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Under the Microscope

Under the Microscope with Juan Dominguez-Bendala, Ph.D.

DRI researchers have shown that replacing the insulin-producing islet cells in patients with long-standing diabetes can restore natural insulin production, normalize blood sugar control and eliminate the frightening hypoglycemic (low blood sugar) episodes common in those requiring insulin therapy.

While we are extremely encouraged by this progress and the results of recent clinical islet transplantation trials, we are not yet able to apply this procedure to all who could benefit. One of the major challenges is the short supply of donor tissue.  With only a few thousand donor organs available each year, we must seek alternative sources of insulin-producing cells for transplant.

At the DRI, we are pursuing several strategies to develop an unlimited cell supply. A major focus is the use of stem cells. These “naïve” cells reproduce quickly and when given “instructions” have the potential to become any cell type of the body including insulin-producing cells.

Dr. Juan Dominguez-Bendala launched our stem cell research program a decade ago and is today Director of the Stem Cell Development and Translational Lab at the Diabetes Research Institute.

Q: How did you first get involved in stem cell research?
I studied biology in Spain and then went to London to do a masters in applied molecular biology and biotechnology. In the late 1990s,as part of my dissertation, I went to Scotland to do a summer project, and I was fortunate enough to go to the Roslin Institute in Edinburgh where Dolly the sheep had just been cloned. I stayed there to do my PhD under the supervision of one of Dolly's creators. At the time, people were saying cloning and stem cell research would revolutionize medicine. Since I had witnessed firsthand the birth of all these breakthrough  techniques, I wanted to apply that training to curing human disease. That's why I came to the Diabetes Research Institute.
   
Q: How has stem cell research evolved at the DRI since you started the program a decade ago?
There's no other discipline in the history of medicine that has been advancing as fast as stem cell research. We continue to make steady progress. We know we're on the right track. We have reason to believe that this may be the next big breakthrough in medicine. The greatest challenge now is to make sure stem cell therapies are safe.

Q: How are you addressing the issue of safety?
Embryonic stem cells are considered the gold standard of all stem cells. They proliferate at a remarkable rate, which makes them an ideal candidate to alleviate the shortage of insulin-producing cells in persons with diabetes. But when left unchecked, wildly dividing embryonic stem cells can cause tumors to form. We're working to eliminate that risk by developing safer, more efficient protocols for the use of these cells. We're genetically engineering embryonic stem cells so that they contain "suicide genes" that will kill cells that keep dividing (leading to the development of tumors) or don't produce insulin-- a kind of double fail-safe mechanism.  We are in the process of building these cells so that we can move to the second phase, which is to test them in pre-clinical models.

Q: What other important advancements are being made in stem cell research at the DRI?
One of the things we've been focusing on is to identify alternate sources of stem cells. I collaborated with Dr. Luca Inverardi to identify unique population of stem cells from umbilical cord blood that can be coaxed into becoming insulin-producing beta cells. They're easily obtained, plentiful, bankable and initial studies are promising. They behave in a manner that's similar to embryonic stem cells and we got insulin-producing cells in our studies. We just reported these findings in Cell Transplantation and we're very excited about the potential for these cells to alleviate the shortage of insulin-producing cells for transplant.

DRI researchers are also looking at the potential of using other adult stem cells, such as those obtained from body fat, as a source of beta cells. In preliminary studies we conducted with our collaborators in Milan, Italy, a portion of these adipose-derived cells were transformed into insulin-producing cells.

Another process we're studying will allow us to turn one type of cell directly into an insulin-producing cell - in one step - as opposed to the progressive education of stem cells. My colleague Dr. Ricardo Pastori and I are testing ways to turn non-islet tissue of the pancreas, the acinar cells, into insulin-producing cells. Acinar cells are plentiful, making up almost 98% of the pancreas, and typically discarded after an islet isolation procedure, which makes them a good candidate for consideration.  And in a preliminary study we've just completed, we used something called modified messenger RNAs to reprogram these cells into insulin-producing cells. So we're very excited about that.

Throughout it all, one of the things I'm most proud of is our discovery of the key role that oxygen plays in the development of insulin-producing cells. We've long known oxygen was essential to the function of beta cells, but we were the first ones to bring attention to the critical role oxygen plays in the maturation of cells in the lab. We developed a device called the “oxygen sandwich” which provides maturing cells with an oxygen environment that’s more like their native pancreas.  As a result, maturing cells in the oxygen sandwich produced 30 times more insulin than those in traditional plastic culture containers, creating a greater supply of islet cells for transplantation.

Q: How will this research lead us to a biological cure for diabetes?
Unlike many other diseases for which cell therapies are being proposed, diabetes is one disease for which we already have a cell therapy: islet transplantation. We know it works. We have the proof of principle that if we can transplant cells that produce insulin, we will correct diabetes. But we cannot yet apply this technology to all the people who can benefit from it, in part because there's a shortage of insulin-producing cells available for transplant. Stem cells offer hope to address the issue of supply and I am personally committed to making that a reality. When children with diabetes and their parents come here to tour the lab and I talk about the work we're doing, I'm reminded that what we do every day has a higher meaning. It's impossible to look into their faces and not feel accountable for the hope we're giving them. And that makes us go back to work with even more enthusiasm.

Juan Domínguez-Bendala, Ph.D.
 

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