When Doug Melton’s Harvard lab made the announcement last October that they had succeeded in turning human stem cells into functional beta cells, Melton, in a conversation with reporters, talked, too, about the other piece of the puzzle that might enable these cells to survive T1D’s autoimmune attack: encapsulation. Melton’s lab is teaming up with a group of scientists in Daniel Anderson’s lab at MIT’s Koch Institute for Integrative Cancer Research, who for six years have been working to create alginate materials that will protect beta cells while flying under the radar screen of the body’s immune system.
The scientist leading the work is Arturo Vegas, a chemist who started at the Koch Institute in 2008 and has led the encapsulation project since then. I sat down with Vegas for an hour or so last month, and he walked me through the work, while showing me images and videos of the materials created and tested at the lab.
Vegas explained that the idea of using alginate (a processed material generated from algae) to protect insulin-producing cells is not new; scientists have been testing the idea for more than thirty years. The first paper showing that you could successfully protect insulin-producing cells in an immune-competent rat came out in 1980. However, when the work was tested on primates and humans, it failed—over and over again. “There have been such good results in certain models, in mice and rats, that this was a very confusing outcome in higher order animals, suddenly you were seeing this very robust foreign-body response. Once this reaction happens if you have living tissue on the inside, it’s not going to survive,” says Vegas.
In 2007, knowing about the lab’s reputation for being able to solve challenges in biomedical engineering, JDRF approached two senior scientists, Daniel Anderson and Robert Langer, and asked them what they needed to take on the complicated problem of protecting beta cells through encapsulation—a holy grail in type 1 diabetes research. (The project is now also funded by the Helmsley Charitable Trust; along with Melton, the lab is collaborating with Dale Greiner at UMass, Gordon Weir at Joslin, and Jose Oberholzer at the University of Illinois at Chicago; at MIT Omid Veiseh, Joshua Doloff, and Minglin Ma have made major contributions to the project too.)
Rather than developing a new material, Vegas decided to stick with alginate (“cells love alginate,” he said), but see if he could modify it so it wouldn’t invite a foreign-body response. The lab, using a robotic arm funded by JDRF, made almost 800 analogues of alginate, each with a slightly different chemical structure. “You kind of have this backbone, and then you can dress it up with different things, to see if you can alter the way the immune system interacts with the material,” he said. The lab then put the analogues through a series of tests, at each point winnowing the number of potential materials. The team was struck by the fact that alginate materials that had successfully encapsulated beta cells in mice in previous studies failed when tested in the MIT lab. The difference turned out to be the strain of mouse being used. The previous studies had been conducted on Balb/c laboratory mice, whereas MIT works with B6 mice—which turn out to have a more aggressive immune system, at least in terms of this type of foreign-body response. In other words, alginate materials used in these MIT mice had to get past the higher hurdle of a more robust mouse immune system. “This gave us a good entry model to start with. The other model, which was more pervasive in the literature, had been giving people a false sense of confidence in the technology,” Vegas said.
Vegas showed me images and videos of the top ten materials, along with the commercial gold standard alginate that the lab had started with. The screen showed the different materials implanted inside the abdominal cavities of mice. In seven out of ten of them, you could see the body’s immune response stained in bright colors, as macrophages (white blood cells that attack and digest foreign substances) started to cluster then buzz busily around the cells (Vegas told me that “if it’s a pretty picture it’s a bad result). But barely any macrophages stayed near the lab’s three lead materials. And those that approached bounced off the surface of the capsules. As Vegas explained it: “They aren’t recognizing the material to attack. If they did, they would start attacking and get others to join the party.”
Next he showed me images of the materials tested under more challenging circumstances: first, in the abdominal cavity of a primate, with an immune system closer to that of humans. I watched a video of a scientist trying to dislodge capsules made from the commercial gold standard alginate from a primate’s abdominal cavity. In just two weeks, the primate’s immune system had effectively destroyed the capsules, encasing them in a fibrous gunk, adhering them in place. But capsules made from one of the leading materials were floating freely, and could be easily removed. Even after six months the scientists could retrieve most of the latter capsules; you could just see the beginnings of an immune response to the material.
Second, he showed me graphics of a test using the Melton Lab’s beta cells in diabetic mice. All of the images I’d seen thus far had been tests of the material itself—empty capsules. But cell material in the capsules spur a stronger immune attack. And human cell material put into an immunocompetent mouse is an even greater challenge, because you’re crossing the species line. Vegas showed me a graph of a diabetic mouse’s blood sugar; the mouse had been implanted with Melton lab beta cells encapsulated in the commercial gold standard material; the blood sugar of the mouse was lowered for only fifteen days. Then he showed me a blood glucose graph from a mouse implanted with beta cells protected by the lab’s lead material; in this case, the blood sugar was controlled for six months, the length of the experiment. This work will be described in three separate papers, which Vegas expects will be published during the coming year.
Anyone who follows the research knows that diabetes has been cured in mice before—many times. The next step is to test the Melton Lab beta cells in primates, a process that Vegas expects will take a couple of years. Only then, and only if the encapsulation material is still a success, could the long process of human clinical trials begin.
For the present, a couple other methods of encapsulation are now being tested in human trials—both of them macro devices, rather than micro technology like what Vegas is working on. One is ViaCyte’s device filled with stem-cell derived islet cells. Another is from Beta-O2, now being tested on patients in Sweden, which relies on injections of oxygen into a device implanted under the skin to keep the beta cells alive.
As with all type 1 diabetes cure research, a solution to the particular problem of encapsulation is elusive and still years (decades?) away. But despite the long timeline and the many hurdles still to be crossed before this material could potentially be used in a clinical setting, Vegas’s enthusiasm for the project is palpable. “It really is an exciting time for this research, and we are all eager to see our technology translate and improve the lives of people living with type 1 diabetes.”