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Doctors Advance in Helping Body to Repair Itself

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    Doctors Advance in Helping Body to Repair Itself

    January 15, 2002

    Doctors Advance in Helping Body to Repair Itself

    nshrined in textbooks, taught in schools and rarely questioned was one truism of medicine: the only organs that can regenerate their cells are the bone marrow, the liver and, maybe, the kidney.

    But now, researchers say, they are not so sure.

    To their astonishment, scientists at Harvard Medical School recently discovered that in mice, the insulin- producing cells of the pancreas could regenerate. Other experts, at New York Medical College, just reported compelling evidence that human hearts can grow new cells.

    The findings have enormous implications, scientists say, although it can be a long and harrowing path from observations like these to medical treatments.

    The encouraging news is that the body has an unappreciated capacity to repair itself. But in making that discovery, researchers also found a potential therapeutic stumbling block: an underlying disease, like diabetes, which kills pancreas cells, may outpace the regeneration of those cells. Even adding new cells, like ones derived from sources like stem cells, may be futile. To regenerate tissues and organs, it may be necessary first to cure an underlying disease.

    Nonetheless, some medical experts are optimistic. "These are really intriguing results," said Dr. Gregory Stock, who directs the program on medicine, technology and society at the University of California at Los Angeles School of Medicine. The results show that "there may be ways of eliciting responses from the body that we would not have dared to look for," he said.

    That, however, was furthest from the minds of the scientists who chanced upon regeneration of pancreas cells in mice.

    The work began, said Dr. Denise Faustman, a diabetes researcher at Harvard, because she was trying to get around a fundamental obstacle to curing Type 1 diabetes.

    The disease usually occurs in puberty and afflicts an estimated half-million to a million Americans. It occurs because islet cells, the insulin-producing cells of the pancreas, die, almost always because they are attacked by cells of the immune system. But the underlying disease that killed those cells also seems to kill any that are transplanted to replace them.

    The problem had become clear in mice. Scientists created diabetes by destroying the animals' islet cells and then, with ease, cured the disease by transplanting new ones. But, they found, transplants did not work in another strain of mice whose diabetes more closely resembled the human disease, caused when their immune systems attacked and killed the islet cells. Despite islet cell transplants, the mice remained diabetic.

    Nonetheless, doctors have spent decades trying to cure severe diabetes by giving patients new pancreases or new islet cells, with generally dismal outcomes, said Dr. David M. Nathan, who directs the diabetes center at Massachusetts General Hospital. The best results by far are from a small study by scientists at the University of Alberta in Edmonton, Canada, who transplanted islet cells to patients with severe diabetes and used a new regimen of drugs to suppress the immune systems.

    Their initial report, nearly two years ago, was that all eight patients who had the transplants no longer had diabetes. Last year, they published an update, on a total of 12 patients who had islet cell transplants. Four no longer had any signs of diabetes - their blood sugar levels were normal. In five patients, blood sugar levels were elevated, an indication that the islet cells were not fully functioning. And in three, diabetes had returned.

    The work is continuing, at Edmonton and at other medical centers, including Massachusetts General, and Dr. Edmond A. Ryan at the University of Alberta said he remained optimistic.

    "It's going well, but it's not perfect," he said.

    Others are less enthusiastic.

    Dr. Nathan said he was now convinced that without stopping the underlying disease, "there is no reason to think the diabetes will not return."

    So Dr. Faustman set out to find a way to suppress the immune system's attack, thinking she could then successfully transplant islet cells into naturally diabetic mice. After years of work, she and her colleagues hit on a method that worked. It involved training immune system cells in the blood not to attack islet cells and, at the same time, killing immune system cells in the pancreas where an attack on islet cells was under way.

    It was time for what the researchers thought would be the ultimate test. First they would stop the underlying diabetes with their new method. Then they would transplant islet cells into the mice. And, to prove that the cells had cured the mice, they would take the transplanted cells out and watch the diabetes return.

    Since it is impossible to pluck transplanted islet cells from a mouse's pancreas, the researchers slipped the new cells into one animal's kidneys. The cells would secrete insulin, just as they would if they were in the pancreas, controlling the diabetes. That way, they could later remove the kidney and take out the islet cells with it.

    That, at least, was the plan.

    At first, the experiment seemed to be a huge success - the mice were cured of their diabetes. "We were very proud of ourselves," Dr. Faustman said.

    Then the scientists removed the kidneys containing the islet cells. To their astonishment, it made no difference - the animals still made their own insulin and no longer had diabetes.

    "I said, `Oh no - how could this have happened?' " Dr. Faustman said. "We moped around." Finally, it occurred to them that maybe the experiment was not a failure. Maybe the islet cell transplant was not necessary because once the scientists blocked the underlying disease, the pancreas could regenerate its own islet cells.

    "It was a total surprise - it knocked our socks off," Dr. Nathan said.

    Dr. Faustman says she still does not know where the new islet cells came from. They may have grown from pancreas cells. Or they may have come from immature cells that originated elsewhere in the body and were stimulated to develop into islet cells by signals in the pancreas.

    But whatever their origin, the islet cells were working normally, raising the question of whether the same treatment strategy would work in humans. That is an ultimate goal, Dr. Nathan said, while cautioning, "we're a long way from that." He estimated it would take at least a couple of years before the investigators were ready to try the most preliminary studies in humans. But, he added, he is excited.

    "This is really cool," Dr. Nathan said. "It provides the possibility that you could take people with Type 1 diabetes or other autoimmune diseases that are involved in the destruction of tissue and, if you interrupt the diseases, maybe these cells would regrow."

    The other organ whose cells now appear to regenerate is the heart. And while some heart disease experts are astonished, the scientist who led the study, Dr. Piero Anversa, a heart researcher at New York Medical College in Valhalla, said he never believed the dogma that the heart did not grow new cells. Last year, his group reported tantalizing evidence that he was right.

    Scrutinizing the hearts of people who had died shortly after having heart attacks, Dr. Anversa and his colleagues reported that there were dividing cells in the damaged hearts and that those cells were most numerous in the heart tissue that was next to the area killed by the heart attack.

    Heart disease experts were overwhelmed. "This is a breakthrough, at least for a new way of thinking about the heart's recuperative power and ways to repair a damaged heart," said Dr. Valentin Fuster, a former president of the American Heart Association.

    But Dr. Anversa wanted to learn where those new heart cells came from. Are they already in the heart or do they come from elsewhere, like the bone marrow? Marrow is known to have immature cells that, in theory, can develop into specialized cells if they are given the right biochemical signals.

    He and his colleagues hit upon a way to find out. They would look at men who had received heart transplants from women. Male cells have a Y chromosome, and female cells do not. So if, on autopsy, the female hearts that were implanted in men contained mature cells with Y chromosomes, that would be proof that the cells originated outside the heart, coming from the man's own cells, possibly from stem cells already present in his body and ready, when signaled, to become heart cells.

    Reporting in the Jan. 3 issue of The New England Journal of Medicine, Dr. Anversa and his colleagues said there were abundant male cells in the female hearts.

    Asked why a healthy transplanted heart would need to grow new cells, Dr. Anversa said the new heart was not necessarily so healthy. "The heart is subjected to a tremendous amount of stress," he said.

    Typically, a donated heart is stored for hours before it is transplanted. And, he said, women tend to have smaller hearts than men, a fact that could strain the female hearts as they tried to supply blood to the larger body of a man. The female hearts may need new cells to replace ones that were injured or died in the process of transplantation and they may need to grow larger to meet the new demands on them.

    Now, Dr. Anversa said, the challenge is to learn where the cells that colonize the heart come from and how to direct the process so that the heart can repair itself.

    Dr. Irving L. Weissman, a stem cell researcher at Stanford, suggested another possible way to repair hearts. "If we knew there was a cell outside the heart that could help regenerate the heart," he said, "we might be able to transplant it into the heart."

    But one question looms over the new research: if the body is so good at growing new cells like heart cells and pancreas cells, why does anyone develop diabetes or heart disease? Why can't the body just constantly regenerate its organs when cells die?

    The diabetes work provides an explanation, Dr. Faustman said. If the environment is wrong - in this case, an underlying autoimmune disease causing diabetes - the body's regenerative mechanisms may be unable to keep up. The same thing could happen with damaged hearts, she said. Patients with heart disease may have such severe damage to their hearts that the organs may no longer have the scaffolding or the chemical signals for new cell growth.

    That observation provides a warning for research on stem cells, she added. It may not be enough to provide new cells to patients if nothing is done to change their underlying disease.

    "Even if you clone vats of these cells, if you don't change the environment of the host, they won't do their job," Dr. Faustman said.

    But the work also provides new hope for medicine, researchers said.

    In an editorial accompanying Dr. Anversa's recent paper, two editors from The New England Journal of Medicine, Dr. Robert S. Schwartz and Dr. Gregory D. Curfman, noted that the findings had enormous implications. They "raise the hope that counter to traditional beliefs, the heart can repair itself," they wrote. That means, they said, that scientists may be able to prompt that repair.

    They believe that is not such an impossible aim. "Such approaches to therapy," they wrote, "which previously were only pipe dreams, are now realistic goals that may soon be within reach."