Scientists unveil new step in less-controversial stem-cell efforts

MILWAUKEE — By fusing mouse and human cells, scientists at Stanford
have uncovered part of the mechanism involved in reprogramming skin
cells back to their embryonic origin, and in doing so have shed light
on the critical role played by a protein.

In a paper published this week in Nature, the
researchers explained that they fused mouse embryonic stem cells to the
cells in human connective tissue and achieved reprogramming far more
rapidly and efficiently than had been done previously.

The new work allows scientists to begin
understanding the crucial “how” of a revolution in cell biology
launched in 2006 when Japanese scientist Shinya Yamanaka reprogrammed mouse cells. That breakthrough, which raised the
possibility of creating embryonic stem cells that would not set off an
ethical debate, was extended a year later when human cells were
reprogrammed by Yamanaka in Japan and James Thomson at the University of Wisconsin-Madison.

Yamanaka and Thomson induced ordinary skin cells to
return to their embryonic origin by inserting different four-gene
combinations into the cells.

“It’s sort of a mystery. You put in four factors.
You wait two to three weeks. And .1 percent of the cells are
reprogrammed,” explained Helen M. Blau, director of the Baxter Laboratory for Stem Cell Biology at Stanford University School of Medicine. “It’s amazing that it works but there’s something missing that we don’t understand.”

The small number of reprogrammed cells returns to
the embryonic state and regain the ability to become any cell in the
body, a power that scientists call pluripotency.

“This provides the first real insight into the mechanism of how these cells become pluripotent,” Stephen Duncan, a stem cell scientist at the Medical College of Wisconsin, said of the Nature paper. “From a science perspective, it’s a really nice piece of work.”

Fusing cells from different species allowed
scientists to identify which proteins were made by human cells and
which by mouse cells and therefore to determine that the human cell was
reprogrammed.

Moreover, the experiment pulled back the curtain on
another aspect of reprogramming, a process called demethylation. To
understand the process, imagine traffic lights in a city. Strands of
DNA contain methylation marks, which prevent genes from being turned
on. It is as if all of the traffic in a city had been halted by a
perpetual red light. The red light keeps the cell frozen in one
identity — a bit of blood, or skin, or nerve.

The Nature paper shows that once methylation marks
have been established they can still be removed, allowing the red light
to switch to green. A green light frees the cell to move toward
pluripotency, to that embryonic state when anything is possible.

The Stanford scientists found that a
protein called AID, or activation-induced cytidine deaminase, is
involved in the process of demethylation. Previously the protein had
been known mostly for its role in generating antibodies for the immune
system.

“We found a whole new function for it,” Blau said, describing the protein as “a critical component in DNA demethylation.

When the Stanford team fused the human
and mouse cells, 70 percent switched on the crucial genes that confer
the power of an embryonic stem cell. And it did not take weeks, as
other methods have, but rather, days.

Blau called the method “a powerful system” for examining how the reprogramming of cells works.