Seattle is an exciting city with a lot to offer, including fish-tossing at Pike’s Place Market, the original Starbucks, a once futuristic looking Space Needle, and fabulous weather for people-watching in the summer. None of the usual suspects, though, were what drew me to Seattle this July; as a diabetic, what I was interested in was the Benaroya Research Institute, a research center tucked beside the Virginia Mason Hospital, dedicated to understanding the immune system and autoimmune diseases like type 1 diabetes.
I came to Benaroya to meet with Dr. Jane Buckner, whom I first met at the American Diabetes Association Scientific Sessions. There Buckner presented on her research concerning a particular gene mutation associated with the development of type one diabetes. Buckner and her team had been following the path of this variation, a flipped pair of nucleotides in the PTPN22 gene, into the body and into the cellular mechanisms that are altered as a result of the change in DNA. This research was compelling enough on its own, but upon meeting Dr. Buckner on her home turf, I found that was just one end of the fascinating immunological and diabetes research being done by Dr. Buckner and the Benaroya team.
Dr. Jane Buckner did not start out as a diabetes researcher; her entrance into the world of immunology came as a physician– a rheumatologist, to be exact. Rheumatology deals with the health and pathology of joints, tissues, and bones, and in practice, this means that rheumatology deals with a wide array of autoimmune diseases, including rheumatoid arthritis, lupus, scleroderma, and vasculitis. And – as many of us with not just type 1 diabetes but also celiac disease, Hashimoto’s thyroiditis, and so on know – autoimmune disorders have a lot in common despite having very different symptoms, treatments, and localizations. Since Buckner has pursued treatments and cures for the patients she sees, she has become intimately involved in many aspects of immunology and autoimmune research, type 1 diabetes included.
At the Benaroya Research Institute, Bucker wears many hats, and she is still a practicing physician who sees patients regularly. Given the nature of the chronic illnesses she treats, Buckner remarked that some patients have been seeing her for almost fifteen years now, and while she loves them as patients, she wishes she had the tools to just fix their problems and let them go. This desire– both to improve the quality of treatment for patients with autoimmune diseases and to cure the diseases– drives Buckner while she is wearing her other hats, serving as the head of a lab focused on tracing the paths of immune cells in the body, and as the Director of Translational Research at Benaroya.
Within her lab Buckner currently directs researchers with two areas of focus. The first subject of study in the lab is regulatory T cells. Buckner and her team look closely at these particular agents of the immune system, hoping to gain a better understanding of how they function and fail to function in diseases such as type 1 diabetes. Animal studies done thus far give direction and insight, but no clear answers. In NOD (non-obese diabetic) mice, researchers have found that there is a lack of a particular cytokine, an immune protein important for communication between cells, called IL-2. Without IL-2, these mice develop deficient regulatory T cells, which are key to the proper regulation and management of immune responses. In human autoimmune diabetics, however, IL-2 is found at levels comparable to non-diabetic patients. But the immune cells in the body do not respond properly to the IL-2 that is there, resulting in a similar scenario to that of the NOD mice, in which regulatory T cells fail to develop and thrive.
By detangling these interactions and dependencies within the immune system, Buckner hopes to develop novel treatments that address the specific pathways in the body that lead to autoimmunity. The second focus of her lab, studies of gene variations relevant to autoimmune diabetes, helps in this regard, both in terms of helping to clarify the pathways involved in type 1 diabetes, and in terms of beginning to tease out the genetic differences between patients that will be crucial to the development and selection of appropriate treatments down the line. By zeroing in on several gene variations that are key markers of diabetes, Buckner and her team have been able to trace the path of autoimmune dysfunction – from a particular gene variation, to the protein it encodes, to the different levels of T cells, B cells, and other immune players found in patients with each variant.
For now, the lab has turned its attention specifically to the gene variant PTPN22, which encodes a protein with the potential to inhibit T cell activation. Paradoxically, Buckner and her team have found that the variation of the protein found in type 1 diabetics may actually enhance the activity of the T cells that cause disease. It seems counterintuitive that blunting T cell activation would lead to autoimmunity, but Buckner’s findings show how delicate the balance of the immune system is, as the variant protein seems to lead a T cell population that is more resistant to the regulatory T cells, and a change in the ratios of the different kinds of cytokines circulated by the immune system. These changes, taken together, lead to an immune system imbalance sufficient to result in self-destructive reactions to the body’s own cells.
Understanding these sometimes counterintuitive and always complex interactions between genetics, molecular pathways, and the immune system is key to ultimately developing treatments and cures for autoimmune diseases like type 1 diabetes. Buckner, from her position as a physician and lab director, understands well the urgency and importance of moving discoveries and insights from the lab to the doctor’s office. It is for this end– translating research into usable treatments– that Buckner wears her third hat at Benaroya, serving as the Director of Translational Research. Translational research, an increasing focus of the National Institutes of Health (NIH) and many research institutes across the country, is the process of turning scientific understanding into practical applications that improve human conditions. In the parlance of the field, then, translational research takes discoveries from “the bench to the bedside.”
Benaroya is particularly suited for translation medicine studies, given that it has access to an estimable group of researchers, and excellent clinicians and patients just down the block at the Virginia Mason Medical Center. This partnership allows Buckner’s colleagues the opportunity to perform clinical trials based on the findings in the research laboratory. For example, an ongoing study, lead by Carla Greenbaum at Benaroya and funded by the Immune Tolerance Network, will take the knowledge gained from the bench about the role of cytokines like IL-2 in immune regulation and apply it to the bedside of adult type 1 diabetics. The trial will look at the effects on regulatory T cell populations of taking both IL-2 and the immunosuppressant rapamycin. In past studies done in cell cultures (that is, not in living bodies) by Buckner as well as other scientists, the combination of IL-2 and rapamycin was shown to increase the total number of functioning regulatory T cells, so the hope is that these findings will be supported by the clinical trials, and that the increased regulation of the immune system within diabetics could offer some novel treatment opportunities.
It is unlikely any one clinical trial like those being run at Benaroya will stumble upon a cure for autoimmune diabetes, or find the secret switch that resets the immune system. Each incremental step, however, towards a better understanding of the mechanisms of the disease brings us closer to an eventual cure, and translational medicine is invaluable to this incremental progress. The feedback loop– from bench to bedside and back to bench for reanalysis and further exploration– will take researchers forward, eventually reaching the point where the path to the cure is within sight.
And, as a type 1 diabetic with a vested interest in eventually reaching that point, I am very happy to have Dr. Jane Buckner and her colleagues at the Benaroya Research Institute on our team, taking a closer look at how the immune system works and what can be done about it.