PT  - JOURNAL ARTICLE
AU  - Carignano, Alberto
AU  - Chen, Dai Hua
AU  - Mallory, Cannon
AU  - Wright, Clay
AU  - Seelig, Georg
AU  - Klavins, Eric
TI  - Modular, robust and extendible multicellular circuit design in yeast
AID  - 10.1101/2021.10.13.464175
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.10.13.464175
4099  - http://biorxiv.org/content/early/2021/10/14/2021.10.13.464175.short
4100  - http://biorxiv.org/content/early/2021/10/14/2021.10.13.464175.full
AB  - 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 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.Competing Interest StatementThe authors have declared no competing interest.