The permanent reversal of Type 1 diabetes in mice may end the wrenching debate over harvesting stem cells from the unborn to treat adult diseases. Researchers at Harvard Medical School killed cells responsible for the diabetes, then the animals’ adult stem cells took over and regenerated missing cells needed to produce insulin and eliminate the disease.
“It should be possible to use the same method to reverse Type 1 diabetes in humans,” says Denise Faustman, the associate professor of medicine who leads the research. Setting up a trial for patients has already begun at Massachusetts General Hospital in Boston.
Type 1 diabetes is an “autoimmune” disease in which the body’s blood cells attack its own organs and tissues. Such maladies include rheumatoid arthritis, multiple sclerosis, lupus, and more than 50 other ailments. Faustman believes that many of them may be similarly cured by poisoning the offending cells and letting adult stem cells regrow replacement organs.
“Once the disease is out of the way, adult stem cells regenerate normal organs and tissues,” Faustman says. “What is more, we should be able to replace damaged organs and tissues by using adult stem cells, thus eliminating, at least temporarily, the need to harvest and transplant stem cells from embryos and fetuses. Of course, it will take years before we know for sure if we can do this in humans.”
Stem cells from embryos have the ability to grow into all other types of cells. They may be able to mature into brain cells to repair damage from strokes, Alzheimer’s and Parkinson’s diseases; into heart cells to heal the ravages of heart attacks; and into organs to replace those ruined by cancer. But problems exist in getting such cells to mature into a specific type of cell and to home in on a specific place. There’s also the problem of stopping them from growing once the repair is made. Uncontrolled growth may lead to tumors.
The existence of adult stem cells raises the question of why the body doesn’t use them on a regular basis to heal itself. It may be because adult stem-cell populations are small and need some sort of outside stimulation. There’s recent evidence that additional adult cells injected into mice start to repair heart attack and stroke damage.
In the diabetes experiments, cells that attack insulin-producing islet cells in the pancreas were destroyed. The researchers intended to follow up the killings with transplants of healthy islet cells but, to their surprise, this turned out to be unnecessary because adult stem cells took over the work.
“It was a miracle that we didn’t expect,” Faustman comments.
Finding a missing connection
An estimated 16 million people have diabetes in the United States. About 10 percent of these patients suffer from Type 1, which used to be called juvenile diabetes because it commonly appears between ages 10 and 16. Type 1 diabetics cannot make insulin to convert blood sugars into energy, so they must inject themselves daily with the hormone to survive. New cases have tripled in the United States in the past 50 years.
Type 2, formerly called adult-onset diabetes, usually occurs gradually after age 40, and often can be managed by diet and exercise. The two types together are the leading cause of kidney failure, adult blindness, and limb amputation, as well as major risk factors for heart disease, strokes, and birth defects.
Faustman isn’t sure if her technique will work with Type 2 diabetes. “We really don’t know if replacing the islet cells will do the job,” she says. “Some experts think that the resistance to insulin comes from outside the pancreas. There’s also the possibility that Type 2 diabetics used up their stem cells at a faster rate,” which decreases their repair capacity.
The Harvard-Massachusetts General Hospital team believes they can move from mice to humans because the same defective pathways exist in both species. “We always begin our projects with human cells,” Faustman explains. “When we observe something important but can’t experiment with patients, we go to mice.”
The defective pathway in both humans and mice has been known for years. It’s been well-studied in cancer and AIDS research, but everyone missed its connection to autoimmune disease until Faustman’s lab hit upon it.
The defect involves a genetic mutation that causes white blood cells to attack the insulin-producing cells. It’s as if the body rejects part of itself because it cannot tell the difference between normal cells and foreign invaders like viruses or bacteria. Faustman’s team found they could destroy the offending cells with drugs.
When given to the mice, a compound known as CFA boosted the production of another substance known as tumor necrosis factor-alpha (TNF). Years ago, researchers tested TNF as a cancer drug, then as an AIDS treatment, but have abandoned it since.
TNF wiped out cells that couldn’t tell self from nonself, but this was believed to be only a temporary respite. Everyone thought it could only last until the body made new white blood cells with the same defect. To counter this inevitability, they planned another treatment to re-educate the new cells so they would not attack insulin-making tissues in the pancreas.
Once the diseased cells were out of the way, however, adult stem cells took over and grew new islets in 40 days.
“At first we thought we had failed,” Faustman recalls. She and her colleagues planned to follow up by transplanting healthy islet cells grown in their laboratory. “But the biological indicators we saw were not what we wanted for such transplants. Then we gradually realized that there were now islet cells where none had existed 40 days before. It was astonishing! We had reversed the disease without the need for transplants.”
“These results are remarkable and surprising,” comments David M. Nathan, the Harvard professor of medicine who will attempt to do the same experiments with humans at Massachusetts General Hospital. “We need careful studies to find out if we can delete the offending blood cells in humans in the same way that it was done in mice. Adult stem cells in these mice were apparently inactive or suppressed until cells that attacked the pancreas were removed. We don’t know yet if human adult stem cells can accomplish the same regeneration. If they can, and it will take years to find out, that opens the way to treating other autoimmune diseases like multiple sclerosis and rheumatoid arthritis.”