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Perfect adaptation, the ability to regulate and maintain gene expression to its desired value despite disturbances, is important in the development of organisms. Building biological controllers to endow engineered biological systems with such perfect adaptation capability is a key goal in synthetic biology. Model-guided exploration of such synthetic circuits has been effective in designing such systems. However, theoretical analysis to guarantee controller properties with nonlinear models, such as Hill functions, remains challenging, while use of linear models fails to capture the inherent nonlinear dynamics of gene expression systems. Here, we propose a reverse engineering approach to infer the kinetic parameters for nonlinear Hill function-type models from analysis of linear models and apply our method to design controllers, which achieve perfect adaptation. Focusing on three biological network motif-based controllers, we demonstrate via simulation the efficacy of the proposed approach in combining linear system theories with nonlinear modelling, to design multiple gene circuits that could deliver perfect adaptation. Given the ubiquitous use of Hill functions in describing the dynamics of biological regulatory networks, we anticipate the proposed reverse engineering approach to benefit a wide range of systems and synthetic biology applications.
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Building molecular band-pass filters via molecular sequestration
Engineered genetic circuits with tailored functions that mimic how cells process information in changing environments (e.g. cell fate decision, chemotaxis, immune response) have great applications in biomedicine and synthetic biology. Although there is a lot of progress toward the design of gene circuits yielding desired steady states (e.g. logic-based networks), building synthetic circuits for dynamic signal processing (e.g. filters, frequency modulation, and controllers) is still challenging. Here, we provide a model-based approach to build gene networks that can operate as band-pass filters by taking advantage of molecular sequestration. By suitably approximating the dynamics of molecular sequestration, we analyze an Incoherent Feed-Forward Loop (IFFL) and a Negative Feedback (NF) circuit and illustrate how they can achieve band-pass filter behavior. Computational analysis shows that a circuit that incorporates both IFFL and NF motifs improves the filter performance. Our approach facilitates the design of sequestration-based filters, and may support the synthesis of molecular controllers with desired specifications.
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- Award ID(s):
- 2107483
- PAR ID:
- 10358957
- Date Published:
- Journal Name:
- Proceedings of the IEEE conference on decision and control
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Accepted Manuscript1.0
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