Technical assessment of the first 20 years of research using mouse embryonic stem cell lines.

This review assesses the effect that mouse embryonic stem (ES) cells have had on biomedical research during the 20 years that followed their isolation in 1981. Notable scientific discoveries enabled by these cell lines--including insights into cell cycle regulation, spatial and temporal relationships during development, and the roles of transcription factors and homeobox genes in developmental pathways--are discussed. The acceleration of basic discovery of gene function and the genetic basis of disease using a breakthrough technology (homologous recombination between modified gene constructs and the ES cell genome) became the principal enabling method to establish transgenic laboratory animals with single targeted genetic change. This review also examines the widespread influence of mouse ES cells as an enabling technology by highlighting their effect on drug development paradigms, directed differentiation to treat specific diseases, nuclear transfer protocols used in cloning, and establishment of methodologies for isolating non-rodent ES cells. This review concludes with a brief analysis of the most influential mouse ES cell lines of the first 20 years as viewed within the twin contexts of human disease application and contributions to the primary literature.