George S. Eisenbarth, MD, PhD, is currently the Executive Director of the Barbara Davis Center for Childhood Diabetes and Professor of Pediatrics, Medicine, and Immunology at the University of Colorado Denver. He was the past president (2006) of the Clinical Immunology Society. His major area of research is the prediction and prevention of type 1 diabetes and related autoimmune disorders. Dr. Eisenbarth has received numerous awards for his work including most recently the Pasteur-Weizmann/Servier Prize in Biomedicine, the Donald F. Steiner Award for Outstanding Diabetes Research, and the Banting Award for Scientific Achievement.
Dr. Eisenbarth, you have devoted your life to the study and treatment of diabetes. When did you make the decision that this would be your life’s work?
It was a pretty straight forward decision, in a way. I trained as a physician at Duke University and was about to return to Duke for my first faculty appointment. I had to decide what I would work on and I was trained as an endocrinologist. So I asked myself, what diseases in endocrinology do we treat badly? Back then it was diabetes and today, it is still diabetes.
How do you mean treat badly?
Insulin is life saving, obviously, but the therapy itself is disruptive to the whole family and it makes for a very hard life. Insulin is one of the most dangerous drugs that we have. There are very few drugs where if you give twice as much as you should have given, at a given time, it could make someone have a seizure or fall unconscious. When I look at type 1 diabetes, the disease, I see acute complications such as hypoglycemia and ketoacidosis- both life threatening- and then I see the long term complications. We are doing much better with improvements in therapy but we are nowhere near the other endocrine disorders. If you are hypothyroid we give you a pill and we know exactly what to measure to say whether you are in about the right range. We are nowhere near that for type 1 diabetes.
You are famous for your work on antibodies in type 1 diabetes. How would you describe that work?
We have helped develop the field such that we can now predict who is likely to progress to type 1 diabetes. Type 1 diabetes is a genetic disorder but it is different from the way we usually think about genetic disorders in that relative risk is inherited – not absolute risk. So 40% of everyone in the US carries a high risk gene for type 1 diabetes. Perhaps 2.4% of newborns carry 2 copies (one from each parent) of these high risk genes. Only 5% of that 2.4% of children will go on to develop diabetes. When I was starting, we didn’t know that type 1 diabetes was a slow chronic autoimmune illness. It took time to develop that concept. With the discovery of anti-islet antibodies came the idea that antibody assays would help in that regard. Pretty early in our studies I had the thought that if my assays didn’t predict well enough it was because my assays weren’t good enough. The field eventually grew as I, and many other contributors, worked to get very good antibody assays so that we can now predict type 1 diabetes in man. We can prevent diabetes in animal models and we are trying to figure out how to prevent it in man.
How many different auto-antibodies do you measure to predict type 1 diabetes?
We measure 4 now. GAD, IA2, insulin autoantibodies, and the newest one that John Hutton here at the Barbara Davis Center discovered, a zinc transporter. Those are the 4 antibodies that have been verified in international workshops and by the CDC. By the way, these auto-antibodies do not cause the disease. They function only as markers for the likelihood of developing disease; evidence of beta cell destruction.
You recently won the Banting Award which is, perhaps, the most prestigious award in the field of diabetes. Was it specifically for your work in the laboratory or was it for running the Barbara Davis Center?
I received the award from my colleagues at the American Diabetes Association. It was, of course, a very nice thing, but it does make me fear that I am coming to the end of my career. (Dr. Eisenbarth laughed heartily while saying this).
In part, I received the award for the long term antibody studies leading to prediction. But also we are very fortunate to be working with colleagues here like Maki Nakiama, a research fellow who is about to be an Assistant Professor, to find that insulin is the primary antigen for our major animal model. That was one of the nicest discoveries that our group has made in a very long time. We’ve done a lot with that now.
How will your new discovery impact type 1 diabetes?
In our mouse model we can change just one amino acid of insulin through genetic manipulations and prevent all diabetes. In man insulin is also an important target so what we think this means is that in man, insulin will also be the primary target. Insulin is what the immune system targets to kill beta cells. This gives us something specific to focus on in terms of developing immunotherapies
In addition to your exciting research there is this center that you run. Could you tell us a little bit about the Barbara Davis Center for the Study of Childhood Diabetes?
This center was established almost 30 years ago by the Davis family because their daughter developed type 1 diabetes. Marvin and Barbara Davis have nurtured it now for all of these 30 years. Marvin Davis has passed away but Barbara Davis continues to support the center by holding a ball every year in Beverly Hills that helps support the center. The center has a great faculty in both the clinical and research arenas. I was recruited here 17 years ago. It has grown organically over time to become one of the best environments I have ever been associated with, where basic research and translational research can go on together and synergize. For example, we’ve taken John Hutton’s discovery of a new autoantibody that I mentioned previously and within a month, we knew what it meant in terms of the ability to predict disease onset.
The Barbara Davis Center website is a huge resource worth looking at. One of our faculty, Dr. Peter Chase has placed an entire book on diabetes on the site.
What are some of the most exciting clinical trials happening now at the center?
There are 2 very different pathways for treating type 1diabetes. One is immunological: beta cell replacement. The other is mechanical devices. Some of our faculty, like Drs Satish Garg and Peter Chase are focused on the utilization of continuous glucose monitoring. They are beginning trials for using these sensors to predict when hypoglycemia will occur and to shut off an insulin pump. If economics does not prevent it I think most patients with type 1 diabetes will be using continuous glucose sensors in the future. We care for 3000 children and 2000 adults. We probably have almost 1000 patients who now use sensors. We have very young children who use them as well as patients in their 60s and 70s. So that is a major area of work at the center that we want to foster. The technology is getting better and better.
The other area is trying to address type 1 diabetes as an autoimmune or immunologic illness. We do that not only for type 1 diabetes but for many autoimmune diseases. Our type 1 patients have a high risk of celiac disease, autoimmune intestinal disease, thyroid autoimmunity, as well as rare autoimmune conditions like Addison’s disease. We can predict those illnesses in the same way. We have large programs where we genetically type children at birth. Our research programs that identify risk measure things like autoantibodies and metabolic function such that we can intervene before the disease progresses.
The main driver, of course, is to figure out how to prevent type 1 diabetes. Again there are two pathways: one is general immunosuppression/immunomodulation and the other is antigen specific. We always have a certain risk benefit that has to be weighed with general immunosuppression, as this itself can be dangerous. Also, these general immunosuppressive therapies can slow, but not yet stop, progression of beta cell killing.
Now antigen specific therapies are the holy grail of our field. We assume those therapies are going to be very safe as compared with general immunosuppressive therapies, as they will be only targeting that which we think is the primary cause of the disease. There are a number of very large trials underway trying to target that specific part of the immune system. There is an oral insulin trial that had a hint of efficacy. [RS: Immunologists try to shut down the immune response to antigens by introducing them orally]. Bayhill Therapeutics, a company I consult for, has an insulin DNA vaccine in clinical trials. Another trial is looking at the GAD molecule. A number of these therapies are now in large phase III trials. I am going to guess that we don’t know enough yet. We will need to be lucky for these trials to accomplish what we want. We don’t know enough yet about the basics of the immune system in man to design a trial where we can say this is going to work for sure.
