Q&A: Gordon Weir on Type 1 Diabetes Research

Dr. Gordon Weir of Joslin Diabetes Center

Monday, July 26, 2010

When type 1 diabetes wipes out the body’s insulin-producing beta cells, how can they be replaced? That’s been a focus of research for decades for Gordon Weir, M.D., and his wife, Susan Bonner-Weir, Ph.D. 

What’s the current state of beta-cell replacement research?

It’s hard and it’s going to take time, but we know where we need to go.

The proof of principle has been established; you can succeed with a cellular transplant. That was done for the first time in 1989. You can take someone with type 1 diabetes, send them to a radiology suite, and they can leave the hospital a day or two later with no diabetes. They can stay that way for five years.

But most of them don’t—within two years they’re back on insulin. It’s a very expensive, difficult, cumbersome procedure. We still have an inadequate supply of islets (the structures in the pancreas that contain the beta cells). The islets we obtain are damaged by the isolation procedure. And the immune-system drugs that are required have important detrimental side effects.

What we’re really talking about in research is what we have to do for the future—the science of getting more beta cells and transplanting them most effectively.  There is also the tantalizing possibility of stimulating regeneration of beta cells in the pancreas.

Which techniques seem most likely?

I think the most promising approaches are embryonic stem cells and what are called induced pluripotent stem (iPS) cells, which are embryonic-stem-cell-like cells created from adult cells.

It’s quite astonishing that two years ago, a company in California (now called ViaCyte) succeeded in taking embryonic stem cells all the way to mature beta cells.

Unfortunately it’s not possible to make these wonderful beta cells in a test tube. They must be put in an animal and allowed to mature, through some magic of the in vivo environment. That means that in order to do the transplant, you’ve got to put in immature cells. And because you’re putting in immature cells, then you increase the risk of forming teratomas, which are a kind of tumor.

But I think you have to step back and assume that these details, as complicated as they are, will eventually get solved. I’m pinning a lot of hope on embryonic stem cells and/or iPS cells.

I’m head of the Harvard Stem Cell Institute (HSCI) Diabetes Program, and we do whatever we can to support the important work of Dr. Douglas Melton, who founded HSCI, and his colleagues in their efforts to turn human embryonic stem cells into beta cells. When they produce promising precursor cells, we put them into mice whose immune systems have been repressed, and study their ability to turn into beta cells or other islet cell types.

We also study “normal” human islet cells obtained after being isolated from cadaver donors, which are transplanted into mice. It’s the only way you really can look at human tissue in an in vivo situation. This work is being done to determine the regenerative potential of these transplanted cells.

How about islets transplanted from animals?

Pig islets continue to be another option. We’ve had quite a bit of assurance that the viruses that are native to pigs won’t cause problems. So some researchers at other institutions are trying to combine pig islets with novel ways to suppress the immune-system reaction that would be tolerable.

Would encapsulating the islets help to protect them against the immune-system attack?

Encapsulation continues to be a maddening and attractive concept. You know the principle: You lock the cells up in a membrane, and that screens out the cells that attack the islets, and yet has holes big enough that nutrients and oxygen get in perfectly well and insulin can get out.

There have been terrific successes with rodent studies. But it’s been hard moving up to larger animals. So, even though the technology has been here for thirty-plus years, people are getting pretty skeptical as to whether it’s really going to work.  However, there are reasons to be optimistic.

We’re collaborating with Massachusetts Institute of Technology researchers, who are developing innovative biomaterials that can be used for encapsulation.

It’s still a cumbersome approach. The reason why it’s so important to keep working on it is that preventing the autoimmune attack safely is turning out to be really hard. I don’t see an immediate silver bullet for the autoimmunity problem.

What about efforts to encourage existing beta cells to make more copies of themselves?

Yes, that’s cell replication. Beta cell replication is pretty exuberant in mice and it’s really slow in humans. The question is, can you unleash that?

Researchers in various centers are examining ways to throw a few cell-cycle switches that make beta cells divide more actively. Dr. Rohit Kulkarni here at Joslin is studying basic aspects of replication. Also, by supplying islets, we’re helping Doug Melton on his project to do high-throughput screening of chemical compounds to identify new compounds that stimulate cell replication.

How about creating new cells from other sources in the pancreas?

That’s neogenesis, the generation of new beta cells from cells in the pancreas other than pre-existing beta cells.  There’s a great deal of circumstantial evidence suggesting that pancreatic duct cells can turn into new islets. Dr. Susan Bonner-Weir is really the pioneer in this, and she’s been working on it for 15-plus years. Her lab continues to explore the therapeutic potential of this route to regeneration.

She works very closely with Dr. Arun Sharma of Joslin, who studies the molecular pathways that become active as beta cells mature and develop the ability to secrete insulin.

Then there are studies of neogenesis after gastric bypass operations, which Drs. Mary Elizabeth Patti and Allison Goldfine are doing here.

After gastric bypasses, some people end up getting severe hypoglycemia and have to have their pancreases taken out. When researchers look at the pancreases, there are a lot of new islets growing out of ducts. Studying this seems promising, although it’s unclear why this apparent excessive islet growth appears in only a small percentage of people who have the operation. Scientists in other research institutions and pharmaceutical firms are trying cocktails of drugs that seem to have the potential to stimulate neogenesis.

What do you tell people with type 1 diabetes overall about moving new beta cells toward actual transplants?

I won’t tell you that it’s going to happen next year.  But we know where we need to go. And the scientific accomplishments are extraordinary.

Dr. Gordon Weir of Joslin Diabetes Center