Refining Ways to Turn Adult Cells Back into Stem Cells

Cells are being given a new lease on life. They are effectively being pushed back in time, forgetting their lives as they were first lived and growing up again with a brand new identity.

Scientists at the Harvard Stem Cell Institute are now refining this process for re-creating stem cells which, once perfected, could help cure diseases or even regrow and repair body parts. Moreover, the new technique could avoid the political controversy associated with other types of stem cells.

Embryonic cells have gotten the most attention within the family of stem cells. As their name implies, these cells come from an unborn fetus, and this issue has been tied in tightly with the anti-abortion movement. In the early days of a fetus, stem cells have a spectrum of possibilities—the potential to become any body part.

“I think the only reason you’d heard of embryonic stem cells is because of the political controversy,” says Willy Lensch of the Harvard Stem Cell Institute.

The Dickey-Wicker Amendment was first passed in 1996, banning the use of human embryos for cell research. Since then, federal funding for embryonic cell research has been a hot and cold issue, with political policies shifting with party power. In 2009, President Obama re-approved federal funding, but that allowance was then revoked and has since see-sawed back and forth during long months of litigation.

But embryos are not the only stem-cell source. The term “stem cell” refers to the capacity for creating any other type of cell. “Stem cell is just a function,” says Lensch. Tissue-specific stem cells exist in all bodies. These “adult stem cells” have been used for bone marrow transplants for decades. More recently, however, scientists have turned back the clock on fully formed cells, manually pushing them back to their stem state.

These Benjamin Button cells are called “induced pluripotent” stem cells. In other words, scientists force (induce) the cells back to a state in which they have multiple (pluri) future possibilities (potency).

“What’s the difference between embryonic stem cells and blood cells? Gene expression,” says Lensch. Genes active in stem cells are different than those in their fully formed final destination. To create stem cells, researchers need to inactivate genes that tell a cell to be blood, for example, and then trigger genes that make its future more plastic.

This is just what Japanese scientist Shinya Yamanaka announced in 2006. He successfully reverted mouse skin cells by forcing the expression of four specific genes. Yamanaka transported these genes via a virus to the cell, which then took over the cell’s original function, essentially changing them back to infants.

This achievement was lauded throughout the stem cell world, but it was not without its problems. The virus used as a transport mechanism was feared to cause certain types of tumors. It was also about 0.02 percent effective—only two cells out of 10 thousand successfully reverted.

Four years later at the Harvard Stem Cell Institute, researchers seemed to have found a way to address these issues. The group, led by Derrick Rossi, used a simplified type of DNA adept at delivering messages to cells. Called messenger RNA, it copies DNA and reads it back to proteins in the cell. Using the RNA commands, proteins turn genes in the cell on and off, effectively changing the adult cell to a stem cell.

Rossi and his team use the RNA to tell the proteins to turn on the four genes that give stem cells their incredible flexibility. Because no viruses are introduced, the cancer danger is removed. And it’s about 100 times more efficient—at about 2 percent, or two hundred in 10 thousand.

Jacob Hanna, Genzyme postdoctoral fellow at MIT’s Whitehead Institute, is cautiously optimistic. “It looks very, very exciting; however you want to wait to see if other people can reproduce it,” he says. Further studies will indicate whether or not this method is as consistently effective as reported in the paper, published in Cell: Stem Cell in early November. “Like most things, time will tell,” he says.

Inducing pluripotency is only the first step, however. The next challenge, for embryonic and reverted cell researchers alike, is pushing the stem cell back into a fully formed state. And this process has difficulties of its own.

“I think of it as a problem of information theory,” says Lensch. The human body on a molecular level is still relatively mysterious to scientists, so they are unsure exactly what genes need to be expressed to form which cells. Organs are complex, and researchers are still figuring out exactly how to push the stem cells forward to fill the nuances of the cells they are replacing. Tedious experiments are underway to uncover the right gene combinations.

There are reverted-cell specific problems, as well. Embryonic stem cells are easy to grow in a Petri dish and they can become anything. Reverted cells also have both attributes, to a point. They grow relatively easily, but they are not always as effective at differentiating into new cells.

Embryonic stem cells were only ever one thing—four genes that can become everything and anything. But the time-traveling cells still have an echo of memory of what they once were. “Blood remembers what it was,” says Lensch. A former blood cell, for example, while still able to form any other type of cell, will be a more efficient producer of blood cells. The same goes for nerve, skin, or any other type of cell. Researchers don’t see any detectable difference between, say, a reverted blood and nerve cell, but that memory must be stored somewhere. Work is being done in attempts to identify and overcome the reasons for this inefficiency.

Using this new method would avoid more than the political difficulties of embryonic cells. Instead of being pulled from a foreign body, reverted cells would be taken from the recipient’s self, so he or she would not need to contend with anti-rejection drugs. On the research side, doctors will be able to monitor the progression of certain diseases and conditions, such as Parkinson’s disease or Down’s syndrome, within the cells to figure how they can be better treated.

David Jones, a science historian, Harvard medical school graduate, and professor of Science, Technology and Society at MIT, is skeptical that stem cell applications will reach the predicted cure-all outcomes. “They’ve made a lot of claims and have very little to show for it,” he points out. “They say it will take five to ten years…they’ve been saying that for a while.” He is wary of premature applications of reverted cells to clinical trials, and many researchers share his concerns.

“If one of [the cells] is stubborn and says ‘I want to stay [a reverted] cell,’ that’s a problem,” says Lensch.

“I’m always afraid that rushing and trying too fast will…have a backlash on the rest of the field,” notes Hanna. Human trials are a way off, with researchers focusing on improving the procedure in experimental animals first.

Andre Terzic, head of regenerative medicine at the Mayo Clinic in Rochester, Minnesota, shares these sentiments and is happy to be a part of the international push for improvements of these methods.

“It’s no longer […] pure science fiction,” he says. Terzic’s work has given him experience with all types of stem cells—embryonic, adult, and time-travelers. “There is such a hope that technologies will really provide a means to get to the root cause of a problem […] not just palliate symptoms of a disease, but to cure it.”

This post first appeared on MIT Scope in January 2011