Alpha to Beta: Changing a Cell’s Identity

By Kevin Gault

To cure diabetes, scientists must devise a way to get the body producing insulin again. That’s a tough task. But several JDRF-funded studies have pointed to a potential path for doing so: converting other cells in the body into insulin-producing cells.

The science is called reprogramming, and JDRF is excited by its potential.

“Under certain conditions in the mouse, it appears now that the body can restore beta cell function either through reprogramming of other cells to become functional beta cells or, as has been previously shown, by increasing the growth of existing beta cells,” says Dr. Andrew Rakeman, JDRF’s Senior Scientific Program Manager in Beta Cell Therapies.

This is an especially hopeful approach for people who have had diabetes for many years. “If we can understand the mechanisms underlying this process in mice and develop ways to reprogram cells in people, it may be a particularly useful way to help people who have had diabetes for a long time and have no, or very few, remaining beta cells,” Dr. Rakeman says.

JDRF’s funding of reprogramming science illustrates how the foundation seeds innovative and potentially game-changing research. It underscores JDRF’s relentless focus on discovering and nurturing new strategies that have the potential to improve the lives of people with type 1 diabetes – and ultimately lead to a cure.

Reprogramming: A Primer

Reprogramming is taking one type of cell in the body and converting it into a different type. In diabetes research, the goal is to end up with a beta cell that produces insulin in response to glucose.

While many cell types have been investigated for their reprogramming potential, recent studies led by JDRF-funded scientists demonstrate that alpha cells are a particularly attractive target. Alpha cells, like beta cells, are found in the islets of the pancreas and secrete hormones. Beta cells produce the hormone insulin, which lowers blood sugar levels. Alpha cells produce the hormone glucagon, which raises low blood sugar to normal levels.

Last year, a group of researchers at the Max-Planck Institute in Germany showed that in mice they could reprogram alpha cells to become beta cells. They did so by forcing the expression of a gene normally restricted to the beta cells, Pax4, in alpha cells. The newly formed beta cells were functional and protected the mice from diabetes.

“The interesting feature of this discovery is that such transformed beta cells are functional and can reverse the consequences of chemically-induced type 1 diabetes in a mouse,” says one of the study’s co-leaders, Dr. Patrick Collombat, who is now working at Inserm in Nice, France.

The study shed new light on the properties of beta cells. “This study provides strong evidence that beta cells are more ‘plastic’ than previously assumed and that type 1 diabetes can potentially be cured using a patient’s own cells,” says Dr. Ahmed Mansouri, who co-led the study.

Another advance was announced earlier this year when a research team at the University of Geneva in Switzerland said it had been able to convert alpha cells to beta cells without any genetic manipulation of the alpha cells. This has important implications for the possibility of using reprogramming to treat humans, since genetic manipulation involves processes that don’t easily translate into therapies for people.

In the Swiss study, scientists first engineered a mouse susceptible to a toxin that would destroy only their beta cells. When the mice were exposed to the toxin, more than 99 percent of their beta cells were gone after 15 days of treatment.

The scientists kept the mice alive with insulin. They found that beta cells recovered over time and that many of the new beta cells arose from alpha cells that had reprogrammed into beta cells.

Eventually, the mice no longer needed insulin replacement to stay alive.

“We observed that if we kept the mice alive with insulin, the pancreas spontaneously reconstituted up to 10 percent of the normal beta cell mass over several months,” says Dr. Pedro Herrera at the University of Geneva, who led the study.

The Geneva team’s results are the first to show that beta cell reprogramming can occur spontaneously, without scientists altering specific genes. “The big breakthrough is showing that alpha-to-beta cell reprogramming can be a natural, spontaneous process,” Dr. Rakeman says.

This breakthrough provides significant information for developing treatments.

“This study opened up the possibility of reprogramming not only as an interesting biological phenomenon, but as something that we could harness therapeutically,” Dr. Rakeman says. “If we can understand the signals that are triggering this conversion, it will open up a whole new potential strategy for regenerating beta cells in people with type 1.”

Dr. Herrera agrees: “The important message is that the adult pancreas can regenerate through mechanisms that we didn’t think were possible,” he says. “We can imagine ways to use this knowledge to foster this process of reprogramming in people with diabetes.”

Challenging the Dogma

It’s too early to rewrite any biology textbooks. But Dr. Herrera says the results certainly challenge the dogma.

“In theory, any cell should be ‘reprogrammable,’ with a few exceptions,” Dr. Herrera says. “But we are only at the beginning of the observation of such cell changes. And such cell plasticity goes against the dogma established in biology textbooks.”

Dr. Rakeman concurs: “Traditionally in developmental biology, it was thought that as a cell matures, the process is irreversible – it can’t go backward on that path and switch into a different cell type. These observations of spontaneous, direct reprogramming where cells convert from one type to another challenge that longstanding dogma.”

JDRF as Driver of Scientific Progress in Reprogramming

JDRF has worked to advance the science of reprogramming in a highly focused way. Over the past year, JDRF hosted a workshop that brought together scientists from all over the globe to discuss this important research and to consider the many questions that still must be answered. Based on the results of the workshop, JDRF initiated a program to fund a series of new studies on reprogramming.

Reprogramming is part of JDRF’s Regeneration research program, which seeks to find ways to regenerate functional beta cells in people with type 1 diabetes and preserve beta cell function. Within the Regeneration program, JDRF is supporting a wide range of projects with scientific investigators at top academic institutions, each targeting ways to replicate beta cells, regenerate them, or reprogram other cells to become beta cells. For example, JDRF has research collaborations with Pfizer, Hadassah Medical Organization, and The Hebrew University of Jerusalem to study the effect of drugs on beta cell regeneration in pre-clinical models. It is also funding studies at institutions such as the Broad Institute of MIT and Harvard, the Genomics Institute of the Novartis Research Foundation, and Duke University. These projects focus on identifying targets, pathways, and small molecules to promote beta cell regeneration.

A Promising Future

For reprogramming science, these are early days. But JDRF is hopeful that the science will lead to new treatments – and perhaps, one day a cure, for people with type 1 diabetes.

“We’re at a point now where we understand that reprogramming can happen,” Dr. Rakeman says, “but we still need to understand how it’s happening. Then we must use that knowledge to design therapeutics and go on to show that those same processes we have already observed in experimental animals will occur in humans.”

Dr. Herrera envisions that this groundbreaking research could lead to better lives for people with type 1 diabetes. “From what we’ve seen in mice, I’m convinced that the pancreas in people with diabetes has the potential to spontaneously produce new beta cells,” he says. If scientists can figure out how to harness this potential and create new beta cells, “this could clearly improve the quality of life for people with type 1 diabetes.”