期刊
NATURE BIOTECHNOLOGY
卷 35, 期 5, 页码 453-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.3805
关键词
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资金
- NSF [DGE-1247312]
- NIH/NIGMS fellowship [T32-GM008764]
- National Science Foundation Expeditions in Computing Award part of the Living Computing Project [1522074]
- NIH Director's New Innovator Award [1DP2CA186574]
- NSF Expedition in Computing [1522074]
- NSF CAREER [162457]
- NSF BBSRC [1614642]
- Boston University College of Engineering Dean's Catalyst Award
- Direct For Computer & Info Scie & Enginr
- Division of Computing and Communication Foundations [1521925] Funding Source: National Science Foundation
- Division of Computing and Communication Foundations
- Direct For Computer & Info Scie & Enginr [1522074] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1614642] Funding Source: National Science Foundation
Engineered genetic circuits for mammalian cells often require extensive fine-tuning to perform as intended. We present a robust, general, scalable system, called 'Boolean logic and arithmetic through DNA excision' (BLADE), to engineer genetic circuits with multiple inputs and outputs in mammalian cells with minimal optimization. The reliability of BLADE arises from its reliance on recombinases under the control of a single promoter, which integrates circuit signals on a single transcriptional layer. We used BLADE to build 113 circuits in human embryonic kidney and Jurkat T cells and devised a quantitative, vector-proximity metric to evaluate their performance. Of 113 circuits analyzed, 109 functioned (96.5%) as intended without optimization. The circuits, which are available through Addgene, include a 3-input, two-output full adder; a 6-input, one-output Boolean logic look-up table; circuits with small-molecule-inducible control; and circuits that incorporate CRISPR-Cas9 to regulate endogenous genes. BLADE enables execution of sophisticated cellular computation in mammalian cells, with applications in cell and tissue engineering.
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