Stem cell superpowers exposed

Conversion factor for adult cells could sidestep cloning controversy.
Biologists say they are close to finding a cellular elixir of youth: a cocktail of proteins that can convert adult cells into embryonic stem cells that are able to grow replacement tissues.

Two studies published in Nature1,2 identify key proteins that endow embryonic stem cells with their coveted abilities to divide again and again, ad infinitum, and to generate all the different tissues in the body.

The papers do not provide a definitive recipe for the sought-after cocktail; either more proteins must be identified or those already known must be mixed in an unknown combination. But if found, this recipe could leapfrog the intense controversy and toil that is currently involved in extracting stem cells from a human embryo, which is destroyed in the process.

Instead, doctors might be able to take a simple biopsy of cells from a patient and reprogramme them, using one set of proteins to first transform them into embryonic stem cells, and then another to coax them into growing new blood, pancreas or other tissue.

"Until a couple of years ago I thought the idea of reprogramming was ridiculous because we had no scientific idea of how to achieve it," says stem cell biologist Austin Smith of Edinburgh University, UK. But now, he says, "it looks really encouraging. We could find a way to do this."

Bye bye, Dolly

When Dolly the sheep was unveiled in 1997, she was living evidence that the DNA in an adult nucleus can be reprogrammed by inserting it into an egg whose own nucleus has been removed. Somehow, the contents of the egg erased the genetic programme stamped on the DNA and established a new programme that could direct the growth of an embryo.

Since then, biologists have been searching for the proteins that drive reprogramming. They now know that cells can also be reprogrammed when they fuse with an embryonic stem (ES) cell. It seems there is something special in both eggs and ES cells that is transferred into adult cells and changes their behaviour.

Smith and his colleagues now show that a central element is a protein called Nanog, which controls other genes and is switched on in tiny growing embryos. They manufactured mouse embryonic stem cells that make four times more Nanog than usual. When fused with cells from the mouse nervous system, the hybrid cells were transformed into ES cells up to 200 times more efficiently than normal. "The result is just spectacular," Smith says.

It shows that Nanog is vital in driving other cells to become ES cells; but Smith says that injecting Nanog alone is not enough. Some other proteins are probably transferred during fusion as well.

A team led by Ihor Lemischka of Princeton University, New Jersey, has developed a way to identify some of these other players. They first screened through most of the known mouse genes for ones that were switched off when embryonic stem cells are transformed into other types of cell. Of the 70 genes they identified, the team then switched off each one individually in embryonic stem cells and examined whether they became other cell types.

Their search threw up Nanog plus a handful of other proteins that each seem to prevent embryonic stem cells from becoming particular tissues. The researchers suspect that some of these proteins, and maybe others, probably work together to reprogramme an adult cell.

The challenge now is to identify those other proteins and how they interact in order to complete the elusive recipe. Lemischka says he has already scaled-up his methods to search out some of these players. "Obviously that's where the field is really headed," he says. "It's a terribly exciting time."

Sources:
Ivanonva N., et al. Nature, doi:10.1038/nature04915 (2006).
Silva J., et al. Nature, doi:10.1038/nature04914 (2006).
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