Type 1 diabetes is one of the most common chronic diseases of childhood. It is associated with secondary complications—such as nerve, kidney and eye damage—and takes a significant toll on individuals affected by it. Kevan Herold, MD, C.N.H. Long Professor of Immunobiology and of Medicine (Endocrinology), studies autoimmunity, particularly as it relates to type 1 diabetes. He hopes to apply lessons from immunobiology to type 1 diabetes in a way that improves human health. In addition to his lab-based research, he also sees patients and runs clinical research studies.
Recently, Herold was appointed chair of Type 1 Diabetes (T1D) TrialNet, an international research network that spans 13 centers in the U.S., including Yale School of Medicine. The consortium also has centers in Canada and Australia, as well as collaborating centers in Europe. Herold is only the third person to assume this role since TrialNet’s origins as the Type 1 Diabetes Prevention Trial (DPT-1) in 1993. We spoke with Herold to learn more about his goals for the organization and the state of type 1 diabetes research.
What is the goal of T1D TrialNet and how did it get started?
TrialNet began about 16 years ago following a number of developments in type 1 diabetes research. This is the type of diabetes that occurs most commonly in childhood, but there are likely nearly an equal number of adults who develop it. It’s different than type 2 diabetes, which is more frequent in adults, and is due to insufficient insulin production and insensitivity to insulin. Type 1 diabetes is caused by an immune-mediated destruction of the insulin-producing cells in the pancreas.
Leading up to TrialNet, experts could identify this autoimmune process years before people actually presented with the disease, and there was also at this time a lot of information that was emerging about the immune mechanisms that may lead to the death of these cells. The possibility of being able to intervene and prevent this from happening inspired TrialNet, with the main goal of preventing type 1 diabetes.
What are you looking forward to the most about your new role?
I think we can have a huge impact. Two years ago, TrialNet ran an anti-CD3 [a monoclonal antibody treatment] prevention trial that was successful and showed for the first time that you could delay or prevent the onset of diabetes in people at risk. This changes the playing field. We’re now in a place where we can completely shift how we think about type 1 diabetes and even potentially prevent the disease. There are opportunities here in terms of really having a significant impact on type 1 diabetes.
TrialNet’s role so far has largely involved screening relatives and people with type 1 diabetes, enrolling them in clinical trials, understanding how immune therapy can change the disease mechanisms, and using this information to understand the immunopathology so that treatments can be improved. I also think that we now have the opportunity to go into the general population. The majority of people who will present with type 1 diabetes don’t have a relative who has the condition. In the past, we didn’t have a reason to start screening the general population. But now, we have something to offer people. I mentioned the success of the anti-CD3 trial, but there may be other interventions that we can offer. We need to think big. Maybe we should be screening all school-aged children, because if we can identify those at risk, we may be able to prevent the disease. These are all discussions that need to occur in the coming years.
Do you have any other ambitions for TrialNet?
TrialNet has the opportunity to be the hub of type 1 diabetes translational research. First of all, I’m hoping that we learn a lot from the clinical studies. Through clinical trials, we will have the opportunity to look at how type 1 diabetes changes human immune responses and test interventions. We can learn a lot about not only type 1 diabetes, but also human immunobiology in general. That’s part of the appeal of this position to me as an immunologist. There are some unique opportunities here that have applications to type 1 diabetes, as well as other autoimmune diseases like lupus, multiple sclerosis, psoriasis, or inflammatory bowel disease. At TrialNet, we can be the center of this because we’re actually doing our studies in people.
How does this research benefit patients and society?
When the results of the anti-CD3 trial first came out, there was a reporter who asked, “So you prevent the disease for two years. If the patient still gets it, what’s the big deal?” And I pointed out to him, if you’re a child in elementary school, and you’re not going to get diabetes until you’re in middle school, that’s a huge benefit. For children, time is extremely meaningful. Type 1 diabetes is a disease that’s with you 24 hours a day every single day of your life. So any amount of time without the disease is significant. Also, it’s not only that children will be more mature at the onset; there’s other work in the field that is beneficial for patients. For example, if you look at how insulin pumps have changed in the last three years—it’s enormous. So if we could delay the onset of diabetes for three years, we could take advantage of other developments. That’s clinically very significant for patients.
Even for patients with diabetes, it may be that we can come up with a regimen whereby we can modulate the immune response that causes the disease with some sort of beta cell replacement therapy. This is one of the things we’re very interested in doing at Yale.
In addition to being a researcher, you also work as a clinician. How does your research inform your ability to treat patients?
My philosophy has been that the best things to be learned are coming from patients. I can think of a number of examples of that in my career. For example, many years ago, when I had just started on the faculty at the University of Chicago, there was a patient I saw who had hypoglycemia, or low blood sugar. It turned out that he had a mutation in an enzyme called glucokinase. The studies in this patient led to the confirmation that glucokinase is the glucose receptor in the beta cell. Another example is checkpoint-induced diabetes. My colleague, Harriet Kluger, referred a patient to me who had developed diabetic ketoacidosis [a serious complication of diabetes]. She had gotten this after receiving cancer therapy. We ended up finding a number of individuals like this, and we tried to figure out the mechanisms that lead to this new disease. That’s another example of where patients teach you about diseases, what the mechanisms are, and how to treat them.
How has being at Yale supported your diabetes research?
The climate at Yale is absolutely spectacular. There’s always ongoing dialogue with many of the people who I always admired and thought of as leaders of the field. To be able to work with them is a unique experience. There’s great collaboration that has happened between my group and others in and outside of immunobiology. I think that the overall academic environment here is terrific for this kind of development. The enthusiasm of the faculty here, the willingness to collaborate, and the extraordinary expertise have been fundamental.