Policy Day

BIO2003: Reporter's Notebook

Washington, DC.—On Tuesday, the second full day of the world's largest biotech confab, I devoted myself to public policy and bioethics. Some small interesting bits of science and technology did, however, sneak in.

One side note—unlike previous gatherings, I have not seen a single anti-biotech protester at this year's conference. The organizers of BIO 2003 must be very pleased with themselves for scheduling their event at the same time as the Sacramento Ministerial, which is attracting a bit of anti-biotech protest activity, though less than the activists had hoped.

Who Owns the Genome?

This early morning panel was packed with legal talent discussing the mess that biotech patents are now in. Early on in the development of biotech patents, merely characterizing the genes and a method for isolating them was enough to claim patent protection. This led to the Gene Patent Rush of the 1990s, which made the California Gold Rush look tame. Now, it's coming time to sort out where scientists and corporations stand.

Discussing patent law, as valuable as that is, causes the eyes to glaze over faster than counting sheep. To cut a long session short, Barbara Caulfield, the general counsel for the gene-chip maker Affymetrix, warned that her company was hearing from researchers that patent licensing hassles were distorting their research agendas. "If a researcher wants to investigate proteins 1, 2, 3, and 4 for their roles in a disease," she said, "and there is an aggressive patent holder for protein 1, the researcher will skip 1 [even if it's more promising] and do 2, 3, and 4 first."

Affymetrix is advocating a controversial shift away from the current system, in which entities like individual genes and proteins can be patented, to one in which things like genes, proteins, haplotypes, single nucleotide polymorphisms (SNPs), and exons are treated as "catalog items"—no more patentable than elements like iron, carbon, and oxygen. Patents, Caulfield argued, should be awarded to functional inventions, such as new diagnostic tests or new drugs. Shifting away from genes to tangible inventions, she claimed, would benefit industry in the long run by providing "more predictability, more rationality, and more stability," which would in turn improve the biotech investment climate. Still, Caulfield acknowledges that some 70 percent of human genes are available, patent-free, in public databases.

Lawyer Reid Alder of the J. Craig Venter Science Foundation looked 10 years into the future, "when each of us have our whole genome available on CD ROM or USB chip or whatever storage media available then. We will then also be able to check the latest genomic research online for new studies to see if our genetic profiles reveal any particular disease susceptibilities." Adler believes that the future medicine involves finding disease susceptibilities based on genetic profiles of combinations of hundreds of genes. But such genetic profiling will only be possible if the testing companies are able to include a large number of probes for a wide variety of gene variants on the test biochips. Adler pointed out that, as of today, researchers have already developed 984 genetic tests—626 for diseases, and 358 for research purposes. If someone wanted to combine all these tests, they would have to seek licenses from the patent holders of all 984.

"What we don't want is for people to throw up their hands and not do genomic research because 984 people want 1 percent of the combined test's income stream," Adler said. "It can't work like The Producers, where every investor gets half of the income from a Broadway show." In this case, at 1 percent each, that would add up to 984 percent. "We need to encourage cost-effective mechanisms to consolidate patent rights that might impede genomic medicine," he declared.

Adler is also concerned because recent court decisions have apparently narrowed the "research exception," in which researchers could use patented products and processes without paying for a license. Another court decision, he said, is limiting researchers' "FDA exemption"—unlicensed use of patented products and processes for the purpose of creating data for submission to the Food and Drug Administration. He thinks both of these decisions will slow and distort research agendas.

Robert Blackburn, vice president and chief patent counsel for Chiron, advised patience. In his view, meddling now would only make things worse. Let the court decisions catch up to where the science is now, is his advice. Blackburn claimed that there is very little evidence that research is being prevented by the plethora of research patents. However, he offered a solution to any patent-created blockage that truly damages public health interests: "My analogy is the military jet," Blackburn said. "There are thousands of patents that cover a military jet, but there is no problem building one. If the U.S. infringes a patent, the only remedy is to go to the Court of Claims and ask for damages. Similarly, where health care is central, the National Institutes of Health should be able to infringe on a patent, and patent holders go the Court of Claims for damages."

To me, this "solution" seems a bit clunky and filled with uncertainties sure to scare off investors. Again, without wading into the briar patch that is biotech patent law, the Affymetrix proposal seems promising—simplistically put, it is a long-established principle that entities found in nature are not patentable. Things that are patentable are new, non-obvious, and useful. This provokes furious argument over exactly what those terms mean, but the fact is that for researchers it is now child's play to isolate new genes and characterize them—this, to me, seems to violate the non-obviousness provision of patentability.

Is There Genetic Discrimination?

Next up was a panel on the vexing question of what should be done about the specter of genetic discrimination. Robert Cook-Deegan from Duke University noted that the number of genetic markers is increasing enormously. When he was an Alzheimer's disease researcher in the 1970s, there were about 70 such markers, including things like the ability to roll one's tongue, and funny smelling urine after eating asparagus. As I heard earlier, there are now nearly 1,000 genetic tests.

The concern is that insurers and employers can use this genetic information to discriminate against employees and clients. Cook-Deegan did note that there is not much evidence to date that this is in fact happening. Later, the panelists would agree that there have been some weird outlier cases, e.g. when Burlington Northern had 36 employees tested for genes associated with carpal tunnel syndrome, with the apparent goal of denying them future compensation on the grounds that they had a pre-existing genetic condition. As we shall see at a later panel, genetic information is not peculiarly susceptible to misuse, and doesn't need any more protection than regular medical information.

Henry Desmarais from the Health Insurance Association of America agreed that there was little evidence that insurers are using genetic information to discriminate against clients. He also noted that the new Health Insurance Portability and Accountability Act regulations already protect the medical privacy of all Americans enrolled in group health plans. However, Desmarais did point to the problem of adverse selection. "Suppose there were a test for whether your house was going to burn down in the next 12 months," he offered. "Fire insurance wouldn't work well if the only people who bought it were people whose houses were going to burn down in the next year." Similarly, neither would health insurance if only people who knew that they were going to need it soon bought it. Insurance works because people are willing to take a small loss now in order to avoid the risk of a large loss later.

Cook-Deegan offered a concrete example of how adverse selection might work in long-term care insurance. There is now a test for three different versions of the APOE gene: APOE2, APOE3, and APOE4. People with either one or two alleles of APOE4 are at higher risk for Alzheimer's disease—APOE4 accounts for between 25 and 50 percent of all Alzheimer's cases-and the disease afflicts a large proportion of people needing long-term care in the United States. A person could take the APOE test and if he or she had APOE4 alleles, he or she could buy long-term care insurance from an insurer who does not know that he or she is at higher risk. Unless they can find out who is at risk, prudent insurers will charge everyone a higher premium on the presumption that only people who know they are at risk will seek out such insurance. This raises the cost for people who want to guard against things like being paralyzed in a car accident. Cook-Deegan asked: what's wrong with this situation? He answered: perhaps nothing, if you're comfortable with the notion that people at higher risk pay higher premiums. For the record, I am generally comfortable with that outcome.

Of course, this being Washington, there is someone who wants to legislate a solution. Cynthia Pellegrini, who honchos health care issues for New York Democratic Congresswoman Louise Slaughter talked about her boss' proposed bill (HR 1910) to prohibit genetic discrimination in health insurance. Pellegrini noted, "Genetic discrimination is not widespread, but wouldn't it be nice to get ahead of the curve for once before the problem becomes endemic?" This effort seems to me like yet another federal effort to solve a nonproblem and unnecessarily complicate the development of markets to handle such issues.

Desmarais noted, "When we buy insurance for a bigger house, we pay more. When we buy insurance for a more expensive car, we pay more. If I'm a smoker, I have to pay more for life insurance. But when it comes to higher risks in health care, no one thinks twice about why lower-risk people should pay as much as higher-risk people." Well, some of us do too think twice about that.

Stem Cells and Cloning Update

This panel, ably chaired by BIO's own in-house bioethicist Michael Werner, looked at where we stand today on the issue of using human embryonic stem cells. The first presenter was Michael Manganiello, a vice president from the national pro-stem cell research umbrella group, the Coalition for the Advancement of Medical Research (CAMR). "The work you do is at risk of being closed down by the Human Cloning Prohibition Act of 2003," he passionately warned the assembled BIO members. Werner noted that President Bush, in his first ever speech to the nation in August 2001, limited federally funded research to only 64 stem cell lines. It turns out that only 11 are in fact available, and that's not enough.

CEO Thomas Okarma of Geron Corp., which paid for the research that developed human embryonic stem cells, spoke next. Geron is working on seven different advanced cell types derived from embryonic stem cells, including islet cells for producing insulin for curing diabetes, neuronal cells for repairing damaged spinal cords, dopaminergic cells for replacing brain cells lost to Parkinson's disease, and cardiomyocytes for replacing tissues damaged by heart attacks.

Okarma showed us a video of a mouse whose spinal cord had been damaged, but which could walk because it had been repaired using human neurons derived from embryonic stem cells. Okarma favors research in both adult and embryonic stem cells, but argues that only embryonic stem cells offer the possibility of large-scale clinical use. Why? Because, unlike adult stem cells, embryonic stem cells can be multiplied without limit. Okarma outlined how a line of embryonic stem cells might be used to treat thousands of people—first, patients would be chimerized (share cells from two different genetic sources) by transplanting bone marrow stem cells into them. This procedure could induce immunological tolerance so that when the neuronal stem cells are transplanted from the same genetic line of stem cells, the patients' bodies would not reject them. Such patients would not have to use immuno-suppressant drugs like other transplant patients must. Okarma boldly predicted that clinical trials for transplanting human embryonic stem cells in patients would begin within the next two years.

Because embryonic stem cell research is under threat here in the United States, Geron has established a lab in the United Kingdom, where stem cell research is welcomed. Okarma did complain, however, that Geron didn't feel very welcome, because Britain's Human Embryology and Fertilisation Authority took 18 months to approve the company's research proposals. In the meantime, Geron has used private funds to already begin deriving new embryonic stem cell lines at Stanford University.

Lawrence Goldstein, a researcher from the Howard Hughes Medical Institute, noted that a lot of the political pressure to ban stem cells comes from the fear that the cloning techniques used to produce them would also be used to produce a cloned baby. Goldstein complained that bioethicists love to talk about banning the precursors to any activity they think might be harmful. However, this is silly. "I could use a hammer to wage war on my fellow citizens, but we don't ban hammers," he noted. "A wise society penalizes the acts it wants to prohibit." If we went around banning the precursors to all types of undesirable activities, we would never get anything done. His conclusion was we should ban reproductive cloning while permitting cloning to produce therapeutic stem cells.

Are Genes Really Different?

Thomas Murray, head of the Hastings Center, the nation's first bioethics think tank, talked on this final panel about his concerns about what he calls "genetic exceptionalism." Basically, is genetic information "different, special, deterministic, occult and toxic?" His answer is no. Murray asked us to consider a thought experiment with two buckets—one labeled genetic and the other non-genetic. First, he asked us to think about Huntington's disease, which is inherited and caused by long repeats in a specific gene, and is uniformly fatal. Is that genetic? Yes. What if I had been killed by a taxi as I walked across L Street to the Convention Center? That's non-genetic. (OK. Perhaps I got run over because I have genes for a risk-taking temperament that makes me an inveterate jaywalker, but let's set that aside.) But what about high levels of cholesterol? Well, genes certainly play a role, but a doctor doesn't tell her patient to change his genes, she tells him to change his lifestyle, eat better, exercise more. Exposure to asbestos and smoking increase one's risk of disease too, and they are not genetic.

Murray's point is that genetic information in the health care context is not different than other types of health-related information. Therefore, he does not believe that we need specific legislation for protecting genetic privacy or preventing genetic discrimination. He is worried that if we treat genetic information as toxic and scary, it will become a self-fulfilling prophecy, and people will begin to discriminate on the basis of genetic information even if there is no good scientific reason to do so. Murray wants to tame and domesticate genetic information.

Bioethicist Pilar Ossorio from the University of Wisconsin essentially agreed with Murray. She warned against "'genetic fetishism,'" which is the excessive mystical power of DNA. Altough, she didn't single anyone out, I would suggest to you that people on the Right like the President's bioethicist Leon Kass, and people on the Left like Jeremy Rifkin, are strong genetic fetishists, believing that there is something unholy about tinkering with DNA in plants, people, and animals. Ossorio also cautioned against genetic essentialism, which is a strong belief that one's particular constellation of alleles is who one is. A person is much more than his or her genes, e.g., a brain and body both deeply affected by experience. There is also an unlovely resonance between genetics and folk beliefs about "blood connections" such as family, nation, and race. "If we do treat genetic information differently, we reinforce incorrect beliefs about DNA," Ossorio concluded.

The final speaker was bioethicist Kathy Hudson from Johns Hopkins University, who has worked on the genetic nondiscrimination bills that are wending their ways through Congress right now. She believes that it is important to make it clear that genetic information is no different than any other kind of health-related information, by making sure that it is specifically protected in federal privacy and discrimination laws.

A curious kind of disjunct occurred during the question-and-answer period over the issue of direct-to-consumer marketing of genetic tests. Ossorio mentioned that she had been approached by a company that wants to market a new genetic test that allegedly predicts subsequent violent behavior in children who have been abused. That does seem problematic—one can envision full-page ads in the journals for criminal lawyers immediately. So all three panelists evidently wanted regulation to stop direct-to-consumer marketing of genetic tests.

Yet, it seems to me that one of the best ways to domesticate this technology is through marketing, by letting consumers become familiar with what genetic tests can tell them, and more importantly, what the tests cannot tell them. Sure, there will be hucksters and initial misunderstandings. But Americans would become much more comfortable with genetic information, and realize that it is not something occult or toxic by encountering it for themselves in the hurly-burly of the market, rather than through the auspices and at the behest of white-coated medical mandarins.

Today is the final day of BIO 2003, and I will take a brief look at some new biomedical technologies that are being devised to keep us alive and healthy longer.