Cellular heterogeneity mediates inherent sensitivity–specificity tradeoff in cancer targeting by synthetic circuits
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Author(s)
Morel, Mathieu
Shtrahman, Roman
Rotter, Varda
Nissim, Lior
Bar-Ziv, Roy H.
Date Issued
July 2016
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Morel, Mathieu et al. “Cellular Heterogeneity Mediates Inherent Sensitivity–specificity Tradeoff in Cancer Targeting by Synthetic Circuits.” Proceedings of the National Academy of Sciences 113, 29 (July 2016): 8133–8138 © 2016 National Academy of Sciences
Version
Final published version
Abstract
Synthetic gene circuits are emerging as a versatile means to target cancer with enhanced specificity by combinatorial integration of multiple expression markers. Such circuits must also be tuned to be highly sensitive because escape of even a few cells might be detrimental. However, the error rates of decision-making circuits in light of cellular variability in gene expression have so far remained unexplored. Here, we measure the single-cell response function of a tunable logic AND gate acting on two promoters in heterogeneous cell populations. Our analysis reveals an inherent tradeoff between specificity and sensitivity that is controlled by the AND gate amplification gain and activation threshold. We implement a tumor-mimicking cellculture model of cancer cells emerging in a background of normal ones, and show that molecular parameters of the synthetic circuits control specificity and sensitivity in a killing assay. This suggests that, beyond the inherent tradeoff, synthetic circuits operating in a heterogeneous environment could be optimized to efficiently target malignant state with minimal loss of specificity. Keywords: synthetic gene circuits; cellular heterogeneity; cancer gene therapy; cell-state targeting; mammalian synthetic biology
MIT Department
Massachusetts Institute of Technology. Research Laboratory of Electronics
Massachusetts Institute of Technology. Synthetic Biology Center
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Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
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DOI of Published Version
https://doi.org/10.1073/pnas.1604391113
