Team:Fudan

ENABLE

To survive, cells must identify and integrate various signals from the environment. Cells utilize their transmembrane receptors to recognize extracellular signals to execute a myriad of tasks ranging from cell-mediated immunity to tissue formation and regeneration.

Therefore, in the field of synthetic biology, it would be especially impactful if cells could be programmed to recognize external environmental signals, generate contact-dependent signaling, and perform reliable logical computations.

Our project ENABLE (ENgineered, Across membrane, Binary Logic in Eukaryotes) offers the first toolbox for mammalian cells to generate contact-dependent signaling from the external environment and Boolean output decisions. We believe this is a foundational advance for synthetic biology, and enables a wide range of opportunities.

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Abstract

Contact-dependent signaling is critical for multicellular biological events, yet customizing contact-dependent signal transduction between cells remains challenging. Here we have developed the ENABLE toolbox, a complete set of transmembrane binary logic gates. Each gate consists of 3 layers: Receptor, Amplifier, and Combiner. We first optimized synthetic Notch receptors to enable cells to respond to different signals across the membrane reliably. These signals, individually amplified intracellularly by transcription, are further combined for computing. Our engineered zinc finger-based transcription factors perform binary computation and output designed products. In summary, we have combined spatially different signals in mammalian cells, and revealed new potentials for biological oscillators, tissue engineering, cancer treatments, bio-computing, etc. ENABLE is a toolbox for constructing contact-dependent signaling networks in mammals. The 3-layer design principle underlying ENABLE empowers any future development of transmembrane logic circuits, thus contributes a foundational advance to Synthetic Biology.