Design principles of biochemical oscillators (original) (raw)

2008, Nature Reviews Molecular Cell Biology

Cellular rhythms are generated by complex interactions among genes, proteins and metabolites. They are used to control every aspect of cell physiology from signaling, motility and development to growth, division and death. By considering specific examples of oscillatory processes, we pick out three general requirements for biochemical oscillations: delayed negative feedback, 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. Biochemical oscillations occur in many contexts (metabolism, signaling, development, etc.) where they control important aspects of cell physiology, such as circadian rhythms, DNA synthesis and mitosis, and the development of somites in vertebrate embryos (see Table 1). In the 1950s and 60s, the first clear examples of biochemical oscillations (in metabolic systems) were recognized in glycolysis1, 2, in cyclic AMP production3, and the horseradish peroxidase reaction4, 5. Soon after these discoveries, theoreticians were thinking about the general requirements for chemical oscillations and the specific mechanisms of these examples6, 7. After the molecular biology revolution of the 1980s, many new examples of oscillations in protein interaction networks and in gene regulatory networks came to light, such as the PERIOD proteins in animal circadian control8, the CYCLIN proteins in eukaryotic cell cycle control9, 10, and the Repressilator11 in genetically engineered bacteria. Understanding the molecular basis of cellular oscillations is more than an exercise in experimental genetics and biochemistry. Oscillators have systems-level characteristics (periodicity, robustness, entrainment) that transcend the properties of individual molecules or reaction partners and involve the full topology of the reaction network. These properties can only be fully understood by viewing experimental data from a theoretical perspective, by quantitative mathematical modeling of chemical oscillatory processes. These models address general concepts of dynamical systems, such as feedback, time delays, bistability and hysteresis.