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 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.''

Copyright © 2004 The New York Times Co.  Reprinted with permission.