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  • Review Article
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Embryonic stem cells in drug discovery

Nature Reviews Drug Discovery volume 3, pages 70–80 (2004)Cite this article

Key Points

  • In the highly competitive industry of drug discovery, pharmaceutical and biotechnology companies must rely on improved high throughput technologies to advance programs from target confidence to pre-clinical evaluation.

  • Embryonic stem cells have recently become highly visible with the identification of pluripotent cell lines derived from human blastocysts or primordial germ cells. Much of the focus of these cells has centered on future opportunities in regenerative medicine, with less emphasis on the near term opportunities in cell-based systems across the drug discovery timeline.

  • Mouse embryonic stem cells have been used extensively over the last 10-15 years by drug discoverers in the development of genetically modified mice for target validation, target selectivity, model development and toxicity evaluation.

  • Advances in the isolation and purification of in vitro differentiated murine ES cells combined with highly sophisticated methods of genetic engineering have afforded opportunities in drug discovery directly in murine ES cells. The strength of an ES cell in vitro approach is time to delivery of results, cost an

Abstract

The completed sequencing of the human genome has identified numerous potential drug targets, which are expected to deliver the next generation of new medicines. However, for drug companies to realize this opportunity, they must rely on improved prognostic applications of high-throughput technologies, from target identification to preclinical compound evaluation. Reducing the timelines and attrition rate of new therapeutics for clinical evaluation requires cell-based methods for testing the efficacy and safety of new compounds. Drug discoverers are beginning to use stem cells as a new resource for increasing confidence in the mechanism of action of new targets and the safety of modulating their activity.

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Figure 1: Applications of stem-cell technology in drug discovery.
Figure 2: ES cell differentiation potential.
Figure 3: Strategies to derive purified populations of in vitro differentiated ES cells.
Figure 4: Growth and delivery of ES cells and derivatives for use in drug discovery applications.

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Acknowledgements

The author acknowledges the contributions of G. Cezar, K. Haskell, M. Roach with figures, J. Hambor and K. Neote in generating Box 1, P. Vickers for critically reading of the manuscript and T. Kelleher for encouragement. Finally without the love and support of my family this manuscript would not have been possible.

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  1. Genetic Technologies, Pfizer Global Research and Development, Groton, 06340, Connecticut, USA

    John McNeish

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DATABASES

LocusLink

CCR2

glucagon receptor

LIF

MEKK1

Myf5

NANOG

nestin

p50

p105

PAX4

POUSF1

RelA

WNK1

FURTHER INFORMATION

Online Mendelian Inheritance in Man

Alzheimer's disease

Parkinson's disease

National Institutes of Health Stem Cell Information

Glossary

TARGET

Gene product that therapeutic approaches are directed against in the search for new medicines.

EMBRYONIC STEM CELLS

(ES). Undifferentiated cells typically derived from the inner cell mass of a blastocyst-stage embryo. In culture, these cells can self-renew in the undifferentiated state or reveal their pluripotentcy on differentiation into cell types of the three embryonic germ lineages. Mouse ES cells readily differentiate into all somatic and germ lineages when incorporated into chimeric offspring through blastocyst microinjection or morula aggregation.

KNOCKOUT MICE

Mice derived from gene-targeting experiments in ES cells with mutations in selected genes that result in the complete ablation of gene expression. These induced mutations are passed through the germline, allowing the derivation of novel lines of gene KO mice for functional evaluation in vivo.

HOMOLOGOUS RECOMBINATION

Genetic recombination between identical (or nearly identical) double-stranded DNA sequences. This process occurs at a relatively high frequency in ES cells, allowing the engineering of gene-targeting vectors to direct pre-planned mutagenesis in ES cells.

DIFFERENTIATION

Process in which a cell progresses in a linear manner to a specialized state. Stem cells can develop into any specialized cell type – for example, neuronal, muscle, hepatic and haematopoietic cells.

EMBRYOID BODIES

Spherical cell clusters observed after spontaneous or induced differentiation of ES cells in culture: Embryoid bodies show differentiation that recapitulates the early stages of mammalian embryonic development, including cell types derived from endoderm, mesoderm and ectodermal lineages.

PLURIPOTENT

The ability to differentiate into all cell types derived from the three embryonic germ lineages: ectoderm, mesoderm and endoderm.

ANEUPLOID

Cells with abnormal number of chromosome sets.

TERATOMA

A rare tumour type that typically arises in the gonads and demonstrates mixed cellular populations of all three embryonic germ layers. Investigators can assess the differentiation capacity of stem cells by injection of pluripotent cells into laboratory animals and inducing the formation of teratomas in situ.

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McNeish, J. Embryonic stem cells in drug discovery. Nat Rev Drug Discov 3, 70–80 (2004). https://doi.org/10.1038/nrd1281

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