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Teaching Old Cells New Tricks: How to Make Insulin
Researchers at UCLA may have figured out how to turn other cell types into insulin-producing cells to ward off diabetes. It's all in the methyl groups, chemical tags bound to DNA.
Their findings aren't likely to help diabetics anytime soon. But they show promise for doing so in the future, as well as helping to solve an ancient scientific puzzle.
Skin cells of the little finger contain the same DNA as heart cells or the insulin-producing beta cells found in the pancreas. But the genes that make insulin are turned off early in fetal development in all but the beta cells. It's never been understood exactly how these genes are turned off. But it has been taken more or less as gospel that once a cell type becomes specialized, that specialization becomes locked into place for life.
The UCLA research says that this isn't so.
The researchers were able to turn pancreatic beta cells into alpha cells in mice. Beta cells make insulin, which removes sugar from the blood; alpha cells make glucagon, which increases the amount of sugar in the blood. Transforming beta cells into alpha cells won't help diabetics. But it points the way toward doing the opposite — turning alpha cells into new insulin-producing cells, which would be extremely helpful.
It's been known for some time that the degree of methylation of the DNA in a gene can act as a kind of volume control on that gene's activity. All genes are methylated to some degree. Raise the amount of methylation and gene activity drops; lower it and the gene's activity rises. But details of how this control mechanism normally operates have been sketchy.
Here, the researchers were able to convert beta cells into alpha cells by eliminating methylation of a gene called Arx, activating that gene.
This suggests that a silent Arx gene is plays an essential role in maintaining beta cell identity. Turn it on, and that identity is lost. Cells that once produced insulin now produce glucagon.
If there's a similar mechanism at work in alpha cells that maintains their identity, perhaps it too, could be tweaked to transform alpha cells into beta cells, a new source of insulin for those who need it.
Admittedly, there are a lot of ifs here. But what's been done so far shows that cell type is nowhere near as fixed as it was once thought to be. Current thinking is that since beta cells can be turned into alpha cells, it's reasonable to assume that alpha cells can also be turned into insulin-producing beta cells.
The researchers achieved their transformation by eliminating an enzyme from mouse beta cells which is needed for DNA methylation to occur (Dnmt1). As these mice aged, their beta cells slowly began turning into alpha cells. Genetic analysis strongly suggests that this was due to a lack of methylation of the Arx gene.
The reason the change was gradual is that DNA methylation normally occurs only when cells divide. Here, newly-made cells contained unmethylated DNA while the old cells continued to contain methylated DNA. So only newly arisen cells were transformed into alpha cells.
The researchers point out that turning off DNA methylation in beta cells did not lead to activation of a large number of silent genes, which would likely have been disastrous. It seems to have only activated a small set of genes, those that are normally turned on in alpha cells but silent in beta cells.
Unlike research with stem cells, this method works on cells that are already present in the body. While it's not likely to be able to turn a skin cell into a heart cell, it may one day be able to convert related cell types into each other. And that may be good enough to make additional insulin producing cells when they're needed.
An article detailing the study appears in the April 2011 edition of Developmental Cell and is freely available.
May 18, 2011