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November 5, 1998

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Hopkins Research Team Cultures Long-Awaited Human Embryonic Stem Cells

A team of scientists has isolated and identified human stem cells and proved them capable of forming the fundamental tissues that give rise to distinct human cells such as muscle, bone and nerve. This feat has for decades been one of basic science's holy grails, and while scientists have found stem cells in mice and higher animals, this is believed to be the first time researchers have cultured human embryonic stem cells.

"The potential of these unique, versatile cells for human biologic studies and medicine is enormous," says John Gearhart, Ph.D., a professor of obstetrics/gynecology and of physiology who led the mostly Johns Hopkins research team. "These cells will rapidly let us study human processes in a way we couldn't before. Instead of having to rely on mice or other substitutes for human tissues, we'll have a unique resource that we can start applying to medicine."

The Hopkins research is reported in this month's Proceedings of the National Academy of Sciences. A related success, but one reached by a different path, is described by a University of Wisconsin team in a study in this week's Science. (The Science issue includes a commentary by Gearhart.)

The key to stem cells' importance rests in their lack of specialization. They're basic cells present in the earliest stages of developing embryos. They spark all the types of cells in a developing organism, while they themselves keep the ability to reproduce continuously.

"Not only should scientists be able to generate specific nerve, muscle, skin or other cells for transplantation, but we should also be able to alter these cells, as has been done in mouse studies, to reduce the likelihood of rejection. We could make universal donors. More specific cells could become transplant therapies for diabetes, spinal cord injury, neurodegenerative disorders like Parkinson's disease, muscular dystrophies, atherosclerosis and wound healing," says Gearhart. Stem cells could prove valuable in studies on birth defects, pregnancy loss and cancer biology by revealing which genes play a role, using a system that's uniquely human and easy to study.

In the Hopkins research, the scientists searched small samples of non-living, human fetal tissue to find what they call primordial germ cells (PGC) cells that eventually would have become eggs and sperm. The single PGCs were placed on a "feeder layer" of mouse connective tissue cells, surrounded by a broth of nutrients and highly specialized growth factors. That provided support and other requirements for the PGCs to develop. "Hitting just the right elements to culture these cells was no simple matter," says Michael Shamblott, Ph.D., a researcher on the project. "We built on earlier mouse studies, trying to do just enough to let the cells develop without going too far and becoming specialized."

Under the right conditions, PGCs develop into a tightly knit cluster of true stem cells. These "pluripotent stem cells," as they're called, met a stem cell ID checklist as part of the study: They displayed various cell surface markers characteristic of stem cells, contained complete sets of normal chromosomes and produced enzymes typical of stem cells. The cells are also capable of many cell divisions.

"But the gold standard," says Shamblott, "was seeing if the cells have true potential if they'd develop into the three basic layers of cells found in all mammalian embryos. And ours did." The pluripotent stem cells sporadically gave rise to small, eighth-inch knots of slightly more advanced tissue. Immunochemical and other tests confirmed that the three layers were there.

"Stem cells aren't useful by themselves," says Shamblott. Their most immediate value, he says, will likely come in the form of tissues clinicians can transplant therapeutically to replace diseased or dying cells. The first step for that, Shamblott says, is learning how to spark the next level of stem cells those with a more narrow mission. Such "lineage restricted stem cells" trigger blood formation, for example. Another line would generate muscle cells.

Other researchers in the study were John Littlefield, M.D., Paul Blumenthal, M.D., and George Huggins, M.D. Peter Donovan of the Kimmel Cancer Institute, Jefferson Medical College in Philadelphia also was on the research team.

Geron, Inc., of Menlo Park, Calif., provided funding for the study described in this release. Under a licensing agreement between Geron and the Johns Hopkins University, Dr. Gearhart is entitled to a share of sales royalty received by the University from sales of the technology described in this release. Both the University and Dr. Gearhart own stock in Geron, the sale of which is subject to certain restrictions under University policy. Dr. Gearhart is also a consultant to Geron. The terms of this arrangement are being managed by the University in accordance with its conflict of interest policies.

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