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This story appeared in the March 20, 1995 edition of The Scientist Magazine. It outlines what NIH is working on and how. Brainstorms Abound At NIH's Neurological And Stroke Institute Author: Neeraja Sankaran RESEARCH PG : 14 Research in the neurosciences is in the midst of a particularly exciting period of discovery, says Zach Hall, director of the National Institute of Neurological Disorders and Stroke (NINDS), as scientists continue to learn more about the basic biology of such disorders as stroke, epilepsy, and degenerative conditions like Parkinson's, Alzheimer's, and Huntington's diseases. Hall's institute has supported and participated in many of these landmark studies. Now the field stands poised on the brink of another, equally fruitful era, as investigators are turning their attention to ways of treating or preventing these maladies. "Until now, all the major achievements in neurology were in diagnosis, but that is about to change," he predicts. "Because of the development of various molecular and cellular tools, and imaging technologies, we are going to be able to think about developing strategies for their treatment." First established in 1950 as the National Institute of Neurological Diseases and Blindness, NINDS has grown to represent the National Institutes of Health's single largest source of funding for the neurosciences (see accompanying story). Researchers supported by its various divisions represent the entire range of scientific inquiry, from those working at the very basic levels of genetics, biophysics, and cell biology, to clinicians and neurosurgeons who come in daily contact with patients. Funding is similarly diverse: The institute supports investigations as different in scale as studies on the sexual orientation of fruit flies to full-fledged clinical trials of therapies for brain tumors. Most of the work NINDS funds is done outside the institute, and managed by one of its four divisions for extramural research. In addition, the institute maintains both basic and clinical research programs within its division of intramural research. Since its inception, two of its former divisions have become separate research institutes under NIH--the National Eye Institute in 1968, and the National Institute on Deafness and Other Communication Disorders in 1988. Hall, who came to NINDS from the University of California, San Francisco, last September, is the institute's sixth director (N. Sankaran, The Scientist, Sept. 19, 1994, page 22). He says that his first few months at the helm have been at once "exciting and exhausting"--for reasons involving more than just the scientific aspects of the position. "I will face my most daunting experience yet when I have to testify before the appropriations subcommittee on behalf of the presidential budget," he notes, referring to congressional budget hearings this spring. In his statement to the subcommittee, the director says, he intends to highlight recent NINDS-supported successes in clinical trials involving stroke; cerebral palsy in infants; understanding neurodegenerative diseases; and localizing the genes for several conditions. "Gene mapping has revealed that a large number of genetic diseases are neurological--for example, ALS [amyotrophic lateral sclerosis] and Huntington's--but we still don't understand the relationship between the genes and how the disease is caused," Hall points out. "That will be the next step--now that we have identified the genes." Disease Detectives As it has in numerous disciplines in biomedicine, AIDS--especially its associated problems of neurological damage and dementia--has drawn the attention and funding of NINDS, mainly from the extramural division of demyelinating, atrophic, and dementing disorders (DDADD). One of the important goals enumerated by division director Carl Leventhal is to "look for animal models with retroviral infections" to investigate HIV's potential for damaging nerve and brain cells. DDADD, Leventhal explains, is the division responsible for diseases caused by the degeneration or damage of nervous tissue resulting from such conditions as viral infections, as in the case of the JC virus; autoimmune reactions, as in multiple sclerosis; and other--as yet undefined--reasons for the atrophy seen in Parkinson's, Alzheimer's, and Huntington's diseases. "There has been a big revolution in the way we look at multiple sclerosis," he declares, citing various advances in diagnostic techniques and imaging capabilities. Having identified T cells as the culprits that damage myelin of nervous tissue, scientists have been able to develop better strategies to slow down disease progression, he adds. "A major therapeutic breakthrough is the use of a-interferon, which seems to have a clear and definite effect in [NINDS-sponsored] clinical trials," he notes (IFN Multiple Sclerosis Study Group, Neurology, 43:655-67, 1993). A second substance--a synthetic polymer called co-polymer I, related to the myelin basic protein that is the target of attack in multiple sclerosis--is also yielding encouraging results in some patients, he says. "We are not sure, but we think the two approaches act via different mechanisms." Funding The Fundamentals Unlike the projects funded by the other extramural departments, the majority of grants awarded by the division of fundamental neurosciences (DFN) do not deal directly with a disease condition. Instead, scientists supported by this department look into a variety of basic aspects of the nervous system--problems of basic cell physiology, cellular communication, and neurochemistry, for instance. But, as DFN director Eugene Streicher points out, "the neurosciences, in general, display an especially close relationship between clinical and basic research, since a number of neurological disorders are characterized by changes in neurotransmitter regulation." For example, "the acetylcholine system is altered in Alzheimer's disease, dopamine in Parkinson's disease, and GABA in the case of Huntington's disease." By and large, DFN-funded research programs include "very, very technical studies on biophysics and membrane channels, and experiments on the learning and memory in lower animals like sea slugs, worms, and fruit flies," he explains." The idea of correlating basic neuroscience with behavior is very tantalizing," and is another area of interest at DFN, Streicher adds. One ongoing project takes "electrical measures [from the brain] of higher cognitive function--such as paying attention." Recently, a NINDS-funded investigator--psychologist Sandra Witelson of McMaster University--published her findings relating anatomical differences in the brain to such behavioral traits as sexual orientation and handedness (C.M. McCormick, S.F. Witelson, Behavioral Neuroscience, 108:525-31, 1994). Engineering Solutions Also falling under the management of the fundamental neurosciences division is the 25-year-old Neural Prostheses Program, which has 14 active projects funded at a total of $4 million to develop devices that can compensate for lesions in the nervous system. "While the program is highly applied in nature, it requires very sophisticated knowledge of both electronics and neurophysiology," Streicher points out. "This was the group that, in the past, developed cochlear implants for improving hearing." Neural prostheses, explains F. Terry Hambrecht, a physician and bioengineer who heads the program, "replace or supplement neural function in neurologically disabled persons by directly connecting with the nervous system." Projects in this program include a Case Western Reserve University-based study to develop a "functional neuromuscular system," for restoring such capabilities as hand grasp and elbow extension to quadriplegic individuals. "The people who are paralyzed have ultra-miniature electrodes placed near their nerves, which can then stimulate the paralyzed muscles," Hambrecht says. "The electrodes are controlled by a small computer about the size of a cigarette case." Another neural prosthesis being developed by the program, in collaboration with the intramural laboratories at NINDS, is a visual system. Hambrecht and colleagues have implanted 38 electrodes into the visual cortex of a blind woman. When stimulated, these electrodes "produce tiny spots of light whose brightness is controlled by the amount of electrical current," Hambrecht explains. "The process is somewhat like 'seeing stars'--one star for one electrode. When several predetermined electrodes are activated, the person can perceive simple patterns." Noting that "there were no adverse side effects from the implantation," Halbrecht has plans for a more extensive system of electrodes, coupled with a television camera to monitor the stimulation: "This should permit the recognition of more complex patterns." In-House Investigations Currently the institute is in the process of recruiting a new director for its intramural division. With a staff of 650 scientists divided between its basic and clinical research programs, the division covers a wide spectrum of research topics, says Hal Gainer, director of the basic sciences program and acting director for the division. "One of the exciting new developments has been the development of methods to culture populations of neuronal cells and the ability to transplant them," he relates. Both Ronald McKay, heads of the laboratory of molecular biology, and Eugene Major, who directs of the laboratory of molecular medicine and neurosciences, have been successful in this area, Gainer says."In science we are always looking for ways of simplifying explanations of how things happen," observes McKay, who found methods to culture stem cells of the central nervous system (P. Renfranz et al., Cell, 66:713-29, 1991). A valuable application of this discovery for studying the nervous system was in defining the "stem cell as the machine that builds the brain. This is the cell that reads the environment and accordingly gives rise to different mature brain cells. We wanted to isolate the cells and see what controls them and how they grow." Giving impetus to McKay and Major's work was the use of fetal tissue in brain cell transplants. "We now have the basis for a better system of quality control since we have the technology to grow cells systematically in the lab and purify them," McKay states. This would provide a distinct advantage over current transplants, which come from a different source each time, he explains. Major points out that the use of cell cultures derived from fetal brain tissue paved the way for many exciting developments. For instance, he notes, work in his laboratory on the development and differentiation of various cell lineages of the nervous system (E.O. Major et al., Journal of Neuroscience Research, 27:461-72, 1990) helped in the production of a "fetal astrocyte cell line which is now being tested as a potential therapeutic in human degenerative disease" (C. Tornatore et al., Neurology, 44:481-7, 1994). Carlo Tornatore, a neurologist in Major's laboratory, is analyzing one such cell line in an "extensive animal protocol involving cell transplantation into rhesus monkeys with induced Parkinson's syndrome," Major adds. The investigation is part of a cooperative research and development agreement, or CRADA, between NINDS and Provirus Inc., a Rockville, Md.-based biotechnology company that focuses on new molecular and cellular therapies. The intramural division has had several breakthroughs on the clinical front, as well. Mark Hallett, director of the intramural division's clinical sciences program, cites as an example a treatment for brain tumors developed by Richard Youle of the biochemistry section, in which a toxic protein called ricin is delivered specifically to the malignant cells in the brain (M. Gadina et al., Therapeutic Immunity, 1:59-64, 1994). "The treatment of brain tumors has always been notoriously difficult," Hallett remarks. "But in clinical trials--administered by neurosurgeons Douglas Laske and Edward Oldfield at the NIH Clinical Center--there appears to be at least some efficacy in treating brain tumors with this approach." The treatment is currently in Phase II clinical trials, according to Laske. In the division's developmental and metabolic neurology branch, Roscoe Brady and his colleagues had two recent advances. He identified the cause and developed a successful enzyme therapy for Gaucher's disease, a disorder characterized by the accumulation of a glycolipid akin to the material in myelin cells of the spleen, liver, bone marrow, and brain, resulting in damage to these areas (N.W. Barton et al., New England Journal of Medicine, 324:1464-70. 1991). "The enzyme defect was identified in 1965, [but] it took us until 1989 to make a successful treatment," recounts Brady. The group is now working on gene therapy as an alternative approach to treatment of Gaucher's disease. Brady's group was also responsible for finding the biochemical basis for Niemann-Pick disease, type C, Hallett notes. This genetic disease, whose symptoms include progressive ataxia, dementia, blindness, and seizures, is "caused by the accumulation of cholesterol in nerve cells," Brady explains. Though they have not yet pinpointed the gene responsible for the disease, the group has localized it on the human chromosome 18 (E.D. Carstea et al., Proceedings of the National Academy of Sciences, 90:2002-4, 1993). "Once the gene is identified we will know what is going wrong," Brady says. "We can then try both protein and genetic therapies. "The nice part is that we already have an animal [mouse] model for this disease, which we did not for Gaucher's disease," an advantage he predicts will speed the development of an appropriate treatment. (The Scientist, Vol:9, #6, pg.14, March 20, 1995) (Copyright, The Scientist, Inc.) John Cottingham "KNOWLEDGE is of two kinds: we know [log in to unmask] a subject, or we know where we can OR find information upon it." [log in to unmask] Dr. Samuel Johnson