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Scientists ‘Reprogram’ Adult Mouse Cells to Produce Insulin

Doug Melton, a diabetes researcher and co-director of the Harvard Stem Cell Institute, announced last week that he had used a technique called direct reprogramming to convert ordinary pancreas cells from a diabetic mouse into the so-called beta cells that produce insulin.

Insulin, a hormone that controls blood sugar levels, is made by beta cells in the pancreas. It moves glucose into muscle, fat and liver cells, where the glucose is used as fuel for the body. Diabetes, a chronic disease that affects more than 20 million Americans, occurs when people can’t control or produce enough insulin and high levels of glucose remain in the blood rather than moving into these other cells.

Diabetes comes in two forms: Type 1, usually diagnosed during childhood,results from the body’s failure to produce insulin. In the case of Type 2, the beta cells wear out as a result of overuse, and the body becomes insulin resistant. Type 2 is more common, usually occurs later in life and can be connected to obesity.

Melton, whose two children have Type 1 diabetes, is in his own words, “kind of obsessed with beta cells.”

“I wake up every day trying to think about how to make beta cells,” he said.

The biologists began by targeting a trio of genes necessary for beta cell formation. Then, using a virus as a carrier, they injected genes into the pancreas of a mouse. Within days, other cells called exocrine cells in the pancreas underwent what Melton called an “extreme makeover.” They transformed rapidly into insulin-producing beta cells.

“You see the first signs in three days,” Melton said. “It’s a rapid conversion. A repurposing of the cell quickly.”

Early experiments were done with normal mice. When cells were successfully converted in healthy mice, researchers turned to mice with diabetes. And indeed, the converted cells functioned to secrete insulin and lower the blood sugar levels of the diabetic mice to near normal levels.

The researchers hope that the new methodology could someday be used to regenerate missing or defective cells for other diseases: motor neurons for ALS or dopamine neurons for Parkinson’s.

However, many questions remain about the technique. It’s too early to know whether it can be successfully applied to people, not just mice, with diabetes. Even if it could, it’s probably years away from being marketed, Melton said.

Also, scientists caution that injecting a virus into the sensitive human pancreas could have dangerous side effects.

Qiao Zhou, a postdoctoral fellow and first author on the study, spent long days huddled over lab benches, staining cells, peering through microscopes and analyzing data. And using tiny needles, he helped to inject the necessary genes inside the pancreas cells of the mouse.

“It turns out that the pancreas is a rather fragile organ,” Zhou said. “One could get pancreatitis quite easily by some type of perturbation. For example, if someone punched you really hard, you could get pancreatitis.”

Liver cells may be a more appealing alternative. The liver has great regenerative capacity. And earlier research has shown that insulin-secreting cells can function and survive in the human liver.

“If you cut away a piece of the liver, the liver can replace completely the missing piece,” Zhou said. “Imagine then, if you could convert a small part of the liver into insulin-producing cells, the rest of the liver could compensate.”

Researchers are now actively studying liver cells and trying to convert both mouse and human liver cells into cells that make insulin.

Melton is also quick to point out that Type 1 diabetes patients will require more than just insulin-producing cells. In the case of Type 1 diabetes, the autoimmune system recognizes beta cells in the pancreas as foreign and attacks them.

He’s also quick to add that this technique does not replace the need for stem cells.

“What we learn from stem cells about the mechanism of disease and early human development is essential,” he said. “We couldn’t do this kind of work without the knowledge we’ve gained from stem cells.”

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