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[IP] Islet Cells

Lab cracks a key letter in body's insulin codeWay seen to prod cells of
diabeticsBy Stephen Smith, Globe Staff, 8/6/2002olving a molecular riddle
that bedeviled scientists for the better part of a decade, researchers at
Boston's Joslin Diabetes Center have identified a pivotal genetic switching
mechanism for making insulin, a major discovery that could lead to a recipe
for brewing insulin-making cells or even repairing damaged cells inside
patients.  Scientists trying to crack the code of diabetes have known since
the early 1990s that the gene responsible for making insulin was turned on by
three proteins, like switches on a car's dashboard. They even came up with
names for each of those molecular buttons.

But how did the switches get flipped? It wasn't much good knowing that the
buttons were there if the chemical key for turning them on proved elusive.

Seven or eight years ago, researchers identified two of the chemical
switching mechanisms. But one remained stubbornly hidden, resisting the
efforts of dozens of researchers - until now.

>Learn more about
insulin production</A>

Molecular biologist Arun Sharma and a team of other Joslin scientists used
knowledge gleaned from the study of birds and countless hours in a
bone-chilling room to pry secrets from the insulin gene.

The discovery dramatically speeds up attempts to take stem cells and convert
them into insulin-producers, said specialists familiar with Joslin's work.
However, making such cells available for transplanting is still years away.

''It is very significant what they have done,'' said Alberto Pugliese, a top
scientist at the University of Miami's Diabetes Research Institute. ''This
research goes to the bottom of how an insulin-making cell works, which is
crucial because we need to understand that in order to produce a cell that
makes insulin.''

The need for such knowledge has never been greater, because the number of
patients with diabetes has never been higher. In the United States alone, 17
million adults and children have the condition, with the incidence of Type 2
diabetes - the variation believed to be caused, in part, by obesity and
sedentary lifestyles - at epidemic levels.

Diabetes unfolds when the body fails to properly manufacture or use insulin,
a hormone crucial to converting food and drink into fuel for all mammals.
There are two main forms of diabetes: Type 1, when the patient's body fails
to produce any insulin, requiring injections, and Type 2, when the body
doesn't make enough insulin or can't use it correctly. At least nine out of
10 diabetics have Type 2.

The pancreas, an organ roughly the size of a banana, sits behind the
abdominal cavity and produces insulin. Specifically, beta cells in the
pancreas make insulin.

''People have been trying to study why insulin is made in the beta cell for a
long, long time,'' Sharma said.

For cells to become beta cells, they need a certain set of genes, and those
genes, in turn, must be switched on. That's where the car dashboard analogy
comes in. The genes have three sites, like buttons on a dashboard. For those
buttons to be activated, specific proteins must bind with each site. In
laboratory parlance, those binding proteins are known as transcription
factors. Without transcription factors, the genes cannot be turned on.

Scientists knew two of the transcription factors.

''And then there was the third one,'' said Dr. Gordon C. Weir, who leads
Joslin's Section on Islet Transplantation and Cell Biology. ''They knew that
button was important and they knew that there was a transcription factor that
went along with it, but they couldn't find the transcription factor. A lot of
people tried and had careers die looking for this thing.''

Sharma began hunting for the factor five years ago, collaborating with three
other scientists. The research, supported by the Juvenile Diabetes Research
Foundation and American Diabetes Association, first received attention in the
scientific community three months ago in the journal Proceedings of the
National Academy of Sciences.

Sharma performed elaborate biochemical tests to derive the transcription
factor, then cloned it, using knowledge harvested from earlier research, into
a chemical that leads to the formation of eye lenses in chickens and quail.

The connection to the avian protein was discovered after studies of the human
insulin protein showed promise and scientists began searching for a roadmap
of how the protein operates. They scanned databases for similar proteins, and
their finding proved that they had peeked behind the correct scientific door.

''We knew that if it works in chickens, this protein in humans could be
equally important,'' Sharma said. ''It saves you a couple of months' work to
figure out how it really works when you have information from a similar
protein in another animal system.''

Finding that third factor proved especially daunting because it exists only
in small quantities in beta cells, said Dr. Michael German, a diabetes
researcher at the University of California-San Francisco. To hunt for it,
Sharma and other scientists spent days cloistered in what's known as a cold
room, a sector of the laboratory chilled to roughly 40 degrees Fahrenheit
where cells are reduced to their component parts.

''What Arun had to do was a very laborious process,'' German said. ''It
really was a difficult task.''

Scientists at Joslin and other specialists in the field believe that now that
all three of the factors have been identified, they can begin devising
strategies for giving birth to insulin-producing cells in the laboratory or
developing methods for repairing ailing cells inside diabetics.

''It's a major advance,'' said Scott Campbell, national vice president of
research programs for the American Diabetes Association. ''If you can
understand the key to development of beta cells and how they function to
produce insulin, you may have the key to curing diabetes one of these days.''

Today, for patients with Type 1 diabetes, the only treatment approximating a
cure is to transplant insulin-producing

cells from the pancreas of a deceased donor. But only 3,000 to 4,000
pancreases are available each year.

''Right now, the only thing we can use is cadaver donors, and there's a
woeful lack,'' Weir said.

The hope is that one day, stem cells - blank molecular slates that become
different organs - can be nudged into insulin-making cells in the lab. That
would present the best treatment yet for patients with Type 1 diabetes.

The Joslin discovery also extends promise to the millions of people with Type
2 diabetes, because if scientists can figure out a way to increase production
of the chemical found by Sharma, they might be able to delay development of
the disease.

''There have been a lot of people working on finding this,'' Campbell said.
''I'm just glad they found it.''

Stephen Smith can be reached at <A
HREF="mailto:%email @ redacted">email @ redacted</A>.

This story ran on page A1 of the Boston Globe on 8/6/2002.
) <A HREF="http://www.boston.com/globe/search/copyright.html">Copyright</A>
2002 Globe Newspaper Company.
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