Nerve Culture Offers New Tool For Scientists, Drug Companies

The successful growth of human brain cells in a dish already has some researchers pondering commercial applications WASHINGTON - When a team of neuroscientists at Johns Hopkins Medical School made headlines this past May for establishing a colony of human neurons that divide and grow in a petri dish, they may have launched a new era on the business side - as well as the science side - of neurobiology. The Johns Hopkins team, headed by Solomon Snyder, reported its achievement in the journal Science (248: 603, 1990). The advance, observers say, will allow researchers to better study the biochemistry and genetics of human brain tissue, since it allows them to manipulate cells over longer periods of time. For investigators working in the field, the ability to grow neurons outside the body provides a powerful research tool. "It's a real leap forward," says Frederick Goodwin, head of the Alcohol, Drug Abuse and Mental Health Administration. Goodwin sees the potential for it to lead to a better understanding of drug addiction and mental illness, as well as a deepening of our knowledge of how the brain works. From the business perspective, time will tell how great an impact the advance has on fostering biotechnology career opportunities for neurobiologists. However, it already is clear that the breakthrough may have dramatic implications for some entrepreneurial ventures. Jeffrey Nye, a 31-year-old neuroscientist, originally planned to become a lawyer. But as a member of his Chicago high school's speech and debate team, Nye became frustrated with the imprecision of the liberal arts, specifically, the ability "to take any claim and turn it upside down." So at Harvard College, Nye studied biochemistry and molecular biology under Mark Ptashne, whose work has helped to explain how proteins control gene expression. In 1981 Nye entered the joint M.D.-Ph.D. program at Johns Hopkins University Medical School. His mentor for his doctoral thesis on receptor sites for THC, marijuana's active ingredient, was Solomon Snyder. While Nye describes Snyder as "a brainstorming partner," the two men are also friends: Snyder, in fact, loaned the financially strapped graduate student the money to buy an engagement ring for his fiancee. Even before Nye was awarded his Ph.D. in 1988, the two had begun to discuss what Nye describes as "a crazy idea" to find a method to transform specific virally infected neurons. The idea was to transplant these cells into animal models of human neurodegenerative disease. But Snyder and Nye needed cultured human neurons as a control. The answer came from Johns Hopkins neurologist John Freeman, who suggested that Nye obtain them during an operation to remove excess tissue from the cerebral cortex of an 18-month-old girl. Nye, now a pediatrics resident at Columbia University and a fellow of the Howard Hughes Medical Institute, works in the lab of molecular biologist Richard Axel. Nye shares with his clinical pediatrics students his current batch of "crazy ideas," including his thoughts on gene therapies for cystic fibrosis and diseases of the central nervous system. He's currently trying to understand how to make neurons stop dividing once they have begun to grow, and why his cultured human neurons continue to divide when most mature neurons have lost this potential ability. --J.D. It is likely, for example, to give a boost to companies like Nova Pharmaceutical Corp. of Baltimore, with whom Johns Hopkins' Snyder is affiliated. One possible treatment for patients suffering from disorders that impair the nervous system, such as Alzheimer's or Parkinson's disease, may be tissue transplants. The recent advance could do a lot to support that goal. Snyder helped launch Nova in 1983 in an effort to put neuroscientific advances to use in treating disease, and he remains its chief scientific adviser. While dozens of companies are interested in biomedical applications in neurobiology, few have Nova's expertise in this area. Nevertheless, even for a company like Nova, it may take a long time for the commercial potential of this advance to be realized. In the meantime, the cell line itself promises to be a boon for Johns Hopkins, which is understandably proud of Snyder. Head of the university's neuroscience department, Snyder - now 51 - has been a full professor since the age of 31, two years after finishing his residency in psychiatry there. In 1978 he earned the Albert Lasker Basic Medical Research Award, and his books and research have done much to push back the frontiers of neuroscience. Snyder's work now promises to be a financial as well as scholarly asset for Johns Hopkins, which has applied for a patent that would include both the team's cell culture and its culturing process. If granted, the patent would prevent other scientists from using Snyder's mix of growth factors and conditions to make their own cultures and from using cultures derived from that cell line for anything other than research purposes. It would allow Johns Hopkins to require that companies and individual researchers get prior permission from Johns Hopkins before using these cells, and it would require those wanting to make a new product pay the university a licensing fee. The university has begun to negotiate with several pharmaceutical companies for a license based on the scientific breakthrough. Officials declined to offer details while negotiations are under way. Once it obtained such a license, a company could put its scientists to work studying nerve cells in more detail so as to be able to design better treatments. Not surprising, one such company is Nova. Its founders include investors David and Isaac Blech and Donald Stark, who financed the company with an initial public offering in 1983 of $6.2 million. Other investors in Nova include Hoechst Celanese Corp., Marion Laboratories, and SmithKline Beckman Corp. A publicly held company, Nova has grown to more than 220 employees and is one of the nation's largest commercial testers of neuroactive medications (The Scientist, May 16, 1988, page 1), with $19 million in research and development expenditures and $15 million in revenue for 1989. "We are obviously very interested because we believe it is a discovery that ultimately has great potential," Hans Mueller, Nova's president and chief executive officer, told stockholders at the company's annual meeting in May. "And, of course, it fits into our expertise." A licensing agreement with Johns Hopkins would give Nova researchers the financial incentive to develop new methods to test the efficacy and safety of new drugs. Snyder says that he has distanced himself from licensing negotiations, owing in part to the potential appearance of conflict of interest in his dual role as faculty member and company founder. "Arm's length transactions" is how he describes the process. Since Nova does not yet have the license, he adds, he declines to speculate on the ways in which the company might benefit. But Nova isn't waiting until it signs on the dotted line. Already one of the company's researchers, Paul Sweetnam, in collaboration with Snyder, has begun experiments in which he infects the cultured cells with AIDS to observe the effect of the virus on the brain. The collaboration is between scientists, not institutions. There is no formal contract between Nova and Snyder or Johns Hopkins for this work, which is funded by the National Institute of Allergy and Infectious Diseases. Nova did not want to comment further on the arrangement. The original cell culture research by Snyder was supported by a five-year, $500,000 grant from the Bristol-Myers Squibb Co. A spokes- person said the pharmaceutical company provided the funds "with no strings attached." Researchers at Nova, according to a company spokesman, also hope to explore the use of the cells for transplants. Their goal is to allow neurosurgeons to implant cultured cells into Alzheimer's and Parkinson's patients as replacements for diseased brain tissue. Recently, neurosurgeons have used fetal tissue for transplants because the immature cells are less likely to be rejected than adult tissue. But those therapies face strong opposition from groups concerned about the welfare of fetuses. A study yet to be published by Snyder's team found that these cultured cells might be a more acceptable alternative for transplants. Those cells, when injected into cavities in the brains of experimental animals, were found to divide until they filled the cavity. But the cells stopped their growth before forming tumors. Researchers also hope some day to insert genes into the cultured cells. Those genes would cause the cells to make neurotransmitters that would otherwise be in short supply, or to make receptors to absorb excess chemicals thought to be responsible for mental disorders. The cultured cells also might give researchers insight into how to regenerate nerve cells in the spinal cord. But researchers acknowledge that any therapies will first require many years of research. Snyder's research collaborator, Jeffrey Nye, describes the development of this advance for medicine as "a long and thorny route." Joe DiLeo writes about biology and the environment from Washington, D.C.

Nerve Culture Offers New Tool For Scientists, Drug Companies

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