Diabetes Program

Program Head: Gordon Weir, MD

Goal: to generate enough insulin-producing beta cells for therapy

There are an estimated 194 million people world-wide with diabetes; 20.8 million of them are in the United States and the numbers continue to rise. Both forms of diabetes are a result of a deficiency in numbers of insulin-producing cells (known as beta cells), because they are destroyed or because they don't produce insulin efficiently. Replacing damaged or lost beta cells can provide the body with the insulin it needs to keep glucose levels within the necessary normal range.

Unfortunately, there is a shortage of beta cells as researchers currently cannot generate sufficient amounts of beta cells for transplantation. As no one has been able to isolate stem cells from the pancreas, studies are suggesting that the dominant pathway for making new beta cells is from pre-existing beta cells rather than stem cells. In order to generate large amounts of beta cells, researchers are looking to new methods of expanding existing beta cell populations.

The Diabetes Program at HSCI was established to determine the best methods of generating adequate numbers of beta cells. This program consists of scientists and clinicians from various backgrounds and institutions whose combined expertise will enable the group as a whole to tackle this shortage of beta cells from two different approaches: generating beta cells from either pre-existing beta cells or from human embryonic stem (ES) cells. This would provide an abundant supply of beta cells, and possibly, a patient-specific supply, for therapies.

Certain methods researchers are studying are:

How to stimulate beta cell replication
Beta cells are generated in the adult body by self-duplication and researchers are looking for molecules that initiate and moderate this process. The techniques used to identify a drug or factor that stimulates beta cell replication - high throughput chemical screening and RNAi library screening - may also permit the expansion of these cells on a very large scale.

In addition, three complementary methods are also taking place, all with the aim of producing sufficient amounts of beta cells for treatment: the creation of a beta cell line that is immortalized and can be grown in culture (in a petri dish) indefinitely will reduce the need for isolating these cells from the limited numbers of organ donors; the encouragement of a natural phenomena, where beta cells briefly regress to a simpler unspecialized form before duplicating and maturing into more beta cells; and the use of animal models to search for molecules that occur naturally within the body that will stimulate replication of beta cells in the pancreas.

How to turn human embryonic stem (ES) cells into pancreatic beta cells
Researchers investigating which molecules and chemicals are responsible for the development of an ES cell into a mature beta cell. Several human ES cell lines with genes that are known to sustain self-duplication and other genes known to promote the maturation of particular tissues are being constructed and tested. Once established, these ES cell lines will be used to conduct small molecule, RNAi and cDNA library screens to elucidate the developmental steps an ES cell must undergo to become a beta cell. Researchers will then be able to grow beta cells in large quantities suitable for transplantation therapies.

How to use tissue engineering to turn ES cells into mature beta cells
Environmental factors such as the microenvironment cells live in and interactions with other cells are critically important during development. Through tissue engineering, investigators can create synthetic scaffolds that mimic many different environments. Seeding cells onto these scaffolds will allow them to closely track the fate of an individual cell as it develops. It will also enable researchers to optimize the interaction of cells and biomaterials and to test multiple chemicals that may be responsible for maturity.

High-throughput screening for small molecules
Two screening facilities, one at Harvard University and one at the Institute of Chemistry and Cell Biology at Longwood (ICCB-Longwood) have been identified for this project. Researchers are aiming to identify small molecules and compounds that influence the maturation of ES cells and the process of duplication of beta cells. Results from these screens will be of great importance for all of the above aims.

Diabetes Program Lead Faculty

There are at least 60 researchers working together in this program.