Scholars and Entrepreneurs: Succeeding in the Science Biz

"It's like a cancer in the body of science," says Yuri Lazebnik of the Cold Spring Harbor Laboratory in New York. "If we don't take care of it, it will only get worse." The cancer, in Lazebnik's opinion, is the runaway commercialization of science. As researchers increasingly view their discoveries as potential blockbuster products, and new biotech companies spring up as fast as weeds along the intellectual highway, some academic scientists may be becoming more guarded about sharing their reagents and discussing their latest finds. Keith Yamamoto Not everyone views the evolution of science into a for-profit venture as a plague, but many agree that it raises issues that need to be addressed. "Doing science has become more complex in many ways," says Keith Yamamoto of the University of California, San Francisco (UCSF). "Science is technology-driven," he says, and as technologies become more specialized, the academic community needs to determine how to preserve scientists' access to unique and invaluable research tools--from antibodies and cDNA sequences to cell lines, transgenic animals, and genomic databases--while protecting the intellectual property rights of the universities and companies that own them. To discuss these issues, Yamamoto organized a session on "Sharing Science" at the annual meeting of the American Society for Cell Biology (ASCB) held in San Francisco in December. Participants at the session described the changing climate in commercial science and offered advice on how academic scientists can survive--and thrive--in the new science-as-business world, where discoveries move from the bench to the boardroom and back again. "As I see it, the academic world is not operating by the same principles anymore; it's governed more and more by the laws of business," says Lazebnik. "We're supposed to act as a brotherhood of science," but as the distance between discovering something and profiting from that discovery grows smaller, Lazebnik remarks, "conflicts arise and things get confusing." Ron DePinho The times are definitely changing, but many feel the prognosis for the future of science is far from terminal. "Compared to business, science still stands pretty near the top of the heap with respect to collegiality and open interaction," says Ron DePinho of the Dana-Farber Cancer Institute in Boston. "It's just that now we think more about how basic science can be applied, for example, in the clinic. And we should." Tak Mak The trick lies in getting the nonprofit sector to coexist with--and benefit from--organizations that hope to profit from scientific inventions. "Scientists should be free to conduct their research," says Stan Fields, a Howard Hughes Medical Institute (HHMI) investigator at the University of Washington in Seattle. "But companies have the right to exist and to make money. It's just a matter of balancing those interests." More specifically, it's a matter of balancing the interests of those who use a tool and those who develop it, says Douglas Hanahan, a UCSF researcher who spoke at the ASCB session. "As a user, you want access to a tool yesterday--with no hassles or delays," he explains. Developers, on the other hand, want to "capture some value" from their inventions. As a result of such conflicts, bench scientists are becoming increasingly frustrated by the difficulties of getting reagents in a timely fashion, says Hanahan, who also sat on the task force that National Institutes of Health Director Harold Varmus convened in 1997 to examine issues concerning access to research tools. Michael Hengartner Some scientists actually report little problem securing reagents from their peers, although researchers in some fields may be better at sharing than others. "People in the worm field have a history of being quite generous," says Cold Spring Harbor's Michael Hengartner. "It's considered proper worm etiquette." What drives this behavior? "It could be that there are no obvious applications close by," muses Hengartner. Lazebnik, who works on programmed cell death in mammalian cells, agrees. "If you study chromatin structure, it's not clear how you can make money," he says. But researchers working on cell death or tumor formation stand to turn their discoveries directly into profit. Yeast people also share, reports Fields. But perhaps that's because the reagents they produce--such as plasmids or mutant yeast strains--are "mostly cheap and simple to make," he says. Other tools such as knockout mice may be a different story, says Fields, because generating and distributing them can be difficult--and expensive. "You can't imagine my mouse bills," says Tak Mak of the University of Toronto, who has generated some 60 different strains of transgenic mice. To keep up with the requests that pour in by E-mail, fax, phone, and post, Mak employs two technicians--one full time, one part time--who do nothing but send out mice. "We're working as fast as we can, but it's never enough." For the most part, researchers make their mice--or cell lines or antibodies--available when they first describe them in a peer-reviewed journal. "It's very simple," says DePinho. "You publish, you provide." Denise Faustman That's true "in theory," says Denise Faustman of Harvard Medical School, who once sent a particularly cooperative colleague a box of chocolate-covered cherries as a little "thanks for the mice." "But there are people who never share and they get away with it." Perhaps, she suggests, the journals themselves should punish researchers who don't play fair by refusing to accept their publications. That's the situation re: sharing among academics. What happens when academic scientists need to acquire reagents from big biotech companies--or the growing number of small start-ups? According to the Association of University Technology Managers, in 1997 research institutions spawned more than 250 new start-up companies licensed to market technology developed at a university. Feelings of ownership--or fear of losing financial control--may run stronger in for-profit companies. "Small biotech companies may ask you to sign away your first born because they want to super-protect the few reagents for which they own the rights," says DePinho. But such contracts--dubbed material transfer agreements or MTAs--are usually configured to prevent users from making a profit on work performed with the company's reagent. In some cases, interactions between academia and industry might actually be smoother than those among academics, says Robert Valentini of Brown University in Providence, R.I., who last year started his own company, Cell Based Delivery. Academic researchers may be reluctant to hand their reagents over to a competitor, whereas companies profit when researchers use their technology, he says. By sending out reagents to trusted collaborators, Valentini says, "We get to do studies that otherwise we might have lacked the time or resources to perform." Further, the company benefits by learning whether its product works in other people's hands. "It seems to me that research institutions and industry are showing signs that they've learned how to share scientific resources," says Jeffrey Labovitz, formerly acting director of UCSF's office of technology management. As an example, of the 300 MTAs bridging academia and the private sector that were processed through the UCSF office, Labovitz says that only two remain unsigned. Trading MTAs has become standard operating procedure for anyone sending or receiving scientific reagents. But there are still some things you should look out for before you sign on the dotted line. The first is your publication rights, says Julia Owens of the UCSF office of technology management. Don't sign any document containing a clause that forces you to "ask for permission from a company before you publish." A more reasonable material transfer agreement (MTA) might allow a company to review your manuscript 30 days prior to submission to ensure that you don't reveal any "confidential information," she says. Also beware of onerous ownership clauses or "reach-through" agreements that would grant a company exclusive rights to any discoveries you ever make using their reagent. Instead, an MTA should offer the company the option to license any products that may result from your work, says Owens. Tools are not, in themselves, responsible for products, says UCSF's Doug Hanahan. "You can use a hammer to build a house," he says, "but the hammer manufacturer doesn't profit when the house is sold." Remember, you have the right to negotiate, says patent attorney Kris Bieker-Brady. "Companies often send their most restrictive MTA," she says. "And why not?" When Bieker-Brady phones to discuss the terms, she finds that "often they'll back down" and send a more reasonable agreement. -- Karen Hopkin In cases in which the research community has found a company's terms totally stifling, NIH has stepped in to negotiate. This past August, Varmus was able to broker an agreement with DuPont Pharmaceuticals, making its popular Cre-lox mouse more widely accessible to researchers at nonprofit institutions.1 Months earlier, NIH drafted a set of guidelines designed to remove some of the barriers inhibiting the exchange of research tools among university scientists and between business and academia. Among the recommendations, NIH aims to encourage researchers to share reagents freely, particularly when "the prospect of commercial gain is remote." Further, NIH hopes to promote the use of a uniform MTA, which could alleviate the need for lengthy, case-by-case review. The form would be "something short and sweet that any scientist could read and understand," says Hanahan. Many institutions, including HHMI and UCSF, already make use of standard MTAs. And reviewing one or two pages of legalese really isn't that painful, says Hengartner, who started his company, Devgen, in 1997. "As long as things are done reasonably quickly and I can do my science, I don't mind." The NIH recommendations will be posted for public review and comment in the Federal Register this month. Until then, there are things you can do to help you navigate the seas of science commerce and avoid being abused. First, develop long-term relationships with researchers you can trust, says Lazebnik. "You really cannot work in isolation." The same applies to small biotech companies, says Valentini: "You want to collaborate with smart people who share your passion and philosophy. In the best relationships, everybody wins." Read any MTA that arrives with your reagents. "Does it seem fair? Can it hurt you?" asks Kristina Bieker-Brady, a patent attorney with Clark & Elbing in Boston. "Don't just sign it--it's not an invoice." Julia Owens Work with your institution's technology-transfer office. "Researchers sometimes see us as impeding their progress," says Julia Owens of the UCSF office of technology management. "But we're really there to get you the materials you need." The office can also help you secure patents or start your own business. Most of all, make your opinion heard. DuPont may have changed its policy in part because "the negative reaction from the scientific community convinced them that maintaining their restrictive terms might not be in their best interest," comments John Barton of Stanford Law School. "Companies need to have good working relationships with universities," adds Labovitz, who's now director of the office of technology licensing and industry-sponsored research at Harvard Medical School. That may be a lesson for the next generation of genomics companies such as Affymetrix--which is currently pricing its "DNA chip" technology beyond the reach of many academic labs--or other companies that are scrambling to stake their claims on gene sequences, polymorphisms, and other bits of the genome, asserts Barton. Once such sequences are patented--and Incyte Pharmaceuticals in Palo Alto, Calif., received the first U.S. patent for gene fragments called ESTs last October--Barton says, "It may be difficult to pursue certain avenues of research without infringing on someone's patent rights." Even these battles may have a bright side, says Fields. In raising the thorny issues of who owns genetic information, genomics companies may be stimulating change for the good. For example, NIH may have accelerated its efforts to finish sequencing the human genome, in part, to prevent companies such as Incyte or Celera Genomics in Rockville, Md., from hoarding such information. "NIH wants to make sure that things that should be available to academic researchers" and remain in the public domain, notes Fields. Perhaps some reagents are now difficult to acquire without yards of paperwork and weeks of negotiation. But even more worrisome, says Lazebnik, is the potential that the commercialization of science may start to hamper the free flow of ideas. "If people stop talking, science will suffer," he says. Researchers may be less likely to present their breaking results at public meetings--until their patents are in place, adds DePinho. Stan Fields NIH recommendations on the use of research tools: www.nih.gov/news/researchtools/index.htm Description of the Cre-lox agreement: www.nih.gov/od/ott/cre-lox.htm Examples of standard MTAs, UCSF Web page: itsa.ucsf.edu/~otm/OTMdocs.html Federal Register--watch for posting of official NIH guidelines for public comment: www.nara.gov/fedreg/ Sharing your results at meetings shouldn't be a problem, says Bieker-Brady. If it is, "you should get a better patent attorney," she says. "Your attorney can file a patent application that will cover anything you're ready to disclose." In fact, Bieker-Brady suspects that researchers may be using the patent system as a scapegoat. "It's much easier to blame your patent attorney than to say, 'I just don't want to talk about this with you because you stole my last idea.'" Is the current climate in science really that bleak? Bieker-Brady didn't think that commercialization presented much of a problem to today's scientist--until she spoke in January at a meeting of the International Embryo Transfer Society, where some researchers disgruntled over the patenting of embryo-transfer technologies greeted her "like Satan at a Bible revival," she says. "Clearly I was out of touch with reality, because a lot of researchers feel that patents are bad." Their attitudes may be driven by fear. "People tend to be skittish about things they don't totally understand," says Bieker-Brady, "especially when it involves something like the American judicial system." And with good reason. "Researchers who are unfamiliar with the patent system are more likely to miss opportunities or get burned," she says. "So you've got to figure it out--or suffer the consequences." Karen Hopkin is a freelance science writer based in Silver Spring, Md. E. Russo, "Technology transfer pact could be a model for future agreements," The Scientist, 12[18]:1, Sept. 14, 1998.

Scholars and Entrepreneurs: Succeeding in the Science Biz

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