While the Chicago Diabetes Project (CDP) has thus far only performed islet cell transplants on a smaller subset of type 1 patients in clinical trials, their ultimate goal is to one day offer the transplant for everyone with diabetes—including type 2s. Jose Oberholzer, MD, director of the CDP, explains why this goal is possible, and how he intends to get there.

By: John Parkinson, Clinical Content Coordinator, DiabetesCare.net
 
An older man is walking down the beach and comes upon a young man collecting starfishes that a storm has stranded on the beach. Seeing the ones that are still alive, the young man throws them back into the ocean. The older man asks the young man, “what are you doing? There are so few starfishes that you can save.”

The young man bends down and picks up a living starfish and throws it back into the ocean, and he says, “it made a difference to this one.” This story came attached to a piece of crystal that is in Dr. Jose Oberholzer’s office and was given to him by one of his islet cell transplant patients. The patient—a long-time type 1 who became insulin-independent shortly after receiving a transplant—inscribed on the crystal, “Thanks for everything, starfish number 62.”

This story serves as a medical parable encapsulating both the hope and negativity surrounding islet cell transplantation. For people who have had a transplant, it has been life-transforming for a majority of them. On the other hand, there has been negative criticism coming from within the medical community that these transplants have served very few people and come attached with challenges like having to take a regimen of immunosuppression drugs. The procedure also still needs to be FDA-approved—some have speculated that might be coming in the next year or so.

Still, Dr. Oberholzer hears these criticisms, and chooses not to stay within these limitations, but rather moves beyond them in trying to transform this novel procedure for greater patient utilization. In fact, contrary to the view this procedure is limited in who it can help, the CDP has ambitious plans to try and treat the vast majority of both type 1 and type 2 diabetes patients with the islet cell transplant.

In speaking with Dr. Oberholzer, hope and resolve resonate through his voice. The fact of the matter is, this surgery is the closest thing to a cure that is out there on the horizon. Some of the patients who have this surgery remain insulin-independent for years.

To tell someone that has taken insulin for years that they no longer have to do so is unparalleled to any treatment out there for people who have type 1 diabetes and gives these patients a much improved quality-of-life. This is especially true in the patients who are the main recipients of the novel procedure through its clinical trials: those with hypoglycemic unawareness.

In describing the procedure, Dr. Oberholzer (pictured, lower left) calls islet cell transplantation a “functional cure,” where people become insulin-independent. He also points out that the underlying disease state is not treated; therefore, it is not a traditional cure.

Dr. Oberholzer is an Associate Professor of Surgery, Endocrinology and Diabetes, and Bioengineering at the University of Illinois at Chicago (UIC), the Director of the Islet and Pancreas Transplant Program and the Chief of the Division of Transplantation at the University of Illinois Hospital . He has trained at the University of Geneva Switzerland, as well as at the University of Alberta in Edmonton, Canada—which was at the cutting of edge in developing the islet cell transplantation.

As director of the Chicago Diabetes Project, Dr. Oberholzer oversees a group of hand-picked scientists who fit a specific criteria. In creating this mini-elite team, the Chicago Diabetes Project has been able to focus on the specifics of creating a treatment for all people with diabetes and trying to deliver it without the use of immunosuppression drugs.

DiabetesCare.net sat down with Dr. Oberholzer recently to discuss his work on the Chicago Diabetes Project including its unique lab protocols, the CDP’s research philosophy, and how they are trying to overcome the post-transplant protocol of immunosuppression drugs by working on cell encapsulation.

DiabetesCare.net: How did you get involved in the Chicago Diabetes Project? 
 
Oberholzer: About 10 years ago, I was involved in a project with several scientists and we were talking about the human genome project. A few people involved in that research were able to pull many people together to focus on coding the human genome.

We wrote a paper where we postulated that in order to find a cure for diabetes we would need a human genome project like-minded model where scientists would commit to work together and share openly the data before it is published.

This type of project would need a common funding source where scientists would not worry about grants and could just focus on their work.

When I came to Chicago to work at the University of Illinois at Chicago, I was approached by the Washington Square Health Foundation. They said they would like to fund my idea of having a small group of dedicated scientists working towards a diabetes cure. They would give me a grant, if I committed to this work.

I was intrigued by it, and the university agreed to help me in whichever way they could to make such a project possible. That was at the end of 2004.

The foundation asked me to bring in key players from the field. We were going to meet for one week and at the end of it, we would come up with a roadmap on how we would go about making islet cell transplantation available to everybody.

The two questions that came out of that week were: how do we get an unlimited amount of insulin producing cells and how can we implant those cells without immunosuppression drugs?

In trying to answer these questions, we had our roadmap.

DiabetesCare.net: What makes the Chicago Diabetes Project unique in its approach and philosophy?

Oberholzer: The uniqueness of the CDP is that everyone on the project has committed to each other, and we share everything including innovations and inventions. We have done this as a simple gentleman’s agreement.

Our philosophy is to make a functional cure available to everybody. The main challenge right now is that we can only do islet cell transplantation for a limited patient population.
 
The main reasons we cannot offer this transplant to more people is that as it is an experimental procedure, we have to pay for all the costs; there are a limited amount of organ donors; and we have to give our patients immunosuppression drugs. While the vast majority of patients tolerate these drugs very well, some do not. And we would be very hesitant to use them in children.
 
We have gotten criticized at CDP that what we are doing is not worth it, because it only helps a few people. I have been in this work for nearly two decades, and people say the stories are very touching but very few can have islet cell transplantation.
 
However, many in the medical community recognize that most type 2s would benefit from having an infusion of insulin-producing cells. We postulate that if we did a pancreas transplant in type 2 patients, it would cure a vast majority of these patients.

DiabetesCare.net: Are you talking about a functional cure or a traditional cure for people with type 2 diabetes?

Oberholzer: I would call it a functional cure because in type 2 diabetes, there is no autoimmune issue like in type 1 diabetes, but there is an inflammatory process. Therefore, there still would be the risk of reoccurrence of diabetes. A potential islet cell transplant cannot be an isolated event; it has to be accompanied by lifestyle changes such as weight reduction in those who are obese.

For someone who has type 2 diabetes and they are on insulin, it is very difficult for them to lose weight, and in fact they often gain weight when on it. For example, if they inject too much insulin, then they have to compensate by eating more, then insulin makes them hungry again. It can be a vicious cycle.

You can interrupt this cycle by giving these people just enough islet cells for their bodies to overcome the insulin resistance.

In the Chicago Diabetes Project, we are not only working on therapies for type 1s but we are looking to help all diabetic patients—understanding we won’t be able to treat everyone, but at least the vast majority of them.

Members of the CDP are successful, academic scientists and we have all climbed up the career ladders starting as assistants and associates and becoming full professors. We have all had NIH grants. We have gone through the academic and scientific world and we know what competition means.

We also realize we are never going to find a cure for diabetes, if we continue to work in the traditional grant-funded research model. It is good for having competitive professors, but it horrible for addressing a cure.

Whatever we do in the lab, we ask the question, ‘is it going to contribute to a direct path to a functional cure?’ We don’t want to ask questions, just for the sake of asking; it has to have a practical implication in either creating more insulin-producing cells or protecting them by other means other than medication.

To be a part of the CDP team, you have to have some specific qualifications. I only chose people that have had their own funding; have made significant findings; and they have to be open to share and continue to work on the project even if their own research did not work.

Initially, this concept was very challenging. We had difficulty keeping some people on the project when they realized their research didn’t work. Still the vast majority of the original scientists are still here. 

DiabetesCare.net: CDP has been a participant in the Phase 3 clinical trial being conducted by the NIH Clinical Islet Transplantation Consortium. Where is the CDP with that now, and is the CDP still actively doing islet cell transplants?

Oberholzer: We are approaching the end of the phase 3 trial. We are still performing transplants in the consortium. This is limited now to patients who have had a kidney transplant and are taking immunosuppression drugs already. This is going to be wrapping up in the summer.  

For patients who have normal kidney function, that part of the trial is finished. However, we have a University of Illinois trial that is still going on, and we are still accepting patients. We have been pretty active this year having performed 6 transplants since January.  We will continue until the end of the year and likely beyond that. 

DiabetesCare.net: One of the more challenging elements to islet cell transplantation is that for those who have successful transplants, and remain insulin-free, they have to take immunosuppressants. The CDP is researching cell encapsulation to overcome this challenge. Can you explain what this is, and how far along in the process the research is?

Oberholzer: With encapsulation, the principle is to place a shell around the cell, which would allow the cell to live, gain nutrients, secrete insulin, sense glucose, and protect the islet from the body’s immune system.

In some ways this would be a semi-permeable membrane that lets through small molecules and keeps out large ones that would go through the cell encapsulation to attack the islet cells.

We have had limited clinical trials of which we were a part of through the Chicago Diabetes Project. We worked with a university in Italy and one in Sydney, Australia. Unfortunately, both trials were not a success.

The trial in Italy showed that the islet cell could survive for some time and continue to produce some insulin, but not enough for the patient to be able to stop taking insulin.

We wanted to do a clinical trial in the United States, so we submitted a proposal to the FDA and they requested we do primate experiments.

In monkeys, these capsules provoke a foreign body reaction, and it leads to a little bit of inflammation and to a small scar around the capsules themselves. That scar impedes the free exchange of nutrients and oxygen and ultimately the cells in the capsule die off.

We have established models in the laboratory and we can do the transplant and screen the transplant for materials that will cause that type of reaction.

The biggest impediment to moving forward with this research is financing it. This is very expensive research and there really is no way around doing it with primates. It is an experiment the primates tolerate very well. We insert empty capsules into their abdominal cavity and we do this as minimally invasive microscopic surgery.

We are not as advanced as we hoped. This is something that is working in mice but monkeys and humans are not reacting the same.

DiabetesCare.net
: How would you characterize the importance of the encapsulation research versus the other projects you are working on?

Oberholzer:
In both energy and finances, we spend equal parts on transplant clinical trials, the capsules, and making the islet cells grow. Therefore, this is a major project. If we can make encapsulation work, it will be a major medical breakthrough and would have consequences that go well beyond diabetes. It would resolve the problems of numerous diseases.

In next week’s Up Close, Dr. Oberholzer’s will provide his clinical perspective when treating patients who have an islet cell transplant.