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Harvard's Melton Converts Mouse Pancreatic Exocrine Cells to Beta Cells

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It would be difficult to overstate the excitement within the stem cell community late last year when researchers first demonstrated that transcription factors could be used to turn adult fibroblasts into the functional equivalent of undifferentiated stem cells.

But at Doug Melton's lab at the Harvard Stem Cell Institute, scientists who had been working on the challenge of creating pancreatic beta cells began to wonder whether a similar approach could turn an adult cell into another type of adult cell without having to go back through the undifferentiated phase in between.

To test the theory using mouse as a model organism, Melton and his team "looked through all 1,100 transcription factors," he says. "We used very labor-intensive, whole-mount in situ hybridizations … one at a time, on every transcription factor in the mouse." That may sound impressive, but Melton is quick to point out the reasoning behind such a large-scale experiment: "That sort of approach is more or less an admission a priori that you don't know which genes are worth looking at, so you're just sort of guessing," he says.

The guesswork paid off. From the initial set of 1,100 genes, the team narrowed that down to an estimate of nine genes. Using a closely related pancreatic exocrine cell as a starting point, Melton's crew put the nine genes "into adenoviral vectors for their expression in a live adult mouse," he says. The abracadabra moment resulted in induced beta cells that appear indistinguishable from regular adult pancreatic beta cells. Three transcription factors wound up being essential to the process.

Melton's lab is already off to the races on the next two challenges: getting the process to work in human cells ex vivo, and seeing if the conversion could work between cells less closely related — changing liver cells, which the body can regenerate, into the far more precious pancreatic beta cells.

While Melton's focus on pancreatic cells won't shift, he says the approach certainly raises the question of how many genes it would take to go from one cell to a completely different type of cell. His guess is that scientists might find motor neurons to be a relatively simple target, which could result in advances for diseases like ALS. "I don't think it should be all that hard to try it right away with cells in the nervous lineage," Melton says.

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