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Scripps strips oncogenes from stem cell reprogramming
12-17-2010
by Lloyd Dunlap  |  Email the author
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LA JOLLA, Calif.—Scripps Research Institute scientists have made significant progress in the drive to find a way to safely reprogram mature human cells and turn them into stem cells, with potentially profound implications for treating many diseases and injuries.

In research published in the Dec. 3 issue of Cell Stem Cell, Dr. Sheng Ding, a Scripps Research associate professor, reports about a novel cocktail of drug-like small molecules that, with the assistance of a gene called Oct4, enables reprogramming of human skin cells into stem cells.
 
"Our ultimate goal is to generate induced pluripotent stem (iPS) cells with defined small molecules," Ding says. "This would offer a fundamentally new method and significant advantages over previous methods, such as genetic manipulation or more difficult-to-manufacture biologics. There are many concerns when the host cell's genome is manipulated. One major worry is that since the four genes are cancer-causing oncogenes, they could induce tumors or interrupt functions of other normal genes."

Because of this danger, scientists have been searching for methods that could induce reprogramming without the use of potentially cancer-causing genes. The method the Ding lab has been pioneering— using small, synthetic molecules—is said to represent a fundamentally different approach from the previous methods.

Using small-molecule compounds to reprogram adult human cells back to their pluripotent state—able to change into all other cell types—also avoids the ethical controversy around embryonic stem cell research, and could pave the way for the large-scale production of stem cells that could be used inexpensively and consistently in drug development. Cures for Alzheimer's, Parkinson's, and many other diseases might be possible if new cells could be created from a patient's own cells to replace those that have succumbed to disease or injury.

Given that the United States is investing billons of dollars in funding stem cell research ($3 billion over 10 years from California's Proposition 71 alone), and other countries such as Japan, Australia and the European Union are also major players, it would be surprising if Scripps were alone in investigating small molecules to replace genetic manipulation. In fact, as has been previously reported, Stemgent and Miltenyi Biotec are collaborating on a process to dispense with some of the four genes originally thought to be required for iPS cell generation. Several alternative defined conditions are capable of improving efficiency and kinetics, generating more homogeneous iPS populations. These defined conditions are now made possible with the use of various combinations of Stemgent small molecules affecting reprogramming, self-renewal and differentiation, the company states.

In 2008, the Ding lab reported finding small molecules that could replace two of the required four genes. Now, two years later, the lab has found a way to replace the third gene, with only Oct4 still actively in the mix. A future goal is to replace Oct4, believed to be a master regulator of pluripotency, in the chemical cocktail.  "That would be the last step toward achieving the Holy Grail," Ding says. "Our latest discovery brings us one step closer to this dream. "

 
Code: E12201004

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