Biological oscillations without genetic oscillator or external forcing

Abstract

Oscillators are fundamental to biological systems, underpinning essential processes such as cell division, circadian rhythms, and developmental cycles. While both natural and synthetic genetic oscillators have been extensively studied, oscillatory behaviors in cells can also emerge without dedicated genetic circuits. In earlier work, we uncovered sustained oscillations in phenotypic switching across diverse cellular systems and gene circuits, occurring spontaneously, without external forcing and linked them to the induction of slow-growing phenotypes. In this study, we identify the conditions that give rise to such intrinsic phenotypic instabilities, leading to population-level oscillations. We develop and analytically solve a simplified mathematical model of a stress-induced phenotype, mapping the range of continuous culture conditions that trigger oscillatory gene expression. This instability range, predicted by the model, was experimentally validated in Bacillus subtilis cultures. Our findings reveal that oscillations can arise in the complete absence of genetic oscillators or external perturbations. Although demonstrated here for a stress response in continuous culture, this phenomenon may occur in any long-term cultivation where environmental feedback links an inducer to the cellular system, broadening the landscape of possible oscillatory behaviors in microbiology and synthetic biology.