Beyond intuitive modeling: combining biophysical models with innovative experiments to move the circadian clock field forward.

Two major approaches have been used to model circadian clocks. Qualitative modeling, used prior to the recent wealth of detailed molecular knowledge, makes general predictions but cannot provide detailed mechanistic insights. The more recent biophysical approach, on the other hand, incorporates the biochemical events that drive the clock and can make detailed and testable molecular predictions. These predictions are being tested using new experimental techniques that measure reaction kinetics and the behavior of individual cells. A joint modeling and experimental approach has recently been used to understand how mutations affecting phosphorylation can lead to a short circadian period in tau mutant hamsters and in humans with familial advanced sleep phase syndrome (FASPS). Another recent study has revealed novel single-cell phenotypes of clock gene mutations, demanding revision of current biophysical models yet validating certain model predictions that were previously overlooked. A new paradigm for clock research is emerging in which modeling inspires new experimental efforts, experimental data inspire new modeling efforts, and joint modeling/experimental studies lead to a deeper understanding of mammalian circadian rhythms.