How could a scientist make one of the biggest discoveries in his field, and yet come perilously close to losing his job? That's what Bruce Gold has been asking himself lately. A researcher at Oregon Health Sciences University, Gold made one of the most promising neurological breakthroughs in recent medical history--certainly one of the biggest ever made in Portland. Since making the discovery, however, Gold has been unable to raise money for research. Equally painful, he has watched another scientist reap the benefits of his efforts. "The way I've been working these last few weeks and months," Gold says, "is just not right." In cruel irony, as Gold's frustrations have mounted, news reports of other researchers' breakthroughs have swept the nation. In the past two weeks, scientists have heralded a drug that shrinks tumors in mice and a major success in the treatment of breast cancer. As the Viagra phenomenon shows, the rewards for bringing basic science to the market can be enormous. But as Gold has learned, the journey from the laboratory to the pharmacy is littered with roadblocks. His discovery could have an impact on hundreds of thousands of lives. And yet, because he's first and foremost a researcher, rather than a businessman, Gold is so fed up that if he doesn't get fired, he might quit. Carved into the hillside behind OHSU is a low-slung bunker that houses the Center for Research on Occupational and Environmental Toxicology. On the building's third floor, hidden behind a warren of labs, is the office of Bruce Gold. With his hairline marching north and a perpetually dour expression, Gold, 43, resembles the comedian Steven Wright, in both appearance and self-deprecating irony. He has the gaunt, driven look of a long-distance runner--he's completed the past five Portland marathons. Gold's office displays similar discipline. It's lined with precisely arranged reprints of articles he has written with titles such as "Axonal regeneration of sensory neurons is delayed by continuous intrathecal infusion of nerve growth factor." His office also displays a lighter side. A model of the Starship Enterprise constructed from spare lab parts hangs from the ceiling; next to a bookcase are Jimi Hendrix and Pink Floyd posters. A "Boycott Gardenburger" sign on his office door echoes his past as a student activist at Boston University. "Make no mistake about it," Gold says, "I inhaled." Gold is one of more than 650 scientists at OHSU. Although he teaches some graduate courses, like many of his colleagues, he is primarily a researcher. OHSU scientists are engaged in more than 1,600 projects; the work ranges from trying to understand how melatonin regulates sleep to the perfecting of artificial heart valves. In recent years OHSU has expanded rapidly, thanks to former Sen. Mark Hatfield, who funneled millions of dollars to the university. Today, its maze of discordant architecture spills across Marquam Hill like a landslide of Lego blocks. More than 8,600 people work at OHSU, making it the largest employer in metro Portland. Although the region's high-tech industry gets more attention, OHSU is on its way toward generating a biotech cluster similar to those that have sprung up around medical centers in Boston and San Francisco. In the past few years, one of the most promising bodies of research done on the hill has been Bruce Gold's. Gold's breakthrough was equal parts genius and luck. In 1983, his younger brother Michael contracted Wilson's disease, a rare liver ailment. Near death, he went to the University of Pittsburgh, then the only place in the country doing liver transplants. At the time, other organ transplants were already common, but the technical difficulty of liver transplants made them extremely rare. Eight months and three livers later, Michael left the hospital. For years, he lived a normal life, working as a physicist in Chicago. Then, in 1991, his body's immune system began to reject the donated liver. His doctor held out one slim chance for survival--an experimental drug from Japan called FK506. Within weeks, Michael Gold's condition stabilized. As his brother recovered, Bruce Gold devoured all the available scientific literature about FK506. He learned that the drug suppressed the immune system by inhibiting calcineurin, an enzyme in the white blood cells that caused the body to reject the liver. Only someone with Gold's background in neurological research could have noticed the startling coincidence he found: calcineurin was also a major component of nerve cells. Gold was intrigued. If calcineurin acted as a switch in white blood cells, might it have the same function in nerve cells? The possibility was breathtaking; no drug that could effectively alter nerve growth had ever been found. With a supply of FK506 borrowed from his brother, Gold rushed back to his lab at OHSU. Two types of nerves exist in humans: peripheral nerves, which occur throughout the body, and central nerves, which occur in the brain and spinal column. When a carpenter smashes his finger with a hammer, peripheral nerve damage occurs. Over time, these nerves will slowly regenerate on their own. Central nerves, which are more crucial and less understood, do not grow back. The high-profile accident of Christopher Reeve, in which the actor damaged his spine, is an example of a central nervous system injury. In 1992, Gold crushed the legs of a group of lab rats. He treated half with FK506 to see if the drug would make the nerves in their legs grow back faster. "It was an emotional roller coaster waiting for the results," he says. He could barely leave work each night. "I used to drag my wife into the lab on weekends," he recalls, " to videotape the rats to see which ones were walking better." After two weeks, the results were in: The rats that had been dosed with FK506 regained nerve function significantly faster than their unmedicated brethren. Gold repeated the tests twice more. His data held up. For Gold, then a promising but undistinguished scientist, his work with FK506 was a major breakthrough. "A discovery of this magnitude comes along very rarely," says Simon Archibald, a leading researcher in nerve regeneration based in New Jersey. "People have been looking for this for 40 years." Others agree that Gold's work was a big stride forward: "The potential is so large," says Dan Santi, chairman of San Francisco-based Kosan Biosciences, "that it is mindboggling." Researchers believe that the most likely human application of Gold's discovery is the treatment of peripheral nerve injuries. Although Gold is cautious, others are more willing to speculate about the broader implications of his work. "What is not widely known or appreciated," Archibald says, "is that any nervous system disease is accompanied by nerve damage. Gold's work has application to Alzheimer's, multiple sclerosis and Parkinson's disease." Speeding regeneration in rats was only the first step. Gold needed more answers. How did FK506 work and what were its side effects? More research was necessary. Gold was very encouraged when his brother, who was taking FK506 daily, began regaining sensation in his lower abdomen. "If there was a defining moment," Gold says, "that was it. That was when I realized FK506 could someday have an effect in people." But as he learned, making a discovery is one thing; trying to develop that discovery to its logical conclusion is quite another. In 1993, Gold first presented his findings at a conference in Japan. But in order to achieve real scientific legitimacy, he needed to publish his results. "Research can't really properly be discussed until it appears in a peer review journal," says Joseph Madsen, a neurologist at Harvard medical school. That same year, Gold submitted his findings to the Annals of Neurology. The paper was rejected. He was told it was inappropriate for the journal. "I asked them to reconsider," Gold says, "and they told me, 'We might have just rejected one of the most important papers of the year.'" Still, the rejection stood. He and others believe that the novelty of his research and the hybrid nature of his experiment--using an immunosuppressant in nerve studies--made reviewers uncomfortable. That rejection was just the first of a series of setbacks that slowed Gold's progress. The most critical problem he faced was and is a lack of funding. Historically, the National Institutes of Health has provided most of the money spent by universities on basic medical research. The NIH awards three- to five-year grants judged by anonymous peer review committees. Competition is heavy, and approval requires more than bright ideas. "NIH funding is extraordinarily difficult to get," says neurologist Madsen, who has conducted basic spinal regeneration research at Harvard. Gold has applied for three NIH grants in recent years, proposing to fine-tune FK506 and study the regenerative mechanism. He still doesn't understand exactly how the drug works and how it could be improved. Those questions must be answered before clinical trials start. Nevertheless, Gold's grants have not been funded. There's an art to asking the NIH for money, it seems. "It's more than just science," says William Mobley, head of neurology at Stanford. "It's often how you pitch the experiments that counts." There are serious consequences to an NIH rejection. Not only does a lack of money curtail research, it may also cost a researcher his job. At OHSU, each scientist is required to fund 50 percent of his salary and all of his lab expenses, including assistants' salaries. Gold is currently surviving on a grant for research into Gulf War Syndrome and money his boss, Peter Spencer, gets from the state. But both men agree he has to find other money soon. Those familiar with Gold's work struggle to understand his funding troubles. "My sense is it could change tomorrow," Mobley says. Archibald adds, "Bruce Gold is someone who fundamentally understands what's going on in nerve regeneration, much more so than anyone in the field." But perhaps the best explanation comes from Spencer, who suggests that Gold's work has moved beyond the realm of basic research that the NIH traditionally supports: "It's possible," Spencer says, "that NIH peer reviewers perceive this as work that drug companies should fund." But drug companies only want to fund something they can own. To attract private funding, says Sandy Shotwell, director of OHSU's technology management office, "you need patent protection to show investors." And Gold never patented any of his discoveries. "I was so naive when I presented my original results in Japan," he says, "that I didn't realize once I talked about my work it was in the public domain." Fujisawa Corp. owns the patent on FK506, but Gold believes that OHSU could have applied for a patent on only the regenerative qualities of FK506. Had it done so, the university would have stood a good chance--and might have been able to control all subsequent drugs that mimicked FK506. Shotwell says OHSU didn't pursue a patent because Fujisawa initially did not want to supply FK506 to the university. Subsequently, however, Fujisawa began cooperating with researchers. In hindsight, the failure to pursue a patent was costly--and not just in financial terms. Because Gold has no patent on his discovery, others are free to take his work, alter it slightly and make it their own. Which is what Solomon Snyder appears to have done. Snyder is perhaps the leading brain scientist in the country. The longtime head of the Department of Neuroscience at Johns Hopkins University in Baltimore, Snyder, 59, is the author or co-author of more than 800 journal articles and a handful of books and is a member of the exclusive National Academy of Sciences. "Sol is enormously successful, incredibly brilliant," says Stanford neurologist Mobley. Snyder began studying FK506 in the early '90s. But although both he and Gold were working with FK506, their interests were different. Initially, Snyder was looking at how FK506 bound to proteins found in the brain. Gold was looking specifically at regeneration and the return of function. And Snyder was experimenting only with cells growing in a lab dish--not live animals. That's a big difference. "Everyone and his cousin has demonstrated regeneration in cell culture," says Archibald, "but then their drug is minimally effective in living organisms." In 1994, Snyder and Gold both published their first journal articles about FK506. As word got out that the drug might have more than immunological properties, Snyder continually received top billing. The New York Times and others published extensive coverage of Snyder's work with the drug, barely mentioning Gold. "It's been very uneven in the amount of press and accolades given," Archibald says. Others see the competition in a more positive light. "Sol is as clever as you can get at exploiting new knowledge," Mobley says. In 1993, Snyder co-founded Guilford Pharmaceuticals. One of Guilford's principal aims is to develop and patent drugs with characteristics similar to FK506. Last October, the bio-tech giant Amgen agreed to pay Guilford $48.5 million to develop and commercialize such drugs. The Amgen deal made Snyder's stake in the publicly held Guilford worth nearly $20 million, although the company's stock price has since declined. Beyond providing Snyder personal enrichment, the deal also gave Guilford substantial research funding--in quantities Gold could only dream about. Ironically, at a conference in 1995, a Guilford official expressed amazement to Gold when he learned that OHSU had never even applied for a patent on FK506's regenerative properties. That conversation was a low point in Gold's career--and no doubt a high point in Guilford's history. Gold has tried to get drug company funding. But without a patent, it has been difficult. He did some contract work for Guilford's primary competitor, Vertex Pharmaceuticals of Cambridge, Mass., but that collaboration has lapsed. And because Snyder is such a towering figure and already owns several patents, Gold worries that companies will continue to be more interested in funding Snyder. There's another problem as well. Gold believes that perceptions of his own work have been tarred by what he and others consider Guilford's excessive optimism. In other words, Guilford's rosy press releases may be overstating how quickly regenerative drugs will be able to help people. "I know for a fact," the OHSU scientist says, "that Sol Snyder's pushing the word out too fast has cut into funding that I might have received." Others agree. "When their initial results appeared, there was a lot of interest," notes Santi of San Francisco's Kosan Biosciences, "and then companies couldn't repeat what they said they'd done." Snyder disputes that notion. "GPI-1046 [the Guilford drug] has been great," he says. "It won't be the one that goes into clinical testing, but we're happy with it so far." He expects that as early the end of this year Guilford will begin the first stage of testing peripheral nerve regeneration drugs on human beings. Whoever gets there first, both Snyder and Gold want to prove that drugs derived from FK506 can improve human lives. As the two scientists look toward the future, they both remain optimistic. "It's clearly been established that these drugs stimulate regrowth of every type of nerve they've been exposed to thus far," Snyder says. Gold is excited about his recent work with rats' spinal cords. "My results show an ability of injured spinal neurons to grow," he says, then adds with characteristic caution, "they are responsive but show nothing with functionality yet." In Gold's view, the greatest disservice researchers can do is to raise people's hopes prematurely. "I got an e-mail the other day from a guy in Virginia who has ALS [Lou Gehrig's disease]. He said, 'I'll be dead in a year anyway, I'll take whatever you've got.'" Gold hopes that regenerative drugs will someday help treat such central nervous system disorders, but that day is far off: "If it comes to pass, it's just too mindboggling to think about; I try not to focus on it because it might not pan out." In order to make the leap to helping humans, both Gold and Snyder believe that scientists must identify the target that FK506 acts upon. Without it, researchers are shooting in the dark. Gold believes he has now found that target. "In my mind," he says, "it's a major advance." Gold has written two new grant proposals and has nearly completed a major paper detailing the discovery. He's more confident about NIH funding now, because his work on the target mechanism will mark a return to the basic science the agency favors. Drug companies have also heard that his new discovery may allow them to sort through the thousands of compounds that may be better than FK-506. This time around, though, Gold won't surrender the details of his work for free--OHSU has already filed a patent on the target. The pressure of writing the grants and the paper while knowing that Snyder and Guilford are moving ahead has made Gold wonder recently whether he should just take a job with a drug company so he can pursue his research without distraction. He hopes response to his new work will put an end to such thoughts. Gold is used to frustration--he's dyslexic. Although his parents and brother were excellent students, he struggled academically as a kid. For a time, school officials in his hometown of Montclair, N.J., even considered holding him back a year--dyslexia was just as unknown as FK506. The frustration he has felt in recent months reminds him of that time, when he couldn't figure out why the other kids could read faster. He's a marathoner, though, not a sprinter. "I've been knocked down a number of times," Gold says, "but I keep bouncing back up." --Ruth Rowland contributed to this report. |
