Abstract
Predicting the behavior of living organisms is an enormous challenge given their vast complexity. Efforts to model biological systems require large datasets generated by physical binding experiments and perturbation studies. Genetic perturbations have proven important and are greatly facilitated by the advent of comprehensive mutant libraries in model organisms. Small-molecule chemical perturbagens provide a complementary approach, especially for systems that lack mutant libraries, and can easily probe the function of essential genes. Though single chemical or genetic perturbations provide crucial information associating individual components (for example, genes, proteins or small molecules) with pathways or phenotypes, functional relationships between pathways and modules of components are most effectively obtained from combined perturbation experiments. Here we review the current state of and discuss some future directions for 'combination chemical genetics', the systematic application of multiple chemical or mixed chemical and genetic perturbations, both to gain insight into biological systems and to facilitate medical discoveries.
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Acknowledgements
B.R.S. is supported by a Beckman Young Investigator Award from the Arnold and Mabel Beckman Foundation and by the NIH (CA097061 and GM085081). C.N. and G.G. are supported by the Canadian Institutes of Health Research (CIHR MOP-81340 and CIHR MOP-84305, respectively).
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J.L. is employed by and has a significant number of options in CombinatoRx, which is engaged in combination chemical genetics as described. B.R.S. is a founder of and holds significant shares in CombinatoRx.
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Lehár, J., Stockwell, B., Giaever, G. et al. Combination chemical genetics. Nat Chem Biol 4, 674–681 (2008). https://doi.org/10.1038/nchembio.120
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DOI: https://doi.org/10.1038/nchembio.120
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