A Better Way to Reprogram Cells

Four years ago, scientists took a major step toward overcoming the biggest ethical hurdle in stem cell research. Instead of using cells derived from embryos, researchers found a way to make adult cells behave as though they were embryonic. Simply inserting extra copies of four genes into these cells gave them the power to develop into almost any cell type in the body—a potential boon for studying and ultimately treating a variety of diseases.

But the technique still had some kinks. The reprogrammed cells, known as induced pluripotent stem (iPS) cells, retained copies of the inserted genes, which made them prone to forming tumors and could potentially muck up experimental results. The method was also relatively inefficient. The best strategies reprogrammed only 1 out of 1000 cells exposed to the treatment, and it took more than a month for iPS cells to appear.

Now stem cell researcher Derrick Rossi of Harvard Medical School in Boston and his colleagues have developed a way to reprogram cells using synthetic RNA molecules. The technique makes iPS cells in about half the time of standard methods, they report online today in Cell Stem Cell. And since the RNA quickly breaks down, the reprogrammed cells are genetically identical to the source cells.

RNA is a messenger molecule in the cell's protein-making process. The genetic code for a protein is stored as DNA. To make a protein, the cell first transcribes the DNA code into RNA, which tells the protein-making machinery how to assemble the protein. Usually cells attack foreign RNA with powerful antiviral defenses, but Rossi and his colleagues discovered that by substituting slightly modified versions for two of RNA's classic components, they could make synthetic RNAs that the cell accepted as its own. When they applied a daily cocktail of synthetic RNAs that code for five classic reprogramming genes to connective tissue cells called fibroblasts, the cells were reprogrammed to embryoniclike cells. (Although the viral techniques typically used four genes, the researchers found that five RNAs worked best.)

To the team' surprise, the process took just over 2 weeks and reprogrammed as many as 2% of the cells in the culture dish. That makes it roughly 100 times more efficient than the viral technique and twice as fast. Other researchers have been racing to find nonviral methods to reprogram cells, but most of them have proved less efficient than the classic technique.

The method can also prompt cells to become nonembryonic cell types. By inserting synthetic RNA that codes for a key gene in muscle tissue, for example, the researchers could turn both fibroblasts and RiPS cells into muscle cells.

The team calls its cells RiPS cells, for RNA induced Pluripotent Cells.

"I'm so impressed … that we are going to turn over our entire iPS core to this new method to make stem cells from patients with all sorts of diseases," says stem cell researcher Doug Melton of Harvard's Stem Cell Institute. "It is a major advance."

Rossi says the synthetic RNAs are straightforward to make, so that the technique should be easy for labs to adopt. "If you have basic molecular biology tools, you can make these RNAs," he says.

Justin Ichida, also of the Harvard Stem Cell Institute but not involved in the study, says the technique "will have a huge impact in the near term." It will also help scientists better understand exactly how reprogramming happens, he says. However, he says, he is not giving up his search for a suite of chemicals that can reprogram cells. For researchers who might want to make thousands of iPS cell lines, he says, RNA reprogramming will still be time-consuming and expensive. A chemical cocktail could prove to be even more efficient, he says.

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