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.)
 
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