If you haven’t heard of the JDRF Network for the Pancreatic Organ Donors with Diabetes aka nPOD, you will. nPOD is not just a research lab or a clearing house for pancreas tissue from donors with diabetes, it’s on the front lines to finding a cure.
Last December, during the International Diabetes Federation World Diabetes Congress in Vancouver, British Columbia, Mark Atkinson, PhD, director of the Diabetes Institute at the University of Florida, Gainesville, presented results from collaborative studies on viruses’ roles in the development of type 1 diabetes.
The objective of this work, he says, was to seek evidence of viral infections in the etiology of type 1 diabetes, and that investigators had “obtained reproducible data further supporting a potential association of viruses or other environmental agents with type 1 diabetes.” An important finding, to be sure, since that could potentially mean the first step in a cure or vaccine for type 1 diabetes.
But what’s also interesting, beyond the finding itself, is the method of obtaining said data – the JDRF Network for the Pancreatic Organ Donors with Diabetes (nPOD), of which Atkinson is the executive director together with Alberto Pugilese, MD. nPOD collects pancreata and other tissues from patients with type 1 diabetes, and disseminates those tissues to approved investigators around the world, with one of the main goals being collaborative research using real-time data sharing. Next year will mark nPOD’s 10th anniversary, and the group is currently tracking more than 180 projects in 19 countries.
“The disease is still killing, and believe me when you get a phone call at three in the morning and they tell you a 12-year-old girl died because of diabetes, it breaks your heart.” – Alberto Pugliese, MD, co-executive director, JDRF Network for the Pancreatic Organ Donor with Diabetes (nPOD)
Atkinson explains that about 2.5 million people die in the U.S. each year, and of those, around 100,000 become some sort of tissue donor. Of those, 9,000 become solid organ donors and 5,000 of those donate their organs to research. All of this is overseen by 58 Organ Procurement Organizations (OPOs) around the country. The nPOD staff is on call 24 hours a day, seven days a week, 365 days a year, for obvious reasons. “We at nPOD have relationships with nearly all of these [OPOs] to the point if someone is an organ donor with type 1 diabetes (or diabetes of another form) and is willing to donate their organs to research, we receive a call,” he says.
The University of Florida is the central hub for tissue collection, and the tissues are transplantable quality and are handled as if they are being transplanted into someone. Investigators who want to use these tissues submit an application, are approved by a scientific committee (comprising some of the top diabetes researchers) based on what they want to study, publish papers, and supply their raw data back to nPOD. All tissues are provided free to investigators with, as Atkinson says, “the hope that major lessons will be learned.”
Playing Catch Up
When nPOD started in 2007, one of its missions was to prove that viable, high-quality pancreata could be obtained from organ donors that were suitable for research about type 1 diabetes. Biopsy of the pancreas in living patients is not practiced because it’s a surgery with potential for complications, and thus organ donors are the only other possible source of human pancreata with type 1 diabetes. Mouse models and in vitro models provide important data, but clinical and translational trials have had limited success; moreover, there are critical questions about the causes and molecular basis of the disease that mouse models cannot answer. Atkinson says that the diabetes-related community had previously elected to deemphasize attempts to study human tissues, especially the pancreas. “I really believe we find ourselves in the current state of diabetes care and research (type 1 and 2) because we have, for decades, ignored what other fields have placed emphasis on, be it psoriasis (autoimmunity) or cancer — that is, on studies of human tissues,” he says. “Pathology is a fundamental basis of medicine but we, as a community, have seen aversion to such notions and placed them elsewhere. With this, we have fallen behind other diseases.”
nPOD currently has tissue samples from 406 pancreata, including 141 from donors who had type 1 diabetes, 41 from donors who had type 2 diabetes, and 160 controls. The tissue samples are collected and stained for various markers, and then converted to digital slides, and stored in an online database. Investigators can access the database and see cases based on different demographics, clinical histories, and histopathological features that characterize each particular pancreas. “They can select cases based on all of this information to choose ones that are better fits for their studies,” says Irina Kusmartseva, PhD, director of nPOD’s Organ Processing and Pathology Core (OPPC).
“This is the first time that the type 1 diabetes community has come together to recover and study the tissues directly involved at the site of autoimmune destruction, the pancreas, and the surrounding lymphoid tissue,” says David M. Harlan, MD, chief of the Diabetes Division at the University of Massachusetts School of Medicine.
So nPOD is providing human tissues to investigators with an interest in the pathogenesis of type 1 diabetes, but these human tissue samples are limited, again, for obvious reasons. Collecting samples from a donor around the time of diagnosis is very difficult, because, fortunately, most people no longer die soon after a diagnosis of type 1 diabetes. “Incidentally,” says Alberto Pugliese, MD, co-executive director of nPOD, “that is the pancreas that everybody wants [to study]. We have a few of those, but by necessity, we have a limited supply.”
But this predicament also led to an opportunity for nPOD and the researchers who utilize these tissue samples – collaborative science using the same materials. It’s a different scenario than say, a researcher taking 10 blood samples and 10 controls and publishing the findings, and then another researcher taking 10 different blood samples and 10 different controls and publishing those findings. “When you have studies where multiple people can look at the same patient, at the same samples, I think you can make a lot more sense of what you’re looking at,” Pugliese says.
Atkinson and Pugliese act as managers for the almost 200 ongoing projects around the world. Neither is very hands on with the research projects. Rather, they act as advocates for all nPOD efforts, attracting researchers who may be working on interesting studies, overseeing the application process for the pancreata (“It’s not like going to the supermarket,” Pugliese says), and encouraging investigators to collaborate with one another. Pugliese is very active in promoting collaboration, the formation of working groups, and in helping nPOD investigators obtain funds for the research. For example, he has obtained funds from both the JDRF and the Helmsley Charitable Trust to support collaborative research conducted by nPOD investigators.
Sorting Cells
In fact, one example of this collaboration comes from Harlan’s institution, where he and his colleague Sally Kent, MD, both have ongoing projects with tissues provided by nPOD. Kent has been working with nPOD since the beginning and is currently studying a number of things. One is to look at B lymphocyte phenotype and function, the cells that secrete autoantibodies and also participate in antigen presentation to stimulate T cells. Another is to study the T cells that are the final killers of the insulin-producing cells in the pancreas. Kent pioneered and continues studies of such cells isolated from the spleen and pancreatic draining lymph nodes (PLN) from control donors and from donors with type 1 diabetes. More recently, she and several of her nPOD colleagues have studied T cells that are present in inflammatory lesions of the pancreatic islets in type 1 diabetes.
Harlan says that he and Kent receive aliquots of isolated islets from nPOD that are also shared with multiple other investigators at several institutions. Kent has recovered live islet infiltrating T cells from these islets, and has expanded the T cells in culture to then determine the antigen target recognized by those T cells. Harlan’s team’s work has been focused on the endocrine cells within the isolated islets. They have developed techniques to break the islets up into their individual cellular components, then sort those single cells into their various cell subsets – insulin-producing beta-cells, glucagon-producing alpha-cells, and somatostatin producing delta cells. Then, using Next Generation RNA sequencing, they have been able to determine the gene expression of those individual cell subsets to compare, for instance, the beta-cell transcriptome found in individuals with type 1 diabetes with that found in age-similar control individuals. “These kinds of studies have only been technically possible within the past few years,” Harlan says.
“Looking at the endocrine cells from donors with type 1 diabetes, we are finding that insulin producing beta-cells can be isolated several years after disease diagnosis,” he continues, “and are just beginning to understand how the immune and metabolic stress on those cells influences their gene expression patterns.”
Harlan says that his team is pursuing gene expression patterns found within donor endocrine cells. “The hope is that we’ll uncover therapeutic targets to either weaken the T cells that are killing the pancreatic beta-cells, or find a gene expression pattern that protects those cells from dysfunction and death,” he says.
Pursuing a Cure
Of course, the main goal of nPOD — and all the researchers the group supports — is finding a cure for type 1 diabetes. No one knows when this breakthrough will come, but nPOD’s work may hold the key. For Atkinson, the answer is to stop relying on what was taught decades ago, pointing to what nPOD has accomplished in just 10 years. “Moving forward, we see notions of big data, genetics, single cell technologies, and integration of clinical data and new and novel ways to represent the future for nPOD,” he says. “We believe this new generation of studies will be vital for efforts for disease prevention/cure.” He invites whoever reads this article to reach out to nPOD in order to identify ways to help them do what they do better. (See “Getting Involved” sidebar).
Kusmartseva says that by being able to look at the entire pancreas, they’re learning that type 1 diabetes is a heterogeneous disease. For example, they’ve learned that a child with type 1 diabetes still has a significant number of insulin-positive islets. They’ve also been able to look at type 1 diabetes-positive pancreata that have some areas totally devoid of beta-cells while other parts of the same pancreas look normal. “The big breakthrough would be finding a cure, and then we’d be out of business,” Kusmartseva says with a laugh. “But I wouldn’t mind.”
“Moving forward, we see notions of big data, genetics, single cell technologies, and integration of clinical data and new and novel ways to represent the future for nPOD. We believe this new generation of studies will be vital for efforts for disease prevention/cure.” – Mark Atkinson, PhD, director, Diabetes Institute, University of Florida, Gainesville
And again, it’s the collaborative nature of these projects that give hope to these investigators. “One never knows where the breakthrough to cure type 1 diabetes might come,” Harlan says, “but nPOD is certain to have played a role when that Holy Grail is found.”
Throughout the year, nPOD holds conference calls and webinars with the researchers, during which they discuss findings, what they want to work on next, and so on. So instead of all the researchers who shared the samples waiting for each other to be published, there’s real-time data sharing and peer review. Because of the very nature of nPOD, dealing with human tissues, donations that mean the worst has happened to someone — Pugliese sees this collaboration as a way of accelerating discovery, which means the sooner doctors can start saving lives. He’s one of the nPOD staff on call 24/7, in case a donation is ready to be made. “The disease is still killing,” he says, “and believe me when you get a phone call at three in the morning and they tell you a 12-year-old girl died because of diabetes, it breaks your heart.”
— Bagley is the associate editor of Endocrine News. He wrote about an encapsulated follicular variant of papillary thyroid carcinoma being classified as a non-cancerous thyroid tumor in the October issue.
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