Design principles and artificial synthesis of biological oscillators

doi:10.12211/2096-8280.2024-096

Abstract

Abstract:

Oscillation plays a crucial role in the proper functioning of 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 theoretical explorations of the criteria of biological oscillations. At the turn of this century, the artificial synthesis of the repressilator system, which was composed of the prokaryotic transcriptional repressors LacI, TetR and λcI, marked the beginning of modern synthetic biology and ushered in a golden age for research on artificially synthesized biological oscillators. This article will review the developments in this field over 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, sufficiently long time delays, and nonlinear regulatory relationships. Time delay can be achieved by directly introducing biochemical interactions with a slower timescale, 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 were 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 achieved at the protein, metabolic, and even multicellular population levels, 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

摘要：

振荡现象在各类生物体系中发挥着关键的生理功能。自上世纪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。进入本世纪，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

CLC Number:

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

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, DOI: 10.12211/2096-8280.2024-096.

Figures/Tables 3

Fig. 1 The Main Requirements for Generating Biological Oscillations(A: Single-node or dual-node negative feedback network (as shown above) with the curves of transcription rate and degradation rate varying with protein concentration A in the system. B: The dynamic behavior of the system gradually changes from damped oscillations to sustained oscillations as the delay increases. C: Three forms of time delay: direct slow steps (left), multi-step intermediate reactions (middle), and additional positive feedback (right). D: The effect of the Hill coefficient n on the shape of the response function curve. E: The relationship between oscillation generation and the Hill coefficient in a simple dual-node negative feedback circuit.)

Fig. 2 Synchronization of Biological Oscillations(A: Schematic diagram of Arnold's tongue, with the blue shaded area in the middle representing the frequency-locking range. The upper graph shows the dynamic curve of the system when synchronization occurs, while the lower graph illustrates the dynamic curve under non-synchronized conditions. B: Schematic diagram of the traveling wave of Hes7 in early embryos. C: The experimental system (left, schematic) and the pattern generated by computational simulation (right).)

Figure 3 Representative Synthetic Oscillatory Circuits(A: The classical repressilator system. B: An oscillator system with intertwined negative and positive feedback. C: The synthetic NF-κB oscillatory system. D: A metabolic-transcriptional oscillatory system. E: An E. coli quorum sensing oscillatory system.)

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