Diabetes Archives

For Walt...from yesterdays NYT.

[Thou shalt not rock the boat!]

http://www.nytimes.com/2004/11/09/health/09diab.html

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Jodi Hilton for The New York Times
Dr. Denise Faustman has cured diabetes in mice. Humans are next on
her
agenda.

A Diabetes Researcher Forges Her Own Path to a Cure

By GINA KOLATA

Dr. Denise Faustman thinks she has a shot at curing diabetes.

She has published one significant scientific paper after another
on the
disease. She has succeeded in curing it in mice, something no one
else
has accomplished.

But when Dr. Faustman, an associate professor of medicine at
Harvard,
went looking for money to finance the next stage of her research,
testing the ideas with diabetes patients, she could find no
backers.
Pharmaceutical companies turned her down. So did the Juvenile
Diabetes
Research Association.

Her approach was criticized, even though in the past, said her
boss, Dr.
Joseph Avruch, chief of the diabetes unit at the Massachusetts
General
Hospital, "most of the things she found turned out to be true."

Only the support of Lee A. Iacocca, the former chief of Chrysler,
who
said he wanted to see diabetes cured in his lifetime, has allowed
her to
pursue her goal. He mounted an $11 million fund-raising campaign
and
wrote a $1 million check to start the fund.

The reason for the resistance, Dr. Faustman and some colleagues
believe,
was simple: her findings, which raise the possibility that an
inexpensive, readily available drug might effectively treat Type 1
or
juvenile diabetes, challenge widespread assumptions. Many diabetes

researchers insist that a cure lies instead in research on stem
cells
and islet cell transplants.

Dr. Faustman's story, scientists say, illustrates the difficulties
that
creative scientists can have when their work questions
conventional
wisdom and runs into entrenched interests. But if she is correct,
scientists will also have to reconsider many claims for embryonic
stem
cells as a cure for diabetes, and perhaps for other diseases.

"I wish Denise well, and I flat out hope she's right," said Dr.
Mark
Atkinson, a diabetes expert who directs the Center for Immunology
and
Transplantation at the University of Florida College of Medicine.
"But
the environment she's trying to move this forward in is so much
like
kids in a sandbox, whipping sand around. It's hard to see with so
much
sand in the air."

With many foundations and universities competing for research
financing,
and with the heated politics of stem cell research, it is no
surprise,
Dr. Atkinson said, that disputes can sometimes become vitriolic.

In addition, he said, the field has been whipsawed by false hopes.

"I've seen a lot of things in diabetes come and go," Dr. Atkinson
said.
"For decades we have been told that a cure is just around the
corner.
That's part of the background, that's why it's emotionally
heated."

Dr. Faustman's research began when she came to Massachusetts
General in
1985 to help start a program to cure diabetes with transplants of
islet
cells, which come from hormone-producing regions of the pancreas.
She
had learned to isolate human islet cells from the transplant
technique's
developer, Dr. Paul Lacey of Washington University, and she was
confident about her skill.

Other scientists had tried the transplants and failed - the islet
cells
died despite immunosuppressant drugs - but Dr. Faustman thought
she
would succeed.

"I thought the secret was that my islets were better than anyone
else's," she said.

But when she and Dr. David Nathan, the director of the diabetes
center
at the hospital, tried using her islets, they also failed. So Dr.
Faustman decided to go back to the laboratory and study the
phenomenon
in mice.

Researchers had reported that islet transplants could cure
diabetes in
mice, but they had been making them diabetic by destroying their
islet
cells. Dr. Faustman decided to look at mice with a strong genetic
predisposition to develop diabetes on their own. When the islet
cell
transplants failed in those animals, she asked why.

Diabetes occurs when a white blood cell, part of the body's immune

system, migrates to the pancreas and mistakenly sees islet cells
as
foreign tissue. It then multiplies and destroys the islets. But,
Dr.
Faustman learned, she could block the white cells by supplying
them with
a piece of protein that signaled that the islet cells were normal
cells,
rather than foreign invaders.

She also had to stop the attack that was under way in the
pancreas. That
required killing the white cells that were doing the attacking.
Her
solution was to give an off-patent drug, BCG, that is inexpensive,
$11 a
vial, and approved for use as an immune system stimulant. It
elicits the
release of an immune system hormone, tumor necrosis factor, that
kills
activated white cells.

After Dr. Faustman gave the mice the two types of treatment, the
attack
on the islets stopped.

Then, to her astonishment, something else happened: the islet
cells grew
back, a development that went against everything known by
scientists.

The implications, Dr. Nathan said, were enormous. The diabetic
mice, he
said, had had extremely high blood sugar levels for weeks and
would die
without insulin. Researchers had successfully intervened earlier
in the
disease with these animals but not once diabetes was so firmly
established.

"No one had cured them," he said. "Here was this treatment that we

thought would get them ready for a transplant but - eureka! - the
diabetes was cured."

If Dr. Faustman's findings could be applied to humans, there would
be no
need for islet cell transplants. Embryonic stem cells, which many
researchers believed might be turned into islet cells, eliminating
the
need to get islets for transplants from cadavers, would also be
unnecessary.

In fact, the work meant that unless the underlying immune system
attack
on the pancreas was stopped, these replacement cells would
eventually be
destroyed anyway, so such treatments would never be a cure.

Dr. Faustman published the work in The Journal of Clinical
Investigation
in 2001.

"We weren't allowed to use the word 'regenerate,' " she said.
"People
didn't believe that an organ could regenerate." Instead, she had
to say
"restoration of insulin secretion by return of blood sugar to
normal."

Even though the islet cells were growing back, it was still
unclear
where the new cells were coming from. Before long, Dr. Faustman
had a
surprising answer. They were from the spleen, a fist-size organ on
the
left side of the diaphragm whose pulpy interior is filled with
blood.

In a paper last year in Science, Dr. Faustman reported that she
had
cured female mice of diabetes and transplanted them with spleens
from
male mice. The islet cells that grew back were male, and they had
come
from the male spleens.

The findings raised the question of what happens to people who
have
their spleens removed. Dr. Faustman went to the medical literature
and
discovered that most spleens were removed in emergency rooms and
that
few patients were followed afterward, with two exceptions.

One was a group of patients in England with pancreatitis. To treat
them,
doctors had removed half of the pancreas. When they removed the
right
half of the organ, the patients were fine. But when they removed
the
left half, along with the attached spleen, patients often
developed
diabetes about five years later.

The other case involved children with beta thalassemia, a genetic
disease involving iron storage. Often, they developed enlarged
spleens,
which were removed. Five years or so later, many got diabetes.

The stories about patients who had their spleens removed are not
proof
that Dr. Faustman's work applies to humans as well as mice.

"Denise's work is remarkable in animals," Dr. Nathan said. "But
does it
apply to humans? As a clinical investigator, I have to remain
skeptical.
Scientifically, is it a long shot? I don't know."

Mr. Iacocca's check, and the money he wants to raise, will pay for
the
initial phase of a clinical trial, the first step for finding out.
Dr.
Nathan, who will direct the trial, will ask whether BCG kills the
islet-destroying white blood cells of patients in the same way it
does
in mice and, if so, at what dose. Dr. Faustman is working on a
blood
test that will immediately assess the effects of BCG by
determining
whether the dangerous white cells are being destroyed.

In the meantime, the Juvenile Diabetes Research Foundation is
financing
an independent effort to replicate Dr. Faustman's work. The
researcher,
Dr. Anita Chong of the University of Chicago, said her studies
were
still under way. But, she added, "so far, what we have done
replicates
what she has done."

For his part, Mr. Iacocca was confident from the start that Dr.
Faustman's work was correct. His foundation's scientific advisers
strongly endorsed it, and Mr. Iacocca, whose wife, Mary, died of
diabetes complications, has a personal interest.

"I can't wait for the pharmaceutical companies or even government
tax
money to fund what looks promising," Mr. Iacocca said. "They are
not
known for high risk and they are also slow to react. We are trying
to
get a cure."

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