In what is being called a major advance on the road toward more effective diabetes treatment, Harvard researchers report that they've been able to grow large quantities of human, insulin-producing pancreatic "beta cells" from human embryonic stem cells. Why is this important?
As the leader of this massive, years-long effort, Doug Melton, the superstar Harvard stem cell researcher said in a news conference Tuesday: "This finding provides a kind of unprecedented cell source that could be used both for drug discovery and cell transplantation therapy in diabetes." And as NPR's Rob Stein put it: "The long-sought advance could eventually lead to new ways to help millions of people with diabetes."
Reporter Karen Weintraub, writing for National Geographic, describes why the research, conducted in diabetic mice, has taken so long, with so many twists and turns:
The researchers started with cells taken from a days-old human embryo. At that point, the cells are capable of turning into any cell in the body. Others have tried to make beta cells from these human embryonic stem cells, but never fully succeeded. Melton's team spent a decade testing hundreds of combinations before finally coaxing the stem cells into becoming beta cells.
"If you were going to make a fancy kind of raspberry chocolate cake with vanilla frosting, you'd pretty much know all the components you have to add, but it's the way you add them and the order and the timing, how long you cook it" that makes the difference, Melton, also a Howard Hughes Medical Institute investigator, said at [the] news conference. "The solution took a long time."
Here's (a lot) more detail from the Harvard news release, written by B.D. Colen:
Harvard stem cell researchers today announced that they have made a giant leap forward in the quest to find a truly effective treatment for type 1 diabetes, a condition that affects an estimated three million Americans at a cost of about $15 billion annually.
With human embryonic stem cells as a starting point, the scientists are for the first time able to produce, in the kind of massive quantities needed for cell transplantation and pharmaceutical purposes, human insulin-producing beta cells equivalent in most every way to normally functioning beta cells.
Doug Melton, who led the work and who twenty-three years ago, when his then infant son Sam was diagnosed with type 1 diabetes, dedicated his career to finding a cure for the disease, said he hopes to have human transplantation trials using the cells to be underway within a few years.
“We are now just one pre-clinical step away from the finish line,” said Melton, whose daughter Emma also has type 1 diabetes.
A report on the new work has today been published by the journal Cell.
Felicia W. Pagliuca, Jeff Millman, and Mads Gurtler of Melton’s lab are co-first authors on the Cell paper. The research group and paper authors include a Harvard undergraduate.
“You never know for sure that something like this is going to work until you’ve tested it numerous ways,” said Melton, Harvard’s Xander University Professor and a Howard Hughes Medical Institute Investigator. “We’ve given these cells three separate challenges with glucose in mice and they’ve responded appropriately; that was really exciting.
“It was gratifying to know that we could do something that we always thought was possible,” he continued, “but many people felt it wouldn’t work. If we had shown this was not possible, then I would have had to give up on this whole approach. Now I’m really energized.”
The stem cell-derived beta cells are presently undergoing trials in animal models, including non-human primates, Melton said.
Elaine Fuchs, the Rebecca C. Lancefield Professor at Rockefeller University, and a Howard Hughes Medical Institute Investigator who is not involved in the work, hailed it as “one of the most important advances to date in the stem cell field, and I join the many people throughout the world in applauding my colleague for this remarkable achievement.
“For decades, researchers have tried to generate human pancreatic beta cells that could be cultured and passaged long term under conditions where they produce insulin. Melton and his colleagues have now overcome this hurdle and opened the door for drug discovery and transplantation therapy in diabetes,” Fuchs said...
Melton, co-scientific director of the Harvard Stem Cell Institute, and the University’s Department of Stem Cell and Regenerative Biology – both of which were created more than a decade after he began his quest – said that when he told his son and daughter they were surprisingly calm. “I think like all kids, they always assumed that if I said I’d do this, I’d do it,” he said...
Type 1 diabetes is an autoimmune metabolic condition in which the body kills off all the pancreatic beta cells that produce the insulin needed for glucose regulation in the body. Thus the final pre-clinical step in the development of a treatment involves protecting from immune system attack the approximately 150 million cells that would have to be transplanted into each patient being treated. Melton is collaborating on the development of an implantation device to protect the cells with Daniel G. Anderson, the Samuel A. Goldblith Professor of Applied Biology, Associate Professor in the Department of Chemical Engineering, the Institute of Medical Engineering and Science, and the Koch Institute at MIT...
Cell transplantation as a treatment for diabetes is still essentially experimental, uses cells from cadavers, requires the use of powerful immunosuppressive drugs, and has been available to only a very small number of patients.MIT’s Anderson said the new work by Melton’s lab is “an incredibly important advance for diabetes. There is no question that ability to generate glucose-responsive, human beta cells through controlled differentiation of stem cells will accelerate the development of new therapeutics. In particular, this advance opens to doors to an essentially limitless supply of tissue for diabetic patients awaiting cell therapy..."
About 10 percent of the more than 26 million Americans living with type 2 diabetes are also dependent upon insulin injections, and would presumably be candidates for beta cell transplants, Melton said. “There have been previous reports of other labs deriving beta cell types from stem cells, no other group has produced mature beta cells as suitable for use in patients,” he said. “The biggest hurdle has been to get to glucose sensing, insulin secreting beta cells, and that’s what our group has done.”
Harvard President Drew Faust even weighed in on the announcement in a statement:
"When the Harvard Stem Cell Institute was created in 2004, the University ventured into uncharted and, some thought, untenable terrain. Today, the possibility of growing in knowledge and in wisdom has given way to the promise of improving health and changing lives. Doug Melton and his colleagues continue to push stem cell science forward with their extraordinary work. This accomplishment is something none of us could have predicted ten years ago, and I am excited to see where it will lead.”
Excitement aside, this is not a done deal yet. For a little healthy perspective, here's veteran health and science reporter Richard Knox's take:
Currently the only cure for diabetes is transplantation of beta cells from cadaver donors – a scarce resource that doesn’t always work and requires perpetual immunosuppressant drugs, which carry risks.
Melton claims that one or 2 flasks of his embryo-derived stem cells might be enough to transplant a single diabetic patient, who would need 340 to 750 million of the transplanted beta cells.
Before we (or Harvard) can declare that Doug Melton has cured diabetes, there is a lot of work to be done — undoubtedly years’ worth. Researchers must:
•Show that the artificially generated beta cells really are identical to normal human beta cells in every way. Right now Melton’s cells do not express all the genes that normal cells do, and it’s not clear what difference this makes in the long-term functioning or safety of the cells.
•Show that the implanted Melton cells function long-term – that is, continue to sense elevated blood sugar and put out adequate amounts of insulin in response. So far in mouse experiments the cells have continued to function for 18 weeks; five out of six transplanted mice were still alive more than four months later, but the paper doesn’t say whether the mice that survived that long were putting out normal amounts of insulin and remained undiabetic.
•Devise a way to protect the transplanted Melton cells from attack by the recipient’s immune system. The Harvard release says Melton is working with Dan Anderson of MIT on a device that does this, but it’s not clear what obstacles need to be overcome. Without such a device, it’s possible that recipients would need a lifetime of immunosuppressants, with attendant risks.
•Demonstrate long-term safety of the implanted cells. One concern is that these manipulated cells might have the potential to revert to a more primitive state – i.e., become malignant.
•And of course, it’s crucial that other researchers replicate Melton’s work and get the same outcomes with his recipe.
So…bottom line: This appears to be a milestone on the long road to developing functional insulin sensing-and-secreting beta cells that might cure diabetes. But there’s still far to travel, and we can expect that the effort will encounter some potholes, twists and turns. And attendant controversy.