Pathway to a cure  pg. 6

That controversy might be avoided by identifying human adult pancreatic stem cells — cells that spin off renewed pancreatic cells, including beta cells. Evidence from several laboratories suggests that these adult stem cells exist, but no one has yet isolated the actual cells.

“In the next couple of years, one may unequivocally identify the adult pancreatic stem cell,” says Douglas Melton, a Harvard investigator studying the development of the pancreas. “The problem is whether it can be replicated, to any appreciable extent, to be useful in a clinical context. Can you coax it to grow outside the body, to make a pile of cells?”

More promising, Melton says, is the embryonic stem cell. “Here, two of the problems have already been solved. This cell is available, and it grows like a weed. You can make virtually an infinite amount.

“That leaves one big problem: how do you direct differentiation into pancreatic cells?”

This is where studies of pancreas development come in — finding the gene switches that turn an undefined bit of embryonic tissue into the specialized cells of the pancreas. Wright’s observations in the frog embryo identified one of the first.

In the mid-1980s, Wright was plugging away as a postdoctoral fellow at UCLA, looking for new members of the “homeobox” gene family — genes that had just been identified as being critical for proper pattern formation in the fruit fly. Of the several they identified, one had an interesting pattern of expression in the developing frog embryo; it was turned on in the area that would give rise to the pancreas and part of the intestines.

Wright launched his Vanderbilt laboratory with the intention of studying the function of the gene, now called pdx1, in mammals, specifically mice. “I was sure it would be exciting,” he recalls. He was right. Mice without the pdx1 gene failed to develop a pancreas.

The pdx1 gene is a transcription factor — it turns on other genes, a cascade of which eventually turn undifferentiated embryonic tissue into the pancreas.

In recent studies, Wright and colleagues have characterized the action of another transcription factor, a gene called PTF1p48 (p48 for short).

The group reported last summer in Nature Genetics a novel and powerful cell marking method that they used to track cells in the mouse that express the p48 gene, starting very early in embryonic pancreas formation. The method relied on genetic manipulations to introduce an inherited marker — a blue color that could be followed in cells that turned on the p48 gene, and in all the cells that came from those cells.

A simple way to think about the technique, Wright says, is to picture the crowd at a football stadium and to imagine that somewhere in the stadium, for a limited time, a man gave away unique blue hats and asked people to wear them. “Now we can follow the people who got hats, no matter where they go,” Wright says. “Whether they go to get a hot dog or leave the stadium entirely, we can find them.”

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