Johns Hopkins Gazette: June 12, 1995

Apoptosis May Provide New Way of Treating Huntington's Disease

Michael Purdy
JHMI Office of Public Affairs

     A built-in cellular "suicide program" vital to early
development of the brain and other organs may be called back into
action by the effects of Huntington's disease and strokes,
according to Hopkins medical researchers.

     Scientists already know a great deal about this "suicide
program," called apoptosis, from research into other disorders.
If the new link proves to be true, it will put them tantalizingly
close to developing new treatments for Huntington's and strokes.

     "We already have several compounds that may block this
self-destruct process," said Vassilis Koliatsos, an assistant
Hopkins professor of pathology, neurology and neuroscience. 

     Examples include interleukin-converting enzyme (ICE)
inhibitors, which stop the production of an inflammatory protein
that may be involved in apoptosis. Another group of compounds,
antioxidants, neutralize damaging chemicals known as oxidants
that may help trigger apoptosis.

     Last year, other researchers at Hopkins linked apoptosis to
Parkinson's disease and amyotrophic lateral sclerosis (Lou
Gehrig's disease).  

     Koliatsos speculates that apoptosis may be the only way
nerve cells know how to die. If so, treatments that can stop
apoptosis may also help patients with a wide range of
neurological disorders.

     Using brain tissue from human autopsies and animals with
Huntington's disease and strokelike disorders, Koliatsos found
that the DNA in dying nerve cells was breaking apart in a pattern
characteristic of apoptosis.  

     Apoptosis results from a series of instructions contained in
a cell's genes.  When "read," these instructions direct the cell
to kill itself. 

     Scientists first observed apoptosis in a worm, C. elegans,
that regularly directs half its nerve cells to kill themselves.
The killing helps the worm maintain its size as it generates new
nerve cells.

     Later experiments showed human immune cells and cancer cells
can self-destruct in a similar manner.

     Researchers previously thought apoptosis only played a role
in the nerve cells of higher organisms during the earliest stages
of life.

     "During development, cells compete to accomplish certain
goals," Koliatsos said.  "For nerve cells, that might be making
connections with other nerve cells.

     "We think a cell that can achieve these goals is rewarded
with a protein or chemical that will sustain it," he added.
"Cells that can't achieve these goals go into apoptosis and die."

     But when a national collaborative research group cloned a
gene for Huntington's disease, the finding suggested to Koliatsos
a link between Huntington's and programmed cell death.  Using two
different methods, he found clear indications of apoptosis in DNA
from Huntington's patients.  

     "My job now is to first test those agents that may block
apoptosis in the laboratory, and then to see what can be done to
transfer those treatments from the laboratory to animal models
and, later, to human patients," Koliatsos said. 

Nancy Wexler To Give 
First Garrett Lecture

     Nancy S. Wexler, a member of the research group that
discovered the genetic marker for Huntington's disease and who is
herself at risk for the hereditary disorder, will deliver the
inaugural Mary Elizabeth Garrett Lecture at The Johns Hopkins

     Wexler, Higgins Professor of Neuropsychology at the College
of Physicians and Surgeons of Columbia University and president
of the Hereditary Disease Foundation, will give a talk titled
"Variations on a Theme by Huntington" at 4 p.m., June 22, in the
hospital's Hurd Hall.

     The Garrett lectureship, which honors outstanding women in
academics, is named for Mary Elizabeth Garrett, who provided
financial support that enabled the School of Medicine to open in
1893. Mary Garrett tied her support to the requirement that at
least 5 percent of the entering classes be women.

     "The lectureship is a landmark event," Catherine D.
DeAngelis said.  DeAngelis is senior associate dean for academic
faculty and affairs at the School of Medicine. "It honors not
only the woman who made it possible for women to have a real
presence here at Hopkins," DeAngelis said, "but also women
anywhere who have made valuable contributions to medical

     Wexler, a clinical psychologist by training, was, in 1983,
an important member of the research team that discovered a
genetic marker, a piece of DNA near a particular gene, for
Huntington's disease. This enabled researchers in 1986 to develop
a diagnostic test to determine, even decades before symptoms
appear, whether a person is affected. The test also gives
carriers the choice of whether to have children, who will have a
50 percent chance of inheriting the disease. Researchers
discovered the gene itself in 1993 and identified the mutation of
the gene. There is no treatment, but researchers continue to
study the protein produced by the gene in an effort to stop it
from causing the disease.

     Huntington's disease is a degenerative brain disorder that
afflicts one person in 20,000. Symptoms usually do not appear
until midlife, with death usually following within 15 years.
Wexler's mother, three uncles and maternal grandfather died from

     The Garrett lectureship is to be an annual event with
presenters selected by the Women's Leadership Council at the
School of Medicine. All women professors are members of the
council, which was formed in 1994 with the goal of advancing
women's careers in academic medicine. The School of Medicine
admitted three women in its first class in 1893, a revolutionary
step in the Victorian era, and last year, for the first time, the
freshman class had more women than men. Women comprised 53
percent of the class of 1998, or 63 in a class of 120.

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