Under the Microscope with Chris Fraker, PH.D.
Over the last several years, the Diabetes Research Institute has shown the extraordinary potential of cell replacement therapy to restore insulin function. While progress has been substantial, islet transplantation, one of the methods being pursued, remains an experimental procedure and we are working to overcome the remaining challenges that limit its widespread use.
One of the major challenges is to identify new sites in the body in which to transplant the cells, as the liver is no longer thought to be an optimal environment. Our goal at the DRI is to identify sites that closely mimic the native environment of the pancreas to give transplanted insulin-producing cells the best chance at long-term survival. The availability of oxygen will be key to creating an optimized site; islets make up only 1-2 percent of the entire pancreas where they reside, yet they use almost 25 percent of the oxygen that flows through the organ.
At the DRI, we are developing ways to deliver that level of oxygen to the islets. We are also testing several strategies to deliver the vital oxygen levels more effectively to stem cells as they mature into insulin-producing cells. Achieving the required amounts of oxygen is critical in our efforts to restore natural insulin production.
At the center of much of this work is Dr. Chris Fraker, research assistant professor of surgery and cell transplantation at the Diabetes Research Institute, who has spearheaded many cutting-edge initiatives aimed at curing diabetes for both professional and personal reasons.
For you, this work is personal, isn’t it?
Yes. I was diagnosed with type 1 diabetes on my 16th birthday. Today, 26 years later, I’m starting to develop low-level complications and my children have the markers for the disease. So, as you can imagine, I’m motivated to find a cure.
How does your work at the DRI impact cure-focused research?
Islet cells need a lot of oxygen to effectively sense glucose and produce insulin. So when we harvest islets from a donor pancreas or develop insulin-producing cells in the lab, we need to make sure we’re providing those cells with an oxygen-rich environment so they can survive and function. Without adequate oxygen, some cells will die before they can even be transplanted. Or worse, cells that are transplanted may not survive their first few days post transplant; a critical time when blood vessels are still forming that will naturally carry oxygen to the cells. So providing an oxygen-rich environment is vital, both in terms of developing a supply of cells for transplant and in the survival of those cells immediately following transplant.
How is the DRI using oxygen to increase the supply of insulin-producing cells?
Stem cells represent one of the most promising sources of insulin-producing cells for transplant, since they have the potential to become any type of cell. In the lab, we’ve shown that oxygen plays a major role in the process of transforming stem cells into insulin-producing cells. We developed and patented a device called the “oxygen sandwich” to provide maturing stem cells with an oxygen environment that’s more like the native pancreas, compared to traditional plastic culture containers. In testing, cells in the sandwich produced an increase in insulin gene expression in precursor cells that was several times higher than control precursor cells.
Once insulin-producing cells are transplanted, how is the DRI using oxygen to enhance the cells’ chances of survival?
During the first few days after transplant, cells are under a tremendous amount of stress; they’re subject to inflammatory reactions and immune attack. We’re using oxygen to help create environments that will shield the cells.
At the DRI, we’ve been working to optimize cell encapsulation technology – the process of coating the cells with a protective shield so they go unnoticed by the immune system. Early in my career here, I worked with the late Dr. Marcos Mares-Guia, a Brazilian researcher whose encapsulation work laid the groundwork for some of our recent efforts.
We’ve come a long way since that time, further developing the Tissue Engineering program at the DRI and building upon this early work and using new biocompatible materials. Recently, my colleague Dr. Alice Tomei developed a type of coating that literally conforms to the unique size and shape of each islet. This “conformal coating,” as it’s called, allows the implanted islets to go unnoticed by the body and avoid an inflammatory reaction, yet still allows oxygen and other nutrients to easily reach the cell. Now we’re taking that research a step further. I’m working with her to develop coating materials that could potentially generate oxygen, which I hope will give the islets an even greater chance to thrive.
I also worked with the DRI’s Dr. Cherie Stabler in her lab, developing a novel biomaterial and a method to deliver a slow but steady stream of oxygen to cells. This material has the capacity to generate oxygen when it’s exposed to water. In testing, the material created an environment that sustained oxygen supplementation for more than six weeks – which could bridge that critical gap between the time islets are transplanted and the time blood vessels are formed to support them. Our hope is that an added infusion of oxygen will make Dr. Stabler’s “scaffold,” a three-dimensional framework designed to promote the survival of transplanted cells, a more viable tool for future clinical trials.
How will this body of research lead us to a cure for diabetes?
A: We know that oxygen plays a critical role in the development and function of insulin-producing cells. By delivering oxygen more effectively to stem cells as they mature in the lab, we can create an unlimited supply of islet cells for transplantation. And, if we can ensure transplanted cells get the oxygen they need, especially during those critical first few days, they’ll have a better chance to survive long term. Both of these need to happen if we’re going to make cellular therapy viable and available to the millions of people who can benefit from it.
Why the DRI?
Early in my career, I was involved in more treatment-based work: designing implantable glucose sensors with the hope of coupling them with insulin pumps. But I knew that was never going to lead to a true cure. I found the cellular-based therapy work being done at the DRI fascinating and I literally badgered Dr. Camillo Ricordi, the Institute’s Scientific Director, or rather his executive assistant, Mabel Luis, until he hired me. That was 15 years ago and there’s a simple reason I’m still here. Everyone at the DRI and at the DRI Foundation is committed and driven to find a cure. It’s a remarkable place.
(DRIFocus Spring 2012)