By Gareth Cook, Globe Staff | May 6, 2004

Harvard scientists declared yesterday that a basic assumption about the biology of diabetes the pancreas is wrong - and that one of the most active areas of diabetes research today could be misguided.

Scientists have long believed that many of the body's vital organs are home to elusive populations of adult stem cells, flexible cells with the ability to rebuild that organ. In the case of diabetes, researchers had been hoping to cure the debilitating disease by finding stem cells in the pancreas that could help the body regain its ability to create insulin.

But now Harvard biologist Douglas Melton has discovered that the cells that make insulin - called beta cells - are rarely, if ever, produced by adult stem cells and that the pancreas may have no stem cells at all.

The results come as the government and private foundations are aggressively funding diabetes research. Scientists in the field said the conclusions are stunning. Many diabetes researchers at leading universities and biotech companies have staked their professional futures on finding pancreatic stem cells. One implication of the experiments is that the diabetes research juggernaut may have to turn its attention from adult stem cells to embryonic stem cells, an ethically charged field for which the Bush administration has sharply limited funding.

''It is an important and very provocative paper,'' said Dr. Joel Habener, a Harvard Medical School professor who has been active in the search for pancreatic stem cells. ''Out of controversy comes enlightenment.''

The research, reported in today's issue of the journal Nature, was conducted in mice. The basic biology of the human and mouse pancreas is thought to be nearly identical, and the experiments represent the most detailed look ever at how the insulin-producing beta cells develop.

The experiments took advantage of a powerful new technique called genetic lineage tracing, which may now be used to settle some of the long-standing controversies of stem-cell science. Although scientists believe many organs have adult stem cells within them, only a few types of stem cells have been identified, including those in blood, skin, and intestine. Lineage tracing allows scientists to place a genetic tag on individual cells and their offspring within a living animal, allowing scientists to precisely track cells in a way not possible before.

For the discovery announced yesterday, led by Harvard scientist Yuval Dor in Melton's lab, the team placed labels on about 30 percent of the pancreatic beta cells in young mice. If there were stem cells in the pancreas producing new beta cells, then the percentage of labeled cells should have decreased as the mice grew. Instead, the percentage of labeled beta cells remained constant, indicating that none of the new beta cells were was being generated by stem cells.

In another experiment, the team removed a large part of each mouse's pancreas, which encouraged the organs to regenerate and would have been expected to stimulate any stem cells into action. Although new beta cells were generated, they appeared to be created only by existing beta cells.

The work was funded by the Howard Hughes Medical Institute , the European Molecular Biology Organization , and the Juvenile Diabetes Research Foundation .

The study does not prove that there are no adult stem cells are in the pancreas, the authors stressed. It is possible that they exist and create cells in the pancreas other than the beta cells. It is also possible that stem cells exist and create beta cells, but they do it so rarely that it it did not significantly dilute the number of tagged cells. and therefore escaped detection.

The work is especially relevant to those interested in type one diabetes, known as juvenile diabetes, in which the immune system destroys the body's beta cells. Doctors have already shown that they can cure the condition, which affects more than a million Americans, by transplanting beta cells from donated pancreases into patients. The problem is finding a source of these cells. Because of the large number of patients, however, organ donation alone would provide less than one 1 percent of the cells needed to treat everyone.

''It is a simple supply-and-demand problem,'' said Melton, who also recently announced that his lab has derived 17 new lines of human embryonic stem cells and is offering them free to researchers. around the world. Melton is also the co-director of the Harvard Stem Cell Institute, which was launched last month.

The dream of many researchers has been to find a stem cell in the pancreas that could be cultivated and ultimately produce beta cells - a possibility that cells from patients' own bodies could be used for treatment. That now looks unlikely. The daunting alternative is to start with embryonic stem cells, the most primordial of cells, and figure out how to push them down the long path of development that eventually makes them become beta cells.

This research could also prove be more difficult because the Bush administration will provide federal funding only for human embryonic stem cell research using cell lines created before Aug. 9, 2001. The approved cell lines can be expensive and difficult to obtain, and any new cell lines of interest to diabetes researchers would be off-limits in many labs.

Another treatment possibility is to focus on the beta cells themselves and look for ways to grow large numbers of them. Researchers have traditionally been more interested in stem cells than beta cells, because stem cells are thought to have more power to divide and survive in the lab. and are thus capable of creating many more new cells.

The paper challenges a long list of experiments that have suggested the presence of pancreatic stem cells. It is expected to spark a series of more rigorous experiments, said Christopher Wright , a professor at Vanderbilt University .

One of the scientists now in the spotlight is Susan Bonner-Weir , a senior investigator at the Joslin Diabetes Center who has published several prominent papers arguing that pancreatic stem cells generate new beta cells. Before the findings announced yesterday were published The Melton team had consulted with her to try to understand the discrepancies between the two bodies of work.

Bonner-Weir now has an experiment underway which that will take advantage of the more precise cell-tracking technique used by the Melton lab to see if determine whether she can find stronger proof for her previous claims. ''We are accepting the challenge and trying to figure it out,'' said Bonner-Weir.

Gareth Cook can be reached at cook@globe.com

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