Seated, left to right, David Piston, Ph.D., and Dr. Mark Magnuson. Standing, left to right, Roland Stein, Ph.D., and Christopher Wright, D.Phil. (photo by Dana Johnson)
Beta cell boost — VUMC team takes leadership role in international consortium
to understand pancreatic development
Vanderbilt is home to one of five programs practicing in an international forum of scientists probing the mysteries of pancreatic beta cells — the cells that produce insulin.
The ultimate goal of the newly formed Beta Cell Biology Consortium is to convert human stem cells into functional beta cells, or complete pancreatic islets, that can be used to treat diabetes mellitus. The consortium is funded by the National Institute of Diabetes and Digestive Kidney Diseases.
“The NIH has become more attentive to the pancreatic beta cell and its role in diabetic diseases,” said Dr. Mark A. Magnuson, assistant vice chancellor for Research and professor of Molecular Physiology & Biophysics. “This consortium approach represents an attempt by the NIH to encourage investigators to work together more closely than they might otherwise.”
A group of Vanderbilt investigators — Magnuson, Roland W. Stein, Ph.D., professor of Molecular Physiology & Biophysics, and Christopher V. E. Wright, D.Phil., professor of Cell Biology — had already been collaborating as part of a program project grant focused on pancreatic beta cells. “As it turned out, we were the only beta cell-focused program project in the country,” Magnuson said. In becoming part of the consortium, the group added a fourth investigator, David W. Piston, Ph.D., associate professor of Molecular Physiology & Biophysics.
“This is significant kudos for these scientists, all of whom have been part of the Vanderbilt Diabetes Center since they began their academic careers here,” said Dr. Daryl K. Granner, Joe C. Davis Professor of Biomedical Science and director of the Diabetes Center.
Because of its established program, Vanderbilt was a natural place for the NIH to turn for leadership. Magnuson is serving as chair of the consortium’s steering committee, which includes two members from each site — Wright is the second Vanderbilt representative. “This is a major new national leadership position for Vanderbilt,” Magnuson said. “Our participation in bringing these groups together and coordinating research efforts is really highlighting what our impact in the area of beta cell biology has been and will continue to be.”
In addition to providing scientific leadership, Vanderbilt is serving as the site for coordination of consortium activities. Lisa Rouse, the program coordinator, has created a Web site (www.betacell.org) and is managing the consortium’s pilot and feasibility grant program, which has been charged with awarding more than $1 million in funding, Magnuson said. Rouse is also planning a November retreat, where more than 70 investigators involved in the consortium will gather to share progress and plan future research activities.
The four other programs participating in the Beta Cell Biology Consortium are the University of California at San Francisco, the University of Colorado, Harvard University, and the University of Minnesota. Several of the programs include investigators at other sites, both in the United States and in Europe.
Assembling such “global super-groups,” Wright said, “is a new way of doing science.” He believes the Beta Cell Biology Consortium will be a test case for refocusing scientific effort and streamlining the discovery process. “This is really a time of remarkable progress,” Wright said, “and I think this consortium approach will help remove redundancy, especially in the generation of research tools.”
The consortium’s steering committee will decide which research tools, such as mouse models, will be most useful and who should generate them. Tools will be shared freely among the group members and experiments will be planned with “high communication,” Wright said. “Because tool generation and other technical aspects of projects will be optimized, we’ll be able to accomplish much more as a consortium than we could as individual labs. It’s really energizing.”
Turning stem cells into therapies
The Beta Cell Biology Consortium has as a major focus the goal of converting human stem cells into functional beta cells, or complete pancreatic islets, that can be used to treat diabetes mellitus. “The NIH is expecting us to achieve more than the ordinary amount,” Magnuson said.
The groups assembled for the task will come at beta cell biology from multiple angles. “There are experts in the physiology of the beta cell, in the identification and manipulation of genes, in transcription factors, in transplantation models, in bioinformatics, and in microarray technologies,” Wright said.
Wright’s own research focuses on the genes that play a role in the very early decisions of a cell to become pancreas instead of stomach or intestines-and after that, to become an insulin-secreting beta cell versus one of the other pancreatic cell types. His findings are “pointing to a new theory of how stem cells decide to turn into downstream cell types,” he said. It’s not just a combination of certain transcription factors, but the relative concentrations of those factors as well.
“We hope that if we can understand the normal processes that determine cell fate, then we can take those programs and put them into an embryonic stem cell or other cell type to send that cell through exactly the same type of program,” Wright said. He cautions that — despite current excitement and optimism — much remains to be learned before stem cell therapies become reality.
“There’s definitely going to be fantastic progress with stem cells,” Wright said. “But if we plan to engineer stem cells for replacement therapies, we first have to understand how the entire process of becoming a pancreas is controlled and regulated. Otherwise things might go wrong that we’re surprised about.”
In addition to the wealth of resources available within the Beta Cell Biology Consortium, the new group will draw on the efforts of a recent NIH initiative called “Functional Genomics of the Developing Pancreas.” The goal of that program has been to identify all of the genes expressed over the life span of the beta cell in mice and humans. The gene set will be used to generate pancreas-specific microarrays — gene chips that can be used to study which genes are turned “on” or “off” in pancreatic cells. Vanderbilt’s NIDDK Biotechnology Center, under the direction of Dr. Alfred L. George Jr., Grant W. Liddle Professor of Medicine, has begun to produce some of these pancreas-specific gene chips, Magnuson said.
Magnuson and Wright expect that Vanderbilt will also play a prominent role in engineering new mouse models, important for the study of pancreas formation and diabetes. Vanderbilt investigators have made particular strides in using site-specific recombinases to generate tissue specific gene knockouts and to even target DNA fragments back into specific locations of a gene. “We’re in a really good situation with respect to methodologies and technologies for manipulating the mouse genome because of the efforts that have gone into building multiple outstanding core facilities such as the Transgenic/ES Cell Shared Resource,” Magnuson said.
Translation of diabetes research findings into improved patient care has an exciting track record, internationally and at Vanderbilt, and a promising future, according to Dr. Steven G. Gabbe, dean of the School of Medicine.
“Since the discovery of insulin in 1921, great strides have been made in our efforts to normalize blood glucose in individuals with diabetes mellitus, including blood glucose meters, new insulins, and insulin pumps,” Gabbe said. “At Vanderbilt, we are committed to providing the most advanced level of care for our patients with diabetes now and in the future. In the near future, that includes the creation of a multi-disciplinary Diabetes Treatment Center. And, hopefully, in the not-too-distant future, through the efforts of Drs. Magnuson, Stein, Wright, and Piston and the Beta Cell Biology Consortium, offering a cure through beta cell transplantation.”