Circadian clocks are seeing the systems biology light

More than 30 years ago, Seymour Benzer started on the quest for the holy grail of behavioral neuroscience, the elucidation of behavior at a molecular and systems level [1]. In part because of his efforts, this quest is perhaps furthest along in the study of biological rhythms, which in mammals are most clearly manifested in the regulation of a very primitive behavior, the sleep-wake cycle. Elegant genetic and biochemical studies in several species have revealed that the circadian clock that controls such daily rhythms is a cell-autonomous transcriptional/translational feedback loop (reviewed in [2]). In mammals, the master circadian clock resident in the suprachiasmatic nucleus (SCN) of the hypothalamus functions to synchronize other oscillators that drive physiological outputs to a 24-hour rhythm. Despite increasingly refined models of how individual clock components function together as a self-sustaining oscillator, the link between their action, transcriptional oscillations (or clock output), and dependent processes such as physiology and behavior has remained elusive.Enter systems biology, which can be broadly defined as the integration and synthesis of information from various subfields to inform a biological question [3]. In this field, changes to biological systems are observed at multiple levels under a set of experimental condition(s). Integration of complex data, such as RNA and protein levels together with phenotypes, facilitates the construction of prospective models, which can inform and be informed by experimental data. The methodologies used may include, but are not limited to, transcriptional profiling, differential proteomics, cell-based screening, and whole-organism phenotypic screening [3]. These studies often produce information-rich datasets that necessitate the use of bioinformatics tools to organize and manage the information and to synthesize testable hypotheses.As a nascent field, many of the initial studies could be viewed as hypothesis-gen