Islet Cell Research

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or 80 years, diabetics have been jabbing themselves three or more times a day with insulin to control their blood sugar, and ever since, patients and doctors have dreamt of an injection-free cure.

A new Islet Cell Resource Center at Columbia hopes to change the lives of diabetics by providing a new therapy for the disease, one that will allow the patient to produce insulin and make daily injections obsolete. Although insulin therapy has been successful in transforming type I diabetes from a fatal childhood disease into a chronic, manageable life-long disorder, diabetics still suffer from a wide variety of life-threatening complications, including kidney disease, heart disease, and stroke.

The new therapy—islet cell transplantation—replaces the insulin-producing cells that are destroyed by the patient’s disease. Islets are not individual cells, but bundles of 50 to 1,000 pancreatic cells, which include the insulin-producing beta cells and other cell types. Besides controlling diabetes, doctors hope transplantation will prevent the disease’s secondary complications from damaging the patient’s kidneys, heart, and other organs. Although researchers have pursued islet cell transplants for 20 years, the method did not work well until Canadian researchers made key advances two years ago.

Dr. Mark Hardy, Auchincloss Professor of Surgery and co-director of the center with Dr. Kevan Herold, associate professor of clinical medicine, says the Columbia center will be the New York City region’s islet cell resource, responsible for collecting donor cells, distributing them to researchers, and also performing transplants soon. Nine other centers, jointly funded by the NIH and the Juvenile Diabetes Research Foundation, are located throughout the country. Four of the 10 centers have begun transplants.

“Initially, the idea will be for each center to develop certain specialty areas and interact with the other centers to increase islet yield, quality, and distribution,” says Dr. Hardy, who is also the director of renal transplants at New York-Presbyterian Hospital. In early February, Dr. Hardy met with the directors of the other centers in Washington, D.C., to approve each other’s research protocols. Most centers are focusing their research on the transplant procedure but they enthusiastically received Columbia’s plan, which will develop very quick methods to determine islet quality before the cells are transplanted into a patient. The technique also should help increase the yield of high-quality cells.

The concept of islet cell transplantation sounds simple—remove islets from a donor pancreas and then transplant them into a patient’s liver, where a rich blood supply nourishes the cells. But until two years ago, the transplants generally didn’t work. The Canadian researchers achieved success by using a cocktail of newer immunosuppressive drugs and increasing the number of injected islets to 10,000 per kilogram, or 750,000 islets for a 165-pound man. Usually, two or three donor organs are needed to retrieve enough islets for one transplant recipient, but recent progress is reducing this to one human cadaveric pancreas per diabetic recipient.

Isolating “happy” islet bundles, however, is tricky, says Dr. Eric Liu, a research fellow with the center and resident in surgery. The islets come from the pancreata (the plural of pancreas) of deceased donors and the tissues are oxygen-starved. Compounding the problem created by limited numbers of donated organs and their condition, the brutal isolation process kills many islets. The process begins by injecting the pancreas with digestive enzymes and then shaking and heating the organ until the tissue breaks apart into a slurry of cells. But if the shaking and baking is too rigorous, islets—which Dr. Liu says look like clusters of chrysanthemums—fall apart. Individual islet cells are useless for transplantation, as the cells cannot survive outside the islet milieu.

Given the abuse islets receive during isolation, researchers in the islet resource center fear the process may yield islets of varying quality. Their goal is to ensure that only high-quality islets are used in transplantation. To determine what makes a high-quality islet, Dr. Paul Harris, associate research scientist in medicine, and Dr. Charles Hesdorffer, associate professor of clinical medicine, are monitoring the expression of many different proteins in the islet cells with DNA microarrays and protein chips in collaboration with Dr. John Baust and his collaborators at the State University of New York at Binghamton. When transplants begin here, researchers will use the two technologies to compare islets from successful transplants to those from unsuccessful transplants. These comparisons should identify a specific signature in isolated islets that will help predict transplant success or failure. So far, they have found many islet cells show signs of oxygen starvation, not surprising after the stress of isolation, but they don’t know starvation’s effect on the transplants.

Once the protein signature of healthy islets is found, a protein chip will be built to measure the level of the proteins in the islets before transplantation. “The overall goal,” Dr. Harris says, “is to come up with very quick methods to determine if islets are high quality. There’s only a one- to two-day window of opportunity after isolation to do tests on the cells before they must be put into a patient.” The protein chips also will be used to fine-tune the isolation process to increase the yield of high-quality islets. Under the direction of Dr. Donna Skerrett, assistant professor of pathology, researchers will develop ways to freeze the cells for preservation and shipping.

The center’s physicians and researchers are gearing up to perform the first transplants this year, if the Food and Drug Administration approves the facility to do the procedure. FDA is scheduled to inspect the facility in March or April. But the scientists ultimately are looking beyond diabetes. “The most important aspect of islet research is that it lays the foundation for the future of transplantation for the 21st century,” says Dr. Hardy, also vice chairman of surgery and program director for surgical residents, “and that future is cellular transplantation.”