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Gordon Weir, M.D.

Research Summary

Dr. Weir is active in clinical care of diabetes and his research is focused on pancreatic islets, which contain insulin-secreting beta cells.  The main research goal of Dr. Weir and his colleagues is to find ways to preserve and replenish the insulin-producing pancreatic beta cells that are deficient in both types 1 and 2 diabetes.

Regenerative potential of human pancreas

A major goal is to understand the regenerative capacity of human pancreas for making new beta cells.  Human islets are obtained and transplanted into immuno-deficient mice, which allows us the opportunity to study the capacity of beta cells for replication, and also the capacity of transplanted duct cells for neogenesis, which is the creation of new islets.  In addition, we can use gene expression studies to compare beta cells in the pancreas with beta cells that have been transplanted. This can provide important insights into the mechanisms of beta cell replication and beta cell death pathways.

Formation of new islets from duct cells in rodents

This work is complemented by studies in rodents to learn more about the regenerative capacity of duct cells in the pancreas.  This work is being done in collaboration with Drs. Susan Bonner-Weir and Arun Sharma.  Work is ongoing on pancreatic duct ligation in rats, which is an injury model, to see whether this stimulates the formulation of mew islets.  This work is being helped by the sophisticated technique of laser capture microdissection, which allows us to look at gene expression on small collections of tissue, in particular the beta cells within the islet.  Another approach to understanding neogenesis is to examine the potential of isolated pancreatic duct cells that are placed into tissue culture.  We are pursuing a particularly promising approach of a three-dimensional culture system using a collagen gel.  This allows branching morphogenesis to produce newly developed ducts, and there are indications that the formation of new islet tissue can be promoted. 

Reprogramming pancreatic exocrine cells

This project is concerned with reprogramming of pancreatic exocrine cells.  This follows up on an important paper in Nature in 2008 by Drs. Qiao Zhou and Douglas Melton of Harvard in which pancreases were injected with three transcription factors, PDX-1, Ngn3 and MafA.  It was found that the exocrine cells could be reprogrammed to become insulin-producing cells.  We are now collaborating with Dr. Zhou and using some of our animal models to test the potential of this exciting new avenue.

Beta cell replication

Beta cell replication is another appealing approach for obtaining more beta cells to replenish those that are missing in diabetes.  To learn more about replication we are collaborating with the group of Dr. Melton at Harvard with a high-throughput screening approach to identify new molecules that can stimulate beta cell replication.  This project is being done with isolated rat islets; the islets are then dispersed into single cells, placed into multi-well plates, and treated with unknown compounds.  Following the treatment, the cells are stained for evidence of replication.  It is gratifying that several new compounds have already been identified.

Islet encapsulation

 For the past 20 years Dr. Weir has been interested in encapsulation to protect transplanted islets from being killed by the immune system.  There is a Juvenile Diabetes Research Foundation funded project in which Drs. Robert Langer and Dan Anderson of MIT are developing new biomaterials and approaches to the challenge of bringing encapsulated islets to the clinic.  Dr. Weir is working mainly on the biological aspects of this problem to determine the efficacy of these new materials in a variety of diabetic animal models.  The plan is to determine the best materials with rodent studies and then move to monkeys with the obvious goal of bringing this to human trials as soon as possible.

Clinical trial with new-onset type 1 diabetes

Dr. Weir is leading a multi-center clinical trial supported by the Immune Tolerance Network of NIH to determine if alpha-1 antitrypsin can slow the destruction of beta cells is individuals with new-onset type 1 diabetes. This follows up on encouraging results in a mouse model of type 1 diabetes (NOD mice) in which diabetes could be reversed with this treatment.

 

Biography

Dr. Gordon Weir is the Diabetes Research and Wellness Foundation Chair at Joslin and Professor of Medicine at Harvard Medical School. He Co-Heads Joslin's Section on Islet Cell and Regenerative Biology and is Director of its NIH-supported Diabetes Endocrinology Research Center. Dr. Weir completed his medical degree at Harvard Medical School and his residency training at University Hospital in Cleveland, OH. Training in endocrinology was obtained at Massachusetts General Hospital. Before coming to Joslin, Dr. Weir was Professor of Medicine at the Medical College of Virginia.

When he first came to Joslin, he served as the Center's Medical Director for 9 years, in addition to conducting a broad research program. Dr. Weir is the recipient of numerous honors and serves and has served on the editorial boards of several prestigious journals, including the American Journal of Physiology, Journal of Clinical Endocrinology and Metabolism, Endocrinology and Transplantation. He served as Editor-in-Chief of the journal Diabetes.  He is also Head of the Diabetes Program of the Harvard Stem Cell Institute

Page last updated: August 23, 2014