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An overview of the process. Note researchers can use any mouse tissue (the blue box) as the starting point for iPS creation. The method features less manipulation, reducing the cancer risk and produces, for the first time genetically identical cells. It also has higher yields.  (Source: Tom DiCesare/Whitehead Institute for Biomedical Research)
Welcome to the stem cell revolution

There has been an ongoing moral debate in the U.S. which has crippled the funding of stem cells and left the future of stem cell research uncertain.  Fortunately, about a year ago, scientists made an exciting breakthrough -- ordinary adult cells in mammals could be reprogrammed with viruses to become pseudo-stem cells.  By eliminating the moral debate, the research reopened the door to one day developing treatments for Parkinson's Disease, Sickle Cell anemia, paralysis, and many other debilitating afflictions.

However, the pseudo-stem cells created from mice skin cells, known as induced pluripotent stem (IPS) stem cells, were not genetically identical like fetal stem cells, and required different methods of triggering for every tissue.  Now scientists with Rudolph Jaenisch's lab at the Whitehead Institute for Biomedical Research have discovered a way to transform any type of tissue into a stem cell and ensure all the produced stem cells are genetically identical.

The transformation is triggered by the simple release of a drug; no additional genetic manipulation is necessary.  Marius Wernig, one of the paper's two lead authors and a postdoctoral researcher at the lab stated, "This technical advancement will allow thousands of identical reprogrammed cells to be used in experiments."

"Using these cells could help define the milestones of how cells are reprogrammed and screen for drug-like molecules that replace the potentially cancer-causing viruses used for reprogramming," added Christopher Lengner, the other lead author and also a postdoctoral researcher at the lab.

Lengner alluded to an important fear with the current method.  Past efforts used viruses to induce the transformation and it was found that the viruses could trigger cancer.  A batch of stem cells could unwittingly contain cancer cells that could do far greater damage to the diseased person's body than the ailment they're being treated for.

While the new research still uses viruses, it is different in two important ways.  First the viruses target a specific spot in the genome.  Past efforts inserted genes anywhere in the genome, raising the likelihood of cancerous mutation.  In the new research, lentiviruses artificial viruses, are used to randomly insert four genes (Oct4, Sox2, c-Myc and Klf4).  All mice cells processed thusly have the same number of viral integrations in the same location within the genome.  This both leads to genetically identical stems cells and cuts the cancer risk.

The second important way the research is different is that in its specificity, researchers can now focus on developing replacement molecules to the viruses, eliminating the cancer threat.  The old research only worked on skin cells, so the focus was on developing different methods that could trigger various tissues to become IPS cells.  The new method can trigger virtually any cell -- including cells from the intestine, brain, muscle, kidney, adrenal gland, and bone marrow -- into becoming an IPS cell.

After the cell is transformed, the cell was further modified to wait to switch on these genes upon a doxycycline trigger.  This allowed researchers to control when they wanted to transform the cells into stem cells, with a simple chemical.  The new method is much more efficient, with yields up from one in a thousand cells to one in twenty.

Jaenisch, who is also a professor of biology at Massachusetts Institute of Technology said, "In experiments, the technique will eliminate many of the reprogramming process's unpredictable variables and simplify enormously the research on the reprogramming mechanism and the screening for virus replacements."

The research can be found here in the July 1, 2008, online issue of Nature Biotechnology.

Funding for the research was provided by the Human Frontiers Science Organization Program, the Ellison Medical Foundation, the Ruth L. Kirschstein National Research Service Award, and the National Institutes of Health.





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