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Modular extracellular sensor architecture for engineering mammalian cell-based devices.

ABSTRACT: Engineering mammalian cell-based devices that monitor and therapeutically modulate human physiology is a promising and emerging frontier in clinical synthetic biology. However, realizing this vision will require new technologies enabling engineered circuitry to sense and respond to physiologically relevant cues. No existing technology enables an engineered cell to sense exclusively extracellular ligands, including proteins and pathogens, without relying upon native cellular receptors or signal transduction pathways that may be subject to crosstalk with native cellular components. To address this need, we here report a technology we term a Modular Extracellular Sensor Architecture (MESA). This self-contained receptor and signal transduction platform is maximally orthogonal to native cellular processes and comprises independent, tunable protein modules that enable performance optimization and straightforward engineering of novel MESA that recognize novel ligands. We demonstrate ligand-inducible activation of MESA signaling, optimization of receptor performance using design-based approaches, and generation of MESA biosensors that produce outputs in the form of either transcriptional regulation or transcription-independent reconstitution of enzymatic activity. This systematic, quantitative platform characterization provides a framework for engineering MESA to recognize novel ligands and for integrating these sensors into diverse mammalian synthetic biology applications.

SUBMITTER: Daringer NM

PROVIDER: S-EPMC4161666 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Natural salinity gradients are a promising source of so-called "blue energy", a renewable energy source that utilizes the free energy of mixing for power generation. One promising blue energy technology that converts these salinity gradients directly into electricity is reverse electrodialysis (RED). Used at its full potential, it could provide a substantial portion of the world's electricity consumption. Previous theoretical and experimental works have been done on optimizing RED devices, with the latter often focusing on precious and expensive metal electrodes. However, in order to rationally design and apply RED devices, we need to investigate all related transport phenomena─especially the fluidics of salinity gradient mixing and the redox electrolyte at various concentrations, which can have complex intertwined effects─in a fully functioning and scalable system. Here, guided by fundamental electrochemical and fluid dynamics theories, we work with an iron-based redox electrolyte with carbon electrodes in a RED device with tunable microfluidic environments and study the fundamental effects of electrolyte concentration and flow rate on the potential-driven redox activity and power output. We focus on optimizing the net power output, which is the difference between the gross power output generated by the RED device and the pumping power input, needed for salinity gradient mixing and redox electrolyte reactions. We find through this holistic approach that the electrolyte concentration in the electrode rinse solution is crucial for increasing the electrical current, while the pumping power input depends nonlinearly on the membrane separation distance. Finally, from this understanding, we designed a five cell-pair (CP) RED device that achieved a net power density of 224 mW m-2 CP-1, a 60% improvement compared to the nonoptimized case. This study highlights the importance of the electrode rinse solution fluidics and composition when rationally designing RED devices based on scalable carbon-based electrodes.

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Modular extracellular sensor architecture for engineering mammalian cell-based devices.

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