Context-aware synthetic biology by controller design: Engineering the mammalian cell

Shakiba, Nika; Weiss, Ron; Vecchio, Domitilla Del

doi:10.1016/j.cels.2021.05.011

Cited by 50 publications

(42 citation statements)

References 282 publications

(455 reference statements)

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“…Recently, work has accelerated to rewire natural signaling pathways and engineer synthetic receptors that sense extracellular inputs 9 – 11 . A desirable engineered signaling system would have tunable input/output responses, low output noise, and drive gene expression that is robust to perturbations coming from the extracellular, cellular, and genetic context of the system 12 . The ability of the signaling system to exhibit such properties depends on how input signals are processed to generate gene expression outputs.…”

Section: Introductionmentioning

confidence: 99%

Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles

et al. 2022

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Engineered signaling networks can impart cells with new functionalities useful for directing differentiation and actuating cellular therapies. For such applications, the engineered networks must be tunable, precisely regulate target gene expression, and be robust to perturbations within the complex context of mammalian cells. Here, we use bacterial two-component signaling proteins to develop synthetic phosphoregulation devices that exhibit these properties in mammalian cells. First, we engineer a synthetic covalent modification cycle based on kinase and phosphatase proteins derived from the bifunctional histidine kinase EnvZ, enabling analog tuning of gene expression via its response regulator OmpR. By regulating phosphatase expression with endogenous miRNAs, we demonstrate cell-type specific signaling responses and a new strategy for accurate cell type classification. Finally, we implement a tunable negative feedback controller via a small molecule-stabilized phosphatase, reducing output expression variance and mitigating the context-dependent effects of off-target regulation and resource competition. Our work lays the foundation for establishing tunable, precise, and robust control over cell behavior with synthetic signaling networks.

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Section: Introductionmentioning

confidence: 99%

Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles

et al. 2022

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“…In this special issue of Biosensors, we build on the concept of context-awareness through establishment of CADS: Context-Aware Diagnostic Specificity, an application specifically focused on diagnostics. The notion of context awareness is a computational discovery framework [ 11 ], and has recently been extended for applications in cell-cell communication [ 12 ], biological inspired design [ 13 ], and synthetic biology [ 14 ]. For application in diagnostics, context awareness is extended to include molecular systems applied for specific detection of a target (or multiple targets).…”

Section: Commentarymentioning

confidence: 99%

Context-Aware Diagnostic Specificity (CADS)

et al. 2022

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“…Besides investigating molecular pathways of directed cell migration, the cellular sensing and processing machinery has been modeled as a biological processor in synthetic biology [29][30][31].…”

Section: Introductionmentioning

confidence: 99%

Cells function as a ternary logic gate to decide migration direction under integrated chemical and fluidic cues

Moon

Saha

Mugler

et al. 2022

Preprint

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Cells sense various environmental cues and process intracellular signals to decide their migration direction in many physiological and pathological processes. Although several signaling molecules have been identified in these directed migrations, it still remains elusive how cells decipher multiple cues, specifically chemical and fluidic cues. Here, we investigated the cellular signal processing machinery by reverse-engineering directed cell migration under integrated chemical and fluidic cues. We exposed controlled chemical and fluidic cues to cells using a microfluidic platform and analyzed the extracellular coupling of the cues with respect to the cellular detection limit. Then, the cell’s migratory behavior was reverse-engineered to build the cell’s intrinsic signal processing system as a logic gate. Our primary finding is that the cellular signal processing machinery functions as a ternary logic gate to decipher integrated chemical and fluidic cues. The proposed framework of the ternary logic gate suggests a systematic approach to understand how cells decode multiple cues to make decisions in migration.

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Context-aware synthetic biology by controller design: Engineering the mammalian cell

Cited by 50 publications

References 282 publications

Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles

Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles

Context-Aware Diagnostic Specificity (CADS)

Cells function as a ternary logic gate to decide migration direction under integrated chemical and fluidic cues

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