Gene detective solves medical mysteries

US pioneer in the use of gene technology was recently awarded the Women & Science Award from the Weizmann Institute.

genetics 88 (photo credit: )
genetics 88
(photo credit: )
It was the death from kidney cancer of her 15-year-old girlfriend, Debbie Williams, that planted in the mind of Mary-Claire King the seed of interest in researching cancer when she was growing up in a Chicago suburb in the early 1960s. But despite this tragic loss, mankind benefited when King - one of the world's most noted experts in genetic epidemiology and cancer and evolutionary biology - learned firsthand the effects of malignant disease. "She must have been diagnosed with Wilm's tumor, the most common kind of kidney cancer in children, when she was seven. She had to have a leg amputated before she died," recalled King 45 years later, in an interview with The Jerusalem Post. "It seemed so unfair. It wasn't a conscious decision, but I said to myself, something needs to be done." She rushed back from Israel to New York last week to receive the $25,000 Women & Science Award from the Weizmann Institute of Science in a ceremony at Rockefeller University. "Widely respected within the scientific community, her monumental accomplishments have the potential to improve the quality of life for millions. She embodies the spirit of the Weizmann award, and is a superb role model for young women," the Rehovot institute stated when announcing the award. King, a powerful advocate of women in science, revealed to The Post that she is donating the money to cover the expenses of young Israeli women researchers who will spend summers at the University of Washington in Seattle. King, for the past 11 years the American Cancer Society professor of medicine and genetics at the University of Washington and last year elected to the US National Academy of Sciences, is responsible for three major findings that are so significant that even laymen have heard of them: In 1990, she mapped the BRCA1 gene that predisposes to breast cancer, which has led to direct diagnosis of the five to 10 percent of breast cancer that is hereditary and alerted carriers in advance. The gene that she spent 17 years identifying was isolated four years later by Myriad Genetics and Mark Skolnick of the University of Utah - but without King's monumental work, that would have been impossible. More recently, a second mutant gene, called BRCA2, has also been linked to hereditary breast cancer; this took two years to map, in 1994, and only one year to clone. Now families carrying one of the genes can be monitored to detect the first signs of breast and ovarian cancer, and even to prevent the development of ovarian cancer by undergoing surgical removal of their ovaries when they have finished having children. KING'S DOCTORAL thesis at the University of California at Berkeley revolutionized evolutionary biology when, through comparative study of proteins, she proved that human and chimpanzee genomes are 99% identical. This places the divergence of the two species from a common ancestor at about five million years ago, rather than the 10 million previously thought. And she developed (with Christian Orrego) a highly efficient and accurate way to identify people - or their remains, including teeth and bones - by comparing even minuscule amounts of their DNA to that of relatives. She used this tool, today routinely employed in forensic medicine and paternity suits, to match up Argentinian grandmothers who protested in the Plaza de Mayo three decades ago when the country was ruled by a dictatorship. The grandmothers, many of them Jewish and political dissidents, were demonstrating against the kidnapping and murder of their adult children, leaving their young grandchildren to be illictly adopted by military and police officers. "In the first cases, the grandmothers had a very good hypothesis of who the children were," King relates. "Argentinian military parents brought children with phony birth certificates for kindergarten registration. The grandmothers knew the ages of their missing grandchildren. Pregnant women had been kidnapped, and midwives or obstetricians were blindfolded and told to deliver babies with a warning not to talk about it later, but many did, and I know of at least one who was shot for supplying the information." BEFORE KING developed her technique, there was a DNA fingerprinting method, but it didn't work well to determine who was a grandparent. The dictatorship would not allow these grandparents to take custody of their grandchildren without "proof" of kinship, but King provided it in the form of a blood test, using genetic markers and mitochondrial DNA sequencing that established with 99.9% certainty whether a given grandparent was in fact related to a given child. "We couldn't use bones, because they are porous, and a lot of hands had touched them. We took the inside of teeth, the pulp, where DNA is very concentrated." As a result of King's work, dozens of families have been formally reunited. A fighter for human rights, King and her lab have become the DNA identification base for the United Nations War Crimes Tribunal. She has been praised by colleagues for this contribution to DNA forensics as having "only intellectual insight and technical acumen, as well as an uncommon caring for people, courage and conviction." King's work, which has shown how genetic technology can directly benefit humanity, demonstrated the technical power and accuracy of DNA forensics. It also became the basis for routine identification of soldiers' remains (including the previously "unknown" Vietnam War soldier at Arlington National Cemetery in Washington, D.C.), and more recently in every kind of mass genocide or disaster. Not surprisingly, this brilliant scientist has some Jewish ancestors. "My mother's father was a Jew of the priestly tribe, a Kohen. It didn't know it until I was an adult. My maternal grandfather's parents immigrated to New Orleans in the 1890s from the Pale of Settlement in Europe. But I am not Jewish." With her husband, ecologist Robert Colwell, she had a daughter named Emily. She visits Israel often, having just made her sixth trip in a decade. She came this time to attend the Tel Aviv University's Center for Middle Eastern Genetic Diseases' first annual conference and lecture about her collaboration with Israeli researchers on inherited breast and ovarian cancer. And she came to Jerusalem's Shaare Zedek Medical Center to see one of her friends and collaborators, Prof. Ephrat Levy-Lahad, director of the hospital's medical genetics unit. King is, with Tel Aviv University geneticist Prof. Karen Abraham, also working on the mapping and cloning of a gene that causes congenital deafness In Israeli Arab and Palestinian and Israeli Jewish families. King was not attracted to the study of medicine. She followed her natural interest in solving puzzles and mysteries. "I started with mathematics. Those who did not go into genetics from medicine came through mathematics. Genetics became analytical with my generation," says King, who earned her BA with honors in math from Carleton College in Minnesota just before she was 20. She halted her doctoral studies at Berkeley for a year to perform environmental research for consumer advocate Ralph Nader and protest against the Vietnam War, but in 1973 returned to complete her doctorate in genetics and epidemiology. Back in 1974, King began to study the DNA of families to try to find out whether breast cancer - especially that diagnosed at relatively young ages - might be hereditary. Her colleagues were skeptical, insisting that an indefinable combination of genes and environment were the cause. Conducting painstaking research for many years, King searched for a genetic "marker" - an identified gene that tends to accompany the gene being searched for - that would flag the presence of the hereditary breast cancer gene in a chromosome. In 1990, after assessing 183 possible markers, King and her team found the right one - on Chromosome #17. They also discovered that the marker is linked to a gene responsible for a number of different inherited breast and ovarian cancers. One woman in 200 inherits the gene responsible for breast cancer, but those who do inherit it have an 80% to 90% chance of developing the disease. A single copy of the gene inherited from either parent increases cancer risks substantially. Men who inherit the gene have a slightly greater risk of pancreatic cancer and less than twice the normal risk of prostate cancer at older ages. She believes that in the near future a "molecular mammogram" will be available to detect altered cells years before they develop into a tumor large enough to be detected by a mammogram. Her research has also provided geneticists with insights into the nature of cancer-caused genetic mutations in general. King has used BRCA1 to develop a number of cancer testing, screening and therapeutic procedures; for these, she has earned one patent and has others pending. "There are thousands of mutations for each of these genes," King explains. "Because Jews of European origin have such a small number of founders and were isolated for many generations, the number of mutations in this population is limited. In England, for example, and in the US, there are many more because of mixed ancestry. So although Ashkenazim are only slightly more likely to have the BRCA mutation than others, it's easier to determine the gene defects in Ashkenazi Jews." KING AND Levy-Lahad are working together to try to find additional genes that cause breast cancer n Ashkenazi Jews; specifically, they are testing mothers and daughters in New York and Israel who have had breast cancer. "Most risk studies are based on models, but we decided to test people," says the Shaare Zedek geneticist. "We are taking 1,000 women with breast cancer to see how many have mutations. Our problem is that Israeli Ashkenazi families are smaller than counterparts in the US because the Holocaust wiped out many cousins and other relatives. Whole branches of living Jewish families here don't know their complete medical history." Women with a BRCA mutation should undergo oophorectomy (prophylactic removal of their ovaries) when they have finished having children, Levy-Lahad advises. "You can kill two birds with one stone, as you reduce your ovarian cancer risk by 95% and your breast cancer risk by 50% because ovaries produce estrogen, which promotes it. But the vast percentage of women don't go for prophylactic surgery unless they have breast cancer on one side." Levy-Lahad recalls one breast cancer patient she tested for the gene, who absolutely refused to come back for her results. Six years later, the medical geneticist called her to ask how she was. "I realize that I should have my ovaries removed," said the woman, now 47, who understood without being told that she had the defective gene. But Levy-Lahad notes that the woman never made an appointment. "Recently I learned she was diagnosed with advanced ovarian cancer; she had never had them removed. I understand her reluctance, but it would have saved her," she concluded.