Beta than the real thing?

Melton_ beta_cellsHuman stem cells implanted successfully in a mouse. Image courtesy Doug Melton.

We know a true cure for type 1 diabetes will require both a new supply of insulin-producing beta cells and a new way to stop the autoimmune attack that wipes out the original cells. We’ve seen great progress in the past decade on the first challenge, as researchers have learned to morph embryonic stem cells and then normal skin cells into beta cells that now might be very much like the real thing. But despite all we’ve learned about the autoimmune attack and all the clever ideas that have emerged to stop it, so far there’s no clear way to do so.

Today the best bet for autoimmune defense is to embed engineered beta cells in intricately designed porous capsules. While most attempts use spherical capsules on a millimeter scale, last fall Viacyte launched a clinical trial for a device the size of a credit card. We’re all rooting for this trial’s success. But even if it works well, the encapsulated cells won’t function quite normally or last forever.

“I want a forever solution,” says Harvard’s Doug Melton, who has led much of the stem cell engineering work.

At a JDRF session in Boston back in March, Melton suggested two approaches to further modify those engineered cells to dodge the autoimmune bullets. “These are two of my favorite ideas, but I’ll remind you that most of my ideas turn out to be wrong,” he said wryly.

One idea follows the playbook of the hot new class of cancer immunotherapies known as “checkpoint blockaders” —or rather turns it on its head.

As cancer researchers began to discover two decades ago, T cells that charge in to wipe out tumor cells are stopped in their tracks if the tumor cells express certain proteins on their surfaces. Well, how about engineering beta cells to defend themselves by expressing these proteins on their surfaces? (Work in mice by other labs indeed has demonstrated protective effects.)

Melton prefers a second concept, which taps into one of the large questions of immunology: Why doesn’t a mother’s immune system attack the fetus she carries?

Cells called trophoblasts that initially wrap the embryo help to provide the immune shield, he notes. So why not express key trophoblast surface proteins in beta cells, so that the beta cells look like fetal cells to the immune system?

While autoimmune researchers have been kicking around both of these ideas for years, it’s still very early days for bringing beta cells with self-protective surfaces toward the clinic.

But some year, Melton told the JDRF crowd, “my dream is to tell you, not only can we make billions of beta cells but we can transplant them into any person and they won’t be rejected.”

I’m looking forward to hearing about more and better betas from him and from other leading researchers this Friday afternoon, at a session during the American Diabetes Association’s annual scientific conference in Boston.

Encapsulating answers to type 1 diabetes

People with type 1 diabetes are understandably excited about progress toward an “artificial pancreas” but they never lose the hope for a true cure, in which they can live like everyone else, without juggling synthetic hormones and hardware clomped on their skin that pierces their skin and will never work perfectly.

A true cure is a blue-sky goal built on two sets of major medical advances, and we have no idea what year those advances might arrive.

One set is to understand the autoimmune onslaught that brings on type 1 and then find a way to stop it. Serious and sometimes brilliant research keeps charging ahead, but autoimmune diseases hold extremely devious secrets and guard them very well.

The second set is to create a cells that replace those wiped out by the autoimmune attack and can generate insulin (and maybe related pancreatic hormones) at appropriate levels. Stem cell research aimed to do so is going gangbusters but is generally a long way from clinical trials.

With one big exception:

Yesterday Viacyte filed with the FDA for permission to run a trial for its VC-01 device, which encapsulates human progenitor cells—human embryonic stem cells that in this case have gone partly down the development path to hormone-producing cells. (The company, then known as Novocell, began work with embryonic stem cells years before the 2006 discovery of ways to create induced pluripotent stem cells, which possess very similar abilities to differentiate into almost any kind of cell but can be created from adult cells.)

Viacyte’s encapsulation container is a Teflonish cartridge about the size of a band-aid and thickness of a credit card, with holes too small for immune cells to enter but big enough to allow oxygen, glucose and other key ingredients to flow in and to allow insulin and other hormones to flow out.

The theory is that the capsule is inserted via an outpatient procedure, the immune system mostly ignores it, blood vessels build up to feed the cells, the cells are driven by signals within their fairly normal local human microenvironment to differentiate into a range of hormone-producing cells, the cells churn out insulin and its hormone cousins, and normal blood glucose levels and related metabolism are maintained. A functional cure, in short, for a year or two or three while the device functions properly.

This all works nicely in mice, but mice are not always man’s best friend in diabetes research. Investigators have struggled with encapsulation techniques for many years, and stem-cell-derived cells are unproven. The list of what could go wrong in the Viacyte trial is very long. Patients might reject the capsule. The cells might die quickly or slowly or never gather suitable blood vessels or fail in other ways. They might generate side effects that no one has imagined.

But Viacyte seems to have the science on its side and its head on straight and a good step-by-step plan. Assuming the FDA agrees, I don’t expect a home run in the first trial, but simply getting on base would be huge. And we should know within a year.

Viacyte Encaptra