The race to create beta cells from stem cells is charging ahead.
Beta cells are the pancreatic cells that produce insulin. In Type 1 diabetes, beta cells are destroyed by the immune system through an autoimmune response, while in Type 2 diabetes, beta cells die off over time and remaining cells are less productive. In both cases, compromised beta cell functionality is part of living with diabetes.
Last fall, two research teams—one at BetaLogics and The University of British Columbia, led by Drs. Ali Rezania and Timothy Kieffer, and another —developed protocols to transform stem cells into cells resembling beta cells in culture.
The two protocols are very similar, and both are important steps toward the goal of developing beta cells that can be used to cure diabetes in humans. Dr. Kieffer notes that while they are close to making beta cells, there is still room for improvement. With additional work, Dr. Kieffer believes protocols will be developed to generate large amounts of homogeneous fully mature glucose responsive human beta cells for transplant.
Kieffer and others are also actively designing and testing “immunobarrier” devices that would protect the newly created beta cells from the autoimmune response characteristic of Type 1 diabetes. Overcoming this autoimmune response would be a central aspect of any true cure for Ttype 1 diabetes; otherwise, the immune system would quickly destroy transplanted beta cells.
As a diabetic and a skeptic, I try not to get too worked up whenever I hear about a development that might lead to a “cure” for diabetes, but this time, the excitement was hard to shake.
Dr. Kieffer graciously answered some questions to help us better understand his research.
Why is there so much excitement about the potential of this work?
The clinical path for a cell therapy for diabetes has already been proven. Fantastic work out the University of Alberta established that it is possible to treat diabetes with the relatively simple infusion of a few teaspoons of islet cells – the so-called ‘Edmonton Protocol’. While the approach works remarkably well, it is severely limited by the reliance on organ donors for the cells. If we can reliably make large quantities of insulin-producing cells from stem cells, this will make the procedure much more widely available for patients.
How would you describe the difference in your protocol from earlier methods that transform stem cells into insulin-producing cells but take much more time?
Dr. Ali Rezania and our collaborators at BetaLogics have now extended the differentiation of the stem cells in culture so they are much further along the path to mature beta cells, prior to transplant. Therefore, it does not take as long (weeks instead of months) for the cells to become fully functional after transplant. We also obtain similar diabetes reversal following transplant using one-quarter of the cells than our previous recipe required. This result was achieved by advances in how the cells are cultured, including exposing the cells to a variety of different reagents that direct the cells to become beta cells.
The conversion from stem cell to beta cell is not complete until after the cells are transplanted into a host. You note that you are close to creating fully functional cells in a dish. Please explain why this will be an important step and why the need to transplant the cells into a host to complete the transformation is a limitation.
At present we do not fully understand what is missing from the culture conditions to make fully mature beta cells. Further research is required to figure this out. The benefit of making mature beta cells entirely in the dish is that they may be a useful resource for research aimed at understanding the causes of diabetes (both Type 1 and Type 2) as well as developing new therapeutic strategies for diabetes. Moreover, ultimately, mature beta cells may prove to be better than pancreatic progenitor cells for transplant into patients with diabetes.
Would the cells necessarily be transplanted into the host’s pancreas? Is it possible that they could serve their function based in a different organ?
We do not envision the cells being transplanted into the pancreas, but rather in a more easily accessed place, such as just under the skin. As long as the cells receive an adequate blood supply, they should be capable of rapidly sensing and responding to changes in glucose levels with appropriate release of insulin, to be carried by the bloodstream throughout the body. As an example, current islet transplant procedures involve infusion of the donor islets into the liver, where they lodge and become functional. Therefore, it seems it will not be necessary to transplant the cells into the host’s pancreas.
If the cells were transplanted into a human, would they trigger an immune response? Do they trigger an immune response in mice?
We used immunodeficient mice such that they do not develop an immune response against the transplanted human cells. However, certainly the cells would trigger an immune response in humans, both as the cells are foreign (alloimmunity) and due to recurring autoimmunity (the process that killed the patients beta cells in the first place, resulting in diabetes). This is why we are investigating the ability of cells to survive and function in macro-encapsulation devices that are designed to protect the cells from an immune attack (see, for example, Diabetologia. 2013 Sep;56(9):1987-98. PMID: 23771205; Stem Cells. 2013 Nov;31(11):2432-42. PMID: 23897760). If successful, this would mean transplant in the absence of any immunosuppression.
Did you observe any negative side effects in the mice treated with transplanted cells? What side effects, if any, do you expect to arise in human subjects?
We observed lower than normal blood glucose levels in the mice, more like human blood glucose levels, likely because the cells we transplanted are of human origin. We do not anticipate any side effects in patients, but more research is required before clinical trials can commence.
What timeframe and intermediate steps do you expect, to the extent that you can reasonably project, leading up to human trials?
This is a good question, but unfortunately, it is hard to predict what additional studies regulatory agencies such as the FDA may require. However, it is noteworthy that ViaCyte was recently approved to initiate clinical trials aimed at testing their human ES derived pancreatic progenitor cells in patients with Type 1 diabetes.
Could your protocol lead to an appropriate treatment for patients with Type 2 diabetes?
We are currently evaluating the effectiveness of a stem cell based therapy for Type 2 diabetes.
Could this be an appropriate treatment for patients with other types of diabetes, such as diabetes secondary to subtotal pancreatectomy (a procedure common among patients with congenital hyperinsulinism)?
In theory, any form of diabetes that results from insufficient production of insulin may be amenable to treatment with stem cell derived replacement beta cells.
Dr. Ben Stanger at University of Pennsylvania is working to convert gut cells into insulin-producing cells. Can you comment on the differences between his research and yours? Is there research in this area (cell therapy to treat diabetes) in addition to yours that you consider especially promising and innovative?
We too have worked on developing gut cells into insulin producing cells (see for example, Science. 2000 Dec 8;290(5498):1959-62. PMID: 11110661). I do believe these approaches are promising, especially as we recently discovered that gut cells producing insulin may not be subjected to the same autoimmune process that kills beta-cells (Gastroenterology. 2014 Jul;147(1):162-171 PMID: 24662331). Until we have a cure for diabetes, I believe there is merit in pursuing multiple approaches.