Researchers turn living cells into insulin-makers

WASHINGTON Wed Aug 27, 2008 2:56pm EDT

1 of 4. An undated handout immunofluorescence image of adult mouse pancreas infected with a mixture of 3 viruses expressing Ngn3, Pdx1, and Mafa. Insulin is shown in red. Nuclear GFP, which labels viral infected cells, is shown in green. Pecam, which reveals blood vessels, is shown in blue.

Credit: Reuters/Joe Zhou/Handout

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WASHINGTON (Reuters) - Researchers have transformed ordinary cells into insulin-producing cells in a living mouse, improving symptoms of diabetes in a major step towards regenerative medicine.

The technique, called direct reprogramming, bypasses the need for stem cells -- the body's master cells which, until now, have been indispensable to efforts to custom-make tissue and organ transplants.

The researchers used three genes carried by an ordinary virus to transform mouse exocrine cells, which make up about 95 percent of the pancreas, into the scarce insulin-producing beta cells that are destroyed in type 1 or juvenile diabetes.

In theory, the same is possible using abundant human cells such as liver, skin or fat cells, Dr. Douglas Melton and colleagues at Harvard Medical School and Children's Hospital in Boston reported.

"It was easier than one might have thought," Melton, a Howard Hughes Medical Institute researcher and one of the world's top stem cell experts, said in a telephone interview.

"These cells are very stable and live for the life of the mouse."

Scientists had been counting on stem cells to show them how to regenerate tissues and organs -- in the case of juvenile diabetes, to regenerate the pancreatic cells that are mistakenly destroyed by the body's immune system.

"I wake up every day thinking about how to make beta cells," said Melton, whose two children have type 1 diabetes.

The most malleable and promising stem cells have been embryonic stem cells, taken from days-old embryos. But U.S. federal law strictly limits funding for such research and they are not easy to create.

CELL REPROGRAMMING

Last year, researchers discovered how to reprogram ordinary skin cells by taking them back to an embryonic-like state. These induced pluripotent stem cells can be used to study disease and might one day make tailor-made transplants.

But now Melton and his team -- using knowledge gained from these earlier studies -- have skipped both steps.

"What this shows is that you can go directly from one type of adult cell to another, without going back to the beginning," said Melton.

Reporting in the journal Nature, the team said they did it in living mice, not in lab dishes.

They worked with diabetic mice that do not have the insulin-producing cells needed by the pancreas to help the body turn food into energy.

Melton's team had to find which genes were needed to make cells function as the precious beta-cells. While every cell carries the full genetic code, only certain genes in any cell are working at any given time.

The researchers had to find out which genes are "on" as an embryo grows its pancreas.

Out of more than 1,000 genes, they found just three were needed -- Ngn3, Pdx1, and Mafa. Then an ordinary cold virus called an adenovirus carried these three genes into the digestive-juice-making exocrine cells of the pancreas.

This converted about 20 percent of the exocrine cells to beta cells that produced insulin, in turn lowering the soaring blood sugar levels in the mice.

The method might work first in people with severe type 2 diabetes, whose bodies no longer make insulin, Melton said.

"For type 1 diabetes we are still faced with the annoying problem of autoimmune attack," he said.

Any transformed cells in type 1 diabetes would be destroyed by the same mistaken immune response that caused the disease in the first place.

Before experiments begin in people, Melton wants to find a way to transform cells without using a virus. Using viruses to treat people, he noted, is risky and makes Food and Drug Administration experts nervous.

(Editing by John O'Callaghan)

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