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Embryonic stem (ES) cells — undifferentiated cells in early embryos that have the ability to form practically any cell type — are present transiently during embryogenesis. Because of their broad developmental potential, researchers knew that such cells could provide a wealth of information about early mammalian development. The problem was how to establish progressively growing cultures of these cells in vitro.

Until the 1980s, attempts to obtain such cultures directly from embryos were unsuccessful, and researchers instead studied related cells that were obtained from teratocarcinomas. These tumours arise when normal 1–7.5-day-old mouse embryos are transplanted to an extra-uterine site. Work with teratocarcinoma stem-cell lines provided information on the culture conditions that are suitable for growing pluripotent cells derived from embryos, albeit indirectly.

However, a breakthrough came in 1981, when two independent labs reported the establishment of pluripotent ES cell lines directly from mouse embryos.

Cells from late pre-implantation-stage embryos (blastocysts) seemed likely to give rise to pluripotent cells in culture, but such embryos contain only a small number of cells. In Nature, Martin Evans and Matt Kaufman showed that, by delaying implantation, they could obtain slightly enlarged mouse blastocysts, and that cells from these blastocysts could be used to establish ES cell cultures. These cultured cells were capable of differentiating in vitro and in vivo.

Reporting in Proceedings of the National Academy of Sciences, Gail Martin used a different approach that avoided in vivo alteration. She reasoned that an ES cell line might be obtained by culturing cells isolated from blastocysts in a medium that had previously been conditioned by an established teratocarcinoma stem-cell line (such a medium might contain a factor that stimulates ES-cell proliferation and/or suppresses their differentiation). Using this approach, she established a cell line directly from normal pre-implantation mouse embryos and confirmed its pluripotency by showing that individual cells of this line could differentiate to form a wide variety of cell types in vitro and in vivo.

These papers made it possible to obtain pluripotent ES cells directly from embyros, including strains that carried interesting mutations. They also provided a method to generate “...new, genetically marked pluripotent cell lines that can be used for studying various aspects of early mammalian development”.

A further breakthrough came in 1998, when, in Science, James Thomson et al. reported the derivation of ES cell lines directly from human blastocysts. After 4–5 months of undifferentiated proliferation in vitro, these cells could still differentiate to form various cell types. Such cell lines will be invaluable to the study of human developmental biology and — once this development is more fully understood — for the generation of specific cell types for transplantation and drug-discovery research. As these authors commented, “Progress in basic developmental biology is now extremely rapid; human ES cells will link this progress even more closely to the prevention and treatment of human disease”.