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

by Lizzie Stark

  Geneticists the world over sent Stratton DNA from their breast cancer families. They’d narrowed down the relevant part of the chromosome to about one million base pairs, a region that could encompass from one to thirty different genes depending on how gene-rich that chromosome happened to be, something that was unknown at the time, as the Human Genome Project was not yet complete.

  Duke University, the Institute of Cancer Research in London, and Stratton’s Sanger Centre collaborated, each doing a component of the research. Stratton is particularly proud of his group’s work—they used a new method of DNA sequencing to burnish those one million base pairs to a highly accurate shine, and released the data publicly. “That was the first million bases of DNA in the human genome to be finished,” Stratton says. The method used is now known as Sanger sequencing.

  “As time went on, we became a little more optimistic,” Stratton recalls. “There were some bad moments—we were phoned up twice by major journals who said they’d heard a rumor that the BRCA2 gene had been found. That was demoralizing.” But demoralizing or not, the rumors were just that—rumors.

  The lab worked at full tilt, collaborating and laboring long hours. “We didn’t waste a drop of energy,” Stratton says. “Everybody really committed themselves to delivering this huge body of work over a short period of time. Great drive, great commitment, great determination…. It was a wonderful time to be there because of that sense of commitment to a single common purpose that they could really treasure. To be part of that atmosphere was a real privilege.”

  That atmosphere lasted right through the day Stratton came to work and found his post-doc, Richard Wooster, waiting with some sequencing results. Together they worked their way through the genetic code until they found exactly the sort of mutation you would expect in a BRCA2 breast cancer family. “At that moment, it looked like we had landed the gene,” Stratton says. He felt excitement, of course, but also pure awe. “It was that feeling of you’ve gotten up to the summit and you’re looking down the other side and that’s amazing. Looking down the other side didn’t reveal anything we could interpret,” but still. He and his team also felt “a sense of the impact this would have in the world. We felt very humble and we also felt slightly petrified for all sorts of reasons.”

  The anxiety of “Will we find it first?” was replaced by the anxiety of “Will someone else publish the results first?” In the coming weeks, Stratton’s team discovered several different mutations in this gene in different families that confirmed the presence of BRCA2. The group took out patents in the UK and Europe to stake the claim to free use. “General consensus was that we would patent it for defensive reasons,” Stratton said. “We would patent it and license it freely.” In 2013 he would be knighted for this discovery and for his many other contributions to cancer research.

  Stratton’s group published their results in Nature on December 21, 1995, and the nonprofit Cancer Research Campaign, which had funded their research, filed for a patent in the UK. The day before Stratton’s group’s paper went to press, Myriad announced to the news media that it also had the BRCA2 gene, had deposited the sequence into a public government databank that day, and had filed for a US patent. The company would publish its slightly more accurate and complete results in early 1996. The genetic race was about to move from the scientific realm to the legal one.

  Though we’ve come a long way from my mother’s plea to her friend to fund research seeking the BRCA mutations, there is still plenty to learn—even in 2014, there are still some cancer families whose disease is not attributable to BRCA1 or BRCA2 mutations, or to any of the other cancer-causing mutations that have been discovered, so there may be some as-yet unknown genetic mutation or interaction at work. And of course, BRCA1 and BRCA2 are both very large genes. Just as there are more ways to misspell “antidisestablishmentarianism” than there are to misspell “pants,” so too are there lots and lots of different ways the large BRCA1 or BRCA2 genes can go wrong. Some misspellings are harmless, and some are cancer causing, and of course, we aren’t sure where many mutations fall on that spectrum. A battle has been won, but not the war.

  4 | Myriad’s Monopoly

  There may be fifty ways to leave your lover and more than one way to skin a cat, but in the United States, before 2013, if you wanted to know whether you carried your family’s grim legacy of breast and ovarian cancer, there was only one way to find out: pay Myriad Genetics—or get your insurance company to pay—upward of $3,000 for DNA sequencing, a process that my husband’s scientist friends assured me they could do in a lab for a few hundred dollars, tops.

  At first, it seemed like an indignity to me, for Myriad to own a patent on something that had been in my family—quite literally inside our bodies—for multiple generations. I felt outraged, as if some bureaucrat had casually strolled inside my house and announced that I no longer owned that nice antique teacup my grandma gave me.

  It took my father, a retired tax attorney who once litigated on behalf of pharmaceutical companies, to help me see the other side. Myriad sank huge amounts of money into the problem of finding the BRCA1 and BRCA2 genes, not knowing, necessarily, what it was going to find or how long it would take, creating its own roadmap of markers and refining algorithms and methods of sequencing DNA in order to pinpoint the genes. What motivated all this investment in learning about a condition I carried? he asked. It was the yearning for profit, of course. Didn’t Myriad deserve to recoup its investment? Didn’t the company deserve a payoff for all its hard work?

  As I followed the Supreme Court case against Myriad, my father’s words rang in my ears. Issues that were easily and clearly answered did not make their way to the nation’s highest court, he had said. There was legitimate disagreement here.

  In order to understand it, it’s necessary to know a bit about how patents work. Our current patent law dates from 1793 and describes patentable material as “any new and useful art, machine, manufacture, or composition of matter.” An act passed forty years later created the Patent Office, and now patent law has restricted patentable subject matter to “nonobvious” and “useful” discoveries—no patenting spoons or washing machines that don’t successfully wash clothes. The courts have interpreted patent law to limit patentable subject matter, according to the US Patent Office website, and it is not possible to patent “the laws of nature, physical phenomena, and abstract ideas.” So stuff like gravity, rocks, and mathematical formulas for the meaning of life are strictly off the table. Ever since a law passed in 1995, patents may now last for twenty years from the filing date, with patentees paying renewal fees at four, eight, and twelve years to keep the patent for the full time.

  Patents reward disclosure with intellectual property rights. The very word “patent” comes from an older Latin verb patere meaning “to be open.” In exchange for describing their inventions and making them available to the public—as opposed to squirreling them away as trade secrets indefinitely—inventors earn the right in the United States “to exclude others from making, using, offering for sale, or selling the invention throughout the United States or importing the invention into the United States.” That’s important—a patent doesn’t give you the right to make or sell something. Rather, it gives you the right to kick competitors out of the market for up to twenty years. “Think about it like a fence,” Kevin Noonan tells me. “I don’t have to own the property, but if I have a fence that keeps you from coming on …” Noonan is a lawyer with a PhD in molecular biology and is the founding author of the Patent Docs blog, which focuses on biotechnology and pharmaceutical patent law. He also filed a friend-of-the-court brief supporting Myriad’s position. Patents, in other words, control how people can access an invention, honoring a creator’s hard work with the potential to nab royalties. After the patent expires, the knowledge passes into the public domain.

  In a way, the question of whether human genes should be patentable is an argument about obsolescence. As Noonan points out to me, in 1994, when Myriad found
the BRCA1 gene, that represented a huge technological undertaking. It took scientists nearly two decades to identify and locate it. The company did BRCA2 in less than a quarter of that time. He asks me to think about how much cell phone technology has advanced since the mid-1990s, conjuring images of clunky car phones versus the sleek pocket computers we carry today. So, too, has DNA sequencing technology advanced. The testing methods Myriad described in its patents “are really a little horse and buggy compared to what people are doing today, and that’s really not surprising,” Noonan says. No wonder my husband’s buddies could sequence my DNA for a fraction of Myriad’s cost—it’s way easier to get text messages on an iPhone than on a car phone. Noonan also points out that the Human Genome Project wasn’t completed until 2003 and that the twenty-year window on patenting means that, as Noonan puts it, “By 2018, 2020, all the gene patent claims, whether they’ve been granted or not, are just going to be expired by the way the law works…. We’ve kind of moved past the gene age in that sense.” A charitable view of gene patenting might simply suggest that what we pay—the thousands of dollars that BRCA women and men shell out to have their blood tested—is simply a temporary state of affairs, the royalty that we donate to future generations who will benefit from the knowledge after the patents have expired. A less charitable view would argue that genes aren’t patentable because they’re part of nature and that restricting access to them hinders meaningful scientific research and penalizes women who take genetic tests by preventing them from getting a second opinion.

  In addition to the legal issues at hand—are genes patentable?—the Myriad court case filed by the American Civil Liberties Union (ACLU) and the Public Patent Foundation (PUBPAT) against the company on behalf of a consortium of researchers, physicians, and individual women includes an emotional, commonsense gut appeal. Though ACLU attorney Chris Hansen is now retired, his job used to be to seek out and litigate new cases. When the organization’s fulltime science adviser told him that human genes had been patented, he told her she must have gotten it wrong. “She said, ‘No, the genes themselves are patented,’ and I said, ‘That can’t be right,’ ” he tells me. Although he was an experienced litigator, he knew little about patents or genetics at the time. On a human level, though “it just seemed really obvious to me,” he says, that human genes couldn’t be patented. He spent the next two years interviewing experts “to see whether the commonsense reaction had any traction in law.”

  After concluding that it did, the ACLU began to put together a lawsuit. Although many human genes had been patented, the ACLU settled on litigating against Myriad based on the BRCA genes for several reasons. For starters, Hansen explains, “Breast cancer is about the most recognizable disease that exists. We knew the case was going to be controversial; we knew it was going to draw a lot of attention.” Perhaps public sentiment might give them the edge. “Everybody in the country has been affected in some way or some form by breast cancer, and we thought it would resonate with judges and the public,” he says. On top of that, according to ACLU cocounsel Sandra Park, Myriad Genetics had aggressively enforced its patent rights, maintaining a monopoly on providing tests to patients. She argued that Myriad’s patent enforcement had “a chilling effect on researchers in the field”—a point Myriad would contest. In the end, she says, it was two factors, “the medical significance of these genes and Myriad’s aggressive enforcement of these patents,” that drove the ACLU’s suit.

  Truth be told, Myriad does have a bit of an image problem—odd considering that the company has done things like helping to identify remains from the World Trade Center bombings and discovering a number of hereditary cancer genes that help save lives, actions that most people would consider noble. I asked patent expert Dr. Robert Cook-Deegan, a medical researcher, biologist, and professor at Duke who worked in Washington for twenty years, including stints on the Biomedical Ethics Advisory Committee, the National Center for Human Genome Research, and the National Academy of Sciences, why. In addition to recounting a little of Myriad’s history of suing people who infringe on its patents—as the company is well within its rights to do—he tells me that one of the reasons “that there is so much pent-up hostility to the company” is its way of dealing with its clientele. “It doesn’t help that they have a product that’s for women in their thirties to their fifties … and all of their spokesmen from time immemorial are white men in their fifties and sixties,” Cook-Deegan says. Mark Skolnick is undoubtedly a brilliant scientist, but for all his accomplishments, he’s not very likeable. When filmmaker and BRCA carrier Joanna Rudnick interviewed him for her film In the Family, he came off as, well, an arrogant mansplainer, denying that there was any controversy around the gene patents. “There’s no controversial patent. It’s all very easy to understand if you take the time,” he tells her, as if to imply that this woman who wants to interview the guy who found BRCA1 has probably not taken the time to try to understand the issues. And of finding the BRCA genes, he tells her, “We did it to win the race. The group that was in that laboratory working seven days a week were doing it to beat the other team, period. And we won.” I guess I’m glad that the genes were found—whether to beat another team or, you know, because women are real humans who deserve to not die of cancer from generation to generation. I mean, the important thing is that his team found the genes. Still, these sorts of public slipups are not going to win Skolnick or Myriad any Ms. Congeniality prizes.

  It’s easy to demonize Myriad as the haunted house on the hill, the big scary corporation coming in and enforcing its mean will on women’s bodies, but that’s not a fair cop either. There’s no rule that says innovators have to be selfless and cuddly—isn’t it enough for them to do the science that uncovers the underpinnings of diseases? Who among us, having discovered a gold mine, or an untapped oil field, would truly give up that tremendous source of wealth and power to the public interest?

  And so, the ACLU and PUBPAT’s lawsuit against Myriad had two components—one was a legal question of whether human genes are patentable subject material, a battle fought in the courtroom. The other, intertwined issue concerned whether it was ethical and right to patent human genes, a question largely tried in the court of public opinion, but one that influenced the legal issues at hand.

  Let’s take the ethical question of gene patenting first.

  On the “it’s not ethical” side, we have the ACLU and PUBPAT, who argued that patenting actual DNA sequences impedes data sharing and research important to the future of bioinformatics. They noted that Myriad sent cease-and-desist letters to some researchers in connection with the patents. If DNA sequences aren’t free, then how can laboratories conduct research on the genes in order to unravel their functions and find therapies? Attorneys for Myriad would cite thousands of papers on BRCA1 and BRCA2 in their arguments in rebuttal. Still, according to cocounsel Sandra Park, Myriad doesn’t have to prevent research in order to harm the development of science. The point, she tells me, is that Myriad could choose to sue researchers if it feels like it; if a researcher’s ultimate goal is clinical applications, “and you know that Myriad will likely go after you at that stage, there is a chilling effect that goes on at the front end.” Would researchers choose to study these patented genes, knowing that they might have their discoveries taken from them? That’s one ethical quandary.

  Another quagmire lies in the fates of researchers who perform clinical studies on BRCA patients. According to Dr. Robert Cook-Deegan, the Myriad patents extended patent protection to a diagnostic test, which means that, for a patent holder, “you in effect become the arbiter of the standard of care for doing that test because no one else can do it.” According to two doctors who provided affidavits in the lawsuit, Myriad didn’t permit researchers to tell their subjects the results of their BRCA1 and BRCA2 tests, forcing them to violate accepted medical ethics.

  Finally, Myriad’s monopoly on BRCA testing, founded on its gene patents, created problems for patient access, as professor Lori Andre
ws of the Chicago-Kent College of Law, who specializes in the legal issues around medicine, points out to me. She also chaired the federal Working Group on the Ethical, Legal, and Social Implications of the Human Genome Project and authored an amicus, or friend-of-the-court, brief supporting the ACLU and PUBPAT. “I received grants from foundations and federal agencies to look at the impact of gene patents and what I found was horrifying,” she says. “Interfering with health care—even someone like Angelina Jolie, even wealthy people could not get a second opinion before cutting off their breasts.” And of course poor women or women without Myriad-approved insurance might not get access to genetic testing to begin with. The plaintiffs also argued that the tests didn’t reveal all known mutations and didn’t use techniques that could do so, meaning that the tests gave false negative results to people who really did have harmful BRCA mutations. One study published in the Journal of the American Medical Association stated that about 12 percent of patients from high-risk families received such false negative results. Of course, it’s unreasonable to expect Myriad to test for a mutation that it is not aware of—it can’t test for things it doesn’t know exists. Still, if the DNA itself hadn’t been patented, the plaintiffs contended, other labs could offer more comprehensive testing using newer techniques, including testing tumor specimens preserved in paraffin from deceased family members, which Myriad did not regularly perform. Myriad’s foes also argued that a lack of independent testing prevented the scientific community from performing research on variations of uncertain significance—alterations detected on BRCA tests that might or might not affect cancer risk. Myriad argued that it permitted some labs, for example at Yale and the University of Chicago, to perform confirmatory testing under narrow licenses but that second opinions wasted resources unless there was some doubt about the original test. As for the original test, the company argued that its testing is the gold standard and that it is continually updating and improving its tests, including efforts to determine the clinical significance of VUSs (variations of uncertain significance), which has resulted in the clarification of 850 VUSs from twenty-one thousand patients.