The Quest for the Cure
With global partnerships, novel discoveries, and unprecedented support, the Diabetes Research Institute may reach its ultimate goal sooner than anyone imagined possible.
The morning Chris Fraker didn’t wake up was just days before his 16th birthday. It was his sophomore year in high school, and he was fitter than most students. No surprise there—he ran track. But Fraker’s body had begun behaving strangely. He went away for spring break and lost 35 pounds in three weeks. Well, he was running more to get ready for the spring track season. He kept falling asleep in class. Well, he wasn’t getting enough rest. He was constantly thirsty. Well, he was working out a lot. He was always using the bathroom. Well, he was drinking a lot of water. But when he didn’t wake up, it wasn’t because he was asleep. He was in a coma.
|DRI physicians Camillo Ricordi and Xiao Jing Wang in the NIH-funded cGMP Human Cell Processing Facility. The first of its kind in an academic center, it provides insulin-producing cells for clinical trials and research around the world.
A normal glucose level for a healthy person, before breakfast, is in the range of 70 to 100 milligrams per deciliter of blood. After breakfast, that reading might spike to 135 or 140. When Fraker was rushed to the hospital and his blood was tested, his glucose reading was well above 400. Fraker had type 1 diabetes.
Twenty-six years later, he still does. It doesn’t go away, and there is no cure—yet. But at 42, and married with three children, Fraker, M.S.B.E. ’06, Ph.D. ’11, has his disease under control—and he is devoting his professional life to finding a cure for it. A research assistant professor at the University of Miami’s world-renowned, cure-focused Diabetes Research Institute (DRI), the UM alumnus is in good company, surrounded by dozens of the best and brightest minds in diabetes research from around the globe.
Focus on a Cure
The Miller School of Medicine has a distinguished history of patient-centered diabetes research dating back to the 1970s. The vision to create a multidisciplinary center focused on curing diabetes belonged to Daniel H. Mintz, DRI’s founding scientific director. Building on this vision, DRI has made extraordinary discoveries over the past two decades under the leadership of Camillo Ricordi, a cell transplantation pioneer who arrived in 1993.
Ricordi holds 11 patents. He invented the machine that made it possible to isolate large numbers of islet cells from the human pancreas, and he’s advanced highly innovative strategies to transplant cells and organs without the ongoing need for anti-rejection drugs. A diabetes-reversing cell implantation procedure he developed now serves as the standard for clinical islet transplants worldwide.
As the Diabetes Research Institute’s scientific director since 1996, Ricordi has accelerated the institute’s efforts in translational—or cure-based—research. If a line of research stops showing promise, it is abandoned. Research is focused primarily on finding ways to cure the more severe type 1 diabetes, the type that nearly killed bioengineer Fraker as a teen.
“We want to arrive at a cure in the fastest, most efficient way possible,” says Ricordi, also chief of the Department of Surgery’s Division of Cellular Transplantation at the Miller School. “Research done in the traditional way was not responding to this need. Scientists worked in isolation, with little communication—often because they were competing with one another.”
Opened in 1994, the 87,000-square-foot DRI facility is no ivory tower for scientists seeking solely to build reputations by publishing in leading research journals. DRI’s main goal is to solve the mystery of diabetes while providing clinical and outreach services that draw patients from around the world.
“We developed our strategic plan after talking with leaders in industry,” Ricordi continues. “I asked them questions: What makes a company successful? What models do they use to be more efficient? In the case of DRI, we have replaced products with patients and the cure, and we took profit away. Beyond bringing all the best science minds together in one space, our current strategy is to link leading scientists worldwide through telescience technology. This allows us to assemble expertise and project teams independent of individual team members’ geographic locations.”
DRI’s 200 researchers and support staff are working nonstop to eliminate an autoimmune disease that targets the insulin-producing islet cells of the pancreas. When sugar from the food we eat enters our bloodstream, it’s the job of islet cells to turn that sugar into energy. When islet cells detect increased sugar in the blood, they’re supposed to make insulin, a hormone that enables energizing sugar to be pumped from the bloodstream into cells.
For reasons scientists don’t yet understand, in people with type 1 diabetes, the immune system begins to perceive islet cells as invaders and snuffs them out. Without the ability to produce insulin, the body is denied energy and blood sugar levels spike. Type 1, or T1 as it’s known in research circles, was formerly called “juvenile diabetes” because it tends to strike children and adolescents.
Only about 10 percent of those with diabetes have T1, which currently requires a lifetime regimen of blood sugar monitoring and insulin injections. The rest of the population has type 2, a condition linked to aging, obesity, and a sedentary lifestyle. Their islets can produce insulin, but their bodies grow less responsive to it, so their blood sugar levels rise, often requiring insulin or other medications. T2 used to be called “adult-onset diabetes,” but with obesity rampant in the United States, it is appearing in teenagers and even younger children. Aggressive lifestyle changes such as diet and exercise can have major benefits for all age groups affected by the disease and may even put it into remission.
Still, the fact that millions of people with diabetes maintain fairly normal lives doesn’t offset its devastating toll: It can cause damage to the cardiovascular system, kidneys, nerves, and eyes, leading to heart attacks, strokes, dialysis, amputations, and blindness.
A Multidisciplinary Approach
If the search for a cure can be depicted as a complex series of interconnected projects, much like the pieces of a jigsaw puzzle, then every piece of diabetes is bound to have someone working on it at DRI.
Collaboration is a hallmark there. Multidisciplinary teams of scientists bridge their respective expertise and work together to overcome complex challenges. An excellent example of how these strategies can produce results is the interrelationship among some DRI projects in cell transplantation, one of four key research areas.
Take DRI director of stem cell development for translational research Juan Dominguez-Bendala, who came to DRI from Scotland’s Roslin Institute (known for cloning Dolly the sheep). Dominguez-Bendala says stem cells are especially promising because of their ability to become other types of cells—such as pancreatic cells, the kind decimated in people with T1.
“The most important development in this area is the advent of reprogramming techniques,” he explains. “It is how we instruct any given cell to become another type of cell.”
DRI researchers have already used stem cells to cure diabetes—in mice. That’s a long step from a monkey, and further still from a human being. Even with mice, scientists must overcome the immune system’s natural response to reject transplanted cells.
|Bioengineers Alice Tomei and Chris Fraker, M.S.B.E. ’06, Ph.D. ’11, search for ways to combat a disease that affects roughly one in three people in the United States. Fraker has type 1 diabetes.
“At DRI, we work with many complementary groups,” says Dominguez-Bendala, one of 29 faculty members. “My research involves inducing stem cells to make insulin. I need to demonstrate that they can cure diabetes, not just produce insulin in a petri dish. I can go elsewhere in the building and have them tested on small animals. I can also consult with an immunologist about avoiding rejection. I can speak with a bioengineer to determine how we implant the cells. I wouldn’t be able to do every step myself. That’s why we have experts in everything here.”
Fraker is one of the bioengineers on his team. “Transplanted cells are very metabolically active and need a lot of oxygen to sustain that metabolic activity,” he notes. “We’re experimenting with thinner and thinner cell coatings. These coatings will protect islet cells from immune response, potentially reducing the need for anti-rejection drugs while permitting oxygen and other nutrients to reach the cells more efficiently.”
Research assistant professor Alice Tomei, who often works with Fraker, came to DRI from the Swiss Federal Institute of Technology. Like many others at DRI—and many of the donors who support their efforts (see sidebar)—she has family members with the disease.
Much of her research involves improving the viability of transplanted cells. The traditional technology of microencapsulation—creating a protective barrier around the cells—often leaves large spaces around the cell, which slows oxygen from reaching it and delays insulin response. Tomei has applied a process called conformal coating to islets that clings to the transplanted cell like plastic wrap, permitting quicker oxygenation and insulin secretion. “A thin layer of polymer disguises the islet so the immune system doesn’t mount a response to kill the cell,” she says. That act of bio-trickery mirrors “how tumors are accepted into the body by fooling it.”
Taking another idea from her previous cancer research, Tomei is testing a protein called CCL21 that she hopes will teach the immune system to be more hospitable to transplanted islet cells in the the way that tumors “expressing” that same protein make the system more inviting to cancer cells.
Ricordi recognized long ago that a cure for diabetes would be found more quickly if the cooperative, translational approach taking place in the DRI building could be expanded globally. In 2006 he founded the DRI Federation, which today has more than 30 centers from China to Brazil sharing resources and research findings. Last year, to further eliminate barriers to sharing information for the good of humankind, he founded The Cure Focus Research Alliance, an association of scientists, physicians, surgeons, and others at the forefront of research in diabetes and other diseases as well as professionals in various fields who share the alliance’s mission.
Renowned experimental endocrinologist Per-Olof Berggren, of DRI Federation member Karolinska Institutet in Sweden, also serves as the Mary Lou Held Visiting Scientist at DRI. He and DRI colleagues have pioneered the transplantation of human and mouse pancreatic islets into the eyes of mice to learn about the basic physiology of the endocrine portion of the pancreas and about the immuno-biology of type 1 diabetes. They are collaborating with researchers at UM’s Bascom Palmer Eye Institute and the Seoul National University in Korea to advance pancreatic islet transplantation into the eye of non-human primate models for potential clinical applications for treating T1.
|Islet physiologist Per-Olof Berggren, the Mary Lou Held Visiting Scientist at DRI, and DRI scientist Midhat Abdulreda, seated, examine in vivo images of islets transplanted in the eye.
“If you want to treat diabetes, which is a disease of nonfunctioning or dying islet cells, then you need to have good knowledge in advance as to why they are not working,” says Berggren, whose latest findings have made the covers of three prestigious research journals. “We need to study the cells in a milieu as close as possible to the real thing, in which we can look at all the functions in the living organism and really begin to understand what is going wrong. You have the opportunity to pinpoint the mechanisms that are ceasing to work. If you can do that, then you can start to intervene and prevent those mechanisms.”
The “why” of diabetes is the big unknown—and represents the chasm between treatment and cure. “Type 1 diabetes occurs mostly in individuals who have the predisposition but not enough protection to keep the body’s immune system from going into self-destructive mode,” says Jay Skyler, a Miller School professor of medicine, pediatrics, and psychology who has been studying the disease for nearly four decades. “This immune attack is the result of a big imbalance in terms of cell regulation versus cell destruction. In the past, we thought it was only about destruction, but now we realize the development of diabetes is about losing that balance. We believe the imbalance may be triggered by something in the environment—an infection, a virus, perhaps something in food or the way food is cooked.”
Skyler is chairing Type 1 Diabetes TrialNet, an international network of researchers who are exploring ways to prevent, delay, and reverse the progression of T1. TrialNet is being conducted with human subjects at risk for developing or recently diagnosed with T1, “people who are right on the threshold of developing diabetes, or who don’t have much imbalance yet,” says Skyler. “We are experimenting with a number of interventional treatments in an attempt to halt its progress.”
Although a true cure is likely years away, the morale in DRI’s research labs is at a constant high. That’s because there is continuous progress. Recently, for example, a DRI team led by Ricordi and Cherie Stabler, assistant professor of biomedical engineering and surgery, and director of the DRI’s Tissue Engineering Program, designed and developed a novel oxygen-generating biomaterial capable of improving islet survival.
“This is like being a painter or an author,” notes Berggren. “It’s not work. If you get caught up in this interest, it’s like a hobby.”
But even Ricordi—scientist, strategist, humanitarian—isn’t immune to personal motivations. “Back when I was in my residency, a cousin was diagnosed with diabetes. I wanted to cure him in a year or two,” he says with a smile, “but I’m a little behind schedule.”
Partners in Progress
The nonprofit Diabetes Research Institute Foundation (DRIF)—founded in 1971 by a group of parents of children with diabetes—is the driving force behind DRI’s commitment to cure-based research and has been able to provide the major financial support that research of this caliber requires. Today, with commitments totaling $225 million, DRIF is the single largest donor in University of Miami history.
|Camillo Ricordi and Bonnie Inserra at DRI
The passion and energy of family members of people with diabetes are still driving the foundation toward a cure. Steven Sonberg, J.D. ’72, is a former chair of DRIF and a UM trustee. In 1978 his 18-month-old daughter Caryn was diagnosed with diabetes. Now in her 30s, Caryn manages her diabetes carefully and is doing well.
“There are plenty of other places where funds get dissipated and spent in ways that don’t relate to the mission,” says Sonberg, who announced DRIF’s $100 million commitment to the institute at the February launch event for UM’s Momentum2 capital campaign (see Fast Forward).
Kentucky banker Harold Doran, chair of DRIF’s national board, says this commitment will challenge DRIF to do its best and “help shorten the timeline for finding the cure.” He says he’s seen considerable progress since his son Will was diagnosed in 1994 at age 2. Now a college sophomore, Will is “a young man living with diabetes, not a diabetic young man,” notes Doran.
Bonnie Inserra’s daughter, Lindsey, has an unusual form of type 1 diabetes. In 1996 Inserra was told her just-diagnosed 11-year-old had only three months to live. Because she can’t absorb insulin through common methods, Lindsey has had a more difficult time of it. But the doctors who predicted a very short life spent in an intensive care unit underestimated her mother’s determination. Because of Inserra’s tireless efforts—“my own research project,” says the New Jersey resident and DRIF national board member—Lindsey became the world’s first child to use the Mini Med intra-peritoneal implanted insulin pump. Today, at 27, Lindsey is a college graduate with a degree in social work who wants to help others. But the mechanical device keeping her alive is not the answer her family, and all the other families, wish for. “We’re watching the research and hoping for a cure,” says Bonnie Inserra. “We’re really all one family.”
—Robert S. Benchley
Online resources: www.diabetesresearch.org and www.TheCureAlliance.org