UNDER THE MICROSCOPE WITH ALICE A. TOMEI, PH.D.
The DRI is pursuing many cell-based treatments to replace insulin function in people with diabetes. Success will largely depend on the ability to protect insulin-producing cells from the body’s strong immunological and inflammatory responses that can inhibit long-term function and health. One potential solution sounds simple enough – encase the cells in a protective barrier (a process called cell encapsulation) that allows nutrients to flow in and insulin to flow out but prevents the recipient’s immune system from attacking the transplanted cells.
Historically, however, this encapsulation technology has been met with many challenges. Scientists have constructed small, bubble-like casings called microcapsules in an attempt to protect islets from inflammatory reactions and immune attacks, while permitting the nutrients to reach the cell. But the very construct of a microcapsule continues to prevent islets from thriving. While invisible to the naked eye, microcapsules are relatively large and the space within them is very big compared to the size of one islet – almost like a pea inside of a balloon. As a result, critical oxygen and other nutrients flowing in do not reach all of the cells within the islet. Many islets die during this traditional encapsulation process and during the transplant procedure itself. Consequently, large volumes of islets are needed for each graft, limiting available sites for transplant.
To overcome these challenges, the DRI is developing a new approach to encapsulate islets called “conformal coating,” one of several cell encapsulation strategies under investigation. Conformal coating significantly reduces the space between the traditional microcapsule casing and the islet contained within, thereby improving oxygen and nutrient delivery. Dr. Alice A. Tomei, assistant scientist in tissue engineering at the Diabetes Research Institute, is working with Dr. Cherie Stabler and Prof. Jeffrey A. Hubbell on the conformal coating effort. Dr. Tomei came to the DRI in May, 2010 from the Institute of Bioengineering at Ecole Polytechnique Fédérale de Lausanne in Switzerland, where she worked with Prof. Hubbell, director of Integrative Biosciences Institute in Switzerland and Adjunct Professor at the DRI.
Q: What brought you to the Diabetes Research Institute?
A: Starting in early 2009 and for more than a year, I worked with Prof. Hubbell to design a new way of coating cells. We wanted the coating method to be simple, controllable, reproducible and easy to scale. Once we got something we thought would work, it was time for me to translate that into a real-world application, which is why I came here. At the DRI, it’s not just about conducting research and publishing papers. The ultimate goal is to treat patients – to deliver something that works in a clinical setting. Here, you look at everything in terms of how translatable it is. In the few short months that I’ve been at the DRI, I’ve already modified many steps in my coating procedure because I realized what I had been doing wouldn’t be applicable in a clinical setting.
Q: Tell us more about the work you’re pursuing here.
A: I’m actually working on two complementary projects designed to prevent the rejection of transplanted islets without the need for immunosuppressive drugs that affect the entire body. The first is the new conformal coating method of encapsulation. With conformal coating, we coat an insulin-producing cell with a thin layer of polymer that disguises the islet – hides it so that the immune system doesn’t mount a response to kill the cell. We needed a different approach from the traditional methods of cell encapsulation because every islet is a unique size and shape. So I developed a device and a process that allows the protective layer to literally conform to the size and shape of each individual cell. That’s beneficial in two ways. First, because the cells are “shrink-wrapped” in the conformal coating, nutrients don’t have to travel far to reach each encapsulated cell. And secondly, because there’s not a lot of wasted space inside the capsule, the entire islet preparation, or graft, takes up less space – giving us more options for where it can be transplanted. The research results to date are promising. We know that the method of conformal coating works and allows us to coat islets quickly and efficiently. Now, we’re working to optimize the coating polymer for long-term islet viability.
Q: And the second project designed to prevent transplant rejection?
A: In the second project, we’re exploring the potential of a molecule called CCL21. We think CCL21 can be used to create an environment that promotes tolerance of transplanted islets by teaching the immune system to accept the cells. In a recent study led by Prof. Melody Swartz, we learned that tumor cells naturally release the CCL21 protein, which attracts a variety of immune cells to the tumor site that prevent tumor rejection. Now the question is, could CCL21 be used for the better – to create a similar, tolerant environment that prevents rejection of transplanted insulin-producing cells? We’ve been able to confirm the results of that earlier study and now we’re going to test the procedure with islets. I’m developing a protein that we’ll use to deliver the CCL21 to the location of the islet transplant. Our hope is, we’ll be able to create an environment within which the islets can thrive without the use of chronic immunosuppression.
Q: What’s the relationship between these two projects?
A: These two projects are complementary because with the conformal coating, we hide the graft so that it’s not seen and the immune system doesn’t mount a response to kill it. While with the CCL21 project, we don’t hide the graft, we teach the immune response to accept the graft as if it were the recipient’s own cells. It will be interesting to see which one will be the most successful therapy. Or, it may be that a combination of both therapies is optimal, which is often the case in clinical trials.
Q: How will this research lead us to a cure for diabetes?
A: We know that patients with long-standing diabetes can achieve insulin independence following infusions of insulin-producing cells. But, remaining challenges limit the procedure’s widespread use – including the need for long-term immunosuppression. The goal of this research is to promote acceptance of transplanted islets in diabetes patients without having to suppress the entire immune system. Here at the DRI, I’m constantly reminded of the goal. The institute is in the same building as the Kosow Diabetes Treatment Center, so every day when I come to work I see diabetes patients. While I don’t treat them for their diabetes, they ask me, “What’s going on in the lab? Do we have something?” They are desperate for a cure and I feel pressure to deliver to them something that works. Fortunately, I’m confident in the research we’re pursuing and I’m honored to be here at the DRI.
(DRIFocus Fall 2010)