Accurate Predictions of Genetic Circuit Behavior from Part Characterization and Modular Composition

Noah Davidsohn, Jacob Beal, Samira Kiani, Aaron Adler, Fusun Yaman, Yinqing Li, Zhen Xie, Ron Weiss

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

A long-standing goal of synthetic biology is to rapidly engineer new regulatory circuits from simpler devices. As circuit complexity grows, it becomes increasingly important to guide design with quantitative models, but previous efforts have been hindered by lack of predictive accuracy. To address this, we developed Empirical Quantitative Incremental Prediction (EQuIP), a new method for accurate prediction of genetic regulatory network behavior from detailed characterizations of their components. In EQuIP, precisely calibrated time-series and dosage-response assays are used to construct hybrid phenotypic/mechanistic models of regulatory processes. This hybrid method ensures that model parameters match observable phenomena, using phenotypic formulation where current hypotheses about biological mechanisms do not agree closely with experimental observations. We demonstrate EQuIP's precision at predicting distributions of cell behaviors for six transcriptional cascades and three feed-forward circuits in mammalian cells. Our cascade predictions have only 1.6-fold mean error over a 261-fold mean range of fluorescence variation, owing primarily to calibrated measurements and piecewise-linear models. Predictions for three feed-forward circuits had a 2.0-fold mean error on a 333-fold mean range, further demonstrating that EQuIP can scale to more complex systems. Such accurate predictions will foster reliable forward engineering of complex biological circuits from libraries of standardized devices.

Original languageEnglish (US)
Pages (from-to)673-681
Number of pages9
JournalACS Synthetic Biology
Volume4
Issue number6
DOIs
StatePublished - Jun 19 2015
Externally publishedYes

Keywords

  • genetic circuits
  • synthetic biology
  • systems biology

ASJC Scopus subject areas

  • Biomedical Engineering
  • Biochemistry, Genetics and Molecular Biology (miscellaneous)

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    Davidsohn, N., Beal, J., Kiani, S., Adler, A., Yaman, F., Li, Y., Xie, Z., & Weiss, R. (2015). Accurate Predictions of Genetic Circuit Behavior from Part Characterization and Modular Composition. ACS Synthetic Biology, 4(6), 673-681. https://doi.org/10.1021/sb500263b