生物振荡的设计原理与人工合成

doi:10.12211/2096-8280.2024-096

合成生物学 ›› 2025, Vol. 6 ›› Issue (3): 516-531.DOI: 10.12211/2096-8280.2024-096

生物振荡的设计原理与人工合成

姜源旭¹^,², 范盈盈¹, 魏平¹^,²

^1.中国科学院深圳先进技术研究院，定量合成生物学全国重点实验室，深圳合成生物学创新研究院，细胞与基因线路设计中心广东深圳 518055
^2.北京大学前沿交叉学科研究院，定量生物学中心，北京 100871

收稿日期:2024-12-18 修回日期:2025-03-04 出版日期:2025-06-30 发布日期:2025-06-27
通讯作者: 魏平
作者简介:姜源旭（1998—），男，博士研究生。研究方向为人工合成生物振荡系统与免疫信号网络重编程。E-mail：jiangyx98@stu.pku.edu.cn
魏平（1980—），男，研究员，博士生导师。研究方向为细胞与基因线路的设计原理研究、人工合成技术及合成生物学设计软件开发；结合蛋白质工程、免疫与细胞工程方法，开发靶向复杂疾病的细胞与基因治疗的技术与应用方法。E-mail：ping.wei@siat.ac.cn
基金资助:
国家重点研发计划(2024YFA0919500)

Design principles and artificial synthesis of biological oscillators

JIANG Yuanxu¹^,², FAN Yingying¹, WEI Ping¹^,²

^1.State Key Laboratory of Quantitative Synthetic Biology，Shenzhen Institute of Synthetic Biology，Center for Cell and Gene Circuit Design，Shenzhen Institute of Advanced Technology，Chinese Academy of Sciences，Shenzhen 518055，Guangdong，China
^2.Center for Quantitative Biology，Academy for Advanced Interdisciplinary Studies，Peking University，Beijing 100871，China

Received:2024-12-18 Revised:2025-03-04 Online:2025-06-30 Published:2025-06-27
Contact: WEI Ping

摘要/Abstract

摘要：

振荡现象在各类生物体系中发挥着关键的生理功能。自20世纪50年代以来，学界就已经开始了关于生物振荡成因的理论探索。进入21世纪，三抑制振荡子（repressilator）系统的人工合成，标志着现代合成生物学的开端，也标志着人工合成生物振荡的研究开启了黄金时代。本文将回顾本领域近二十余年的发展成果，从设计原理、人工合成与实际应用三个方面加以论述。生物振荡产生的三个主要条件是负反馈网络结构、足够长的时间延迟和非线性调控关系；通过调整网络拓扑结构或引入外界周期信号，可以提升振荡的可调性与稳定性。最早的合成振荡系统完全基于转录调控，而时至今日，在蛋白、代谢乃至多细胞群体水平的合成振荡都已实现。这种人工合成的振荡系统将有助于调控种群生长、提高发酵效率、影响细胞命运，并有望为免疫治疗提供全新的思路。

关键词: 生物振荡, 调控网络, 网络拓扑, 同步化, 人工合成

Abstract:

Oscillation plays a crucial role in functioning properly for various biological systems, including circadian regulation, cell cycle, neuron activity and intracellular signal transduction. Ever since the first discovery of glycolysis oscillation back to the 1950s, more and more researchers have been engaged in the theoretical exploration of criteria for biological oscillations. At the turn of this century, the artificial synthesis of the repressilator system, which composed of the prokaryotic transcriptional repressors LacI, TetR and λcI, marked the beginning of modern synthetic biology and leading to a golden age for research on artificially synthesized biological oscillators. This article reviews the development in this field that was achieved within the past two decades, discussing them from three aspects: design principles, experimental synthesis, and practical applications. The three main conditions for generating biological oscillations are a negative feedback network structure, sufficient delay over long time, and nonlinear regulatory relationship. Time delay can be achieved by directly introducing biochemical interactions with slow timescales, adding multiple intermediate reaction steps, or forming interlinked positive feedback loops. By adjusting the network topology or introducing external periodic signals, the tunability and stability of oscillations can be enhanced. With computational approaches, researchers are able to scan all the possible network topologies with less than three nodes for robust oscillation emergence and noise resistance. The earliest synthetic oscillatory systems were entirely based on transcriptional regulation in E.coli, yet now synthetic oscillators have been developed at the protein, metabolite, and even multicellular population levels as well as in biological chassis ranging from bacteria, yeast and mammalian cells. These artificially synthesized oscillatory systems have been demonstrated to be able to potentiate the precise regulation of population growth and drug delivery, improve fermentation efficiency in engineered strains, reprogram cell aging, and potentially offer new perspectives for immunotherapy and beyond.

Key words: biological oscillation, regulatory network, network topology, synchronization, artificial synthesis

中图分类号:

姜源旭, 范盈盈, 魏平. 生物振荡的设计原理与人工合成[J]. 合成生物学, 2025, 6(3): 516-531.

JIANG Yuanxu, FAN Yingying, WEI Ping. Design principles and artificial synthesis of biological oscillators[J]. Synthetic Biology Journal, 2025, 6(3): 516-531.

图/表 3

图1 产生生物振荡的主要条件

Fig. 1 Main conditions for generating biological oscillations

图2 生物振荡的同步化

Fig. 2 Synchronization of biological oscillations

图3 各类代表性合成振荡线路

Fig. 3 Representative synthetic oscillatory circuits

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生物振荡的设计原理与人工合成

Design principles and artificial synthesis of biological oscillators

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