In the case of type 1 or type 2 diabetes, the problem, ultimately, is that the beta cells of the pancreas don’t produce enough insulin. In type 1 diabetes this occurs when the immune system gets confused and attacks the beta cells, located in the islets of Langerhans, as if they are foreign to the body. In type 2 diabetes we understand less about why beta cells stop functioning. In either case, the “ideal” treatment would be to have cells available for transplant which have the ability to produce insulin. Diabetics would then no longer need to inject insulin and would, in effect, be cured.
Currently, islet cell transplants are rare and complicated for a number of reasons, the most important two being that they require a donor pancreas of which the supply is limited, and once implanted, the cells face rejection. Professor Shimon Efrat, Professor of Human Molecular Genetics and Biochemistry at the Sackler School of Medicine at Tel Aviv University and incumbent of The Nancy Gluck Regan Chair in Juvenile Diabetes, is conducting research to try to solve the problem of the limited supply of beta cells. In his work on cell replacement therapy for diabetics he has developed ways for differentiating human tissue stem/progenitor cells into insulin-producing cells.
Your research has shown that while adult human beta cells can be expanded in tissue culture, they lose their ability to secrete insulin in the process. Is that right?
This is correct. We have shown that beta cells from adult human islets can be made to multiply in tissue culture, but during this process they lose their ability to produce insulin. Fortunately, we have also shown that the genes important for beta cell function, such as insulin, remain in an open state, although they are not active. This state is defined by the proteins which bind to the DNA of these genes. This indicates that it might be easier to restore their normal function compared, for example, with differentiation of other cell types into beta cells.
What can you do to make the cells secrete insulin again?
We already have successes in restoring insulin production in the expanded cells by changing the culture conditions. We are in the process of testing the reconstituted cells for function in diabetic mice. If they do well, we will proceed to larger animals, and then to clinical trials…
Are the mice you’re using spontaneously autoimmune diabetic mice, or were they given a chemical to destroy their beta cells?
The mice are immune deficient to allow transplantation of human cells. Therefore, we can not test these cells in an autoimmune animal model. To make them diabetic, we give the animal a chemical which destroys their beta cells.
There are other types of cells which can be made to produce insulin, and in your lab you have made liver cells start producing insulin. Can you tell us more about that?
There is a possibility to reprogram other cells into beta-like cells. All the cells in the body have the same set of genes. What sets apart one cell type from another is the sub-group of genes that are open and active, while the rest of the genes remain closed and inactive. These differences are regulated by proteins which bind to the DNA, and are reversible. So in principle one can take a liver cell, close the liver genes, and open the beta-cell genes. This is likely to be easier between two related cell types, which share part of the open genes. There are successes in turning liver cells and other pancreatic cell types into insulin-producing cells. However, the conversion is inefficient and incomplete, so more work is needed.
What about embryonic stem cells? Do you believe they are a good source of potential beta cells?
Embryonic stem cells maintain an ability to turn into all the cell types of the body. There are successes in preferentially directing them towards beta cells, however, the protocols are not yet robust enough. Over the past few years it’s become possible to reprogram adult cells into a state resembling embryonic stem cells, so in principle in the future it may be possible to get any cell type from the patient, reprogram it to embryonic state, then into beta cells. This could become an alternative to direct conversion (e.g. liver into beta cells), and has the advantage that embryonic cells have a virtually unlimited replication capacity.
What about the immune response? Would the body attack these new beta cells the same way it attacked the original ones?
Most likely. Therefore it may not be possible to convert another cell type to beta cells in the body, or induce beta-cell regeneration from its normal sources, without suppressing recurring autoimmunity. Working with cells in culture provides an opportunity to equip them with protective mechanisms, such as cell encapsulation.
We all try to be optimistic and hopeful that a cure is on the way. As a person who is at the forefront of cure-related research, do you think a cure is possible anytime soon, say within a decade?
The progress in the field of cell engineering is very rapid, but we are still facing basic biological questions, such as phenotypic stability. Although we may encounter unexpected surprises, I am quite optimistic that cell therapy for diabetes will mature into a treatment within a decade.
Description of top photo:
Proliferation of cells derived from human beta cells in tissue culture. Cells from human islets were labeled with a green fluorescent protein which labels specifically beta cells. Following about 70 days in culture label-positive cells, which are derived from beta cells, show expression of a marker present only in replicating cells (purple), thus attesting to their expansion capacity. (Russ HA et al. Diabetes 57:1575-1583, 2008).
Shimon Efrat is the editor of the book Stem Cell Therapy for Diabetes