Reasons for Optimism
The collaboration between Harvard, Boston IVF and HHMI is just beginning. Renovation of a laboratory dedicated to the stem cell project has just been completed. It will enable Melton to study, in great detail, the various steps in the development of insulin-producing beta cells in humans.

Melton points out that he'll benefit from the experience of National Institutes of Health (NIH) scientists who recently succeeded in coaxing mouse ES cells to develop into pancreatic cells that make insulin. "The cells self-assemble to form three-dimensional clusters similar to normal pancreatic islets," reported Ron McKay, chief of the Laboratory of Molecular Biology at the National Institute of Neurological Disorders and Stroke, and his associates in the May 18, 2001, issue of Science. "When these cell clusters were exposed to glucose, they released small amounts of insulin. They continued to function even when injected into diabetic mice"—although at levels too low to make a real difference in the health of the mice.

Melton intends to reproduce these findings and extend them to human ES cells. He is convinced that if he succeeds in producing human beta cells that pump out enough insulin, he'll be able to implant these cells into diabetics and cure them. The evidence comes from Canada, he says. Last year, a group of physicians in Edmonton took pancreases from cadavers, obtained islets from them and then transplanted the islets (which contain beta cells as well as three other kinds of pancreatic cells) into patients who had very hard to control diabetes. "The results are extremely encouraging," says Melton. "All of the patients are doing well. They are no longer taking insulin injections."

The procedure is not perfect, however. "The patients have to be kept on immunosuppressant drugs so they won't reject the foreign islets," Melton explains. "For this reason, you would not at this point treat a child with such implants, since it's unknown whether taking daily insulin injections and having imperfect glucose control is better or worse than having perfect glucose control but taking immunosuppressants all your life."

The problem of immunity will be solved, Melton believes, when "some clever immunologists figure out how to induce tolerance and block rejection. Or maybe scientists will develop a special net to enclose the transplanted beta cells and keep them away from the body's immune system."

But there is another big problem: supply. "There just aren't enough cadavers to treat the one million type I diabetics in the U.S., plus another million type II [adult-onset] diabetics who take insulin," he says. "The very best estimates say that there are only 1,000 to 2,000 pancreases available from cadavers in any one year. Why? Because the pancreas is exquisitely sensitive to the loss of oxygen.... You only really have access to patients who first of all are organ donors and, secondly, who you know are about to die."

For this reason, Melton places his hopes on the production of fresh beta cells from a renewable source, human ES cells. He envisions two promising outcomes. First, if functioning beta cells are implanted into type I diabetics, such as his son, the cells will squirt out just the amount of insulin each patient needs. This will occur internally, eliminating both the need for injections and the fear of crises.

Second, as scientists learn which signals tell the ES cells to become beta cells, they may be able to mimic these signals with drugs and stimulate patients' own stem cells to make more beta cells. If this is possible in type I diabetes—if these patients still have some pancreatic precursor cells to stimulate—"you would need to combine such therapies with some block to the immune system," Melton warns. "Otherwise, the person would get more beta cells, but the immune system would be there saying 'whack, whack,' and just killing them off. But in type II patients, where there is no autoimmune attack, a stimulus to the patients' own cells might provide a cure."

A Need for Additional ES cell lines
Melton knows that the clock is ticking, that he must work rapidly and that the hunt for a cure would be speeded up considerably if he and other scientists were studying human ES cells. Until recently (August 2001), however, the majority of U.S. bioscientists—those who receive funds from government agencies—were forbidden to use the funds to work with human ES cells; some legislators were concerned that human embryos, which are potential life, would be destroyed in the process of deriving these cells.

There was much discussion about possible alternatives—using stem cells from adult tissue such as blood or bone marrow, for instance, or those derived from umbilical cords or placentas. Such cells can generate several kinds of specialized cells and are certainly worth pursuing, Melton says, but he warns that because these cells have already started down a particular path, they cannot generate all of the estimated 200 types of cells of the human body. Besides, he points out, adult stem cells "are very rare and difficult to find, and in most cases, no one can get them to grow outside the body. An ES cell, by contrast, has no trouble growing in a culture dish."

On August 9, 2001, President Bush tried to settle the controversy about federal financing of research on human ES cells by allowing it to proceed only as long as the cells came from human embryos that were left over from fertility treatments and that were already destroyed by the day of his speech. These constraints were apparently meant to ensure that government funding of stem cell research was kept separate from, and did not encourage, the further destruction of human embryos.

NIH then produced a list of 64 human ES cell lines that already existed or were in various stages of development in the United States, Australia, Sweden, Israel and India. At the Senate hearing called by Senator Edward M. Kennedy a few weeks later, however, new issues were raised.

Senator Arlen Specter argued, "many of the lines cited are not robust, viable or usable." He also pointed out that because all the human ES cell lines produced so far were grown on layers of mouse feeder cells, they may be unsafe for human use. Melton added that the August 9 cutoff date "was not chosen for scientific reasons, and its arbitrary selection will have an effect on the progress of research."

Although ES cell lines may live indefinitely, Melton said, "decades of experience with mouse ES cells" have shown they can lose their full potential with increasing age. For example, the cells can lose their ability to remain in the undifferentiated state. In addition, they can become contaminated in the lab or accumulate harmful mutations. Thus, under the President's restrictions, Melton told the Senate committee, by the time research on human ES cells advances to the point at which clinical applications can begin, "the viability of the existing cell lines will have been exhausted.

"If we can turn human ES cells into pancreatic beta cells, we would want to use additional, new ES cell lines," he emphasized. In that quest, he hopes that the privately funded HHMI-Harvard-Boston IVF collaboration can help him along.

Photo: Kathleen Dooher

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Reprinted from the HHMI Bulletin,
March 2002, pages 10-17.
©2002 Howard Hughes Medical Institute