Unimagined potential. That's how Dr. James Thomson described the impact that human embryonic stem cell research could have on the future of medicine. In 1998, Thomson, a developmental biologist at the University of Wisconsin, was the first to isolate and culture human embryonic stem cells (HESC). He now directs one of three NIGMS-funded exploratory centers for human embryonic stem cell research launched in 2004 to focus on the basic biology of HESC and on training scientists to work with them. Thomson predicts that, much like the dramatic impact of recombinant DNA technology, HESC-based discoveries will revolutionize biomedical research and medicine in ways we can't even foresee.

Thomson made these comments at a recent workshop titled "Human Embryonic Stem

Establishing signatures for human cells at various points in the differentiation process will help scientists better understand how embryonic stem cells become specialized cell types.

Cell Research: Recent Progress and Future Directions of NIGMS Grantees." Participants included scientists from the three HESC centers as well as recipients of individual grants and grant supplements for pursuing HESC research. Central to the meeting's discussions were the basic research questions that must be addressed before the clinical use of HESC. Among these questions are what molecular features characterize stem cells, how genes are regulated in the cells, how best to maintain the cells in their undifferentiated state in the laboratory, and how biochemical pathways signal HESC to differentiate into specialized cell types.

Dr. Meri Firpo of the University of California, San Francisco, and Dr. Carol Ware of the University of Washington described their careful characterization of some of the stem cell lines approved for use in federally funded research and offered guidelines on how best to maintain and propagate them.

Drs. Ali Brivanlou of Rockefeller University and Mark Levenstein of the WiCell Research Institute in Madison, Wisc., described growth factors and natural products that can substitute for the mouse "feeder" cells that are currently used to support the growth of stem cells in the laboratory. Finding an alternative to feeder cells would be a significant breakthrough because these cells can contaminate stem cell cultures, limiting their medical usefulness.

Dr. Ren-He Xu of WiCell described his recipe for turning stem cells into trophoblasts, which comprise a tissue that surrounds the developing embryo and eventually develops into the placenta. Trophoblast development is an important early step in embryonic development, so understanding how the tissue forms from stem cells is of great interest.

One workshop session focused on new technologies to facilitate embryonic stem cell research, including ways to identify genes required for maintaining "stemness" or for differentiation into particular cell types. Dr. Rick Young of the Whitehead Institute for Biomedical Research in Cambridge, Mass., reported on whole-genome analysis of gene activities in HESC, which revealed that master regulators of gene activity in embryonic stem cells work together in a network to bring about gene activity patterns. Young also found that approximately a third of all genes are active in HESC while the remainder are inactive.

Dr. Blake Meyers of the University of Delaware described a technique called massively parallel signal sequencing that he has used for comprehensive analysis of the gene activities of plant cells. The technique yields a gene activity pattern, or signature, for a particular cell type under a specific set of conditions. One of the strengths of the technique is that it can quantitatively analyze the expression of certain genes such as novel genes and non-protein coding genes that cannot be analyzed using other methods. Establishing signatures for human cells at various points in the differentiation process will help scientists better understand how embryonic stem cells become specialized cell types.

Dr. David Russell of the University of Washington described how he made use of viral genome fragments called vectors to target genetic information to embryonic stem cells, while Dr. Natasha Caplen of the National Cancer Institute described her progress in using RNA interference to selectively silence genes. These and other approaches will improve scientists' ability to control stem cell differentiation.

According to Dr. Marion Zatz, chief of the Developmental and Cellular Processes Branch of the NIGMS Division of Genetics and Developmental Biology and the workshop organizer, "The meeting underscored the importance of understanding the basic biology of human embryonic stem cells before embarking on clinical applications. While many hurdles remain, it was gratifying to see how much progress has been made in the few years since NIH funding for stem cell research became available, and how many NIGMS grantees are now engaged in addressing fundamental questions in human embryonic stem cell research. NIGMS's initiatives to stimulate research and training are already yielding valuable knowledge and tools to advance this exciting field."

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