Design Principles of Biological Oscillators through Optimization: Forward and Reverse Analysis

From cyanobacteria to human, sustained oscillations coordinate important biological functions. Although much has been learned concerning the sophisticated molecular mechanisms underlying biological oscillators, design principles linking structure and functional behavior are not yet fully understood. Here we explore design principles of biological oscillators from a multiobjective optimization perspective, taking into account the trade-offs between conflicting performance goals or demands. We develop a comprehensive tool for automated design of oscillators, based on multicriteria global optimization that allows two modes: (i) the automatic design (forward problem) and (ii) the inference of design principles (reverse analysis problem). From the perspective of synthetic biology, the forward mode allows the solution of design problems that mimic some of the desirable properties appearing in natural oscillators. The reverse analysis mode facilitates a systematic exploration of the design space based on Pareto optimality concepts. The method is illustrated with two case studies: the automatic design of synthetic oscillators from a library of biological parts, and the exploration of design principles in 3-gene oscillatory systems.

从蓝细菌（cyanobacteria）到人类，持续振荡协调着诸多重要的生物学功能。尽管学界已对生物振荡器背后复杂的分子机制有了诸多认知，但连接结构与功能行为的设计原则仍未被完全阐明。本研究从多目标优化（multiobjective optimization）视角出发，探究生物振荡器的设计原则，并考量相互冲突的性能目标与需求之间的权衡关系。基于多准则全局优化方法，本研究开发了一款用于振荡器自动化设计的综合性工具，该工具支持两种运行模式：(i) 自动化设计（正问题），(ii) 设计原则推断（逆分析问题）。从合成生物学（synthetic biology）视角来看，正问题模式可用于解决设计问题，以复刻自然振荡器所具备的部分优良特性。逆分析模式则基于帕累托最优（Pareto optimality）概念，助力对设计空间进行系统性探索。本研究通过两项案例研究对该方法进行演示：其一为基于生物元件库自动化设计合成振荡器，其二为探究三基因振荡系统的设计原则。