Brief Communication | Published:

Accelerated discovery via a whole-cell model

Nature Methods volume 10, pages 11921195 (2013) | Download Citation

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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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.

Author information

Author notes

    • Jayodita C Sanghvi

    Present address: Institute for Quantitative Biosciences, University of California Berkeley, Berkeley, California, USA.

Affiliations

  1. Department of Bioengineering, Stanford University, Stanford, California, USA.

    • Jayodita C Sanghvi
    • , Sergi Regot
    • , Silvia Carrasco
    • , Miriam V Gutschow
    • , Benjamin Bolival Jr
    •  & Markus W Covert
  2. Graduate Program in Biophysics, Stanford University, Stanford, California, USA.

    • Jonathan R Karr

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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.

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.

Corresponding author

Correspondence to Markus W Covert.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–5, Supplementary Tables 2 and 3, and Supplementary Results

Excel files

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    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.

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DOI

https://doi.org/10.1038/nmeth.2724

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