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    Harvard's Cell `Makeover' May Spur Diabetes Therapy

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    Harvard's Cell `Makeover' May Spur Diabetes Therapy

    Post by sang_garuda on Thu Aug 28, 2008 8:28 am

    Using a kind of biological alchemy, Harvard University researchers have turned one type of cell found in the pancreas of mice into the variety that secretes the hormone insulin.

    If the technique can be used safely in humans, it may one day provide a treatment for diabetes, which occurs when the body either can't produce, or else makes too little of, the insulin needed to process blood sugar. The same approach might be used to make heart, brain, or liver cells from other existing cells and treat diseases in those organs, said Jeanne Loring, a stem-cell scientist who wasn't involved in the findings.

    The technique marries gene therapy and stem-cell research ``in a completely novel way,'' said Loring, the director of the Scripps Research Institute's Center for Regenerative Medicine, in La Jolla, California. ``It turns the whole field on its head.''

    The research team was led by Douglas Melton, a cell biologist and co-director of the Harvard Stem Cell Institute, in Cambridge, Massachusetts. The scientists injected viruses bearing three genes into the mice, transforming a common pancreatic cell known as an exocrine cell into the much rarer beta cell that makes insulin. Their findings were published in the journal Nature.

    Melton said he aims to refine the technique, show that it can be done safely, and begin human clinical trials within two to five years in diabetes patients.

    ``We were able to flip the cell from one state into another, what one of the younger students in my lab calls an extreme makeover,'' Melton said yesterday in a conference call with reporters.

    'Direct Reprogramming'

    The Harvard researchers are calling the process ``direct reprogramming.'' Previously, Shinya Yamanaka of Kyoto University turned adult cells into stem cells that can then be made into other cell types for therapy. Unlike Yamanaka, the Harvard scientists converted one adult cell into another without first making it into a stem cell.

    The research exploits the fact that every cell in a person or animal contains DNA with the complete set of genetic instructions required to create that individual. By turning select genes on and off, scientists can transform existing cells so they start looking and acting like others.

    Melton and his team spent three years searching for so- called transcription factors, which control proteins that in turn switch other genes on and off. They started with 1,100 candidate genes and narrowed the field to 28 that are involved in forming the part of the pancreas where beta cells are found.

    Nine Genes, Then Three

    Finally, they settled on nine genes they guessed might be involved and began a trial-and-error process, injecting them into the pancreases of mice and eliminating one at a time. Eventually, they found that just three genes were needed and that 20 percent of the exocrine cells they injected turned into beta cells, Melton said.

    ``Once the switch happens, you're changed from a Celtic to a Laker, if you like,'' Melton said in an interview on June 12. Unlike trades of players between professional basketball teams in the U.S., this represents ``a stable, permanent reprogramming,'' he said.

    The two cell types have different appearances under a microscope. Exocrine cells look like cobblestones, while beta cells are smaller and shaped like spindles, the team reported in the Nature paper. To be certain the same cells transformed, they stained the original exocrine cells with special dyes and found the dye in the beta cells.

    Safer Viruses

    The viruses used to ferry the genes by Melton's team are known as adenoviruses and are considered safer than the retroviruses used in Yamanaka's work, Melton said. Adenoviruses have been widely used in gene therapy trials. Also, none of the three genes used are known to cause cancer, unlike the genes Yamanaka used, according to Melton.

    Still, Melton said he aims to find still another method of transforming cells without using viruses at all, to ensure the process is safe.

    He and his team will be exploring two different strategies for using the technique as a treatment, Melton said. One would involve directly injecting the genes into a human pancreas, as they did with the mice.

    In the other, the scientists would take exocrine cells from the cadavers of organ donors, convert them in the laboratory to beta cells, coax them to congregate into clusters known as islets, and transplant those into patients. This may be the safest way to proceed, Melton said.

    Researcher's Children

    Melton, who has two children with the Type 1 form of diabetes, said he wakes up every days thinking about how to make insulin-producing beta cells. People with that condition have a defect in their immune system which causes it to attack and destroy their own beta cells.

    Most of the almost 24 million people in the U.S. with diabetes have the Type 2 form, which generally develops in adulthood and is linked to obesity. Both forms can damage the kidneys, eyes, heart, limbs and nerves.

    The most immediate application of Melton's work would be to replace the depleted stock of beta cells in people with severe Type 2 diabetes whose bodies can no longer make insulin. It wouldn't help people with the Type 1 form, like Melton's children, because the new beta cells would most likely be attacked by the same autoimmune process that causes the disease. Other strategies will be needed to block or reverse the immune attack, Melton said.


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