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Design principles of biochemical oscillators

Nature Reviews Molecular Cell Biology volume 9, pages 981–991 (2008)Cite this article

Key Points

  • Many physiological behaviours of cells are repeated periodically in time, such as hormone secretion, second messenger signalling, cell-division cycles and circadian rhythms.

  • Oscillatory behaviour is a systems-level property of the interactions of genes, proteins and metabolites in the cell.

  • All biochemical oscillators are characterized by negative feedback with time delay.

  • Time delay can be due to a chain of intermediates between the 'cause' and 'effect' of the negative-feedback loop or to a positive-feedback loop in the network.

  • For a biochemical reaction network to oscillate, the kinetics of the reactions must be sufficiently nonlinear and their timescales must be properly balanced, in quantitative terms that are predicted by theoretical analysis.

  • These conditions are satisfied by various specific network topologies that provide the basis for a classification of biochemical oscillators.

Abstract

Cellular rhythms are generated by complex interactions among genes, proteins and metabolites. They are used to control every aspect of cell physiology, from signalling, motility and development to growth, division and death. We consider specific examples of oscillatory processes and discuss four general requirements for biochemical oscillations: negative feedback, time delay, sufficient 'nonlinearity' of the reaction kinetics and proper balancing of the timescales of opposing chemical reactions. Positive feedback is one mechanism to delay the negative-feedback signal. Biological oscillators can be classified according to the topology of the positive- and negative-feedback loops in the underlying regulatory mechanism.

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Figure 1: Time-delayed negative-feedback oscillator.
Figure 2: Multi-component negative-feedback oscillator.
Figure 3: Hysteresis-driven negative-feedback oscillator.
Figure 4: Sources of nonlinearity.
Figure 5: A classification scheme for biochemical oscillators.
Figure 6: Chaotic oscillators.

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Acknowledgements

J.J.T. acknowledges financial support from the National Institutes of Health and the hospitality of Merton College, Oxford, UK, during the writing of this review. B.N. acknowledges support from the Biotechnology and Biological Sciences Research Council and from the European Commission Seventh Framework Programme (EC FP7). Our understanding of biochemical oscillations has developed over many years of delightful conversations with A. Goldbeter, L. Segel, A. Winfree, M. Mackey and L. Glass.

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Authors and Affiliations

  1. Department of Biochemistry, Oxford Centre for Integrative Systems Biology, University of Oxford, South Parks Road, OX1 3QU, Oxford, UK

    Béla Novák

  2. Department of Biological Sciences, Virginia Polytechnic Institute & State University, Blacksburg, 24061, Virginia, USA

    John J. Tyson

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  1. Béla Novák
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Correspondence to Béla Novák.

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Glossary

Somites

Early segmentations of the body of a vertebrate embryo that are laid down in a temporally and spatially periodic pattern.

Robustness

The notion that a control system should function reliably in the face of expected perturbations from outside the control system and from inevitable internal fluctuations.

Entrainment

The process whereby two interacting oscillating systems, which have different periods when running independently, assume the same period. The two oscillators may fall into synchrony, but other phase relationships are also possible.

Bistability

A reaction network with two coexisting stable steady states (separated by an unstable steady state). Which stable state the network adopts depends on the initial concentrations of the reacting species.

Hysteresis

A property of systems with bistability. The control system can be switched from one stable state to the other by a transient signal, and switched back again by a different transient signal. Hence, the state of the system depends not only on its present conditions, but also on its recent history.

Chemical chaos

Refers to oscillatory chemical systems with aperiodic unpredictable behaviour. Chaos requires at least three interacting components.

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Novák, B., Tyson, J. Design principles of biochemical oscillators. Nat Rev Mol Cell Biol 9, 981–991 (2008). https://doi.org/10.1038/nrm2530

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