Chicago Diabetes Project Collaborates Globally to Find

[admin]

Nearly every time that I mention islet transplantation in a conversation about diabetes, the person I'm with responds with a sniff that it's never going to work because of the immune suppression problem.

Dr. José Oberholzer, however, is not one of those skeptics. An MD at the Chicago Diabetes Project (CDP), he's betting the farm on convincing the world's experts to work together. It's a concept that runs counter to the tendency of most researchers to guard their breakthroughs and hoard their knowledge. Nevertheless, Dr. Oberholzer and a team of experts from around the world have joined together under the umbrella of CDP to contribute to what they bill as a "global collaboration for a faster cure."

In addition to being Director of the CDP, Dr. Oberholzer is an Associate Professor of Surgery, Endocrinology and Diabetes, and Bioengineering at the University of Illinois at Chicago (UIC). He has headed UIC's Islet Transplant Program since 2003 and is the Chief of the Transplant Division. The UIC islet transplant program has performed over 250 human islet isolations for both transplant and research. It is a federally funded islet cell resource center that provides islet preparation for researchers around the world.

Islet Cells

The pancreas makes insulin and enzymes that help the body digest and use food. Throughout the pancreas are clusters of cells called the islets of Langerhans, which are made up of several types of cells, including beta cells that make insulin. Living pancreatic islets control blood glucose levels much better than insulin injections because they release insulin at the proper times to decrease blood glucose and release glucagon when necessary to increase blood glucose.

Transplantation

Adding islets to the human body has the potential to restore the natural signal-response mechanism for controlling blood glucose. This control can prevent many of the devastating effects of long-term type 1 diabetes.

The goal of the Chicago Diabetes Project is to produce an unlimited source of islet cells that could control blood sugar levels and be safely transplanted. These transplanted cells would be encapsulated to protect against the assaults of immune cells and allow the recipient to live with little or no dependence on medication to prevent their rejection.

Recently, Diabetes Health interviewed Dr. Oberholzer about his work on islet transplantation and the Chicago Diabetes Project.

In a video interview on the CDP website, you mention that all scientists have "key moments in their life when they decide about their career." What experiences made you choose diabetes?

There were two moments for me. When I was a child, my cousin Lorenz was diagnosed with diabetes. He almost died from DKA. I was horrified by the huge needles he had to use and all the effort to sterilize them-it was like a surgical act to inject insulin back then. When we grew up and I told Lorenz I was going to med school, he insulted me by saying that I was going to join "the club of losers." He thought all endocrinologists were losers because they could not cure diabetes, but could only refine the treatment. He felt the treatment was a torture.

Lorenz told me a joke that I often tell. It's about an orthopedic surgeon, but it sums up how he felt. The joke goes: A man in a wheelchair goes to see his orthopedic surgeon. The surgeon tells him that today is a great day because he has great news for him. The guy in the wheelchair gets very excited because he thinks the surgeon has discovered a way to let him walk again. The surgeon then tells him that it's a very great day because he has a new set of wheels for the wheelchair.

My cousin feels like every time some new diabetes advancement is announced, it is just a finer needle or a faster meter. Things don't change that much.

So I took this as a challenge, and when I entered medical residency and wanted to do some research, I discovered islet transplantation and I thought that here was something my cousin might not consider a loser.

My cousin lives in Norway now and he is doing well, but fighting weight gain. He is making the right choice not to do islet transplantation because he is [handling his diabetes] very well. He has the healthy view that his current treatment is better than an islet transplant.

My dream is that we will get to the point where the side effects of an islet transplant should be minimum. I want to be able to call my cousin one day and say "the orthopedic surgeon changed."

Why is your project called the Chicago Diabetes Project?

Well, the older generation immediately gets the reference to the Manhattan Project. We are a group. We believe that no one single person can come up with the answer to the diabetes question. We are a diverse group of engineers, physicians, and scientists, with everyone pooling their best resources and sharing information. The name "Chicago Diabetes Project" helps us locally, but since our scientists work all over the world, our new website helps people to understand that we are a global project. We hope the CDP will become [as well known] as the JDRF. But a lot of people still don't know anything about us, so we have a ways to go.

Why is it so hard to raise money and get donors for CDP and diabetes?

When I go to donors to raise money, I always say that it is the silent disease. It's not spectacular like AIDS, where people panic, and it's not like cancer-everyone is afraid of cancer. It's not like a spectacular heart attack. It's a very slow killer. Most people think it's your fault if you have diabetes. They think you ate too much and you didn't move enough. They're not differentiating between type 1 and type 2, that's my impression. Even if they do know the difference, they think that there are not very many people affected by type 1.

But as you know, that is totally not true. Not everyone who eats a lot and doesn't move has diabetes. And you can move a lot and not eat much and still become type 2.

Funding is also affected because what I'm doing is not seen well by my peers. To do research, to become a professor, I had to go through the normal channels of applying for grants. This kind of research is frustrating because it doesn't really move the field forward.

Everyone does research the same way: You have a hypothesis that is allowed to address only one question. Then you work two to three years on that one question and it turns out "Yes" or "No." Then you move on with the next grant.

These grants are important for scientists personally, and [they allowed me to] climb up in my academic career. But if I were a patient, I would be very frustrated about those grants because they don't address the pertinent questions in the way that they should be addressed. They should be investigated by a group of people, not a single scientist.

Getting funding for a group of people is extremely complicated. The problem is that all the people united in that effort will have to reapply and compete against each other to get funding again. That leads to the situation where you are very unwilling to share information because your peer might have a competitive advantage in several years.

I get criticism, for example, from the JDRF, which tells me to stop prostituting myself. I go out and present my work and ask people for money. As a scientist, I get criticized, but if we want to work this way [as a group], then I have to do this. Scientists and researchers who join our project have to give up a little of their intellectual independence by working in a group, by becoming a part of a bigger idea. For a scientist, this is not so easy. We have to make sure that we can academically survive.

How do you select researchers for the project, compared to other organizations like the JDRF or NIH?

Typically, money is distributed based on a peer-reviewed process. This process is supposed to be transparent and objective and fair, with equal access and everything. What we are doing is totally the opposite-there is no peer review. Our selection is based on the person's ability to contribute to a specific question we have, their ability to work on a team, their willingness to share, and their desire to share the dream that such an approach could actually solve the problem. The last is almost the most important.

What is the difference between islet transplant and stem cell research?

Islet transplant takes pre-existing islets from a pancreas (cadavers at the moment), isolates those islets, and transplants them to a patient in need of them.

Stem cell research has two potential approaches: One, instead of isolating the islets, you recreate them, starting from a stem cell. That could fit into what we are doing. Our focus is not so much on embryonic stem cells, but on other kinds of stem cells and on pre-existing islets and how can we make more or create new islets.

Stem cells can be an additional source of implantable material. One part of stem cell research will ultimately lead to islet transplantation. It will be a newly created islet that will be transplanted.

Two, the JDRF is particularly interested in stem cell research leading to knowledge that will allow the patient to regenerate their own islets inside their body without transplantation. The major limitation to that is that diabetes as a disease is still there. That is often not made very clear. You cannot just have the islets regenerate without taking care of the diabetes. Otherwise they are just destroyed again. There would have to be some sort of medical change or process that would allow these newly generated islets to survive. That is very, very far away. I don't think it will happen before I retire.

Our approach is a little more primitive, but at least we have the proof of concept that it works, even though it's not perfect. We have successfully gotten patients off insulin for many years, even if it doesn't work in all patients. (It is true that some patients have had to go back on insulin after several years.) There is a patient out there from 1996 (from the first series I worked with in Geneva with 13 patients) who is still off insulin more than 12 years later. It can work.

This is huge because it is proof of concept. We are not saying it is a solution that is now ready for everyone. That would be totally wrong. It is ridiculous right now to try to find something that will work on everyone. In the last ten years, I have transplanted 50 to 60 patients-that's nothing. But if I look at the progress...ten years ago I was successful in two out of 10 patients, then five out of 10, and now, in our last trial, all 10 patients got off insulin, and long term, eight out of 10 stayed off.

The success rate has increased significantly, but it is still a very small number of patients. Some organizations feel that if you cannot address the greater good [right away], then they are not interested. The JDRF cut all support of clinical trials in islet transplantation because they say it will benefit only a small number of patients. I think this is a very short view.

Of course it is a small number of patients! But we gain the knowledge and expertise of doing those transplants because maybe in the very near future we will have resolved the problem of getting more cells, and then we can offer what we have while we are still working on getting rid of the [immune suppressant] medications, using micro-encapsulation in our case, or other approaches.

We can't just cold jumpstart. It's better to have the train rolling, and then we can add some better wagons on the train. I think we have to keep going on the clinical trials.

Does the immune suppression problem and possibility of needing insulin again in the future mean that islet transplantation isn't viable?

I wouldn't offer islet transplantation to my cousin Lorenz because he is doing very well with his diabetes. The patients we transplant come with their luggage, plant themselves in front of my office, and say they won't go away until they get a transplant or something to get their lives back in control. We are working with patients who wake up in the hospital with no idea in which city they are because they went into a coma in an airport somewhere. These are people who wake up in their car in their backyard because they drove the car through the [back of the] garage [when they became hypoglycemic]. When I talk to these people about immunosuppression, they look at me and smile and say that the side effects are nothing compared to what their daily life is like. This is a small group of patients who have tried everything, and they are really bad off. They have gone from endocrinologist to endocrinologist. In these cases, the transplant makes perfect sense. These patients are willing to have the side effects.

Also, even if the [immunosuppression] medicines were perfect, we don't have enough islets to transplant. There are just 6000 organ donors in the United States. We have millions and millions who could benefit from this.

Why are up to three donors needed for each transplant right now?

The islet isolation procedure is a limitation. It's an art. It's worse than cooking, where you can follow a cookbook and get a halfway decent meal. Islet isolation requires an additional thing. It just doesn't work all the time, and even when it does, we lose a relatively large amount of islet cells during the processing. We end up transplanting half of the islets in the pancreas. Once we transplant, there will be an inflammation and a proportion of those cells will die off within minutes or hours. We are working to improve that.

We are working to avoid having to transplant that many cells by giving meds that can reduce the inflammation and improve the cell survival. This has allowed us to get the patient now off insulin with one [donated] pancreas. In the last eight patients, we achieved this. But we feel this is not good enough. We [are working to be able] to use one pancreas and modify it to get enough islets for 10, 20, or 50 patients.

Why not use pig islets like some other foundations?

The idea of pig islets is that they would be an unlimited source. There aren't ethical issues because if you can eat pigs for dinner, you can use them for this. There are some fears of transmission of animal disease to humans. The CDC [Center for Disease Control and Prevention] worries about this.

Another limitation is that animal tissue causes a much stronger immune reaction by the human body. We are limited right now by how much immunosuppression [medication] we can give to a patient. It should be possible to do pig islets, but it has a very high price in terms of side effects for the patient. I hope that I will be proved wrong because if it works, then that will be great news for the patients. I am just a little skeptical. We already have a hard time making human islets survive, and current medicines may not allow the animal cells to survive because they provoke a strong rejection reaction.

What is the micro-encapsulation the CDP is working on to combat the body's rejection of the islet cells?

There are a number of groups and companies doing micro-encapsulation. It has a bad reputation, and a lot of bad work was done. There were wrong premises and premature reports. We felt we needed to re-visit this area in an academic, open way and really critically address it. We can now test a lot of different technologies objectively in parallel and choose which is the best.

The capsule is a little shield around the islets that allows certain molecules to go in and out, and it impedes larger molecules and cells from going into the capsule and attacking the islet. It shields the islet from the immune system.

The islet can still do its job. There is a very small delay in the islet recognizing the blood sugar fluctuation, but it's an insignificant delay. The islet can still sense the glucose and secrete the insulin the same way [from inside the capsule].

Most caps are based on alginate that comes from seaweed. And then we add different chemical components to it to modify the permeability and strength of the alginate. We make it mechanically stronger and less permeable by adding chemical compounds. The alginate is a liquid solution mixed with the islets. Then it goes through a droplet generator, and then, in theory, every drop contains one islet. And then the droplet falls into a chemical solution (called a chelation bath). The droplet then undergoes a chemical reaction in the bath that makes it solid.

Is islet transplantation the cure for diabetes?

I like the expression "functional cure" because the patients feel that they have been cured. From a medical point of view, it is not a cure because if the patients stop taking the medication, their bodies will reject the islets and diabetes will reoccur. As far as the encapsulation technique, if the capsules don't work or the islets are destroyed, the patient will have diabetes again. The disease is still hanging around: we just push it away.

But we feel this is the way to go because it works today, and we can build up on the current proofs of concept. It's the closest we have to a cure of diabetes that is realistic....

How can people support the Chicago Diabetes Project?

Funding is our main limitation. Having the necessary funding each year will accelerate our research progress so we can stay on track to develop a functional cure in our proposed five-year time frame. We want to go the public academic way and not work via start-up companies. All our research is supported by philanthropic donors who recognize that the extraordinary mix of scientists in the CDP have what it takes to find a functional cure for diabetes. Anybody who can volunteer time to help us in fundraising or wants to make a direct contribution is very welcome. Because we work through the University of Illinois Foundation, we do not have any overhead costs, and every single dollar donated goes into the research.