The Wandering Gene and the Indian Princess

by Jeff Wheelwright

  In New York, Chicago, Los Angeles, and other cities, demand for the tests surged, in part because Myriad Genetics promoted the service directly to doctors and consumers. The company reported in 2008 that the number of people taking the test was growing by 50 percent every year. The negative findings well outstripped the positives, but that didn’t dent the demand to know. Myriad estimated that half a million BRCA carriers in the United States remained to be detected, including 150,000 who were Jewish. Among five million American Ashkenazim you could figure on fifty thousand carriers of 185delAG. To be sure, nobody in the genetics profession was calling 185delAG an Ashkenazi mutation any longer, that is, specific to that group of Jews, because by this time it had turned up in a dozen distant places along the spidery trail of Jewish migration—as in the ex-Kingdom of New Mexico.

  After Jeffrey Shaw’s counseling session for the Medina-Martinez clan in the summer of 2007, three of the Medina sisters, Wanda, Lupita, and Louisa, along with their mother, Dorothy, and Wanda’s husband, Bill, went to Colorado Springs to sign up for a 185delAG test. Thanks to a state grant, the cost to them would be minimal. Joseph Medina and Iona meant to go too, but they didn’t make it. A mix-up in communication or something.

  Shaw remembers that everyone was in good spirits. They weren’t worried about the gene, he said. They weren’t worried about the, quote, little bit of cancer, unquote, they might have in them already. No gloom and doom. They talked about cleansing their livers with diet and resetting their bodies. When the DNA results came back from Myriad, Dorothy (the obligate carrier) and Wanda and Lupita were positive for the mutation. Louisa was negative. Three more positives atop Shonnie’s positive and Chavela’s positive.

  Bill and Wanda had never doubted that Wanda already was battling breast cancer, since a lump had appeared on her ultrasound scan earlier that year. They did not want a biopsy. Bill and a local nutritionist, who was, like the others, a Jehovah’s Witness, took over Wanda’s care. For many months everyone believed that the special diet was working.

  In March 2009, Wanda was hospitalized with end-stage metastatic breast cancer. A hurried mastectomy came too late, and she died in June, at the age of forty-seven. In the weeks before the end, she tried frantically to rearrange her life.

  The educated medical consumer was used to the notion of risk factors for disease. He or she tended to regard them as painless early warning signs. To live in a state of risk wasn’t alarming when risk factors like eating and exercise habits could be met head-on. In principle, you could control your health environment, although the informed medical consumer also knew that diet and exercise went only so far.

  When your doctor spoke of your probability of illness, the risk was said to be high or low, a relative risk, that is, compared with a murky average, not your personal numerical odds. Supporting your risk profile was an array of screening tools, such as cholesterol measurements, blood-pressure tracking, and various scans, whose findings might elevate your risk, but usually drugs could be prescribed to drive it back down. The situation was manageable. If risk was like a clock, the patient figured she still had plenty of time.

  DNA analysis pushed back the start of the risk–to–disease continuum. When DNA was added to the risk calculation, through a session with a genetic counselor at a medical center or through a commercial testing service, the patient might discover that her clock for one or more conditions had been ticking for much longer than she knew, and that the vague risk factor known as family history had converted to a hard number, a probability with her name on it. At that point, a lump rising in her throat, she was likely to go for additional testing and to consult one or more specialists. The collusion between American medical technology and the patient’s empowerment—the self-affirming need to gather as much information as possible in order to have a strong voice in her care—might shift against her. Now when she stepped onto the conveyor belt of monitoring, instead of reassurance she got glitches, benign spots and masses, equivocal readings, the nerve-racking false positives, which only delayed the day of diagnostic reckoning. The 185delAG carrier has pioneered the way into the risk–disease limbo, and many more people, the potentially sick and the worried well, will follow for other conditions.

  Doctors are unhappy when they can warn but not treat. The prospect of a cancer coming sooner or later was extremely stressful to their BRCA patients, as doctors appreciated. To spare women both the anxiety and the jeopardy, prophylactic surgery is recommended: bilateral mastectomy to prevent breast cancer, and for ovarian cancer, bilateral salpingo-oophorectomy, which removes the two fallopian tubes as well as the two ovaries. In the mid-1990s, when BRCA was new, cutting out the problem was the nuclear option, and patients shrank from it, but today doctors can show statistical proof that the operations sharply reduce the occurrence of tumors. Although breast cancer can be treated successfully, ovarian cancer is a bad cancer to have, since 70 percent of the cases are advanced by the time the doctor sees them. If a carrier insists on preserving her breasts, ovarian removal alone should lower her chances of breast cancer, because of the elimination of estrogen from her system. If she wants children, the ovarian surgery can wait until she is through childbearing. Encouraged to look past the trauma, the patient could get back to normal with surgically reconstructed breasts and without the reproductive organs she no longer needed.

  The advice, so very rational, took hold. According to an international survey published in 2008, American BRCA carriers had the highest rate of bilateral mastectomy in the world, about a third of U.S. women choosing to have preventive surgery and about two-thirds of the carriers also having the ovarian procedure. BRCA helped to fuel a trend, as even noncarriers with breast tumors were choosing to have the other breast removed.

  Yes, knowledge was power. Women did their research and shared notes about their surgeries. There was a righteous solidarity in the name that mutation carriers picked for one another: previvors, meaning the survivors of a predisposition to cancer. The name came out of an online organization called FORCE (Facing Our Risk of Cancer Empowered), which was founded in 2000 by an Ashkenazi carrier. More recently, when the blogosphere took up the issue, you could follow The Secret Life of a BRCA1 Mutant, in which a 185delAG carrier told of the events surrounding her pbm (prophylactic bilateral mastectomy). Her blog was not to be confused with I’m a Mutant: The Life and Times of a BRCA1 Previvor, by another 185delAG carrier who was looking forward (not!) to her surgically induced menopause. The bloggers at Cut the B*tches Off and Goodbye to Boobs, respectively, worked themselves into a cold fury over the logic of slice-and-gut (slice the breasts, gut the ovaries). Collectively, as their blogroll put it, they were the Sisterhood of the Mutant Bloggers, defiantly complying with their medical advisers.

  The previvors included more than Jewish women, but all were regarded with pity by Rabbi Josef Ekstein. Remove the breasts, remove the ovaries? he grumbled. Next they will say to remove the brain. . . . I’m against BRCA testing, Ekstein emphasized. Why test? To prevent a disease? To heal a disease? Or to put a stamp on a person that she has the gene? It does more damage than good—you label the family, you kill the family, he said, for a moment sounding overwrought. He liked to quote King Solomon’s declaration in Ecclesiastes: More knowledge, more pain. This is not to say, Ekstein elaborated in a written commentary, that one should be a fool. However, although Solomon was the wisest of all men, he recognized that in certain instances it is more helpful not to be informed.

  Occasionally when the rabbi ventured out of Brooklyn to lecture, genetic counselors would press him to justify his position. His critics stood strongly for science, which shaved away the uncertainty of nature in slices, as a CT scanner does, and advanced patiently toward the day when all things would be known. In the meantime medical information should be transparent and every patient was autonomous. Ekstein faced the questioning politely—a roly-poly, yarmulked figure with a shaggy white beard and brows as dark as thunderclo
uds—and he gave not an inch. He had nothing against science, he said, only its hurtful applications to those who were psychologically vulnerable. He flashed a slide on the screen: EXPERIENCE SHOWS THAT EVEN THE MOST HIGHLY EDUCATED OF INDIVIDUALS HAVE DIFFICULTY USING INTELLECT TO DOMINATE EMOTIONS.

  When pressed further, Ekstein put forward a series of arguments, the effect of which was to compound the uncertainties of BRCA testing and undermine its medical utility. First, even if she weren’t a carrier, a woman had a one-in-eight chance of getting breast cancer during her lifetime, owing to the sporadic or background risk. Second, genes other than BRCA, including genes still unknown to doctors, were responsible for some of the heritable cases. Third, because of BRCA’s incomplete penetrance, its faulty guarantee, as it were, a significant portion of the women who had mutations would not contract the disease. Fourth, turning now to the surgery, even that harsh measure could not completely preserve their health, since malignant cells were sometimes missed.

  Ekstein advised that women who were worried about BRCA should step up their vigilance and be screened more often, by MRI as well as by ultrasound and X-rays. If her family history indicated she was at risk, she must take all the precautions of breast health—things she should be doing anyway, Ekstein said, without the need of a test, without putting a blot on her relatives and living her life in terror.

  All in all, the rabbi made a forceful presentation. Except that he ignored the poison pill of ovarian cancer, a fifty-fifty probability, roughly speaking, for the mutation carriers who chose to preserve their ovaries. The risk of ovarian cancer was what frightened the doctors and counselors, and any potential BRCA carrier, Jewish or not, ought to be aware of the danger, since neither the screening methods nor the treatments for ovarian cancer were reliable, while preventive surgery has been shown to cut mortality dramatically. Perhaps that is why, when he finished defending his position, Ekstein made a slight bow and said, We cannot set a general rule for the whole world.

  Coming to grips with their BRCA risk, some Ashkenazi professionals have asked again if they should have a national screening program, patterned on the old Tay-Sachs testing model. While Canada, Britain, and Israel started programs offering BRCA testing to Ashkenazi citizens regardless of family history, the U.S. Jewish community cautiously aired the pros and cons. On the one hand, according to a study by Wendy Rubinstein, a BRCA expert in Chicago, a moderately successful screening program would save about five thousand lives on the ovarian-cancer front, not to mention the lives threatened by breast cancer. The most ambitious scenario was that the three deadly mutations would be expunged from the Ashkenazi population via adult screening, prenatal genetic diagnosis, and termination of fetal carriers.

  On the other hand, Harry Ostrer asked, why should Jews be the forerunners, the elites, in this effort? Qualms from his quarter were surprising, given that Ostrer worked to stamp out the recessive Jewish disorders through communal screening. I’m for equal-opportunity testing, Harry explained, not just for 2 percent of the population. I mean for everybody else. Gentiles should be offered BRCA screening. I could develop good tests for the WASPs of Connecticut [i.e., tests for their mutations], but I’m not empowered to do that.

  Ah, the Myriad patents again, crimping independent research on the two genes. In one of his NYU research projects, Harry was looking at the question of penetrance—specifically, why some Ashkenazi women with BRCA mutations didn’t get cancer—and the research would be cheaper if he didn’t have to pay Myriad for sequencing the two genes. In fact, Harry had joined a class action against Myriad over the patent issue. Though a district court ruled favorably, the lawsuit, he admitted, would be a long shot in the higher courts because of the precedents supporting the company. It did seem wrong that a piece of nature could be patented commercially, but for thirty years courts have upheld the principle, not so much on the ownership of genes as on their transformation into biomedical tools.

  Ostrer also voiced a concern about widespread BRCA screening that made him sound a bit like his rival, Rabbi Ekstein. Some have called this no-brainer testing, Harry said at a symposium. But is this true? Genetic testing without adequate genetic counseling can lead to fear and anxiety. Indeed, there were even instances, as Ostrer knew well and Ekstein knew better, in which a woman with a positive result had dropped out of the medical system altogether, refusing to return calls from her genetic counselor or doctor, so frightened was she of finding a tumor. Those people took no comfort in being previvors. They were better off not knowing, yet they knew.

  Another Medina sister, Lupita, having tested positive for the mutation in 2007, was diagnosed with breast cancer in 2009. She opted to have a bilateral mastectomy.

  Shonnie’s, Wanda’s, and now Lupita’s cancers made it impossible for Iona to put off her BRCA test any longer. She was having trouble sleeping. I realized I was being selfish, Iona said. It would be selfish of me to put people through what Wanda and Shonnie did, if I could do something about it.

  Leaving a blood sample at the lab, Iona went home to await the result. Her heart started beating rapidly. To work off steam, she did kickboxing exercises against a heavy punching bag, and one day she felt a stabbing pain in her chest and was taken to the emergency room, believing she’d had a heart attack. Instead, she had pulled a muscle.

  Then the genetic counselor phoned: Iona, like her late sister and at least ten of her close relatives, was positive for 185delAG.

  In hindsight BRCA1 and 2 were the last truly important human genes to have been discovered. Although many subtle findings have been extracted from the human genome since the mid-1990s, they are a large cast of bit players making small impacts on health and illness. The newfound DNA markers and genetic variants contribute tiny, incremental pluses and minuses to the risk of disease, of negligible importance to the individual patient. Almost certainly there are no undiscovered stars left in the genome, no genes that might be given makeovers by the drug companies and brought forward to cure the common illnesses of mankind.

  Nor did BRCA itself provide insights into the general pathway of breast cancer, because it has become clear that breast cancer comprises several overlapping conditions. The kinds of tumors that BRCA carriers usually developed weren’t like the tumors of common, sporadic cancers. The cell pathology was different, and the outcome for BRCA patients tended to be worse. However, targeted therapies were arriving. Much could be written about the new class of anticancer agents, which attack individual features of cancer cells instead of bludgeoning all cells indiscriminately, as conventional chemotherapies do. Genomic technology was helping to distinguish among the breast-cancer types; the typing of a tumor was the first step to tailoring a treatment. Genomic laboratories spewed As, Ts, Cs, and Gs into the cancer data banks as if from a firehose, for it was easier to gather the data than interpret it.

  Ten years into the new century, the DNA age was moving sideways. A paradoxical sign that genetic science was adrift was that consumers were having fun with it. Recreational genomics—the specialists’ dismissive phrase—was where the action was. Scientists watched uneasily as people explored their genealogies and their potential health risks through direct-to-consumer testing companies like 23andMe, Knome, and Navigenics. These services were accessible on-line. For several hundred dollars and a mailed-in swab of your cheek cells, you could see narrowly into your biological past or future.

  Harry Ostrer championed the old-fashioned approach: You made an appointment with a medical geneticist or genetic counselor and took a DNA test when one was warranted, not just because you were curious. The consumer tests being marketed might be valid for aspects of ancestry, Harry believed, but not for a medical profile. I fear that the purveyors of direct-to-consumer genetic testing, with their faulty claims, will scare away our patients and betray the public’s trust in medical genetics, he warned. Compared with the deliberative process that had introduced BRCA screening to the American public, the curren
t gene scene was the Wild West. Harry and others called for federal regulation, and the Food and Drug Administration began to respond.

  Lacking fresh insights, scientists brought the genome back into the shop and popped the hood. For all its power, the technology of genomics was still running too slowly. The mechanics worked to make the technology of DNA run faster while pushing down the cost of sequencing. Their hope was that one day everybody might be able to afford to have their genomes transcribed, all three billion letters’ worth. Faddishness still seemed to drive the field. It was more about buzz than science when actress Glenn Close, aging rocker Ozzy Osbourne, and Archbishop Desmond Tutu had their genomes sequenced. A dozen or so individuals got together on a stage in Cambridge, Massachusetts, and described how they felt to be the first human beings to have their DNA read in full. It felt good.

  When Iona found out that she carried the mutation, she promised to increase the frequency of her mammograms. Uninsured, she couldn’t afford the cost. But in 2010 she enrolled in a new program at Penrose Cancer Center in Colorado Springs. It was called the High Risk Breast Clinic. The plan was to offer BRCA carriers a free consultation with a breast surgeon, along with mammography or an MRI scan, thanks to a grant from the local chapter of Susan G. Komen for the Cure. As it was, Iona hadn’t had a mammogram in more than a year, a dangerous gap.

  In a sense the medical circle had closed, for Susan Goodman Komen, in whose name the foundation was created, was a Jewish woman who died of breast cancer when she was thirty-six. She was Iona’s age and a mutation carrier. Shonnie also had received financial aid from the Komen foundation.

  Signing up for the new program made Iona feel better. Her first MRI was negative. In her mind, she had taken her breast- and ovarian-cancer risk under control through the strategy of watchful waiting, the strategy Rabbi Ekstein advised. Preventive mastectomy was off the table, and after learning more about the ovarian surgery, Iona decided she didn’t want that operation either. The fact that she had taken birth-control pills for years was somewhat protective against ovarian cancer. Maybe when I’m fifty, she said about the oophorectomy.