Cerami's New Lab Aims For Bountiful Blend Of Basic Research And Product Development

Investigations on aging lead the Long Island institute's efforts to combine the best traits of 'pure' and 'applied' research Just over a year after launch, the Picower Institute for Medical Research in Manhasset, N.Y., is gathering momentum, and confidence among institute researchers is growing. The institute came into being Oct. 1, 1991--although it was created on paper July 31--with the near-total transplantation of top researcher Anthony Cerami's group from the Laboratory of Medical Biochemistry at Rockefeller University, Manhattan, to quarters in the Boas-Marks Biomedical Research Center at North Shore University Hospital, Long Island. The goal of the Picower is to "apply the insights gained through basic laboratory and clinical research to the discovery of new approaches to curing and preventing disease and improving human health," according to its mission statement. This aim will best be accomplished, say Cerami and the researchers who have joined him, by channeling the institute's efforts toward both basic and applied goals, and by consciously positioning its operating procedures between those of traditional nonprofit and profit research settings. Picower researchers coming from university and industry labs say the new institute's structure frees them to focus their science with a unique mix of fundamental investigation and medical purpose. The study of diabetes and the search for therapies to counter its complications have occupied much of Anthony Cerami's life as a scientist. So, when Jeffry Picower, whose mother died at an early age from the disease, decided to underwrite a new biomedical research institute, Cerami was a logical choice to head it--but not only because of his research work. "My mother was a diabetic, also," Cerami says. "When she was about 55, she started having bad complications." Cerami, now in his early 50s himself, earned his Ph.D. in biochemistry at Rockefeller University in 1967 and became head of one of the larger labs there in 1972. He was in a unique position to help his mother with her medical problems. "I started a program in diabetes to try and understand it better," he says. "My mother was the first person that we studied. She volunteered to come into the Rockefeller hospital, and she lived there for about a year. We brought her into very good control. The complications, for the most part, stabilized." Eventually, his mother did die--but of leukemia, not of diabetes. "The nice thing about working on this was that I felt that I gave my mother 10 years of better life," Cerami says. --F.H. "One of my main interests is in having a flow of scientific advances from the academic to the commercial world," says Cerami, the institute's founding president, "because that's the only way it'll ever get applied to use. You can keep working in academic labs and publishing libraries, but it never gets anywhere until somebody is interested in making a product. "I would like to see us somewhere between an academic and an industry kind of lab," he adds. "I think industry has some very good attributes that are not necessarily taken into academic labs and vice versa." An initial gift of $10 million from Florida-based investor Jeffry M. Picower and his wife, Barbara, founded the institute. Cerami says that additional funds will come from grants, further contributions from the Picower family, and various agreements with companies. The goal is an endowment of $100 million. For 1993, Cerami says, the institute will have an operating budget of approximately $6 million. About 20 researchers came to the Picower from Rockefeller University, most of the original lab group; now, the total is more than 50 and climbing. Cerami anticipates the research group will grow to about 75 by mid-year and then level off. The move from New York City went smoothly, Picower researchers say, and the group got back on track quickly, resuming longtime research aimed at problems of aging, metabolism, and infectious diseases. Cerami estimates that 80 percent of the institute's activities deal with problems of aging, such as atherosclerosis, hypertension, and kidney disease. The primary goal of the institute is to do basic research to discover new approaches to disease therapies, but a secondary aim of the institute, he says, is to raise the prestige of research into aging. "If you ask scientists in general," says Cerami, "aging research has an almost pejorative connotation to it. And yet it's one of the major problems that we face, as a society. One of our main objectives is to apply modern science to the complications of aging." The motives for creating the Picower were a combination of push and pull, according to Cerami. Increasingly, he felt, Rockefeller did not provide the ideal environment for his research enterprise. And philanthropist Picower's offer of support presented an irresistible opportunity for resource security and research independence, he says. "The Rockefeller had a unique character, which was the reason I stayed there for 30 years," Cerami says. "There was always an excitement about trying to do things that no one would do and about not having the economic difficulties that you would have at other institutions. And, when I first went there, it was a very cooperative place." But that unique character was changing, Cerami says, toward the end of his time there. Rockefeller, from its inception, had been divided into laboratories largely under the control of individuals. These labs were, in some cases, quite powerful. According to Cerami, there were efforts to change that structure to be more like "any other institution." "Some people felt that the heads of the labs were taking advantage of the situation," Cerami says. "But I felt that the reason the Rockefeller was successful was because of its structure and because of the independence of the laboratories." Joshua Lederberg, president of Rockefeller from 1978 until mid- 1990, declines to comment on Cerami's move and views on research priorities at the university. But Rodney W. Nichols, executive vice president at Rockefeller until October 1990 and now CEO of the New York Academy of Sciences, says there was no policy aimed at breaking up the larger labs. He acknowledges, however, that there were changes taking place. "We were deliberately selecting some young investigators who would have the title of assistant professor and who would be the head of their own small laboratories," Nichols says. "[Those labs] would be outside the existing framework of established labs and superstars of the sort that Rockefeller, for better or worse, has been famous for." Nichols says that David Baltimore, Rockefeller president in 1990 and 1991, made a number of statements that were perceived as threatening to the independence of the larger labs, of which Cerami's was one. "It would be a strange argument, however, to attribute to David Baltimore the idea that large labs are bad," says Nichols, "because, in many ways, the Whitehead Institute [in Cambridge, Mass.] was a big Baltimore lab." Baltimore was director of the Whitehead in the 1980s. Cerami was one of 15 professors at Rockefeller who opposed Baltimore's presidency, in part because of Baltimore's controversial defense of Thereza Imanishi Kari against charges that she falsified data published in a paper on which Baltimore was a coauthor. Press spec- ulations that continuing tensions between the two men contributed to Cerami's decision to move were downplayed by both at the time. Today, Cerami continues to minimize problems at Rockefeller and to focus on his new position. "I would have taken this job even if nothing were happening at the Rockefeller," he says, "because it's an opportunity to take the best aspects of the Rockefeller and capitalize on them." Researchers at the Picower see the institute as bringing together positive attributes of both academic and industry research settings. In addition, Cerami says, he has worked to bring together an interdisciplinary, cooperative group of investigators--free of "prima donnas"--that will have the necessary intellectual and financial resources to solve "the hard problems." Richard Bucala, for example, is an M.D.-Ph.D., with training in rheumatology and molecular genetics. His group is advancing long- standing research into advanced glycosylation products (AGEs), research originally based on studies of diabetics. These compounds have been implicated in a number of age-related pathologies, including cataracts, kidney disease, hypertension, and atherosclerosis, as well as diabetes. AGEs also may be responsible for certain genetic transpositions in DNA. Apparently, long-lived proteins in the body undergo a series of nonenzymatic changes in the presence of glucose that lead, eventually, to unwanted cross-linking between the proteins to form AGEs. A compound that inhibits AGE formation, aminoguanidine, developed by the group now at the Picower, is currently in efficacy testing. "People are excited to be here because there's a lot of interaction," Bucala says. "Everyone is working on more than one thing, and people are teaching each other. For young investigators, it's a very stimulating, very eclectic place." Helen Vlassara, an M.D. with a subspecialty in endocrinology and metabolism, has also worked for many years to extend understanding of AGEs, particularly their role in normal aging. The body's ability to clear the potentially harmful AGEs has been a focus of hers. She feels fortunate that she was able to move to the Picower with a familiar, trusted group of people. "A number of individuals made the same decision, which maintained the cohesiveness of the place," Vlassara says. "The strengths were there, and also our acquaintance with each other and with the leader. It was basically a transplantation of an existing, very well-functioning, extremely productive unit." Picower researcher Kevin J. Tracey is also a neurosurgeon on staff at North Shore University Hospital. "My responsibility in coming here was to do research in a clinical setting," Tracey says, "and to restrict my neurosurgical practice to keep 80 percent time committed to research. In essence, I'm setting up one of the laboratories at the institute, but it's also a laboratory of the department of surgery [at North Shore]. So it really bridges the gap." For most of the past decade, Tracey's research focus has been on a cytokine called tumor necrosis factor (TNF), or cachectin. TNF mediates many of the immune system's responses to infection or invasion. But TNF is also implicated in septic shock and in the wasting syndromes that accompany many chronic illnesses, such as AIDS, cancer, and parasitic diseases. An antibody that blocks TNF is currently in clinical trials for patients with septic shock, Tracey says. He is now looking at how the brain and cytokines "talk" back and forth to control metabolism and plans to branch into studies of stroke. Biochemist Andrew Slater last year announced new findings about how the malaria parasite metabolizes hemoglobin and the mechanism by which traditional quinine-based drugs combat malaria (A.F.G. Slater, A. Cerami, Nature, 355:167-9, 1992). The drug's action had not been fully understood, despite centuries of use. Quinine- resistant malaria is on the rise in the world, and Slater's discoveries may lead to more effective therapies. Another biochemist, Barbara Sherry, is studying cytokines at the Picower, too. TNF is one of these, but she has also worked to identify, clone, and characterize a series of macrophage inflammatory proteins. Cyclophilin, a protein that binds the immunosuppressive drug cyclo-sporin, has been a recent research target. Richard Currie, a biochemist and molecular biologist who has worked with transcription factors and gene regulation, recently joined the Picower from the University of Colorado. He will continue work with lipoprotein lipase, an enzyme important in energy metabolism, and expects to help in cytokine studies. A new lab in formation under molecular virologist Michael Bukrin- sky will study HIV pathogenesis. This past September, molecular biologist Michael Vitek was recruited from Lederle Laboratories, Pearl River, N.Y., to establish another new program, this one to study Alzheimer's disease. His work has targeted the 42-amino-acid beta-amyloid peptide associated with lesions in the brains of Alzheimer's patients. In industry, he says, he ran into "road blocks" that hampered his research. In particular, company lawyers made it difficult to freely exchange ideas with outside scientists. "It got to where my hands were getting tied," Vitek says. "Science just doesn't work that way." At the Picower, he sees the opportunity to do the basic research needed to understand the underlying mechanisms of Alzheimer's disease, while keeping drug development firmly in view. "I wanted to go to an institute that would allow me to be between industry and academia," Vitek says. "I didn't want either one." One distinguishing feature of Cerami's research effort, at Rockefeller and now at the Picower, is his close attention to pushing research advances through to the clinical market. The focus on useful products derived from well-supported basic research is one way in which the Picower is moving to straddle the ground between academia and industry. Kirk Manogue, a neurobiologist and vice president of the institute, is crucial to the institute's goals in this area. His primary role is to oversee intellectual property protection for the institute's research. Manogue's efforts will likely lead to increased income for the Picower, he acknowledges. But, like Cerami, he insists that additional income is not the main reason to closely track the licensing and patenting of research. "Hopefully, the development of commercial products will bring in a stream of dollars that can be plowed back into the discovery enterprises," he says. "But there are several reasons why, even in traditional academic settings, people are paying more attention to patenting early and patenting often. Most importantly, it's nave to think that [research] will ever lead to anything that's put into service unless it's properly protected." The stance that Cerami has taken on commercializing research results from his labs was, perhaps, a source of some tension at Rockefeller. "In a certain sense, there's always been a high tolerance for applied science [at Rockefeller]," says Rodney Nichols, "for very disease-oriented work, but looking into fundamentals." But he adds: "I think it would be fair to say that Rockefeller has been a little more standoffish, when it comes to commercialization [of research], than some of the more buccaneering campuses." The group of researchers that came to the Picower from Rockefeller had many reasons to expect that the institute would survive and be a success. Even so, they are glad to have new researchers arriving and to see the work reaching full stride. "If you were here a year ago," says Kevin Tracey, "people would have said, `Let's wait and see what happens.' Today, I can tell you with confidence, this place is going to work." Barbara Sherry agrees, but doesn't think the hard work of setting the institute on course is altogether behind them. "We're beginning to see the vision that Tony saw all along," she says. "But it will take another couple of years for it to really be what it will be."

Cerami's New Lab Aims For Bountiful Blend Of Basic Research And Product Development

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