Skin cell is made to mimic stem cell

Times Staff Writer

Scientists have succeeded in reprogramming ordinary cells from the tips of mouse tails and rewinding their developmental clocks so they are virtually indistinguishable from embryonic stem cells, according to studies published today.

If the discovery applies to human cells -- and researchers are optimistic that it will -- it would offer a straightforward method for creating a limitless supply of cell lines tailor-made for patients without ethical strings attached.

For the record:

12:00 a.m. June 9, 2007 For The Record
Los Angeles Times Saturday June 09, 2007 Home Edition Main News Part A Page 2 National Desk 1 inches; 37 words Type of Material: Correction
Stem cell research: A graphic in Thursday’s Section A accompanying an article about mouse tail cells reprogrammed to mimic stem cells labeled a part of a cell as the cell wall. That component is the cell membrane.

The studies were hailed by scientists and social conservatives, who have frequently clashed over the morality of embryonic stem cell research.


“This would be a win for science, ethics and society,” said Richard M. Doerflinger of the Pro-Life Activities department of the U.S. Conference of Catholic Bishops in Washington, D.C. “It may offer a way for people of all faiths and all ethical backgrounds to study, use, subsidize and enjoy any therapeutic benefits of ... stem cell research.”

Three research groups said they accomplished their feat in mature cells by turning on four genes that are always active in days-old embryos. Some of the rejuvenated cells grew into new mice, demonstrating the cells’ ability to create every type of tissue in the body.

“This is truly the Holy Grail -- to be able to take a few cells from a patient, say a cheek swab or some skin cells, and turn them into stem cells in the laboratory,” said Dr. Robert Lanza, an embryonic stem cell researcher and head of scientific development at Advanced Cell Technology Inc. in Worcester, Mass., who was not involved in the research. “It would be like turning lead into gold.”

MIT biologist Rudolf Jaenisch, who worked on two of the studies, said there were still “lots and lots of technical hurdles to overcome.” Some of the thorniest problems might take years to resolve despite the fact that mice and humans share many fundamental aspects of cell biology.

But if those hurdles are cleared, reprogrammed cells could become the long-sought substitute for embryonic stem cells, which are at the heart of the nascent field of regenerative medicine.

President Bush and other social conservatives have long opposed human embryonic stem cell research because the cells can be obtained only by destroying embryos.

Government funding of such research is a top political issue in Washington, where the House is scheduled to vote on the issue today.

Reprogrammed cells could allow scientists to sidestep the ethical dilemmas surrounding an area of research known as therapeutic cloning, in which scientists seek to create a human embryo that is genetically identical to a sick patient by inserting the patient’s DNA in an unfertilized egg.

The resulting stem cells harvested from the embryo could theoretically be used to generate neurons for patients with Parkinson’s disease or insulin-producing cells for diabetics without running the risk of tissue rejection.

Stem cells derived from reprogrammed cells would allow scientists to create genetically matched tissues without having to create and destroy a cloned embryo.

They also would eliminate the need to harvest human eggs, a procedure fraught with risk for donors.

“This would be an exciting discovery,” said Nicanor Austriaco, a Dominican friar and molecular biologist at Providence College in Rhode Island, who was not involved in the research. “In a sense, they make the arguments for therapeutic cloning moot.”

The notion of turning back the clock on adult cells has long intrigued scientists and ethicists. A white paper issued by the President’s Council on Bioethics in 2005 eagerly anticipated such a discovery.

Japanese researchers made substantial progress last year, publishing an influential study in which cells from the tails of adult mice were reprogrammed to become “pluripotent” -- able to grow into many kinds of tissues.

“Nobody believed it,” said Kathrin Plath, a researcher with the Institute for Stem Cell Biology and Medicine at UCLA who set out to replicate the findings with colleagues at UCLA, Harvard and MIT.

The Kyoto University researchers found they could prompt the cells’ transformation by turning on genes that produce four key proteins -- Oct4, Sox2, c-Myc and Klf4 -- related to cellular development. They accomplished that by using a disabled virus that inserted itself into the cell with new genetic instructions.

Some of the resulting cells had reversed their development toward an embryonic stage, but not far enough to behave like stem cells.

In one of the new studies, published in the journal Nature, the Japanese scientists modified their procedures and succeeded. When the resulting cells -- which they dubbed induced pluripotent stem cells, or iPS cells -- were injected into mouse embryos, they contributed to the development of all parts of the animals.

Some of their offspring also inherited genes from the iPS cells. Senior author Dr. Shinya Yamanaka, from Kyoto University’s stem cell biology department, said that genetic inheritance was an important sign because only cells that behave like embryonic stem cells can be passed from parent to child.

Meanwhile, Plath’s group tweaked the Japanese researchers’ recipe and found additional evidence of their finding. The study by Plath’s team was published in the journal Cell Stem Cell.

Female cells contain two copies of the X chromosome, and one of them is silenced as part of normal development. Plath and her colleagues surmised that if a female cell were truly reprogrammed to an embryonic state, both X chromosomes should be active. They were.

The team also studied the pattern of genes that were turned on and off in the reprogrammed cells and embryonic stem cells and found the patterns were nearly identical.

“We were very surprised that it’s so perfect,” Plath said.

The third group, headed by Jaenisch at the Whitehead Institute for Biomedical Research in Cambridge, Mass., injected mouse embryos with iPS cells and tagged some of the genes. Then they bred the resulting pups with other mice.

The researchers figured that if the tagged genes were functioning like embryonic stem cells, the offspring had a 50-50 chance of inheriting them.

It turned out that five out of nine animals had inherited the reprogrammed cells in their bodies, according to a study in Nature. “We would expect 50% to have it and 50% would not, and that’s exactly what we got,” Jaenisch said.

The researchers then injected the cells into embryos that had four sets of chromosomes instead of the usual two. Such embryos die early in a pregnancy, but in the experiments, the reprogrammed cells took over and allowed the embryos to develop at least halfway through gestation before the researchers killed them to study them.

That test proved the cells could create an entire organism, said Jaenisch, who added that the team had to publish its research and didn’t have time to wait for the embryos to make it all the way to birth.

Now some of the scientists are turning their attention to human cells.

Plath said it could take as little as two months to reprogram cells from people, but others said it could take years or even decades.

The process will have to be modified to create cells that could ultimately be used as therapies.

One concern is that if the reprogrammed cells grew into tissues that were transplanted into a patient, the virus used to turn on the four key genes might pose a health risk, several scientists said.

Another is that one of the four key proteins, c-Myc, has a tendency to cause tumors. More than 10% of the mice in the latest Japanese study developed tumors that were attributed to the protein.

Paul J. Simmons, director of the Center for Stem Cell Biology at the University of Texas Health Science Center in Houston, said scientists would look for ways to reprogram human cells without using c-Myc or disabled viruses.

In the meantime, however, researchers could use the cell lines to study diseases in the lab.

“This technology isn’t simply for therapeutic purposes,” Simmons said. “The major use will be in creating cell line models of complex diseases that we don’t really understand.”

The studies were funded by government agencies and private foundations in the United States and Japan.