The world is experiencing and epidemic of diabetes mellitus, a serious disease characterized by the body’s inability to secrete adequate amounts of insulin. Diabetes is the leading cause of blindness, kidney failure, amputations and nerve disease and the seventh leading cause of death in America. Recent work suggests that one way to treat diabetes is to surgically transplant those very cells that normally produce and secrete insulin. These cells, called pancreatic beta cells, normally secrete insulin after a meal, when blood sugar rises. However, the transplanted beta cells must be obtained from organ donors, and there are too few donors to treat everyone who needs treatment.
A promising way to produce a potentially unlimited supply of transplantable tissue for diabetes treatment would be to use human embryonic stem cells. Human embryonic stem cells can turn into any other cell of the body, as occurs normally during development. The problem is that there is no known laboratory technique to completely turn these special cells into fully functional beta cells. We can make cells that produce insulin, but they do not secrete it, in response to a rise in blood sugar, as would be needed to function normally. Scientists have shown, curiously, that when these cells are transplanted into mice, they do learn to secrete insulin when sugar rises, but it takes months for the change to occur, and we do not know whether this would happen, if the cells were transplanted into humans.
We aim to find the genetic switches, called "microRNAs" that will turn on the production of the cell machinery that enables beta cells normally to know when blood sugar is higher than normal and to respond by secreting insulin. If we can find these genetic switches, we may be able to speed up the production of cells useful for transplantation treatment of diabetes. The approach we are pioneering may have broader application to turn human embryonic stem cells into almost any other desired tissue, which would then be useful for transplantation treatment of other diseases, including Alzheimer's disease, Parkinson's disease, and Huntington's disease, for example.
The genetic switches we are looking at, microRNAs, are normally present in all cells and participate in the turning on and off of cellular machinery at strategic times during development. If we could compare the laboratory-produced cells (that make insulin but do not secrete it when sugar is high) with real beta cells (that both make insulin and secrete it when sugar is high), we may be able to identify which microRNAs need to be there (or may not there), and use this knowledge to get cells to turn on the sugar-response machinery.
We have an outstanding team includes scientists who are the experts needed (1) to identify the key microRNAs, (2) to check the microRNAs' ability to turn on the sugar-response machinery, and (3) to transplant the treated cells to see whether they can treat diabetes in mice.
California is the largest state and has the largest economy of the USA. It, therefore, suffers the lion's share of the health and economic costs of diabetes -- a devastating disease of sugar metabolism. The total cost of diabetes has been estimated at over $170 billion for the USA (diabetes fact sheet, ADA). Scaled to the GDP of California, the total cost can be estimated to be on the order of $20 billion. The total number of people in California suffering from diabetes is estimated at over 3 million, of which about 300,000 suffer from type 1 diabetes, the kind of diabetes that has been shown to be treatable by human islet transplantation. Any advances in treatment of diabetes, such as might result if our project is successful, would have the important potential to dramatically reduce the disease burden on the state of California.
Our proposal is designed to address the major bottleneck for islet transplantation therapy of type 1 diabetes, which is an inadequate supply of transplantable tissue. We aim to identify the genetic switches to turn on the machinery that will enable laboratory-treated human embryonic stem cells to become fully functional pancreatic beta cells. While the approach of identifying and manipulating genetic switches of beta cells has obvious medical and economic payoffs specifically for diabetes treatment, the general approach may have much broader significance for stem cell therapy, as it may point the way to speed differentiation of stem cells into any particular cell type.
As the approach here is novel, and it is being applied to create tissues that can be used for medical treatment, the proposed work has the potential to spawn a completely new biotechnology industry, which would therefore benefit California not only by providing efficacious medical treatment for a major disease, but also provide jobs to a burgeoning industry.