Modular, robust and extendible multicellular circuit design in yeast

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Abstract

Division of labor between cells is ubiquitous in biology but the use of multi-cellular consortia for engineering applications is only beginning to be explored. A significant advantage of multi-cellular circuits is their potential to be modular with respect to composition but this claim has not yet been extensively tested using experiments and quantitative modeling. Here, we construct a library of 24 yeast strains capable of sending, receiving or responding to three molecular signals, characterize them experimentally and build quantitative models of their input-output relationships. We then compose these strains into two- and three-strain cascades as well as a four-strain bistable switch and show that experimentally measured consortia dynamics can be predicted from the models of the constituent parts. To further explore the achievable range of behaviors, we perform a fully automated computational search over all two-, three- and four-strain consortia to identify combinations that realize target behaviors including logic gates, band-pass filters and time pulses. Strain combinations that are predicted to map onto a target behavior are further computationally optimized and then experimentally tested. Experiments closely track computational predictions. The high reliability of these model descriptions further strengthens the feasibility and highlights the potential for distributed computing in synthetic biology.

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Figure 1 - Source Data 1, Figure 2 - Source Data 1, Figure 3 - Source Data 1, Figure 4 - Source Data 1, Figure 5 - Source Data 1 contain the numerical data used to generate the figures

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Alberto Carignano

Department of Electrical and Computer Engineering, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3306-9365
Dai Hua Chen

Department of Electrical and Computer Engineering, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Cannon Mallory

Department of Electrical and Computer Engineering, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Clay R Wright

Department of Biological Systems Engineering, Virginia Tech, Blacksburg, United States

Competing interests
The authors declare that no competing interests exist.
Georg Seelig

Department of Electrical and Computer Engineering, University of Washington, Seattle, United States

For correspondence
gseelig@uw.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3163-8782
Eric Klavins

Department of Electrical and Computer Engineering, University of Washington, Seattle, United States

For correspondence
klavins@uw.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3805-5117

Funding

Office of Naval Research (N00014-16-1-3189)

Alberto Carignano
Georg Seelig
Eric Klavins

National Science Foundation (1807132)

Alberto Carignano
Eric Klavins

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.