Research Breakthrough

Diabetes researchers convert pancreas cells to produce insulin

The Harvard study may ultimately shift treatment options away from stem cells for a variety of diseases.

By Karen Kaplan, Los Angeles Times Staff Writer 

August 28, 2008

Injecting a cocktail of proteins directly into the bodies of diabetic mice, researchers have converted normal pancreas cells into insulin-producing cells -- a genetic transformation that could pave the way for treating intractable diseases and injuries using a patient's own supply of healthy tissue.

The Harvard University scientists activated a trio of dormant genes that commanded the cells to transform themselves, much as a person might upload a new operating system onto a computer to change a PC into a Mac.

Within 10 days, the pancreas cells ceased their normal function -- making gut enzymes to digest food -- and instead produced insulin to regulate blood sugar, according to a study published online Wednesday in the journal Nature.

Doug Melton, co-director of the Harvard Stem Cell Institute and the study's senior author, said the same approach could be used to generate motor neurons for patients with amyotrophic lateral sclerosis, to make cardiac muscle cells for heart attack victims or to create other crucial cells that can repair damage wrought by a range of illnesses.

"We were able to flip the cell from one state into another," Melton said, adding that the approach should be useful in treating disorders in "any case where there's a cell type missing and there are neighboring cells that are still healthy."

The method has been tested only in mice and is at least two to five years from being tried in humans, he said. Applying the technique to other diseases will involve a tedious process of searching for the right combinations of dormant genes and the most effective means of turning them on.

Still, Patricia Kilian, who heads regeneration therapy research at the Juvenile Diabetes Research Foundation, said the technique would sidestep some of the complexities inherent in the highly touted but controversial research involving embryonic stem cells.

"You wouldn't be transplanting cells, so you wouldn't be dealing with immune issues," she said, calling the research remarkable and "very unexpected."

The process, which the researchers call direct reprogramming, relies on the fact that all cells contain a complete library of genes in their DNA.

As cells mature, different genes are turned on and off through a still-mysterious process that ultimately leads to the creation of a muscle fiber, neuron, cardiomyocyte or some other type of cell.

When certain types of cells are damaged or destroyed, there is no easy way to replace them.

Over the last decade, scientists have focused on stem cells as a solution because of their natural ability to grow into new tissues that can be transplanted into patients.

Of particular interest were embryonic stem cells, which can grow into any type of cell in the body with the proper chemical prodding -- though figuring out those regimens has not always been easy. The research was also controversial because the cells had to be harvested from days-old embryos, which were destroyed in the process.

In recent months, researchers have embraced a new technique that involves rewinding adult cells to an embryonic state by turning on a set of four genes that are active during early development.

The Harvard researchers wondered if they could find a shortcut.

"We just asked, sort of like an undergraduate, the simple question, 'Why should you have to go all the way back to the beginning? Could you go directly from one cell type to another?' " Melton said.

They chose to study diabetes, a disease that has been a central focus of stem cell research.

Patients with Type 1 diabetes need new beta cells to make insulin because their original beta cells have been destroyed by their immune systems.

Insulin is crucial for metabolizing sugar, and without it, patients must monitor their blood-sugar levels every few hours and inject themselves with insulin up to five times a day.

Melton said he is obsessed with finding a way to treat patients with Type 1 diabetes, including his own children Emma and Sam.

"I wake up every day thinking about how to make beta cells," he said.

Once he decided to try direct reprogramming, his team identified nine key genes that are active in mature beta cells and their close relatives.

They started turning them on and off using specialized proteins, known as transcription factors, that bind to specific parts of DNA. Every possible combination was tried to determine which were necessary to make insulin-producing cells. The researchers ultimately determined that only three were essential to the process, and they were activated by the proteins Ngn3, Pdx1 and Mafa.

The researchers injected mice with a virus that specifically infects pancreatic exocrine cells, the type that make up about 95% of the pancreas. The proteins carried by the virus turned on the dormant genes.

Three days later, the cells started making small amounts of insulin. After 10 days, up to 20% of the exocrine cells had lost their cobblestone appearance and took on the distinctive spindle shape of beta cells. Their insulin production was comparable to that of normal beta cells, the study said.

To test their therapeutic potential, the researchers turned dozens of mice into Type 1 diabetics by wiping out their beta cells. Animals that were treated with the three proteins showed a significant improvement in their fasting blood glucose levels compared with controls that got a placebo.

The process turned out to be faster and more efficient than methods involving stem cells, the study found.

The transformation should also be safer than methods involving immature stem cells, which have a tendency to grow into tumors, said Konrad Hochedlinger, a scientist at the Harvard Stem Cell Institute who was not involved in the research.

He said he expected to see "many more examples" of direct reprogramming that target diseases and injuries, although each would require its own search for the exact combination of tissues, proteins and genes needed to create the biological repair kits.

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BREAKING NEWS!

Also check out this new study that was released today that JDRF funded. The first link is to the JDRF press release and the second to the actual study:

▪JDRF Press Release: http://www.jdrf.org/index.cfm?fuseaction=home.viewpage&page_id=33E55217-1321-C834-039BF1AA72DA90E4

▪Study Article from the New England Journal of Medicine:http://content.nejm.org/cgi/content/full/NEJMoa0805017