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See Inside December 2006

Putting Up with Self

Critics warned of bad experiments and false hope. But Denise Faustman seems to be right about a strategy to regrow insulin-making cells killed off in diabetes
DENISE FAUSTMAN: ISLET RESTORATION



KATHLEEN DOOHER
Five years ago Denise Faustman stunned the biomedical world--and not in a good way, it seemed. She declared that she had cured diabetic mice by getting them to regrow their insulin-producing beta cells, a finding that, if it could be translated to humans, would spare the million-odd Americans with type 1 diabetes their daily needle pricking and insulin dosing. Since her announcement, the academic establishment has given Faustman little money and a lot of flak. Researchers complained that they could not replicate the experiments and that the Harvard Medical School researcher had cruelly raised hopes that would only be dashed.

Faustman's vindication, however, finally seems to be at hand. In March three groups reported separately in Science that they had repeated Faustman's protocols and reproduced her most important result, stopping the disease process in about half their mice and getting the animals to recover normal function. "The results are fantastic, coming from these groups, which were each paid $1 million to spend three years showing that I was wrong," she remarks. "I mean, they were all funded by the JDRF."

The Juvenile Diabetes Research Foundation, the leading nonprofit source of research money in the field, had declined to back her work. The foundation states that it cannot fund all the research proposals it receives, but Faustman says that it had bowed to the tyranny of preconceived notions. Until recently, she says, it was taken for granted that once the beta cells are lost, they can never grow back. She had to go instead to a foundation set up by Lee Iacocca, the former chairman of Chrysler Corporation, whose wife died of diabetic complications. In total, Faustman has raised $11 million and is preparing preliminary human trials of an adaptation of her mouse therapy.

The 50-year-old Faustman says her work also undermines an important rationale for a favored subject of diabetes research, embryonic stem cells. The hope has been to get these stem cells to turn into beta cells and thereby furnish an ample supply of the scarce tissue. The JDRF and many diabetes activists support re?search on such stem cells, but the Bush administration has curtailed federal funding for it after coming under pressure from some conservative and religious groups.

Faustman got her idea by chance while transplanting islets, the pancreatic bodies that contain beta cells, from normal mice into others that had lost theirs to type 1, or juvenile, diabetes. In this form, the immune system mistakenly attacks its own islets as if they were foreign invaders. Such autoimmunity--or inability to tolerate "self"--impairs the islets' function and eventually kills them. Patients must then inject insulin many times a day to control the fluctuating level of glucose in their blood.

To suppress the autoimmunity, Faustman injected mice with a cocktail of bacterial irritants called Freund's complete adjuvant, which made their bodies churn out a signaling chemical called TNF-alpha. This compound destroyed the activated immune cells, particularly those that targeted islets, so that when a surgeon implanted islets on the kidneys of each mouse, the transplants could take root, make insulin and restore normal blood sugar control.

That was when Faustman took a trip to the land of Serendip. "I wanted data for a figure showing how the blood sugar went up again after you take out the kidney with the islets in it," she recalls. The kidneys of two mice were removed, and "the day after the surgery, the mice were about 110 [milligrams of sugar per deciliter of blood--a normal reading], and both the animals were running around in the cage." In a 2001 paper she concluded that the mice had grown new islets.

Unfortunately, the cure was not permanent: the bad immune response returned. To eliminate the problem for good, Faustman borrowed an idea from the transplant specialists, who have found that liver or spleen cells can "reeducate" a graft recipient's immune system to treat the graft as native tissue. Here spleen cells from a nondiabetic mouse would teach a diabetic immune system how to be nondiabetic.

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