Biological rhythms: Clocks for all times

The development and harmonious functioning of an organism depend on the exquisite coordination of myriad intertwined biological processes. As illustrated by this issue of Current Biology devoted to the ‘biology of time’, temporal organization plays crucial roles in coordinating dynamic phenomena as diverse as progression through the cell cycle, the processing of information, adaptation to the periodic environment, and the response to extracellular or intracellular signals. Here I will focus on one of the most conspicuous manifestations of temporal organization, that which takes the form of rhythmic behavior. If rhythms did not exist, would we see the passage of time? The alternation of day and night, and the cycle of the seasons remind us that life’s environment is inherently periodic. Life itself is rhythmic: from the periodic generation of action potentials in neurons or cardiac cells to the cell division cycle and circadian rhythms, many key cellular processes possess a repetitive, oscillatory nature. Rhythmic behavior also occurs at the supracellular level, as exemplified by the ovarian cycle and by annual rhythms such as flowering, migration, hibernation or reproduction in some mammalian species. The period of biological rhythms spans more than ten orders of magnitude, from a fraction of a second up to tens of years (see Table 1). Why are there so many biological rhythms? The answer is: regulation. Cellular regulatory processes are multifarious and can all give rise to oscillations [1]. Thus, activation and inhibition of ionic conductances as a function of the membrane potential combine to produce periodic behavior in electrically excitable cells. The regulation of enzyme activity underlies metabolic oscillations, while control of transport between different intracellular compartments Guest Editorial gives rise to oscillations of cytosolic Ca2+. Regulation of gene expression is involved in the origin of circadian rhythms and of the segmentation clock that controls somitogenesis. A common property of regulatory feedback loops is their capability of inducing instabilities. Of relevance to rhythmic behavior is the situation where the regulated system undergoes sustained oscillations around a steady state that has become unstable beyond a critical value of some control parameter or in a parameter range bounded by two critical values [1,2]. For example, intracellular Ca2+ oscillations occur in many cell types subjected to intermediate levels of hormonal stimulation. Below a critical value of stimulus intensity, the level of Ca2+ stabilizes at a low constant level, while above a second, higher critical value, cytosolic Ca2+ reaches a high steady-state level. Likewise sustained oscillations occur in glycolysing yeast extracts in a range bounded by two critical values of the substrate input rate. Because they occur beyond a critical point of instability of a nonequilibrium steady state, biological rhythms can be viewed as temporal dissipative structures [3]. A flurry of cellular rhythms have been discovered during the last decade. Among these is the segmentation clock which controls the periodic formation of somites in vertebrate development. This system is of particular interest because of its key role in embryogenesis and the fact that it records a temporal structure as a permanent pattern of spatial organization [4]. The clock is also expressed in cell cultures in the form of oscillatory transcription of the gene Hes1 [5]. Other recently observed rhythms include oscillations in both the tumor suppressor p53 [6] and the transcription factor NFκB [7], stress-induced oscillations in the nucleocytoplasmic shuttling of the transcription factor Msn2 in yeast [8], and the periodic organization of the yeast transcriptome [9]. Because rhythmic behavior cannot be ascribed to a single gene or enzyme, and rather constitutes a systemic property originating from regulatory interactions between coupled elements in a metabolic or genetic network, cellular rhythms represent a prototypic field of research in systems biology. Models help unraveling the dynamics of cellular rhythms and show that sustained oscillatory behavior often corresponds, in the concentration space, to the evolution toward a closed curve known as a limit cycle. Cycling once around this trajectory takes exactly one period. The closed trajectory is generally unique in a given set of conditions, and is particularly stable as it can be reached regardless of initial conditions. The limit cycle is a central figure in the study of biological rhythms [1,2]. The major questions regarding cellular rhythms pertain to their molecular mechanism and to their physiological function. With regard to mechanism, an oscillation can be divided into a succession of phases: understanding the mechanism of the rhythm amounts to clarifying how one phase brings about the next one, and why the process is repetitive — why the first phase is necessarily induced by the last phase of the preceding cycle. This analysis is facilitated by the use of models that present the advantage of allowing us to freeze the behavior of an oscillatory system at any given moment over the period,