Researchers View Genetic Testing With High Hopes, But Caution

But Caution Author: Steven Benowitz The human genome has become extremely big business. IN DEVELOPMENT: Myriad CEO Peter Meldrum sees increasing industry-academia ties in genetics Taking the lead from the Human Genome Project, an ambitious $3 billion, 15-year federal effort aimed at analyzing the entire human genetic heritage, industry has begun treading cautiously into the relatively uncharted waters of genetic testing. Several companies, often along with academic collaborators, have begun to make their mark (see accompanying story). Myriad Genetics Inc., a genetic testing company in Salt Lake City, Utah, recently announced it would begin offering large-scale testing to detect a mutated gene for inherited breast cancer, BRCA1. Myriad, which owns the patent for the gene, has spent some $7 million to isolate and characterize it, and has licensed the therapeutic rights to Eli Lilly and Co. of Indianapolis for an undisclosed amount. Another company, OncorMed-a subsidiary of Oncor Inc., a genetic testing company in Gaithersburg, Md.-is already offering limited BRCA1 testing services for use in research settings for women at high risk. Amgen Inc., a Thousand Oaks, Calif.-based biotechnology firm, put $20 million into the coffers of Rockefeller University in February 1995 for the rights to a putative obesity gene, and may owe the university as much as $70 million more for patent-development milestones. But as industry and academe begin to enter the brave new world of genetic testing, the rules of the road remain unclear. Some scientists see industry participation as energizing and beneficial to the field and the only vehicle through which it will grow. Others wonder whether an increasing corporate presence will make science more secretive. They worry that concerns about patent rights will take precedence over sharing data, thus delaying publication, restricting access by others, and slowing down progress. They question if high-stakes competition to find elusive and potentially lucrative genes has a chilling effect on traditional scientific collegiality. For now, many scientists view a potentially lucrative-and as yet unregulated-genetic testing market with guarded optimism. "It's amazing, the amount of money companies feel they should spend on identifying genes," says molecular geneticist Stephen Friend, director of molecular pharmacology at the Fred Hutchinson Cancer Research Center in Seattle. Myriad Genetics scientists were part of the team that in September 1994 announced the discovery of BRCA1, which when mutated is believed to account for more than half of all inherited breast cancers (S. Benowitz, The Scientist, Jan. 23, 1995, page 1). The company's scientists were also part of the group that recently announced the discovery of a second hereditary breast cancer gene, BRCA2 (R. Wooster et al., Nature, 378:789-91, 1995). While companies such as OncorMed and Myriad either currently are offering or plan to offer testing for BRCA1, the usefulness of such an exam for the general population is still questionable. Scientists and physicians openly debate whether the test should be limited to research studies and families in whom a history of the disease is known. One problem is that the gene is large, with many possible mutations, and researchers are not yet certain what risk each genetic error entails. Many argue against testing because there is little that women who carry the gene can do to prevent disease, beyond being vigilant with mammograms. Psychologically, the effects of a positive test could be devastating. The growing business of the human genome is sparking discussions on questions of access to information and secrecy. For example, geneticists at Washington University in St. Louis and at the Sanger Centre in Cambridge, England, apparently concerned that increasing worries over gene patent rights may impede research, published a large stretch of chromosome 13 on the Internet (D. Dickson, Nature, 378:425, 1995) in late November. Two teams of scientists from Myriad and from the Institute of Cancer Research in London subsequently used the information to corner BRCA2. Interestingly, the teams currently are negotiating over rights to a patent they both filed for, days apart. A March article in Scientific American (T. Beardsley, 274:100-5, 1996) quotes geneticist Francis Collins, director of the National Center for Human Genome Research (NCHGR), part of the National Institutes of Health, as calling a race to patent every sequenced gene "destabilizing," endangering cooperation among researchers. "Patenting genes is making people a lot more nervous," states molecular geneticist P. Andrew Futreal, an assistant research professor of surgery and assistant professor of genetics at Duke University. "The trend used to be to put them [gene sequences] on a public database, but the trend now is to hold back and wait until publishing or patenting and publicly release the data." That could adversely affect the progress of science, he asserts, "particularly in the traditional way, through scientific collaboration." Futreal, who was a member of teams that successfully identified BRCA1 in 1994 and BRCA2 earlier this year, would like to see more of the openness shown by the Washington University-Sanger Centre group in placing sequences in a public database."It's hard enough cloning genes, but we want to get to understand them-just getting the gene is not what we're all about," he says. "We want to understand what the gene does and how it causes disease. That's what the genome project should be doing -generating resources." He wonders what the effects will be "if companies keep dumping in huge amounts of money. Small teams of researchers are going to say, 'What's the use? The larger companies have the resources.' Funding organizations are going to say, 'It's so competitive, why give the money to individual researchers?'" COMPETITION IS GOOD: Human Genome Scientces CEO William Haseltine contends that "if you weaken the patent system, you invite secrecy. Some argue that these concerns are overblown. William A. Haseltine, a molecular biologist and chairman and CEO of Human Genome Sciences (HGS), a gene sequencing and products company in Rockville, Md., contends that scientists have always been extremely competitive. "The whole point of competition, whether patent filing or publishing, is that knowledge is shared," Haseltine says. The race to be first to publish encourages innovation, and patenting only helps spread scientific knowledge, he maintains: "If you weaken the patent system, you invite secrecy." Examples abound of scientists teaming up to achieve a goal, he notes, pointing to the multi-team, four-year international competition to identify BRCA1, involving "highly coordinated, international collaborations." He notes differences among academic and industry priorities: "The academic scientist asks, 'What is the role of the gene in causing disease?' The pharmaceutical company researcher asks, 'How can the gene be used in creating a product?'" Myriad CEO and president Peter Meldrum sees industry as having an essential role in bringing academic discoveries to the marketplace. "The academic role in basic science in the Human Genome Project has been important, but you need the commercial involvement to bring products into the market to improve health care." He notes that such relationships are growing, and adds that he hasn't seen any reluctance among Myriad collaborators in sharing data. Patent issues notwithstanding, "we haven't found collaborations any more or less difficult," he says. Despite questions of patenting rights and potential delays in reporting data, the Hutchinson Cancer Research Center's Stephen Friend doesn't anticipate much problem with industry support in the genetic discovery and testing process. "Industry presence only helps-it energizes the discovery process," he maintains. William Dietrich, an assistant professor of genetics at Harvard Medical School and a Howard Hughes Medical Institute investigator, favors the influx of industry cash in "these tough fiscal times." He thinks that "companies have been very good about sharing data and collaborating with academe. In general, industrial laboratories, except in scale, do things much like other labs. "Industry has been very good in discovering things," he says, suggesting that maybe patenting laws need to be modified to circumvent potential delays in public reporting of data. "Science gets on by being open," he adds. LUCRATIVE: NCHGR geneticist Lawrence Brody believes that the potential for gene-based therapeutics will attract pharmaceutical companies Such high-profile science in some cases may influence research paths. On one hand, many researchers agree that high-profile science usually isn't a consideration in choosing research interests: Curiosity continues to be a primary motivator (F. Hoke, The Scientist, April 17, 1995, page 1). Geneticist Lawrence Brody, an investigator at NCHGR, believes that most scientists continue to pursue science to "answer interesting questions." Yet on the other hand, many scientists participate in high-profile projects because success brings new opportunities for collaborations, grants, lectures at scientific meetings, even promotions. Brody says that intense competition to publish, to be the first to discover the gene of the week, can up the research ante and frequently chill collaborative environments. Advancement in science, he notes, is based on individual achievement, not on team success. With research funding tighter than ever, many scientists say they can't always afford to follow their curiosity. The opportunity to engage in potentially lucrative research can influence a scientist's professional agenda. "I'm sure it [high-profile science] does [influence research choice] to a certain extent," says Roger Wiseman, a biologist at the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., and a member of the successful BRCA1 discovery team. "It can sway your interest away from certain projects. Some of us at NIH are encouraged to work on certain projects, but we have a stable source of funding and we are encouraged to participate in risky science." He contrasts this with the experience of academic researchers, who must apply for grants from funding agencies that tend to be conservative. PATENT PENDING: Duke researcher P. Andrew Futreal wonders if patenting genes might delay scientific progress. "In cancer research, for example, scientists have to be aware of hot areas, such as colon or breast cancer, because that's where the funding is," notes Duke's Futreal. "You spend so much of your time writing grants, and you have to find time in the lab to generate the preliminary data to justify your proposal. You may have to modify your interests to the areas where the money for grants are. To a certain extent, it's still publish or perish." NCHGR's Brody isn't so sure that the genetic testing industry will actually reach the big time. Brody, a veteran of the BRCA1 wars-he was a member of one of the losing teams in a four-year international competition to uncover a gene responsible for hereditary breast cancer-says that the big dollars lie with pharmaceutical companies willing to invest in gene discovery in hopes of developing therapeutics based on those genes. He believes that drug companies aren't counting on genetic testing to be a major income earner. Testing presymptomatic individuals may have limited value and may ultimately be used only in research studies. Rather, companies are counting on the next generation of therapeutics coming from the new genes being discovered today for Alzheimer's disease, diabetes, cardiovascular disease, and cancer. Such drugs would be targeted at a gene's activities-its protein products as well as cellular and molecular pathways. Some company representatives acknowledge that it's not necessarily the gene they seek, noting that they would prefer random genetic sequences to be part of the public domain and thus accessible to all. In the case of BRCA2, placing a certain nucleotide sequence in a public database sped up the discovery process. As Brody explains, pharmaceutical companies want the "technologies and novel discoveries" protected by patents. A growing list of biotechnology and pharmaceutical companies are willing to invest in a next generation of therapeutics, anticipating potential gold mines in drugs springing from genes. Companies such as Amgen; Myriad; and Millennium Pharmaceuticals in Cambridge, Mass., seem to agree that controlling disease genes will be the key to new drug research and development in the coming decades. Myriad, for example, has alliances with three drug companies-Ciba-Geigy Corp., in Tarrytown, N.Y.; Bayer Corp. of Pittsburgh; and Eli Lilly-that provide support for the discovery and characterization of disease-predisposing genes. HGS has a number of drug-development deals with companies such as Philadelphia-based SmithKline Beecham. If the multimillion-dollar Myriad investment in BRCA1 appears extravagant, Haseltine points out, it pales in comparison with a pharmaceutical company's research and development spending to usher a drug through the federal approval process. But Haseltine doesn't see presymptomatic testing becoming a thriving industry any time soon. He's convinced that neither the marketplace nor the public is ready for such testing, certainly not on a widespread basis. In fact, he thinks Myriad is taking a huge gamble in banking on a diagnostic test for BRCA1. "There's no demonstrated market for predictive genetic tests," he says. Futreal argues otherwise. He acknowledges that companies such as Myriad and OncorMed have invested millions of dollars in isolating genes "under the notion that there will be a huge market for these diagnostic tests without knowing what the genes will be, even when they are isolated, and how applicable they'll be for drug therapy." Yet, he says, "it's not that big a gamble because you can always test for a gene mutation for a predisposition, and that's useful to identify people at risk. It's a potentially huge market, particularly when you consider the larger number of diseases, such as Alzheimer's, heart disease, and cancer." Indeed, a news article in Science (R. Nowak, 265:464-7, 1994) shortly before the announced discovery of BRCA1 suggested that "like prenatal testing in the 1980s, predictive presymptomatic genetic testing for diseases that hit later in life is destined to become a medical boom industry." But a genetic testing or a disease drug market is "not there yet," Futreal comments. "We still don't know what either of the breast cancer genes do, for example-that's the next step. We know when they're not working, but the question is, what does it do when it's normal? There's no way to predict how long that step will take." Teams led by researchers at Vanderbilt University and the University of Washington recently took that initial step when they reported the first direct evidence of BRCA1's normal function (J.T. Holt et al., Nature Genetics, 12:298-302, 1996; R.A. Jensen et al., Nature Genetics, 12:303-308). The Hutchinson Cancer Research Center's Stephen Friend agrees that the task of biotech companies will not be in discovering new genes, but rather, "sorting them." "The coming puzzle in the post-genomic era-once the genes are sequenced-is to define their roles," he notes. "The money spent on finding genes will have to be switched to validate the targets worthy of drug discovery." It's hardly an easy job. Take the obesity gene, for example. Friend points out that the therapeutic target of the gene "had to be redefined-is it the ligand, the receptor, or the output of the receptor?" And while he agrees with Haseltine regarding Myriad's testing gamble, Friend also predicts that "the analysis of tumor suppressor genes will unquestionably be a growing market." Industry is also complicating life for the traditional genetics testing provider-the university-based diagnostic laboratory, says Elliott Hillback, president of Framingham, Mass.-based Integrated Genetics (IG), a division of Genzyme Corp. Academic labs can't compete with the growing number of corporate-based, genetics diagnostics labs, Hillback believes, which will likely put the former out of the business of commercial testing. "We don't want to usurp the clinical piece of what academia does-they have the primary-care physicians and specialists for that," he notes. "We can do the laboratory piece. We can offer an ongoing contract for clinical services to interface with customers. "You'll see a consolidation of the genetics industry and genetics academic community," he contends. "They'll be linked to service laboratories outside the university." Hillback predicts that "we're moving toward the era of gene-based medicine where the underlying genetic causes of diseases are better understood." He suggests that genetic testing will range from disease predisposition to diagnosis to differential diagnosis in order to plan individual therapy. "On the therapy side, you'll have different ways to use genetics to design better drugs and gene therapy," he says. "Industry is saying that gene medicine will offer huge opportunities in the next 20 to 30 years and we better get our feet wet. "The good news is that it will be a great opportunity," he asserts. "The bad news is, no one knows when."

Researchers View Genetic Testing With High Hopes, But Caution

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