes in regulation in different organ systems and different time of development are responsible.”
For a while, she left graduate school to work with the famous American political and consumer-protection activist, author, lecturer and attorney Ralph Nader. In 1976, King accepted a faculty appointment at Berkeley in genetics and epidemiology and remained there until 1995.
Interested in human rights, she began working in 1984 with the Grandmothers of Plaza de Mayo in identifying children who had been stolen from their families and adopted illegally under the military dictatorship. King integrated several genetic identification techniques to match up children with their biological families.
“Mothers were killed, many shortly after delivering their babies. The grandmothers organized after hearing that these infants were kept alive. My task was very difficult, as it required matching children to grandparents, not parents. I started with HLA (human leukocyte antigen) testing for reconstructing genotypes. It worked very well for the first cases, but not so without four living grandparents,” said King. Mothers pass on their mitochondrial DNA. We combined that technique to sequence DNA and polymerase chain reaction (PCR) to amplify one or a few copies of DNA into thousands of copies. We put two and two together to determine relationships between grandmothers and even maternal aunts and uncles who were looking for their grandchildren.”
The latest case was solved only a few weeks ago, when a young man who suspected he was one of the kidnapped grandchildren came forward and asked to be tested. “He matched 83-year-old Estela Carlotto and is ‘Grandchild Number 114’; she had never met him before.”
In the late 1980s, King and her colleagues extended this new technique to identification of human remains. “We extracted DNA from the pulp of teeth taken from corpses.
“We used a sterile cleaver to open each tooth and remove the pulp. Then we matched the DNA with that of surviving relatives.”
Now, she said, this technique is used everywhere, including after the September 11 terror attack in New York. “We also used this approach after the1994 bombing of the AMIA Jewish cultural center in Buenos Aires that killed 85 people.” The genetic detective work was “very challenging. We had burnt pieces of bone. We worked on each separately and tried to extract DNA and compare sequences, all by hand. All of the victims were ultimately identified, and we were able to help.”
KING’S 16 years of work at Berkeley on discovering and sequencing the BRCA1 gene has revolutionized the prevention and early treatment of hereditary breast cancer. In 1990, she finally showed that the gene, named BRCA1 for “breast cancer” (and “Berkeley, California”), was responsible for inherited breast and ovarian cancers in some families. The gene was cloned four years later by another team, and the BRCA2 mutation was discovered and clone in yet another lab.
Before King discovered the gene, which with BRCA2 cause an 80% life risk of the tumors, most geneticists thought that breast cancer resulted from multiple genes interacting with environmental influences. But based on her work, she was certain that in certain families, there was a direct genetic link for breast cancer.
“Today, every time I learn now of young woman carrier who died of breast or ovarian cancer, I feel like I’ve been stabbed in the gut. It didn’t have to be. If they knew, they could act on it. They could have their ovaries removed (oophorectomy), which greatly reduces not only the risk of ovarian cancer but also breast cancer, as it significantly cuts the amount of natural estrogen in their bodies. Replacement estrogen for those without ovaries doesn’t have be nearly as high. I think it is best for young women to be tested at about age 30. Those who learn they carry a BRCA1 or BRCA2 mutation need a 10-year plan to consider intense examination of the breast, risk reducing surgical removal of the ovaries, and/or mastectomy.
Only last week, her friend Levy-Lahad and her research team, including King, published a breakthrough study in the Proceedings of the [US] National Academy of Sciences (PNAS) recommending that all Ashkenazi Jewish women undergo testing for BRCA1 and 2 from the age of 30 instead of only if a blood relative or the women themselves contract breast cancer.
“My father as a math professor, and I learned that experiments usually don’t work. You have to enjoy the process, and sometimes there are successes,” said the SZMC geneticist. She noted that while neither she nor King ever suffered from overt discrimination as women scientists, it is harder for women because they usually have families. “After getting a doctorate, Israelis are expected to go abroad for a post-doctorate. It is hard to move one’s whole family. The research community here is too small and insular. You have to go abroad to the big world and get a wider perspective and make connections and collaborations,” said Levy-Lahad.
King donated a $25,000 prize that she received from the Weizmann Institute of Science in Rehovot to help young women scientists arrange family life to go abroad for a post-doc. She recommends that the Israeli government invest more in scientific research infrastructure and manpower. “It’s a false economy not to do it. If you invest in bright people, it pays off. The Gulf States have a lot of money and import scientists and doctors, but that does not create innovation among their own people.”
King has close friends among Palestinian scientists on the West Bank and visits them when she comes to Israel. She has also been to Kuwait, and she made a trip with Levy-Lahad to Egypt. “I don’t feel like I’m caught in the middle. My role is not to make political statements, but to do what I can to help good scientists to work together.”
Asked if she had any professional regrets, King said: “If I knew then what I know now, I probably would have studied medicine as well as basic science. I see the kind of wisdom that people with medical training bring to scientific problems. You learn a lot by working both with patients and in the lab.”