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WIREs Syst Biol Med
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Engineered genetic information processing circuits

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Abstract Cells implement functions through the computation of biological information that is often mediated by genetic regulatory networks. To reprogram cells with novel capabilities, a vast set of synthetic gene circuits has recently been created. These include simple modules, such as feedback circuits, feed‐forward loops, ultrasensitive networks, band‐pass filters, logic gate operators and others, with each carrying a specific information processing functionality. More advanced cellular computation can also be achieved by assembling multiple simple processing modules into integrated computational cores. Further, when coupled with other modules such as sensors and actuators, integrated processing circuits enable sophisticated biological functionalities at both intra‐ and intercellular levels. Engineered genetic information processing circuits are transforming our ability to program cells, offering us extraordinary opportunities to explore biological mechanisms and to address real‐world challenges. WIREs Syst Biol Med 2013, 5:273–287. doi: 10.1002/wsbm.1216 This article is categorized under: Models of Systems Properties and Processes > Cellular Models Analytical and Computational Methods > Computational Methods Models of Systems Properties and Processes > Mechanistic Models Biological Mechanisms > Regulatory Biology

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Genetic circuits have been engineered to exhibit ultrasensitivity. (a) A synthetic transcriptional cascade was constructed with a controlled number of reaction steps. In this system, the sensitivity for responding to the same input signals increases with the cascade depth and the number of reaction steps.106 (b.) In a receptor‐transcription factor based signaling system, ultrasensitivity was generated by introduction of a positive feedback loop. A linear signal response was converted to a ‘switch‐like’ response with ultrasensitivity.110,111

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The FFL is a common motif in biological networks. (a) A FFL with three genes has eight possible configurations depending on the regulatory nature of the connections in the network. Based on the direction of information flow through the FFL, the eight types can be classified into two groups, coherent and incoherent.96 (b) A synthetic feed‐forward gene expression network was constructed with its final output being fine‐tuned as a function of the promoter strength.100

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Feedback control, both positive and negative, is used extensively in engineered genetic regulatory circuits. (a) A system composed of the λ promoter and a TetR‐GFP hybrid gene utilizes negative feedback to stabilize a distinct level of output protein concentration. The TetR‐GFP hybrid gene expresses fusing proteins that suppress the λ promoter upstream of the hybrid gene. (b) The output protein distribution is narrowed (orange histogram) compared with the un‐regulated counterpart (gray histogram).88 (c) A system composed of phage λ's PRM promoter and the cI and GFP genes utilizes positive feedback to establish bistable behavior. Transcription factor expressed from the cI gene activates the production of phage λ's PRM promoter. (d) The system exhibits bistable behavior under appropriate conditions.86

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Many systems, both engineered and naturally occurring, contain modules that act as sensors, processors, and actuators to interact with the environment. (a) A sensor, processor, and actuator are commonly employed to reliably respond to stimuli in engineered and naturally occurring systems. (b) During an ultrasound, a signal is sent form the transducer to a computing core for processing. The processed signal is then transmitted to a video and audio device. (c) In bacterial chemotaxis, receptor proteins bind to a chemical signal, triggering interactions with other regulatory proteins (the processing unit). The bacterial flagellum is then activated to respond to the stimulus. (d) Both electronic and cellular circuits provide inspiration for a new generation of synthetic biological technology. A synthetic gene circuit that performs edge‐detection utilizes three distinct modules to sense surrounding light, process the input, and produce black pigments to transmit information.

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By combining sensor, processor, and actuator modules, engineered genetic circuits are able to implement sophisticated cellular functionality. (a) The genetic circuit is used to detect cancerous cells through sensing the levels of six miRNAs.116 R1 and R2 are double‐inverted regulatory modules used to repress the expression of hBax for decreased levels of miRNA input. Expression of hBax transmits the signal for apoptosis to the host cell if the appropriate pattern of miRNA levels is present. (b) The genetic circuit is used to synchronize the oscillations of a bacterial population.28 AHL serves as the signaling molecule to enable intercellular communication. Within each cell, AHL activates its own expression (positive feedback) and degradation (negative feedback) to establish oscillations. Cells synchronize oscillations through the detection and transmission of AHL.

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Biocomputational circuits have been constructed to implement the foundational logic gate operations. (a) The genetic circuit uses both transcriptional control (transcription factors TF1, TF2) and translational control (RNA binding proteins), to implement complex logic operations.59 An N‐IMPLY logic gate is implemented in which output fluorescence is observed only if one input (red) is present and the other input (green) is absent. By linking multiple N‐IMPLY gates together, an XOR gate can be constructed. (b) Clusters of cells (Cells 1, 2, 3, 4) are spatially arranged to communicate through molecule concentration.63 Each cluster performs a specific logic operation, NOR or buffer, to produce an XOR response to the initial inputs. The colored wires represent distinct molecular species.

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Band‐pass regulatory circuits have been constructed to tune gene expression. (a) Under the band‐pass control, E. coli exposed to two antibiotics, tetracycline negative selection and ampicillin positive selection, survived only with the intermediate activity of β‐lactamase (BLA) that keeps the two antibiotics within their nonlethal range.65 (b) E. coli, harboring a band‐selection circuit, exhibits controlled target gene expression only with a certain intermediate concentration of inducer. The represented GFP expression (green ring) of the cell was controlled as a function of distance to the center of inducer diffusion.62

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