Determining How Other Cells (Non-Beta) In The Pancreas Affect Diabetes
Jeffrey D. Serrill, Ph.D. – City of Hope, Los Angeles, California
Type 1 diabetes (T1D) is an autoimmune disorder in which a patient’s pancreatic endocrine cells fail to secrete insulin in the presence of blood glucose. While insulin injections allow patients with T1D to stay alive, they do not cure the disease or prevent the possibility of the serious effects of the disease, including blindness, kidney failure, nerve damage, heart attack, or amputations.
T1D is a disease that can be cured in our lifetime. This project has the potential to not only provide answers regarding optimal methods for developing pancreatic islets for therapeutic purposes, but to also improve upon methods which are already being utilized by other scientists. More specifically, the goal of this research project is to identify the ways in which different endocrine cells in the human pancreas interact with one another to produce coordinated responses to glucose challenges, and then use this information to produce fully functional pancreatic tissue that can later be administered to patients to cure their diabetic symptoms. Currently, the most successful treatments for T1D rely on transplantations from donors with healthy pancreatic tissue, but there simply aren’t enough available donors to meet the demands for such therapies. We’ve recently developed a molecular tool which will allow us to produce different types of pancreatic cells in the laboratory, and we can use this tool to dramatically improve our current understanding of how these cells interact with each other to achieve normal blood glucose regulation in normal humans. Previous researchers have made impressive strides with regard to producing insulin-producing cells in the pancreas, but the role of alternative cell types in the pancreas in affecting the function of these insulin-producing cells has been largely overlooked. If we can use this information to produce functional pancreatic cells which mimic those which arise during normal development, then we’ll have taken a significant step forward in eventually eradicating this disease, so that no one has to live with T1D anymore.
Pancreatic islet transplantation represents a promising treatment for patients with T1D, but a shortage of available healthy islet donors means that there is an insufficient supply of insulin-producing islets to meet the demands for such therapies. Thus, research efforts over the last decade have focused on generating artificial islets from human pluripotent stem cells (hPSCs) as a prospective solution to this scarcity. While these studies have yielded impressive results, current methods are still incapable of producing functional islets that fully recapitulate the activity and glucose responsiveness of normal human islets.
To address this discrepancy, this project seeks to more adequately characterize the role which different pancreatic islet subtypes have on the functionality of pancreatic islets. Aside from the insulin-producing beta cells of the pancreatic islet, there are also four other hormoneproducing cell types, and the communication between these different cells has been shown to dramatically affect the ability of islets to respond appropriately to changes in physiological blood sugar levels. This regulatory relationship between cells has not yet been adequately characterized, and my project aims to address this discrepancy.
During normal embryonic development, pluripotent stem cells must go through a series of molecular changes to eventually become a specific mature cell type, in a process known as differentiation. In the laboratory, we can attempt to reenact this process in a petri dish, using cocktails of specific molecules which promote differentiation into specific cellular identities. During this process, these cells express specific molecules known as transcription factors, which contribute to overall differentiation process. My project aims to take advantage of a specific transcription factor known as Neurogenin 3 (NGN3), which has been previously shown to direct progenitor cells toward specific islet cell fates. Our lab has generated a molecular tool which will allow us to induce NGN3 expression and generate specific islet cell subtypes. Once achieved, we aim to aggregate these individual cell types into functional pancreatic islets (made up of all five islet subtypes), and assess the effects that each cell type has on the overall functionality of these islets. These analyses will allow us to more adequately characterize the conditions necessary for generating artificial pancreatic islets, which we can then use in clinical settings to treat patients with T1D.
I started my science education at Western Washington University, where I earned degrees in both Psychology and Cell Biology. While this initially led me to seek out opportunities in Neuroscience, I was lucky enough to identify a Pharmacology laboratory at the Oregon State University where I could conduct research on natural product pharmacology and drug discovery while also becoming trained as a scientific diver. That was really exciting to me, as it allowed me to bridge the gap between the natural world and the lab bench in a very exciting manner. A connection at OSU helped me identify the Shih laboratory at the City of Hope as an exciting place to conduct my postdoctoral research, which is where I’m currently working on research projects focused on type 1 diabetes. T1D represents a disease that can be cured in the next decade, which makes this work extremely exciting for me. Though I’ve only been focused on T1D for the last year, my postdoctoral advisor has provided a laboratory environment where it’s difficult not to get excited about developing cutting-edge research projects to ultimately cure this disease.
I’m a self-described outdoor junkie, and love to get out into the wilderness on backpacking, mountaineering and fishing trips. The idea of helping diabetic patients find a cure for their disease so that they can also enjoy similar hobbies without having to worry about blood glucose and insulin levels on a minute-to-minute basis is an extremely exciting prospect for me.