Sci. Aging Knowl. Environ., 22 October 2003
Eyes Wide Open
Science academics who take the path into commerce might find rude surprises awaiting. An insider's guide to the pros and cons of getting involved with the biotech industry
Ingfei Chenhttp://sageke.sciencemag.org/cgi/content/full/sageke;2003/42/nf19 This article comes to you through a collaboration between SAGE KE and Science's career development Web site, Next Wave. The joint venture is supported by the AARP Andrus Foundation. In 1992, when molecular biologist Carol Greider joined the scientific advisory board at Geron Corp., it seemed like a good fit: The biotech start-up was inspired by her research on telomeres, the repeated stretches of DNA that cap and protect the tips of chromosomes. Greider, a young new investigator at Cold Spring Harbor Laboratory (CSHL) on Long Island, New York, and her collaborator, molecular biologist Calvin Harley of McMaster University in Hamilton, Ontario, had shown 2 years earlier that telomeres shorten with each cell division. The scientists speculated that when chromosome tips get too stubby--a process that can be reversed by telomerase, an enzyme made up of protein and RNA--cells cease replicating and enter a state called senescence (see "More Than a Sum of Our Cells"). Building on this "telomere hypothesis," Geron's big idea was that tinkering with telomerase in cells could stave off their senescence--and prevent aging.
In addition to tapping Greider's expertise as a consultant, Geron was also supporting research in her lab to the tune of $90,000 a year for 3 years, starting in 1993. But over time, the partnership soured from conflicts over turf. Greider and Ariel Avilion, a grad student working in her lab toward a Ph.D. from the State University of New York, Stony Brook, were attempting to find and isolate the gene for the RNA portion--dubbed hTR--of human telomerase. Geron's team of investigators, including Harley, who had moved to the company and is today its chief scientific officer, was eager to jump on the problem. According to Harley, after initially respecting Greider's wishes to keep the project within her lab, the company worked out an agreement with her to collaborate and put its people on the hunt, using different approaches from hers.
The Geron crew identified the DNA sequence of hTR in 1994, publishing it in September 1995 in a Science paper with Greider and Avilion. After isolating the gene, the company "started being fairly aggressive about protecting its rights in terms of who actually did what," says Greider. When it filed for a patent on the gene, it didn't list the academic collaborators as co-inventors, although Greider maintains that her lab contributed biochemical protocols for purifying telomerase that were crucial to Geron's discovery. And in spring 1995, when Avilion wanted to include the hTR sequence in her dissertation, the company tried to stop her out of concern that doing so would harm its patent application, Greider recalls.
Geron's position, says Harley, is that it cloned hTR without using the Greider lab's protocols. Ultimately, Greider and CSHL's intellectual property office decided not to pursue the patent dispute--"I would rather just do science than spend my time in court," she says--but she prevailed in ensuring that Avilion could cite the gene sequence in her dissertation.
For Greider, the final straw came in 1996 when she wrote an article for the Annual Review of Biochemistry. The idea that shrinking telomeres play a role in organismal aging had been hyped in the media and by Geron's public relations division, she says. Greider pointed out in her paper that longer telomeres do not correlate with greater longevity in animals. After the article was published, she recalls, "I got a phone call from Cal Harley, and he told me that he felt that I wasn't supportive enough of the telomere hypothesis. And I explained to him, 'You don't support a hypothesis. You test it.' "
Harley recalls the conversation differently; he says he told Greider that she had not presented a "balanced perspective" of evidence suggesting a potential role of telomeres in age-related diseases. "That was not corporate pressure; that was scientist to scientist, talking about logical interpretations of the data," he says.
But with the complaint coming as it did from the chief scientific officer of the business she consulted for, Greider didn't see it that way, and shortly thereafter, she cut her ties with Geron. In retrospect, she says she walked into the situation with too much naiveté and not enough skepticism. "I wish that I knew then what I know now, because I would have dealt with it differently and been more sophisticated about it," says Greider, who currently heads the department of molecular biology and genetics at Johns Hopkins University School of Medicine in Baltimore, Maryland.
Greider's experience--recently highlighted in Merchants of Immortality (see "Advanced Sell Technology")--is a cautionary tale for any academic who's considering a foray into industry, whether by joining, founding, or collaborating with a company. Commercial science and academic inquiry hold fundamentally different goals--the generation of profitable products versus the generation of knowledge--that are often at odds. Researchers in academia, who generally have little knowledge of how the private sector works, can find themselves unprepared to handle the conflicts that naturally arise between the two worlds.
"The rules of the game are different, and I think you really have to have a sense of who you are and how you like to do things as a scientist," says molecular biologist Neil Howell, who spent 30 years in a university setting before becoming vice president for research at MitoKor, a San Diego, California, biotech company, in 2001. Veterans with corporate science experience advise that academic investigators interested in engaging industry should walk in with their eyes wide open: They should understand the underlying motivations that drive commercial ventures, carefully weigh the upsides and downsides of the company science culture, and, in partnerships, negotiate compromises that they can live with.
The Profit Motive: Turning Industry's Wheels
Leaving the ivory tower for the corporate sector requires a basic shift in mindset about scientific goals and how to achieve them. Academic investigators typically thrive on exploring an area--presuming that funding is available--for the sake of learning what makes things tick. The mission for industry scientists, however, is conducting applied research to develop a profitmaking product for the company, says molecular biologist Matt Kaeberlein, who co-founded a start-up called Longenity in Waltham, Massachusetts, and served there as vice president after finishing his Ph.D. at the Massachusetts Institute of Technology in 2001 (see "Rookie Rising"). "If you can learn something really cool about science in the process, that's great. But the primary goal is not the accumulation of knowledge, it's the accumulation of wealth." Scientists in biotech or pharmaceutical companies might feel motivated by their role in bringing to society drugs that would never be invented otherwise, says Kaeberlein. "But again, that's only going to happen if the company can make money from it. That's capitalism."
Corporate success, says Howell, hinges on two ingredients: brilliant ideas and patents. Patents are the lifeblood by which companies stake out intellectual property and survive. So at each step of the research process, he says, "you have to evaluate what you have done and say, 'OK, does this have commercial value?' If it has commercial value, you want to build a fence around it."
The Power to Pursue Hot Science
When biotech companies decide to pursue an idea, they can do it with a speed and commitment of people, money, and resources seldom seen in university labs. "We will sit down and [ask], 'What is it going to take to do this?' And you can make it happen very quickly and easily," says Howell, who spent his academic career studying the genetics of mitochondria--the energy generators of the cell--before moving to MitoKor, which is targeting mitochondrial defects that contribute to illnesses including Alzheimer's disease and diabetes.
Howell, who retains a part-time appointment at the University of Texas Medical Branch (UTMB) in Galveston, recalls that one of his frustrations with academia was that "the bureaucracy is suffocating at times." For instance, at UTMB, scientists who want to protect good ideas with patents must file paperwork that goes through various university offices and the state board of regents, an approval process that can take months. But at MitoKor, he can authorize spending the money to file for a patent--and get the paperwork submitted by the following week. "That's almost aphrodisiacal," he says, "in terms of feeling like, 'Wow, I can really get things done.' "
The ability to make things happen in corporate biotech was "a profound eye-opener for me," says geneticist Kenneth Carter, co-founder and CEO of Avalon Pharmaceuticals, a start-up in Germantown, Maryland. A company's leaders can swing dozens of scientists toward a single problem without having to worry about the politics of sharing equipment or skills. "It's tremendously exciting to have 40 people around you focusing on the same thing," he says. Carter and his colleagues set up Avalon to aggressively tackle harnessing genomic information to speed up the preclinical drug discovery process. The company's scientists are examining gene activity in cancer tissues "at a level that you never dream of in an academic laboratory because you wouldn't have the funding to do it," he says.
The opportunity to feed his addiction to cutting-edge science lured Carter away from academia. In 1993, after 4 years of postdoctoral training at the University of Massachusetts Medical Center in Worcester, he took a job at then-fledgling Human Genome Sciences (HGS) in Rockville, Maryland, where he developed the company's gene-mapping program. At a time when the rest of the scientific world had identified a total of 500 human genes, HGS and its nonprofit collaborator, The Institute for Genomic Research, were finding 500 new ones every month. "I just thought, 'This is just the most exciting place I could possibly be,' " Carter says.
Similarly, when Frederick "Fritz" Roth finished his Ph.D. at Harvard Medical School in Boston in 1998, he found that the best work in genomics and bioinformatics--his main interests--was being done in industry. He had spent half of his graduate years working with one small DNA microarray data set, but Millennium Pharmaceuticals in nearby Cambridge was "printing microarrays to beat the band; they had hundreds." One of the company's subsidiaries, Millennium Information, was building a paid-subscription database of genomic and proteomic information and creating software to analyze it. The chance of access to that gold mine of data tantalized Roth. "The science was good, and there was the potential to make more money," he says, so he joined the subsidiary.
Tradeoffs in Scientific Freedom
But jumping onto the corporate bandwagon requires giving up the reins, and a major downside of industrial science, says Roth, who is also a co-founder of Longenity, is "not being able to choose your project." If you can't convince company management that your research idea is potentially profitable, "then you don't get to do what you most want to work on." Furthermore, the project you're assigned to can get dropped, because a company's research plan is always evolving in response to changes in funding or to feedback from investors or the board of directors. "You've got to really be flexible," says Kaeberlein. "In academics, you can sort of take the time to follow leads, to follow weird results; in companies, you really can't."
For Roth, the lack of control over his research destiny at Millennium wasn't worth it. Although he enjoyed the highly social environment of the bioinformatics subsidiary that hired him, within a few months the group changed goals when it merged with Millennium's predictive medicine subsidiary. The resulting entity was later absorbed back into the parent corporation, prompting further changes in research focus. "One day I was asked to drop everything for a week and work on a project I didn't find very interesting," Roth says. At about that time, he saw an advertisement for a position in computational biology at Harvard, and he decided to apply for it. In 2000, he left Millennium for an assistant professorship at the university.
Perhaps the greatest point of tension between the academic and commercial worlds arises over the exchange of information. "Almost everyone who comes out of an academic environment is bred pretty strongly to believe that publication of scientific data and having your individual name on [a publication] is a very valuable thing," says Carter. But that view is often incompatible with the goals of for-profit organizations, which are loath to present results at conferences or in journals for fear of jeopardizing their intellectual property portfolio or losing a competitive edge.
Kaeberlein found company restrictions on sharing and discussing his science "very, very frustrating. You can't call up your friend who's a professor somewhere else or who works at another company and tell them what you're doing and get their opinions on it." Carter, too, acknowledges that when he first moved to industry, adjusting to restrictions on publication was "a pretty big deal." Although HGS placed a relatively high priority on putting out papers early on, he still couldn't write as many articles as he wanted. "It took me, frankly, quite a while to come around to understanding that unlike the $10 zillion endowment that U. Mass Medical School had, if we didn't hit our business goals at HGS, HGS would cease to exist." Running the next experiment to get HGS's candidate drugs closer to market was more important than writing a paper. And no company wants to alert the competition to what it's doing.
At Avalon, Carter says he and the scientific management constantly weigh the implications of publishing data for the company's intellectual property strategy against the benefits for its reputation and individual scientists' careers. For instance, company researchers have recently identified a promising new genetic marker for a particular cancer; because Avalon already has all the patents filed on the discovery, Carter and the management team recently gave the scientists the go-ahead to write up two papers on the work.
Similarly, Howell says, each paper that MitoKor publishes undergoes review by him, the business development division, and a patent lawyer; scientific presentations for meetings are similarly vetted, "because we need to know, are we disclosing the wrong thing at the wrong time?" Some publications can sail through within a day or two, Howell says. But other articles take months or longer to clear--or never see the light of day--because they contain sensitive material. The company has to consider whether it needs to file for a patent or whether it's in negotiations with another outfit that might be interested in the technology, Howell says. Some companies won't publish anything until the appropriate patent has been issued, which can take well over a year.
On the whole, Carter and other industry scientists argue that companies' tendency to withhold data is not so different from what goes on at universities. "Anybody who's been in serious, aggressive science in academia can tell you stories about people holding back key parts of data," he says, "because they want to get a little bit farther down the road before they publish it."
The opposing perspectives on data sharing can clash most fiercely in collaborations between professors and companies, but academics can help avoid disputes by determining up front the details of their ability to write up their results. With Geron, for instance, Greider says she was lucky because in negotiating the details of the research agreement, CSHL was adamant about ensuring that she could publish any of her company-sponsored findings. "Not all institutions have the same rules," she says, noting that some research centers have let their scientists sign a contract that bars them from publishing at all. "No investigator at Cold Spring Harbor would ever have been allowed to sign that."
Under her agreement, Greider permitted Geron 30 days to review any article resulting from their collaboration before she submitted it to a journal, so that company officials could determine if they wished to file a patent on the science. If one plays such a deal carefully, she says, it doesn't pose much of a burden: She would give Geron a preprint of her paper at the same time that she was working with the people in her lab to produce a final draft--a process that typically took a month anyway.
But even when lab heads who accept corporate funding preserve their freedom to publish after a relatively short, 1- or 2-month review period by the company partner, Boston University gerontologist Thomas Perls warns of another potential downside: Their reputations within academic circles might take a hit. In 2002, Perls (see "Chasing 100") and his associates turned to venture capitalists to kick-start a company, Centagenetix (which later merged with Elixir Pharmaceuticals; see "Joining Forces"), to facilitate an expensive, high-risk hunt for longevity genes in centenarians. After he established the company, Perls says, some of his academic colleagues seemed to demote him to "second-class citizen" status because they believed he was no longer on the same playing field in terms of openly sharing information and having access to funds and resources.
Some university professors are wary of scientific data that companies release. Steven Austad, an evolutionary biologist who studies aging at the University of Idaho in Moscow (see "Taming Lions, Unleashing a Career"), says that when colleagues express outright disbelief about a particular scientist's results, it is usually because that investigator holds a major stake in a business that's close to producing a product. Austad says he views any paper or presentation from the CEO of a company as pure advertising: "When people have a financial motive for their experiments to turn out one way and not another, then I'm always going to be suspicious of the results." In academia, scientists are expected to present their results for better or for worse, Austad says. Although university researchers might spin their results in a favorable light when trying to get a paper published or seeking their next grant, companies are more likely to release only positive findings and not negative ones that could hurt their corporate standing, he says: "I just look at it as a species of dishonesty."
Another major consideration in joining the private sector is job stability--or the potential lack thereof. Given its reliance on investment capital, the biotech industry runs through hot and cold cycles. Anyone who's thinking about joining a small or even medium-sized company has to realize that it's a risky gamble, biotech veterans warn: "Things can go south; they can go really bad," says Steven McKnight, head of biochemistry at the University of Texas Southwestern Medical Center in Dallas, who left academia for 5 years in the 1990s to co-found and direct research at a start-up called Tularik in South San Francisco, California.
Case in point: When Avalon opened its doors in Maryland's I-270 corridor 3 years ago, says Carter, there were approximately 20 other brand-new companies in the area. He roughly estimates that since then, a third of them have gone out of business. A third of them are still operating, doing more or less what they set out to do. And the last third have merged with other companies or are pursuing an entirely different scientific goal than they were originally.
The fight for funding can be trying, says Kaeberlein. Building a company around the topic of aging poses particular challenges (see "'Gero-Tech' Sprouts, But Will It Bloom?")--the lack of a practical means for testing therapeutic effectiveness, for instance--and because of the dismal economy, Longenity was unable to attract enough venture capital to do all the experiments he wanted to do. Although he still consults for the business, Kaeberlein left Longenity last May, mainly because he and his wife wanted to move back to their home state of Washington; he is now a postdoc in molecular biologist Stanley Fields's lab at the University of Washington, Seattle.
Anybody who's considering working for a start-up, Kaeberlein advises, should make sure the enterprise has obtained commitments for the first year or two of funding and has a well-developed research plan. "I think it's OK to ask, 'At the current burn rate, when will the company need to obtain additional funding? Or go out of business potentially, or cut back its workforce?' " Before signing up, find out how large the staff is and what kind of lab space the company has--anything that will help you gauge the stability of the enterprise, Kaeberlein says.
Layoffs are always a possibility in industrial science, but the flip side is that companies offer substantially higher salaries than those available at universities or the National Institutes of Health (NIH)--and, in some instances, stock options that can pay off big if a venture hits the jackpot. Other lifestyle considerations figure attractively: Personality-wise, those with a hard-driving, entrepreneurial streak might find the fast-moving atmosphere of a start-up a better fit than the halls of academe. At the same time, although postdocs who opt for corporate R&D face pressure to deliver results and prove their value to the enterprise, down the road they won't have to sweat the high-stress race to make tenure that is singular to universities. Furthermore, young professors find that the amount of time they have for experiments shrinks as teaching, grant writing, and running a lab come to dominate their days; whereas at large, well-established biotech or pharmaceutical outfits, researchers can work at the bench as long as they wish--with few worries about funding. For those who desire it, science can be a 9-to-5 job that they leave behind at the end of the workday.
At smaller companies, however, the pressures of raising money for research can be intense. Researchers who join a start-up, in particular, find themselves routinely pitching their work to venture capitalists and potential corporate partners--giving the "dog and pony show," as one scientist put it. When McKnight was research director at Tularik, which is targeting cancer and other diseases with drugs that alter the cell's production of specific proteins, he spent 30% to 40% of his time scraping together dollars. "That was perhaps my most vital job: If you don't get money, you can't have a company. I remember going to Japan one time and visiting 15 companies in 10 days. And out of that, we got one partnership that gave us $3 million or $4 million a year for 3 years," says McKnight, who remains on Tularik's board of directors and has founded another company to create new antibiotics.
And grant writing isn't necessarily out of the picture: Small biotech enterprises can apply for Small Business Innovation Research grants from NIH, the National Science Foundation, and the U.S. Department of Energy; the National Institute of Standards and Technology also offers funding for high-risk R&D through its Advanced Technology Program.
Teamwork Versus Going It Alone
Compared to universities, the culture of commercial science relies more heavily upon teamwork. In academia, which emphasizes individual brilliance, investigators largely work independently. "Your success depends on your own ability to run your own show," says McKnight. Even in the most collegial settings, he says, that reality tends to foster selfishness, pitting one investigator against another in a competition for finite resources--lab space, equipment, and funding. Politics also plays a greater role in academia than in industry, he says, influencing who gets grants, wins awards, and gets inducted into societies. But at a company, "everyone's rowing together," he says. "You really work as a team, because the company sinks or sails based on everyone's effort to be pitched in toward the same goal. And some people like that." At a start-up, an individual's contributions make a huge difference, says McKnight. Established academic institutions aren't going to flop or fly based on one person's work, but a small business might.
Industry scientists work together closely and communicate frequently not just with their research colleagues but also with investors and potential corporate partners. "If you don't like people, if you can't work with people, you probably don't want to work for biotech," says Howell. And as a person advances "up the food chain" toward the executive ranks, people skills become even more crucial, he adds, with more meetings to attend and more employees to manage. Researchers fresh out of a university setting aren't trained for such a role. Howell says that learning to supervise employees and communicate better has been "something that I've had to work very hard on."
Industrial Partnerships: Promises and Perils
Meanwhile, teamwork between academics and companies offers the potential for cross-fertilization, especially on costly research proposals that won't win funding from traditional sources such as NIH. "A lot of times you take that idea to the right company, and they say, 'You know what, we think that's a helluva good idea, and we're going to help you with it,' " says Howell. As a result, an increasing number of professors have their fingers in the commercial pie. According to an analysis published last January in the Journal of the American Medical Association, roughly one-fourth of academic biomedical investigators receive some research funding from industry. And a 1998 report in Psychotherapy and Psychosomatics that surveyed 789 scientific and medical articles found that for one out of three papers, at least one author had some sort of financial interest in the results.
Such growing entanglements have stirred significant concern over conflicts of interest (see "Wearing Two Hats" and "University-Industry Collaborations: Whose Data?"), especially in research that involves human subjects. Lab heads with ties to companies need to carefully walk a tightrope to balance the often-opposing interests of academia and industry.
Lesson From Geron
But as Greider's fallout with Geron illustrates, academic-industrial collaborations can deteriorate like an unhappy marriage. Greider says that the company elbowed in on her research at a time when she was the equivalent of an assistant professor at CSHL trying to establish her own lab; even though both teams informally agreed upon the separate experiments each would pursue, she says that Geron "would end up working on what we were working on anyway." The root of the conflict, she says, was that she was dragged into working with the business by virtue of her prior academic collaborations with Harley; when he moved his lab to Geron in 1993, suddenly her lab's experiments fell within the company's purview. The biggest problem, adds Greider, was that "I was naïve enough to think that I didn't have a choice--which is not a very good negotiating position."
For his part, Harley says Geron got involved in cloning hTR because Greider and Avilion didn't seem to be making significant progress, and finding the gene was "potentially crucial to our survival." Greider "was very upset to have that project taken out of her exclusive domain," he recalls. What many academic scientists don't realize, he adds, is that a company has to move forward as quickly as it can, without giving much consideration to individual territories. Had he and Greider discussed at the outset that she wouldn't be happy if Geron got involved in cloning hTR, he says, "we wouldn't have collaborated with her, because it would be impractical and unfair to people in the company and our shareholders to ever make such an agreement."
In retrospect, Greider says, her rocky relationship with Geron was no different from any pure academic collaboration that goes bad. University research labs can behave just as aggressively as for-profits because they want to be the first to publish, she points out. The best partnerships, whether between two academic labs, or between a company and an academic lab, require mutual respect and arise when each group brings something unique to the joint venture, she says--a set of skills, a set of techniques, or a set of knowledge. "As soon as you have both parties feeling like they have the same skills and knowledge, you have a potential for one wanting to take over the other." With Geron, she says, the company had 40 scientists who were itching to work on the same problems as Greider and Avilion. If she could do it over again, Greider says, she would realize that she did have a choice about collaborating. She would have negotiated stronger boundaries in the relationship, by clearly delineating which lab would do what experiments in a formal legal agreement. Before diving into a project with a company, Greider says, academic scientists should determine their negotiating position by learning exactly what their rights are. Greider recommends that they seek advice from a variety of people--such as the intellectual-property lawyers in their institutions' technology-transfer office, and colleagues or friends who've consulted for or started companies.
Avalon's Carter seconds that recommendation. "There are absolutely ways, both verbally and in contractual form, to avoid many of these kinds of pitfalls," he says. Lab heads dealing with industry should become as savvy as they can about the commercial world. Learn how to read contracts. Check out seminars on the business of science, which many university extension programs now offer. "Go to your friends in industry and say, 'Can you give me examples of contracts that you've written, or can you give me some advice about someone I can call up?' "
As trite as it sounds, Carter says, for any partnership to work, it has to be a "win-win" scenario. Regardless of who's involved, the key to building a satisfying collaboration is understanding colleagues' motivations and what constitutes a "win" for them. For professors, he says, the better they can understand and empathize with the legitimate needs, desires, and bottom lines of a corporation, the better equipped they'll be to craft a contract that precisely addresses intellectual-property issues, such as what would constitute an invention.
Founding a Company, Juggling Conflicts
The same advice holds for academics who want to launch a biotech company. Would-be founders have to recognize the separate agendas of many different players, including the venture capitalists supporting the start-up, and the technology transfer office and conflict-of-interest review committee at their university or hospital, says Boston University's Perls. "All come from very different points of view that can initially be quite opposing. One has to resolve them so that everyone ends up on the same page," he says. If that proves to be impossible, he adds, then the scientist might want to walk away from the project.
Early in the game of creating a company, says Perls, perhaps the most important player with which an academic scientist should communicate is the institutional conflict-of-interest panel, whose job is to assure that financial stakes with a commercial entity don't bias research results or compromise the safety of human subjects. The investigator can visit his or her university's Web site to read up on its conflict policies and consult the technology-transfer office before going to the committee to clear the company proposal. If the panel decides it would be inappropriate for a faculty member to personally own stock in the start-up, an alternative might be possible; for instance, the university or hospital could hold the equity and use it to support the researcher's lab or department and also enter into a licensing agreement with the company.
Also critical: If an investigator's lab runs on federal funding from NIH, he or she should talk to a scientific officer at the agency early on, to double-check that the start-up plans won't run afoul of government conflict-of-interest rules. "It's extremely important that the NIH is on board with what you're doing," says Perls--otherwise it could jeopardize the grant.
For better or for worse, the intersection of academia and commerce in the biological sciences has triggered conflicts of interest and turf wars that can't be wished away. As a field, Carter observes, biology is still growing up and dealing with the fact that major societal applications are arising from the science developments of the last 30 years, ranging from new drugs against disease to the cloning of livestock. Everyone needs to understand the economics of bringing discoveries to market, he says: "We all, as a culture, have to figure out how to do that in a responsible way."
October 22, 2003
Like academic scientists, Ingfei Chen, a SAGE KE contributing editor based in Santa Cruz, California, must publish or perish.
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