Collaboration Involves Six HMS Affiliated Hospitals and Research Institutions
James Mulvihill, president and CEO of the Juvenile Diabetes Foundation
(JDF), and Joseph Martin, HMS dean, listen as Leah Mullin, chair of the
JDF government relations committee, speaks at a press conference held after
the scientific symposium on islet cell transplantation.
Once given low priority for funding, juvenile diabetes has just become the target of one of the most tightly focused and coordinated campaigns ever directed against a major disease. Working under the auspices of a $20 million, five-year grant from the Juvenile Diabetes Foundation (JDF) and donors Lawrence and Florence DeGeorge, more than 30 researchers from HMS, HSPH, Harvard University, Joslin Diabetes Center, and other institutions will join in the new JDF Center for Islet Cell Transplantation. Their mission: to find a cure for juvenile, or type I, diabetes--one that goes beyond the stopgap measure of daily insulin.
"This level of collaboration in the Harvard and Boston medical community is, to my knowledge, unprecedented," said Joseph Martin, dean of HMS, at a JDF-HMS symposium on September 10. "This is a unique arrangement. It is also a prototype for what I hope will be an approach for solving other major medical problems here at the medical school." The center not only draws together a diverse array of scientists from numerous institutions, including six HMS affiliated hospitals, but does so with a singular purpose.
The Research Paths
The explicit goal of the center is to find a way to replace the body's insulin-producing islet cells without provoking the immune system to reject the new tissue. In juvenile diabetes, the immune cells turn against the islets, leaving the body unable to remove excess sugar from the blood. High sugar levels lead to a host of problems--kidney disease, blindness, necrosis, stroke, and heart attack--which daily doses of insulin may delay but do not always avert.
"We know it's possible to cure this disease," said Hugh Auchincloss, associate professor of surgery at HMS and MGH and director of the center. One of his own patients received a transplanted pancreas, the organ that produces islet cells. She has not had to take insulin for the past ten years, though she must take immunosuppressive drugs that can produce serious side effects.
Convinced that islet transplantation without immune suppression would be a safer and less cumbersome approach--and one that could become a reality if enough researchers were drawn to the problem--Auchincloss and Laurie Glimcher, the Irene Heinz Given professor of immunology at HSPH, approached the medical dean in February with the idea for the center. Yet developing a cure for juvenile diabetes will require overcoming many challenges.
Joslin Celebrates Centennial with Symposia
Looking back over a century of progress and ahead to a cure (see story p. 1), the Joslin Diabetes Center celebrates its centennial this year.
Started as the Kenmore Square private practice of Elliott Joslin in 1898, the center moved to the corner of Longwood and Brookline in the early 1950s. It has been a world leader in diabetes treatment and research and counts more than 400 physicians, researchers, and other staff at its Boston location. The center also has been franchised to more than 20 leading hospitals in 11 states.
A timeline in the long hallway of the clinic's second floor notes key moments in Joslin history. Center researchers have discovered how to identify pre-diabetics years in advance of their symptoms and are helping lead nationwide diabetes prevention studies. Joslin researchers developed laser surgery for diabetic eye disease, saving thousands from going blind. And due to Joslin clinical research, fetal survival rates for pregnant women with diabetes have increased from 54 percent to 96 percent, nearly identical to those for women without the disease.
Despite the progress, diabetes affects 16 million Americans and kills 187,000 annually. New research findings will be presented at two international symposia next month: "Diabetes Mellitus: From Patients to Genes and Back," Oct. 2124, and a "Diabetic Complications Conference," Oct. 2325. Both meetings will be held at the Seaport Hotel and Conference Center, Boston World Trade Center. More information is available at http://dnacore.joslab.harvard.edu/symposia/.
--Carol Cruzan Morton
First, the same immune cells that perversely kill the original islet cells may be primed to destroy transplanted ones. Even normal immune cells are designed to detect invaders and may become intolerant and reject the therapeutic cells. In addition, there is the problem of developing an adequate supply of transplantable islets. And, finally, there is the challenge of performing the actual transplantation.
Taking a divide and converge approach, each of the researchers will tackle one of the aforementioned problems--autoimmunity, tolerance, islet cell supply, and transplantation. Symposium participants gave an idea of where these lines of research begin and how they might lead to the overall goal of islet transplantation:
* Killer T cells do not work alone to kill islet cells but are aided by helper T cells. The helper cells come in two varieties--one that promotes destruction of islets and the other that gives protection. Early in their development, these destructive and protective cells differentiate by expressing the gene for one of two growth factors, interleukin-12 and interleukin-4, respectively. One way to dampen the autoimmune response of people with juvenile diabetes, said Glimcher, is to get cells destined to be destructive to express the gene for the benign growth factor, interleukin-4, instead of the deadly version.
* Transplanted cells or organs--which are often rejected by the immune system before they even have a chance to set up camp--may have more success if they are introduced inside the Trojan horse of the thymus, an organ that serves as a sort of school for T cells. David Sachs, the Paul S. Russell/Warner Lambert professor of surgery at HMS and MGH, described how he transplanted a pig's thymus into the kidney of the same pig and then transplanted the "thymo-kidney" into a different pig. "There was no rejection," said Sachs. Indeed, the hybrid performed the functions of both organs. He believes similar isletkidneys or thymoisletkidneys could help islet cells engraft more quickly, with less chance of rejection.
* One way to shore up the supply of islet cells is to see how they develop naturally from precursor cells and then mimic the process, said Doug Melton, professor of molecular and cellular biology at Harvard University. Using new DNA chip technology, he plans to see which genes are expressed--and at what points during development--and then use the genes to induce the growth and differentiation of islet cells.
"The goal is to obtain a reproducible and inexhaustible supply of pancreatic [islet] cells," said Melton.
--Misia Landau
Focus September 18, 1998