One of the key challenges to developing a biological cure is to identify an unlimited source of insulin-producing cells, which are destroyed by the immune system in those with type 1 diabetes (T1D). Replacing these cells in patients through islet transplantation requires a steady supply that falls far short of the potential need due to the scarcity of donor pancreases from which these cells come.

Dr. Ricardo Pastori, director of molecular biology and research professor of medicine, immunology, and microbiology, is focused on finding alternative sources of islets to address this shortage. One potential cell source is human pluripotent stem cells (hPSc), as they are capable of becoming any type of cell in the body. However, the use of hPSc cells poses some safety risks for patients, such as the formation of tumors. Working together, Dr. Pastori and Dr. Juan Dominguez-Bendala, director of stem cell development for translational research, are at the forefront of engineering innovative “safeguard” approaches to eliminate these risks.

The researchers are also looking beyond transplantation to regenerating a patient’s own insulin-producing cells. They previously reported first-ever results using a single molecule that is already approved by the Food and Drug Administration for use in patients. Dr. Pastori tells us more about these groundbreaking initiatives underway.

What is your area of research at the DRI?

My research focuses on the development of molecular strategies to advance treatments, and ultimately a cure, for type 1 diabetes. Currently, Dr. Dominguez-Bendala and I have joined efforts to develop regenerative approaches for pancreatic islets and beta cells, among other projects.

How did the collaboration between the two of you come about?

My main background is in molecular biology, which is the study of the composition, structure and interactions of molecules that make up the body’s cells and carry out their functions. I also interface with DRI colleagues from other disciplines, which is critical for our mission to discover a cure. The pancreatic progenitor cell/islet regeneration project is the result of having explored these disciplines. Many aspects of this project are of molecular biology in nature. That has led to Dr. Dominguez-Bendala and I working together in a holistic way and bringing our respective expertise to these projects.

The team recently published some exciting findings. Can you explain more about this research and next steps?

We first reported that a natural protein called bone morphogenetic protein 7 (BMP-7) was able to convert the exocrine cells of the human pancreas (the cells in charge of secreting digestive juices) into functional endocrine cells when cultured in the lab. We later found that this process actually activates progenitor cells (stem cells) in the pancreas, which we confirmed by conducting a series of tests. This discovery opens the door to the possibility of reawakening these cells in patients, sidestepping the need for transplantation. We will soon be reporting more exciting findings related to this project.

Additionally, Dr. Dominguez-Bendala and I are Principal Investigators on a grant that was awarded by the National Institutes of Health’s (NIH) Human Islet Research Network (HIRN). The grant support will allow us to further investigate these progenitor cells to better understand how they regenerate. We will use an array of state-of-the-art technologies, including a method to examine human pancreas sections in a special dish invented at the DRI that offers us a unique window through which to monitor live beta cell regeneration in real time.

We’ve been reading a lot in the news about a new technology called CRISPR, which you are also using in your research. Can you explain more about this project?

CRISPR is a powerful gene editing tool that can be used to investigate and treat human diseases. Dr. Dominguez-Bendala and I are collaborating on a project to improve the safety of stem cells for the treatment of diabetes. The approach will overcome the relatively high incidence of tumors (teratomas) and enrich the numbers of insulin-producing cells we can “grow,” which are hurdles that stand in the way of the routine transplantation of these cells. In order to address these problems, we set out to engineer stem cells with “suicide genes” that will be activated in (a) any cell that is not a beta cell; and/or (b) any cell that may form a tumor. Our research team has just wrapped up the first phase of this project and a comprehensive report of these findings was recently submitted for publication. A second phase of this research will take steps to further improve the safety of generating human stem cell lines using CRISPR gene editing techniques.

What makes this research so exciting?

These projects have great potential to be translated to patients. The demonstration that pancreatic stem cells can be stimulated to generate beta cells through non-genetic manipulation may open the door for designing regenerative therapies for people with diabetes. On the other hand, the generation of a safe human stem-cell line will be a key contribution for therapies based on beta cell replacement strategies.

(DRIFocus Fall 2018)

Keep Up With Our Progress Toward A Cure & More