IN THE LONG, difficult struggle to understand - and do something about - the
brain ailment called Huntington's disease, scientists have decided the best
approach may be to go fishing.
The target is a strange jellyfish that has a natural ability to glow in the
dark when pestered, showing its irritation in eerie green light.
The glow, they hope, will lead toward a cure for Huntington's disease, a fatal
brain disorder first noted among people living on Long Island's East End in
1872 by Dr. George Huntington. It was the first completely dominant genetic
disease - meaning anyone who inherits the faulty gene gets the disease -
described. It has always been untreatable.
In the new research, the glowing protein takenfrom the jellyfish will become a
marker, allowing scientists to see whether, and how well, candidate drugs might
work. It may allow them to find a few drugs among thousands that could treat
the disease.
Oddly enough, water - and fishing for a gene in people - also played a role in
the original saga that led to finding the mutant gene, the cause of
Huntington's disease. The gene-fishing expedition was sent to the shallow
waters of Lake Maracaibo, Venezuela, where 20 years ago Nancy Wexler and her
colleagues found vital clues that led to discovery of the mutant gene. Wexler,
professor of neuropsychology at Columbia University, is also president of the
Hereditary Disease Foundation, which was founded by her father, Milton Wexler.
The search for the gene took Nancy Wexler to study the largest known extended
family with Huntington's disease, people who live in stilt houses on the huge
Venezuelan lake. Many of them are burdened with the inherited disease, and
population studies of these people, and other families, allowed geneticists to
finally track the dangerous gene to one end of chromosome 4.
Ten years later, in 1993, a research team led by Dr. James Gusella, at
Massachusetts General Hospital, in Boston, actually found the gene itself.
But what they haven't been able to isolate and study is the whole protein made
by the gene, a substance called huntingtin. Without the entire protein to
study, scientists find it hard to decipher what happens in the brain as a
result of the mutation; why nerve cells in the basal ganglia gradually die off.
The brain damage occurs because the protein made by the mutant gene is altered
or disabled, setting it up to kill off nerve cells. Similar die-off of specific
nerve cells, but for different reasons, is seen in other brain disorders such
as Alzheimer's disease and Parkinson's disease.Wexler said that even though
they haven't isolated the intact protein the researchers are not slowing down
their work. Their new strategy is to leapfrog ahead and begin an intensive
search for drugs that can treat the disease. Their ultimate goal, of course, is
to find a cure.
What they're setting up is an assay system that can quickly analyze the
potential effectiveness of drugs among the many thousands of chemicals that
already exist. They expect the drug search to be greatly speeded up by use of
the glowing substance from jellyfish, which they call green fluorescent
protein, or GFP. This test system was devised by a small biotechnology firm in
San Diego, Calif., Aurora Biosciences Inc.
According to Wexler, biologist Roger Tsien, in San Diego, has re-engineered the
jellyfish's GFP gene so that the protein it makes glows much brighter than
usual. As a result, it can be used in very rapid test systems meant to spot
potential drugs.
According to biologist Ethan Signer, one of Wexler's colleagues, testing is
done by linking a known portion of the huntingtin protein - including the
damaging polyglutamate section - to the light-emitting GFP protein. Then, when
tested against a potential drug, they'll watch the light, the glow, to see if
it changes, behaving more like GFP linked to a normal fragment of the
huntingtin protein, including the short repeat calling for a shorter string of
amino acids as found in normal brain tissues, not a longer string as seen in
the disease. A change in the glow may show that a drug is forcing the mutant
protein to act more like the normal protein.
Within the next 18 months, Wexler added, the collaboration with Aurora promises
to screen through about 500,000 different drugs that are already in the
company's "library" of drug candidates. Agents that look interesting can then
be tested in different systems, including animals engineered to get a form of
Huntington's disease.
"We'll be looking for drugs that can make the mutant [proteins] look more
normal," Wexler explained. "Any drug that can do that" would be an interesting
candidate for further study. In fact, she said, they expect to encounter drugs
that interact with the huntingtin protein "in ways that we didn't even dream
of. We hope our first screening will give us a number of hits," a number of
drugs to study for purposes of therapy.
This search for drugs was spurred recently by a discovery in genetically
engineered mice. It was shown experimentally that the brain damage done by
Huntington's disease can be stopped, and by surprise that the brain can even
repair the damage. The discovery was made by scientists at Columbia University.
"Now we have an agreement with Aurora Biosciences to look for a cure," Wexler
said.
Among the diseases plaguing humanity, Huntington's is not one of the most
prominent. But it does loom large among types of diseases that are inherited;
it is about as prevalent as cystic fibrosis. According to the Hereditary
Disease Foundation, between 35,000 and 50,000 people in the United States are
affected, and as many as 250,000 are thought to be at risk for Huntington's
disease.
The brain disorder is caused by a most unusual type of mutation, what
scientists call an expanded triplet repeat, an expanded polyglutamine disorder.
Like a few other nervous system diseases - such as Fragile X syndrome, an
ailment caused by a damaged gene on the X chromosome - Huntington's arises
when the cell's gene-copying system stutters. The normal gene's spelling calls
for up to 36 amino acids, glutamines, to be strung together in a row.
But when the stretch of glutamines accidentally becomes too long - going beyond
40 glutamines - something goes haywire. If there are too many of these
molecules lined up in a row, the protein somehow begins killing off neurons in
the basal ganglia. And the bigger the error - say as many as 100 glutamines -
the worse the disease. In most cases the symptoms strike at about age 40. But
in really severe cases the symptoms arise as early as age 2.
Interestingly, because of the genetic stuttering that occurs, the disease can
become worse and worse in succeeding generations. The gene-copying mechanism
seems to keep adding extra polyglutamine repeats, making a family's mutation
ever more serious.
The symptoms of the disease are bizarre. The victims begin exhibiting jerky,
uncoordinated body movements - sometimes seeming to be intoxicated. Eventually
they lose the ability to walk, stand and talk. They also suffer memory
problems, have severe depression, and generally die 15 or 20 years after
symptoms begin. There is no treatment or cure.
The disease is called an autosomal dominant trait, meaning the mutant gene is
not on the sex chromosomes - so there is no difference between male and female
patients. Every child in a Huntington's family has a 50 percent risk of
inheriting the mutation.
Wexler's vital interest in Huntington's disease is very personal. Her mother
and three uncles were all victims of the disease, and her father, Milton, set
up a foundation in 1968 to encourage research.
He explained: "My two daughters, Alice and Nancy, had a sword of Damocles over
their heads, with a one-in-two chance of dying in the same dread manner" as
their mother. "Almost nothing was known about this disease, and there was - and
still is - no treatment."
Now, he added, "this new partnership [with Aurora] is the fitting culmination
of these years of arduous effort" from biological researchers.
