Abstract
Biological computation requires in vivo control of molecular behavior to progress development of autonomous devices. miRNA switches represent excellent, easily engineerable synthetic biology tools to achieve user-defined gene regulation. Here we present the construction of a synthetic network to implement detoxification functionality. We employed a modular design strategy by engineering toxin-induced control of an enzyme scavenger. Our miRNA switch results show moderate synthetic expression control over a biologically active detoxification enzyme molecule, using an established design protocol. However, following a new design approach, we demonstrated an evolutionarily designed miRNA switch to more effectively activate enzyme activity than synthetically designed versions, allowing markedly improved extrinsic user-defined control with a toxin as inducer. Our straightforward new design approach is simple to implement and uses easily accessible web-based databases and prediction tools. The ability to exert control of toxicity demonstrates potential for modular detoxification systems that provide a pathway to new therapeutic and biocomputing applications.
Highlights
Biocompatible information processing is critical for developing autonomous biological therapeutics or biosensors
Our results provide a new pathway for application of Cytochrome P450s towards personalized medicine, and support the development of miRNA switches as controlling elements for biocompatible information processing systems
We investigated the ability of miRNA switches to turn on and tune the activation of an enzyme scavenger using a toxin, by harnessing the cells natural RNA interference system
Summary
Biocompatible information processing is critical for developing autonomous biological therapeutics or biosensors. Designing molecular systems to regulate behaviour requires programming high degrees of functionality into biochemical networks Such advancement of synthetic gene expression control is critical to progress synthetic biology tools[18]. MiRNAs make excellent candidates to design engineered switches as synthetic biology tools for gene regulation applicable in higher eukaryotes. Such engineered post-transcriptional control networks have been demonstrated using artificial miRNAs with embedded aptamers[23,26], including engineered reversibility (7). While miRNA-based gene expression control systems produce ON states close to maximal gene expression, OFF states show leakage[23] This is a critical limitation when regulating enzyme turnover function, because only highly stringent switches. Our results provide a new pathway for application of Cytochrome P450s towards personalized medicine, and support the development of miRNA switches as controlling elements for biocompatible information processing systems
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