Removing one transcription factor allows others to drive cellular destiny.

In normal nematodes, there's only one ASE neuron (green dot), but researchers have now coaxed other cells to turn into ASE neurons.

Converting one cell type directly into another is a kind of modern-day alchemy, an ultimate goal in biological research. But unlike turning base metals into gold, changing a cell's identity is feasible, new research shows.

While many scientists attempt to convert cell types by beginning with the clean slate of a stem cell, HHMI investigator Oliver Hobert wanted to skip a step and change one cell to another without using stem cells. But in his study organism, the nematode Caenorhabditis elegans, the factors required to produce neurons from stem cells had no effect when expressed in other cell types.

Hobert and his colleagues at the Columbia University College of Physicians and Surgeons hypothesized that the problem wasn't the factors—it was that cells have a protective mechanism in place to prevent reprogramming.

To find the key that makes cells impervious to reprogramming, Hobert's lab group individually blocked expression of different genes in thousands of C. elegans worms and then induced expression of a neuron factor. In one line, which could not make a protein called Lin-53, the germ cells—precursors to sperm and egg cells—changed to neuron cells.

Lin-53 plays a role in controlling gene expression in a cell by altering its chromatin, or DNA packaging. But the protein has never before been linked to the ability to reprogram a cell.

Hobert's team was able to convert the germ cells to three different types of neurons by using different neuron factors. In each case, within 6 hours of receiving the Lin-53 block and a neuron-specific factor, the cell changed its gene expression and underwent morphological changes. The results appeared online in Science on December 9, 2010.

"This is a potential first step toward being able to generate any cell type you want," says Hobert. "By removing Lin-53, we have put a foot in the door to allow other transcription factors to drive cell fate." His team has also found ways to convert skin cells into neurons by removing a separate factor, also involved in chromatin biology. Hobert thinks that each tissue type has its own reprogramming deterrent in place. Releasing these brakes allows cell switching to speed ahead.

Photo: Hobert Lab