I BEG TO DIFFER; A
Diabetes Researcher Forges Her Own Path to a Cure
November 9, 2004 - NY Times
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
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.
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.''
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.''
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.
had tried the transplants and failed -- the islet cells died despite
immunosuppressant drugs -- but Dr. Faustman thought she would
''I thought the
secret was that my islets were better than anyone else's,'' she
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
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.
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
Then, to her
astonishment, something else happened: the islet cells grew back, a
development that went against everything known by scientists.
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
''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
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.
published the work in The Journal of Clinical Investigation in 2001.
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
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
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.''
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
Copyright © 2004 The New York Times
Co. Reprinted with permission.