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Accelerated discovery via a whole-cell model

Abstract

To test the promise of whole-cell modeling to facilitate scientific inquiry, we compared growth rates simulated in a whole-cell model with experimental measurements for all viable single-gene disruption Mycoplasma genitalium strains. Discrepancies between simulations and experiments led to predictions about kinetic parameters of specific enzymes that we subsequently validated. These findings represent, to our knowledge, the first application of whole-cell modeling to accelerate biological discovery.

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Figure 1: Model-driven discovery and the quantitative prediction of growth phenotypes.
Figure 2: The whole-cell model quantitatively predicts rate constants of metabolic reactions.
Figure 3: Model-driven discovery.

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Acknowledgements

We acknowledge support from: an US National Institutes of Health Pioneer Award (5DP1LM01150-05) and an Allen Distinguished Investigator Award to M.W.C.; Siebel Scholars, US National Science Foundation and Stanford University Bio-X Fellowships to J.C.S.; an European Molecular Biology Organization Fellowship (ALTF1371-2011) to S.R.; US National Defense Science and Engineering Graduate Fellowship, US National Science Foundation fellowship, and Stanford Graduate Fellowship to J.R.K.; and Weiland and Rensselaer Engineering Fellowships to M.V.G.

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Authors and Affiliations

Authors

Contributions

J.C.S., J.R.K. and M.W.C. performed the simulations and computational analysis; J.C.S., S.R. and S.C. performed the enzyme expression and kinetic assays; J.C.S., J.R.K., M.V.G. and B.B. performed the growth rate measurements; J.C.S., S.R. and M.W.C. wrote the paper; and M.W.C. supervised the project.

Corresponding author

Correspondence to Markus W Covert.

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Competing interests

J.C.S., J.R.K. and M.W.C. are listed as inventors on a Patent Cooperation Treaty (PCT) international patent application (PCT/US2013/051167) related to whole-cell modeling.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5, Supplementary Tables 2 and 3, and Supplementary Results (PDF 1751 kb)

Supplementary Table 1

Details of the chromosome map and growth assay data. Table listing all of the genes in the M. genitalium genome, together with the model/experimental comparison category, as well as the model predicted and experimentally measured (where applicable) growth rates for each disruption strain in the study and wild type. The sample size, standard deviation, t-test, and Wilcoxon test results are also listed. Six of the genes (MG051, MG112, MG271, MG291, MG385 and MG437) were reported as isolated, but unculturable in our growth assay; we considered these genes essential for the purposes of our study. #N/A = not applicable, this was used in cases where the genes were essential and no quantitative growth rate data could be obtained. (XLSX 67 kb)

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Sanghvi, J., Regot, S., Carrasco, S. et al. Accelerated discovery via a whole-cell model. Nat Methods 10, 1192–1195 (2013). https://doi.org/10.1038/nmeth.2724

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