Design principles and artificial synthesis of biological oscillators

JIANG Yuanxu; FAN Yingying; WEI Ping

doi:10.12211/2096-8280.2024-096

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Design principles and artificial synthesis of biological oscillators

Invited Review | 更新时间：2025-07-07

- Design principles and artificial synthesis of biological oscillators
  封面论文
- Synthetic Biology Journal Vol. 6, Issue 3, Pages: 516-531(2025)
- 作者机构：
  
  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
- 作者简介：
- 基金信息：
- DOI：10.12211/2096-8280.2024-096
  CLC： Q81
- Received：18 December 2024，
  
  Revised：2025-03-04，
  
  Published：30 June 2025
- 稿件说明：
移动端阅览
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
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 DOI： 10.12211/2096-8280.2024-096.

JIANG Yuanxu， FAN Yingying， WEI Ping. Design principles and artificial synthesis of biological oscillators［J］. Synthetic Biology Journal， 2025， 6（3）： 516-531 DOI： 10.12211/2096-8280.2024-096.

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。

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 introdu

cing 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

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.

关键词

Keywords

references

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