Beta Cell Breakthroughs
How scientists are sneaking insulin-producing cells into the body in the hopes of no more insulin injections
Take a business card and cut it in half. Now imagine the thin strip in your hand is fashioned out of microscopically perforated plastic and packed with hundreds of thousands of beta cells, the specialized factories that produce the insulin you need to control blood glucose levels.
In October, a man in San Diego with type 1 diabetes had two of these thin strips implanted just under the skin of his lower back. It's the first time a device using beta cells grown from stem cells has been tested in a human. For the next two years, doctors at the University of California–San Diego will monitor how the container and the cells inside perform—and whether the combination is able to partially replace regular insulin injections.
The long-awaited announcement made waves in the diabetes research community. The slim plastic box was developed by ViaCyte, a San Diego company. ViaCyte's product is one of many different "encapsulation" devices, all essentially boxes or balls designed to keep beta cells protected and contained while letting glucose and other nutrients in and the insulin the cells make out. If the devices work, they might be the replacement pancreas of the future
"Is this going to work in the long run? I don't know. But it's worth working on," says Gordon Weir, MD, a researcher at the Joslin Diabetes Center who has spent decades studying type 1 diabetes. "I'm cautiously optimistic."
Encapsulation is a work-around to a problem that has bedeviled researchers for more than a century: For reasons scientists haven't yet figured out, sometimes the immune system goes haywire and attacks the body's beta cells, mistaking them for dangerous invaders.
Once the process starts, it's impossible to reverse. "The problem with type 1 diabetes is the human body is not tolerant to its own beta cells," Gordon Weir, MD, says. "A treatment to reset the immune system is what we're all dreaming of, but we've had decades of smart people working on it and so far no results."
For most of human history, the immune reaction that caused type 1 diabetes was a death sentence. With no way to replace beta cells, the body had no way of producing its own insulin. When in 1922 researchers discovered how to inject insulin, the disease was transformed from terminal to chronic—manageable, but far from cured.
Despite the tremendous advances made in the decades since that breakthrough, life with type 1 diabetes remains a constant challenge. Even tight blood glucose control can"t compare with the sensitivity of the body's innate insulin control system, beta cells. Insulin therapy by injection or pump attempts to control the resulting blood glucose ups and downs, but is imperfect. "A cell does that better than any glucometer," says Douglas Melton, PhD, a biologist at the Harvard Stem Cell Institute. Fluctuating blood glucose levels do damage that accumulates over decades, resulting in the complications so familiar to people with diabetes: kidney, eye, and nerve problems, plus cardiovascular damage that results in an increased risk for heart attacks and strokes.
For some people with type 1 diabetes, the need for insulin-producing beta cells is even more pressing. Hypoglycemia unawareness, for example, keeps people from sensing low blood glucose until it's too late to fix. The results can be deadly.
That's why transplantation has always been a top goal for diabetes research.
Even before the discovery of insulin, doctors were trying to cure diabetes with transplants: In 1893, a German researcher tried putting bits of sheep pancreas in a 15-year-old boy with diabetes. (Unsurprisingly, the experiment failed, and the boy died three days later.) "You can make a lot more people insulin independent for a lot longer with islet transplants," says JDRF Scientific Director Albert Hwa, PhD.
History in the Making
1892: German doctor Oskar Minkowski discovers link between diabetes and the pancreas.
1893: Minkowski's first pancreas transplant attempt is a failure.
1966: First successful pancreas transplant in a human.
1994: Experiments with islet transplantation begin.
1999: "Edmonton protocol" results in successful islet transplants from cadavers. Immunosuppression drugs required to prevent rejection.
2014: Human beta cells successfully grown in a lab. First U.S. clinical trial of an encapsulation device begins.
A Medical Breakthrough
It took more than a century of research before the first successful transplantation of islets, clusters of hormone-producing cells in the pancreas that include beta cells. Researchers at the University of Edmonton in Canada successfully transplanted islets from cadavers into patients with type 1 diabetes, announcing their initial results in 2000.
Though complex, the Edmonton experiments managed to succeed where so many others had failed. Patients were able to produce their own insulin and stop their regular insulin injections, at least for a time. "It was a landmark finding," Hwa says. "You could transplant enough islets into a patient to achieve insulin independence."
The so-called "Edmonton protocol" has some major drawbacks, though. For one, the procedure depends on organ donation for a supply of pancreases. Organ donations are hard to come by in the best cases, but donor pancreases are in particularly short supply—about 3,000 viable organs per year in the United States. Because each islet transplant requires at least two cadaver donors to get enough cells, there's an annual limit of 1,500 transplants at most—a tiny, tiny fraction of the estimated 1.25 million Americans with type 1 diabetes. The cost, about $200,000 per procedure, also remains a barrier.
Finally, and most important, islet transplants don't solve the underlying cause of type 1 diabetes: an off-kilter immune system. That makes every islet transplant an unattractive bargain. Transplant recipients face a lifetime regimen of powerful and expensive immunosuppressant drugs and their potential side effects in order to keep their immune systems from ravaging the new beta cells.
In effect, people with type 1 diabetes must trade a long list of serious side effects, from kidney damage to increased risk of cancer, for the improved glucose control that comes with transplanted beta cells. "Here we are, 15 years later, and only doing a small number of islet transplants," says Weir. "We still need immunosuppression. The results aren't what we're after."
Ever since the Edmonton researchers announced their initial results, a race has been on to find a way to keep beta cells alive without immunosuppressant drugs. Researchers have had to overcome two major barriers. The first is finding a reliable, safe, and effective supply of beta cells to transplant, eliminating the need for cadaver donors. The second is protecting those cells once they"re successfully transplanted into the body. "We have to remove those two barriers," says JDRF's Hwa.
JDRF, with its focus on type 1 diabetes, has been a major supporter of research into islet and beta cell transplantation, working with scientists and industry to coordinate and support different approaches to the problem. The ADA has also sponsored research into encapsulation ("ADA Grants," below). Last year, the effort and resources showed signs of finally paying off.
A major step toward toppling the first barrier—a consistent, safe supply of beta cells—was announced in late 2014. In a paper published in the journal Cell, Melton reported that his team at Harvard managed to turn human stem cells into beta cells in a lab, consistently and in huge numbers. "Instead of getting beta cells from cadavers, we can now make them—and make billions, not millions," he says.
|How encapsulation devices differ|
Beta cells in a box
Pros: Tens of thousands of beta cells fit in one box; easy to implant and monitor
Cons: Difficult for cells in the middle of the box to access the body's blood vessels and oxygen
Beads of betas
Pros: Tiny beads provide easier access to the body's blood supply for cells
Cons: Often covered over by scar tissue; too small to easily monitor
Melton starts with stem cells, which are cells capable of transforming into any specialized cell type. They're pure potential, with the ability to transform into anything from skin cells to nerve cells to insulin-producing beta cells. "What we've done is really quite obvious—if you have a cell that can make any other cell, any grade school student would tell you to use it to make a beta cell," Melton says. "In practice, it turned out to be not so easy."
In fact, Melton says, it took 15 years of painstaking research, involving more than 50 scientists in his lab alone. And the procedure is still tricky and time-consuming. It takes a month and 15 different steps to turn stem cells into beta cells. Another, privately funded group, BetaLogics, has come up with similar results.
Melton likens the process to educating an infant. "Cells don't decide what their fate should be—they get signals from their neighbors," he says. "The cell has to be taught to become part of the gut tube, then the pancreas, then islets. We had to figure out which genes come on and off at every stage, and how we can tickle them to turn on and go in the right direction."
The end result is a billion beta cells, enough to supply one person's insulin needs. Floating in a coffee cup–sized flask of reddish liquid in Melton's lab, stirred gently 70 times per minute, they might be half of the solution to the transplantation problem.
Melton's announcement sparked a rush of interest in the remaining part of the puzzle: getting beta cells into the body and keeping them alive. "The reason for all the interest is we finally have cells to transplant, now that embryonic stem cells can be turned into beta cells," says Weir.
That's where encapsulation devices come in. Encapsulation's goal is to offer a drug-free way to put beta cells in the body while protecting them from immune system attacks. The goal is to put transplanted clusters of beta cells and other cells, known as islets, in a flexible container with holes small enough to keep immune cells out, but large enough to let oxygen and insulin through. "Think of it as a teabag—the tea leaves are kept inside the device, but the essence is allowed to move in and out," says ViaCyte CEO Paul Laikind, PhD.
Though ViaCyte's Encaptra device is the first one to be tested in a human, there are lots of other people working on the problem, with product ideas that range from hockey puck–sized implants that pipe in oxygen each day to tiny beads scattered throughout the body. "There are two major ways to encapsulate things—put them in a big box, or macroencapsulation, or microencapsulation," Weir explains (see "Case Closed").
Getting the body to accept the "teabag" isn't easy. First, the cells inside need to be hooked up to the body's plumbing system, the blood vessels that feed cells with nutrients and oxygen and transport their waste away. If the box is too big, only the outermost cells will be able to connect. Imagine a long, skinny office building: Everyone inside would have a desk near a window. The boxier the building, the more people are stuck in the middle, hoping for a bit of sunlight. The situation in a box full of beta cells is similar: Only the beta cells with a window have access to the blood supply.
Microencapsulation takes the opposite approach: Each cluster of beta cells gets its own house in the suburbs. (Actually, a bead half the size of the period at the end of this sentence, large enough to hold a few thousand beta cells inside.) In early experiments, researchers have found the immune system continues to be a stumbling block with the so-called microencapsulation approach. The tiny beads are often treated as invaders by the body and covered over by scar tissue. Or they settle in clumps inside the abdominal cavity where they're implanted, blocking each other's access to the blood supply.
A New Hope
Researchers know that making encapsulation devices an everyday reality for people with diabetes won't be easy. Yet after decades of frustration, there is a new sense of optimism about encapsulation. "I'm really excited about recent progress," says Hwa.
Others have been more cautious. In a review published in response to Melton's article in Cell, Baylor College of Medicine researcher Jake Kushner, MD, argued that the lab-grown beta cells haven't proven themselves yet. "The extent to which these cells are representative of "functionally mature" adult beta cells remains unclear," Kushner wrote. Adding to the problem, he explained, is the fact that researchers can't agree on what "functionally mature" means.
Kushner and his coauthors also argued that it was too early to celebrate a victory—let alone raise the hopes of people with type 1 diabetes that a cure is right around the corner. First the beta cells need to be thoroughly tested for safety and effectiveness. "My mind reels when I think about all the issues," he says.
For starters, Kushner worries the lab-grown beta cells aren't meeting expectations. The cells don't secrete insulin in a dish nearly as well as human beta cells do in the body when stimulated by glucose (such as in response to a meal). On the other hand, there's also the risk that the cells could produce too much background (basal) insulin, leading to uncontrolled hypoglycemia.
Then there's the threat of "systemic autoimmunity," a sort of full-blown immune attack. Kushner likens the encapsulated beta cells to a scuba diver protected by a cage in shark-infested waters. "My fear is you could be provoking the sharks—autoimmunity—by the presence of cells they're not normally exposed to." In the ensuing frenzy, the immune cells could damage other organs in the body.
In theory, the transplanted cells could even continue growing and multiplying inside the body, causing cancers. "Could these cells ultimately decide to become some hormone-secreting tumor? It remains a theoretical possibility that needs to be considered," Kushner warns.
And even if cells are shown to be safe and effective and a reliable "teabag" is developed, for the foreseeable future encapsulation will be a costly, complex procedure, requiring minor surgery to implant and a lifetime of attentive maintenance. Practical questions, like how much the procedure might cost and whether insurance would cover the expense, are impossible to answer this early, JDRF spokesman Christopher Rucas says.
But to the community of scientists searching for solutions, recent developments represent a light at the end of the tunnel, no matter how distant. For Melton, the research has a deeply personal element: Two of his children have type 1 diabetes. After his son was diagnosed with the disease as an infant, Melton devoted his career to searching for a cure.
More than 20 years have gone by, but Melton says his kids always thought Dad would get the job done. "If you tell your child you're going to do something, they'll believe you," Melton says. "They never doubted, they just said, "Why is it taking so long?" Now they are asking me, 'When is it going to be in people?' "
Now, at last, Melton thinks he has an answer. "I tell them the truth—it's not going to take 15 years, but I don't know exactly when," he says. "If everything goes perfectly, it could be in patients within four to five years."