DNAX Immunologists Work To Balance Industry, Academia

The fence between industry and academia seems like a precarious place to sit. But a team of California scientists makes the balancing act look easy. Their perch on that fence has been the perfect place for cranking out highly cited research, including four “Hot Papers” identified by The Scientist in the past year (May I, 1989, page 12). The laboratories of immunologists Robert Coffman and Tim Mosmann are side by side on the secondfloor of DNAX Research Institute in Palo Alto. Seven years ago, in the early days of the company, Coffman and Mosmann were assigned to neighboring labs by chance, and they immediately began developing a formula for a practical combination of academic and industrial science that has been working for them ever since. And even after subsequent moves, they have continued to work side by side. DNAX (pronounced “Deen-x”) was designed as a hybrid biomedical research company from the beginning. Its founders, explains Coffman, wanted to create a company that worked at the interface between academia and product-oriented industry, doing academic-style basic research that would be rapidly applicable to products. In 1982, just one year after its founding, DNAX merged with Schering-Plough Corp., a New Jersey-based pharmaceutical company. Because Schering already had product development groups, DNAX because purely a discovery arm. With this freedom to pursue basic science without the pressure to also develop new products, DNAX evolved a more academic-style environment in the midst of its corporate world. From the beginning, Mosmann and Coffman, each working on different aspects of immune system control, have reported significant findings that, when examined in terms of each other’s results, are starting to answer some of the major questions of immunology. In the 1960s and 1970s, scientists found that the immune system could respond in basically two ways to attacking pathogens—using a cell-mediated or an antibody-mediated response;It was also obvious that the immune system decides for each infection which response is appropriate. But the mechanisms of control for these two different responses remained a mystery. In 1985, while studying clones of T cells—key components of the immune system—Mossman ‘s lab found evidence for two types of helper T cells (THI and TH2), which may be responsible for regulation of the two fundamental immune responses. At the same time, Coffman’s lab was focusing on the regulation of IgE antibodies, the central component of allergic reactions. In the course of studying the T cell control of IgE antibodies, they learned that TH2 cells stimulated production of IgE, while T-l cells inhibited production. I think that was a very nice synergy,” says Mosmann. “What Bob was finding out about the immunoglobulin regulation made sense if you looked at in light of what we were finding out about different types of T cells, and vice versa. The two scientists think their findings may be able to explain some very old observations. “We’ve got another few years to go before we find out if all our current suspicions are true, but it’s looking an awful lot like that,” says Mosmann. “It’s kind of an exciting time to speculate like crazy on what might be going on; so, we speculate.” What they’re finding may pin down the mechanism of control for cell-mediated versus antibody-mediated response. For a long time in many infectious diseases, it has been known that it’s not the virus or the parasite or the bacteria that is directly responsible for the severity of an illness. Instead, the course of a disease is determined largely by the response of the immune system. The correlation between immune response and the course of a disease has been clearly established in leishmaniasis, a disease Coffman is studying. Caused by a protozoan parasite, leishmaniasis can take three diverse forms. In the most mild state, it causes individual sores that eventually heal and, at worst, leave a scar. But it also can cause a nasty, disfiguring disease affecting wet mucosal tissues, often destroying the nose and the lining of the mouth. A third form gives no external signs but results in massive infection of the liver and spleen, often leading to death in children. Similar forms of the disease in mice have been shown to correlate with activation of one or the other helper T-cell subsets. To develop treatment methods for such infectious agents, the team is now trying to determine how the immune system recognizes the agent, and how it chooses an appropriate reaction. “If we understand how these decisions are made at this very early level,” says Coffman, “then we might be able to develop therapeutic agents, drugs, whatever, that will shift things and create a different reaction.” Coffman and Mosmann attribute their progress toward a better understanding of the immune system to careful planning, teamwork, intelligent and creative colleagues, and a supportive company atmosphere: In the early days, Coffman explains, “we all sort of agreed on what kind of adaptations to the normal academic style of science one would have to make to be successful in this scheme. One of the key adaptations was that a lot more science would be done in a multilab collaborative mode, rather than each lab getting its funding from someplace different and doing its own thing.” Another strategy was the decision to keep the labs small, with senior scientists staying close to the bench, “instead of just administrating a few layers of people,” says Mosmann. “The result is, the intensity of the work here is higher than anywhere I’ve seen.” Biochemist Martha Bond is a colleague who has been particularly integral to the Coffman-Mosmann team. She supplies the biochemical expertise that the two immunologists lack, and has enabled them to move efficiently at a rapid pace. “Other scientists no smarter or dumber than Tim and I,” says Coffman, “had seen inklings of some of these same things, but without the ability to really get a handle on the molecule and some biochemical definition.” Bond, who floats among labs, seems pleased with her role. “It has been enormously efficient,” she says, “because one experiment that I do can be assayed by several people for several things. We continually have had some really nice surprises, simply finding out all of a sudden the molecules we’ve been working on under the guise of one activity will also mediate the second.” Mosmann and Coffmann also credit the postdoctoral fellows and even the technicians in their labs with much of the success of the team. One technician, Holly Cherwinski, now at Syntex, was lead author on one of the “Hot Papers.” “We have very few graduate students here,” says Mosmann, “so four technicians] tend to get more interesting projects than technicians in a university lab.” “Technicians fill that intellectual and cultural niche that graduate students often fill at universities,” says Coffman. “They’re young, bright, fresh-faced, open-minded, with crazy ideas and lots of questions that keep you honest. And, of course, we have a lot of postdoctoral fellows here. They’re really the backbone of a lot of the new and interesting basic research nowadays.” It’s fairly unusual for a large drug company like Schering-Plough to own a group such as DNAX, which focuses exclusively on basic research, the team leaders say. But they think it is an effective approach. The Mosmann-Coffman team is primarily interested in finding out how the immune system functions, and Schering-Plough is supportive of the basic research, because it may lead to interesting products. “It’s sort of a double motive for how you set things up,” says Mosmann. “The primary motive is, ‘How does it work?’ And the the other stuff is just keeping your eyes open for little things off to the side which may be fundamentally important. If you find a real key part of the system, then having control over that gives you therapeutic power.” And therapeutic power means pharmaceutical products. For the most part, the DNAX team looks more like an academic group than a corporate group. It’s not unusual to find folks working at 2 A.M. or taking a couple of hours off in the afternoon for a game of volleyball or basketball. Coffman and Mossman speculate that neither of them would function as effectively in a more structured corporate lab. “For discovery work you need the crazy researcher that wants to go discover things and doesn’t do the experiment the same way twice,” says Mosmann. “A lot of company research is much more focused, and people need to be much more disciplined.” He says it’s difficult to combine the two in the same place. As a result, the distance between New Jersey and California has been beneficial. “They’re very different cultures,” adds Coffman, “and we’re sort of sitting on the fence between academic and corporate culture. They’re both important to the ultimate development of the product, but they’re very different scientific traditions. Laurel Joyce is a science writer based in Mountain View, Calif.

DNAX Immunologists Work To Balance Industry, Academia

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