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"Magical state" of embryonic stem cells may help overcome hurdles to therapeutics

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Red fluorescent "reporter" molecules indicate that these early embryonic cells are exhibiting genetic activity.

With their potential to treat a wide range of diseases and uncover fundamental processes that lead to those diseases, embryonic stem (ES) cells hold great promise for biomedical science. A number of hurdles, both scientific and non-scientific, however, have precluded scientists from reaching the holy grail of using these special cells to treat heart disease, diabetes, Alzheimer's and other diseases.

In a paper published in Nature, Salk scientists report discovering that ES cells cycle in and out of a "magical state" in the early stages of embryo development, during which a battery of genes essential for cell potency (the ability of a generic cell to differentiate, or develop, into a cell with specialized functions) is activated. This condition, called totipotency, gives ES cells their unique ability to turn into any cell type in the body, which may make them useful for therapies.

"These findings," says senior author Samuel L. Pfaff, a professor in Salk's Gene Expression Laboratory, "give new insight into the network of genes important to the developmental potential of cells. We've identified a mechanism that resets embryonic stem cells to a more youthful state, where they are more plastic and therefore potentially more useful in therapeutics against disease, injury and aging."

ES cells are like Silly Putty that can be induced, under the right circumstances, to become specialized cells in the body—for example, skin cells or pancreatic cells. In the initial stages of development, when an embryo contains as few as five to eight cells, the stem cells are totipotent and can develop into any cell type.

Pfaff and his colleagues performed RNA sequencing (a new technology derived from genome sequencing to monitor what genes are active) on immature mouse egg cells, called oocytes, and two-cell-stage embryos to identify genes that are turned on just prior to and immediately following fertilization. Pfaff's team discovered a sequence of genes tied to this privileged state of totipotency and noticed that the genes were activated by retroviruses adjacent to the stem cells.

It is too early to tell if this "magical state" is an opportune time to harvest ES cells for therapeutic purposes. But by forcing cells into this privileged status, scientists might be able to identify genes to assist in expanding the types of tissue that can be produced.

"There's tremendous hype over the practical applications of embryonic stem cells in clinical situations," Pfaff says. "The struggle in labs throughout the world is that the smallest changes in environmental conditions could subtly and unpredictably have an effect on these cells. So, the more we know about the basic requirements needed for these cells to be able to generate a full range of tissue types, the better off we'll be."