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A New Way to Make Stem Cells

Using RNA instead of DNA could avoid the health risks–and the political pitfalls–of stem-cell treatments.
October 1, 2010

A Harvard researcher has developed a way to make pluripotent stem cells that solves several of the major impediments to using them to treat human diseases.

New cell: This microscope image shows neurons (colored green) created from pluripotent stem cells using modified RNA.

Derrick Rossi, an assistant professor at Harvard Medical School, created pluripotent stem cells–which can turn into virtually any other type of cell in the body–from non-stem cells without using viruses to tinker with a cell’s genome, as conventional methods do. This means that Rossi’s method could be substantially safer for treating disease. The work is published today in the journal Cell Stem Cell.

“Rossi has figured out how to turn a skin cell into a stem cell without genetic modifications, and to do it efficiently,” said Doug Melton, codirector of the Harvard Stem Cell Institute, where Rossi is a principal faculty member, at a press conference.

Rossi’s innovation, which has not yet been tested in people, was to use messenger RNA instead of DNA to produce the four proteins needed to reprogram the cell. He has started a company called ModeRNA to commercialize this use of messenger RNA. He said the approach may also have potential in gene therapy, which also relies on viruses to deliver treatment, but he declined to talk further about the company or possible gene therapy applications because the work is at such an early stage.

Improving the usability of man-made stem cells is key to helping patients and ending the political morass that has slowed stem-cell research. On Tuesday, a U.S. federal appeals court allowed federal funding of embryonic stem-cell research to continue while a legal case against such funding proceeds.

The human embryonic stem cells used in research were mostly derived from embryonic tissue grown a decade ago. These are the most versatile cells in the body, and the gold standard by which man-made cells are judged.

Four years ago, Japanese researcher Shinya Yamanaka showed that regular cells could be turned into embryonic-like stem cells–called induced pluripotent stem (iPS) cells–through the introduction of four specific proteins. Theoretically, this meant that doctors could take skin cells from a sick or disabled person, transform them into stem cells, and then into a specialized cell to treat them–an insulin-producing islet cell for someone with diabetes or a nerve cell for someone who is paralyzed, for instance. Using iPS cells avoids the need to destroy embryos and, because they can be derived from the patient’s own cells, means less risk of rejection.

But only one in 1,000 or one in 10,000 skin cells could be transformed into a stem cell using Yamanaka’s method. It also changes a cell’s genes in ways that might trigger cancer or other problems.

Rossi ‘s idea was to produce Yamanaka’s four proteins in a different way. Instead of using the DNA that holds the instructions for making proteins, he wanted to use RNA, which carries those instructions to the place in a cell where proteins are made.

His first several attempts were miserable failures. When he tried to change the messages the RNA carried, he triggered a serious immune response and most of the cells shut down or self-destructed. Rossi then tried modifying the RNA chemically and eventually figured out a way to allow his changes to escape immune detection while delivering the message. “This was key to our success,” said Rossi, who is also a researcher at Children’s Hospital Boston. “We could encode RNA for any protein we wanted to express and insert it into a cell.”

Rossi said it was a happy coincidence that using RNA instead of changing the DNA was as much as 100-fold more efficient. He said the effect was possibly because the process more closely reflects how cells themselves transform.

Rossi successfully differentiated his stem cells into muscle cells using RNA, a process that may offer promise in gene therapy and other treatments. His method does not alter the cell’s underlying genome, though Rossi admits that he does not yet understand what it does to the cell’s epigenome, which controls expression of genes.

Rossi said that his cells, which he’s named RiPS, for “RNA induced Pluripotent Stem” cells, are more like embryonic stem cells than traditional iPS cells because they have not been genetically altered.

Melton said the Harvard Stem Cell Institute, which includes several hundred stem-cell researchers from across Harvard University and its affiliated hospitals, will now be making its standard iPS cells with Rossi’s method.

In a prepared statement, Yamanaka, now at the University of California, San Francisco, said Rossi’s approach to generating stem cells seems promising, and he would like to have someone in his lab try it.

“The quality of the induced pluripotent stem cells generated by this method should be carefully examined because their characteristics vary depending on the induction methods and the origins of the resulting cells,” he said. “The standard method to generate iPSCs for clinical applications has yet to be established. I think this method has the potential for it.”

Jacob Hanna, a postdoctoral fellow at the Whitehead Institute for Biomedical Research in Cambridge, said he’s also eager to begin working with the cells.

“I think it’s a very exciting paper with a very promising method,” said Hanna, who was not involved in the research. When asked if he was jealous that Rossi had developed the method first, Hanna said, “Yes, of course! It’s a very nice paper,” quickly adding, “Jealous in a very positive and supporting way.”

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