The Wandering Gene and the Indian Princess

by Jeff Wheelwright

  If you ask people to name the greatest triumph of the DNA age, they probably will say the high-tech human genome project, not the discovery of BRCA1 and 2, the last great genes from the simpler world of Mendel. With each year that passes, the argument looks better for reversing that judgment, because BRCA has had a large impact on medical decision-making in the United States, and the genome project feels to have been hyped. The project, which began in 1990, took the form of a competition between government and private research teams to be first to inventory all three billion letters of human DNA. Construed as both a catalog and a map, the project aimed to guide scientists through the four-letter wilderness of the genome to places of medical value. (The genes themselves occupy only 2 percent of the genome, with the function of the rest unclear. Most DNA is extraneous, if not useless.) When the two research teams declared a tie and published the human DNA sequence in 2001, there was much cap-flinging and commentary about the impending transformation of medicine, along with some nervousness about what the knowledge would mean for individual privacy and for racial and ethnic identities.

  To talk about the human genome, singular, is somewhat misleading. There is not one human sequence but billions, each highly similar, each slightly different. The variation in human genomes underlies not only people’s physical diversity but also their different vulnerabilities to disease. DNA variation explains why, under equal conditions, some people will be disposed to high blood pressure, diabetes, asthma, or heart disease, and some people won’t. Diet, lifestyle, and landscape—the environmental variants of health—have critical parts to play in the disease process, but these familiar factors were outside the bailiwick of genomic technology and to science journalists weren’t nearly as exciting as the new information spewing forth from DNA.

  Understanding the so-called complex disorders of medicine was the ultimate purpose of the human genome project. Previously, researchers had been nickel-and-diming their way through the DNA. They had netted genes for the rare mendelian conditions, such as Huntington’s disease, cystic fibrosis, and the Jewish genetic disorders. Collectively these were orphan diseases because there weren’t enough patients to warrant big investments by pharmaceutical companies. The profits lay in the complex disorders and their large cohorts of patients. With the advent of genomics, the search for single genes having a big impact on a relatively few people shifted to multiple genes having a modest impact on a lot of people.

  Where did breast cancer fit in? Breast cancer straddled the old and new paradigms in genetics, the mendelian or single-gene model versus that of genomics. With two hundred thousand new cases in the United States each year and forty thousand deaths, breast cancer was far from an orphan disease. Breast cancer’s incidence was high, yet its pattern was scattershot and its causes were murky. Attention fell upon the roughly 10 percent of cases that clustered in families. The inheritance pointed to a mutation operating in a dominant, not recessive, mode. Here, the silent possibility of healthy carriers didn’t seem to apply. Although the unknown gene could not take in all of breast cancer, the pathway it followed in the body might provide a handle on the sporadic disease. Identify the gene, already dubbed BRCA, and you might hook into the cancer pathway and learn how to interrupt the broader condition. If the transition between the eras of Mendel and genomics was going to succeed, breast cancer was the bridge, or so it was hoped. The drug companies were keen for it.

  There turned out to be two BRCA genes. The first was identified in 1994 and the second the next year. The subtext of the hunt for the genes was the snippy rivalry between Mary-Claire King, then at Berkeley and now at the University of Washington, and Mark Skolnick of Myriad Genetics in Salt Lake City. Skolnick was a breezy scientist. In an interview he referred to himself as a Jewish kid from New York joking around with Mormons. He had found that Mormons made good subjects for DNA studies, thanks to their large families and their thorough genealogical records. As for Mary-Claire King, well, she was not breezy and not Jewish. A decade later, King revealed that her grandfather was a Jew and that her mother had concealed the fact because of antisemitism when she was growing up.

  Both researchers had collected pedigrees of heritable breast and ovarian cancer since the 1970s. King, taking the lead, showed that chromosome 17 contained what would be the BRCA1 gene. Knowing the chromosome was akin to knowing the street where a suspect lived. For months the two research teams worked the street up and down, looking for BRCA’s molecular address. Most of the technology they used was pre-genomics and thus rather slow. But it was Skolnick’s lab that won the race to publish the sequences of BRCA1 and BRCA2, and Skolnick’s company that became rich from patenting the BRCA genes and marketing tests for them. The assiduous King, with a string of accomplishments before and after, earned the greater reputation in genetics.

  Since BRCA1, as has been noted, is a very long gene, thousands of possible misspellings can occur along its sequence, and in fact more than two thousand mutations have been recorded to date, affecting all ethnic groups. One mutation quickly emerged ahead of the others. Although Skolnick and King hadn’t keyed on Ashkenazi Jews in particular, other researchers, now that they knew where to look, noticed the prominence of the 185delAG mutation in their study samples. They immediately established its Jewish tie. Those samples had come from Ashkenazi families with a lot of cancer.

  The next question was, how prevalent was the mutation in the general population of Jews? Researchers went back and looked for the mutation in DNA that had been stored from the Tay-Sachs and cystic fibrosis screening programs a generation earlier. The prevalence of 185delAG was 1 percent—meaning that one of a hundred Ashkenazim was walking around with a gene that could kill by itself, unlike the recessive mutations. Commenting on the surprisingly high frequency of the mutation, Francis Collins, the government’s top medical geneticist, said that the breast and ovarian cancers attributable to 185delAG might be the most common, serious, single-gene disease yet identified in any population group.

  A less-frequent BRCA1 mutation, called 5382insC, was identified next, followed by 6174delT on the other gene, BRCA2, making for a trio of characteristically Jewish breast-cancer mutations. They had stemmed from three different founders in Jewish history. There were hardly any other BRCA mutations in the group to speak of. In most other ethnic groups, the prevalence of BRCA mutations is low, about one in four hundred. On the basis of their small set of three, the BRCA carrier rate among Ashkenazi Jewish men and women is one in forty, ten times higher than the background rate. Comprising only 2 percent of the American population, Ashkenazim learned they represented up to a third of the country’s BRCA carriers.

  Being the oldest of the three mutations and the first to enter Jewish consciousness, 185delAG became the most studied, most worried-over piece of DNA in the world. Largely because of it, more people have been tested for BRCA1 than for any other human gene. The initial screening of the Jewish population, conducted by the National Institutes of Health (NIH) in 1996, followed the procedure that had succeeded with Tay-Sachs testing. Some five thousand volunteers in the Washington, DC, area were recruited with the aid of rabbis and community health officials. They provided researchers with DNA samples and histories of any cancers in their families. As before, the people who stepped forward to have their blood taken were relatively liberal and well educated, and they offered to help even though, in this first snapshot of the problem, they were not given their individual test results.

  From the NIH study and others, scientists determined that not every BRCA carrier was going to be affected, for the mutations were not fully penetrant. Penetrance is a technical term signifying that a powerful gene may pull its punches. Because of incomplete penetrance—because of healthy, elderly carriers like Shonnie’s grandmother, Dorothy—the risk of cancer from 185delAG and other BRCA mutations must be expressed as a probability. As genetic counselor Jeffrey Shaw had explained to the Medina-Martinez family, the estimates are wide—the most
hopeful studies suggesting that just half the carriers will get breast cancer during their lifetimes, the least hopeful that 90 percent will. The penetrance of ovarian cancer is lower, in the neighborhood of 40 percent. Something blunts the thrust of the gene, but no female who is a carrier can count on that happening.

  Since Ashkenazi women have more BRCA than other ethnic groups, while being just as susceptible to sporadic or “regular” cancers, they might reasonably be expected to have more breast and ovarian disease overall. The question could be resolved if scientists were to make the effort, but they haven’t chosen to study it comprehensively. If there is an incremental impact on the group from BRCA, it is relatively small.

  The impact of the mutations has been easier to measure in Jewish families where breast or ovarian cancer already was an issue. If a woman was ill, what was the likelihood that a mutation was the reason? The odds of a Jewish woman’s being a BRCA carrier were especially strong if she had ovarian cancer or if other members of her family had cancer too. Another tipoff was the early onset of a breast tumor—say, in a woman in her thirties. In the late 1990s, a rule of thumb was put forward in the medical literature: the younger the Jewish patient with breast cancer, the more likely she would test positive for 185delAG. This finding in Jews influenced the official name of the newfound gene: breast cancer #1, early onset.

  In 1998, hospitalized in San Diego and close to the end of her life, Shonnie was advised to have a BRCA test. Her age, just twenty-six when the tumor appeared, must have rung a bell with someone at last. Joseph and Marianne went into their depleted savings and paid $2,800 for the analysis, which was not covered by her insurance.

  Hmm, said the genetic counselor, your daughter is a carrier of 185delAG . . . but that’s the Ashkenazi mutation. The counselor must have been puzzled indeed. Given all that was going on with Shonnie, they put it out of their minds. The test was of no use to the patient—it was a warning to the rest of the family, but either the information wasn’t delivered properly or didn’t sink in.

  When the news of the Ashkenazi BRCA was conveyed to the Jewish community, it was oversimplified in the direction of alarm. Women tended to overestimate their risks of carrying a mutation if there were any reports or hints of breast cancer among their relatives. Newspapers and magazines published articles by or about Ashkenazi women agonizing over BRCA. According to surveys, Jewish women were much more likely to visit a genetic counselor than other minorities were. The women knew that if they took the test and it was positive, the next dilemma would be whether to have a preventive mastectomy or to try to circumvent the risk with extra mammograms and closer surveillance. The knowledge was like the apple that Eve offered Adam. A single bite of the apple tempted another, as sisters, aunts, fathers, and daughters submitted their DNA for analysis. Positive results brought fear and shame, and negative results relief and guilt, the riptides of emotion dividing families.

  Pressing to save lives, some scientists recommended large-scale screening of the Ashkenazi population, while others said no, it’s too soon, better wait for additional studies to be completed. But how would such studies be used? Would health-insurance companies call BRCA a preexisting condition and deny coverage? There were laws against genetic discrimination in health policies, but they didn’t apply to life-insurance policies. Would Jews become an uninsurable class of people?

  Orthodox Jews wrestled with all of these anxieties and more. Within their circle, a diagnosis of breast cancer could prompt a woman to seek treatment in another city, lest the people at home find out. High in the patient’s mind was her children’s marital prospects. If a young person learned that a BRCA mutation had been detected in her family or, G_d forbid, that she carried a mutation herself, at what point in her courtship was she obliged to disclose the information to her possible spouse? Should she then be rejected? Rabbi Ekstein, unable to devise a work-around for couples in his care, found the situation deplorable. What is the advantage of screening for a condition, a mutation, that has no treatment? he demanded to know. It is just making more tragedy. For the rest of her life and her future generations, she will be burdened with worry. Ekstein came out strongly against the BRCA test.

  DNA crossed the millennium under something of a cloud. From the beginning of the human genome project, a contentious body of literature and commentary had gathered around the ethical, legal, and social implications of genetics (ELSI for short). As with no other national research endeavor, the government funded sociologists, psychologists, and ethicists to look over the shoulders of scientists. The vetting was problematic, because the ELSI scholars fanned the very fears they were asked to assess, publishing warnings about the commercialization of genes, about discrimination and ethnic stereotyping, and about the manipulation of human traits under the guise of DNA repair.

  The stalking horse for these dire scenarios was BRCA and its notorious mutation, 185delAG. In reaction, some Jewish leaders advised people not to participate in genetic studies any longer. This is what we get for helping? they asked, linking concerns about Jewish genetic defects to Nazi racial classifications and the Holocaust. To be fair, the ELSI scholars did not play upon the Holocaust. Still, with very few exceptions, the genetic abuses that critics warned about haven’t materialized, and the dehumanizing scenarios remain very far in the future. The courts are the place to look for evidence about discrimination. Since BRCA was discovered, there have been no court cases documenting discrimination by health insurers or employers over a person’s BRCA result.

  One of the better works of ELSI scholarship was “Ashkenazi Jews and Breast Cancer: The Consequences of Linking Ethnic Identity to Genetic Disease,” published in 2006. The authors, social scientists at Columbia University, complained that to target Jews as a group for the study of breast-cancer mutations was undesirable and perhaps unwarranted. Other groups had BRCA mutations that weren’t being examined to the same degree, they wrote; hence their medical needs might be neglected. The authors pointed out that two of the three so-called Ashkenazi mutations had turned up in populations that weren’t Jewish, 185delAG especially. It was careless reasoning, the paper reiterated, to brand the mutations Jewish and wrong to saddle Jews with BRCA while underserving others in the same predicament.

  BRCA researchers did not dispute that they sampled Jewish women disproportionately, but as Harry Ostrer and several of his colleagues observed, it made good scientific sense to explore the nature of BRCA through Ashkenazi DNA. Quite apart from their willingness to cooperate, Jewish subjects were efficient to study. It made sense to solicit DNA from a group that you knew, going in, contained five or ten times as many BRCA carriers as any other you might choose. An enriched population greatly reduces the number of DNA tests that have to be performed on a hard-won collection of patients, not to mention the savings in hours of genetic counseling.

  An example of the approach was the New York Breast Cancer Study, directed by Mary-Claire King. With assistance from Ostrer and a dozen New York area investigators, King pulled together a group of one thousand Ashkenazi women with breast cancer. Ten percent duly tested positive for BRCA. From the one hundred carriers, King scaled up the sample to encompass seven hundred of the carriers’ relatives. She tested their genetic status and recorded their health histories, whether they had cancer or not. From the enlarged pool of families, she calculated that the penetrance (the proportion of carriers who got the disease) of BRCA was 82 percent, a high-end projection for breast-cancer risk. There was somewhat happier news in King’s finding that physical exercise and staying thin could help a younger carrier forestall the disease. Because the statistical analysis was robust—biomedical science really appreciates large sample sizes—the results of the New York Breast Cancer Study, published in Science in 2003, have been cited many times in the literature and the mainstream media.

  Not to be overlooked was the cost benefit of working with Jewish subjects. Protected by its patents, Myriad Genetics sets high fees for
sequencing the BRCA genes, charging around $3,000 per test for a consumer and half that for researchers. They have a stranglehold on the test, Harry groused. He had to ship his samples to Myriad in Utah when his own lab was perfectly capable of running the analyses. But the company charged only $400 to read a Jewish subject’s sample, since it looked for only three mutations. The sequencing zeroes in on just those two sites on the BRCA1 gene and the one site on BRCA2 where a misspelling might occur, rather than scanning the full length of the genes and searching for any number of mutations, a procedure that obviously is more expensive. The discrepancy between what a Jewish woman (or her insurance company) had to pay versus a non-Jewish woman’s cost was part of the reason why screening lagged in other communities. Access to care—the rich and well-informed able to buy genetic services, the poor not—was a bona fide issue for ELSI.

  Like it or not, the Jewish BRCA carriers were the vanguard. Thanks to the 185delAG mutation and its two companions, BRCA has become a metonym of cancer risk for every woman. A genetic aberration conceived in isolation from the rest of the world was donated to the world through science, adding to knowledge of BRCA’s universal behavior. If there was one disadvantage to using Ashkenazim in genetic studies, it was that their blood relatives were harder to come by than in other groups. Their extended families tended to be smaller, their pedigrees pinched off, because of the Jewish losses in pogroms and the Holocaust—a deficit that Rabbi Ekstein was trying to correct by encouraging healthy breeding, even as he complained about the harmfulness of BRCA testing to families.