Robust, tunable biological oscillations from interlinked positive and negative feedback loops

Science. 2008 Jul 4;321(5885):126-9. doi: 10.1126/science.1156951.


A simple negative feedback loop of interacting genes or proteins has the potential to generate sustained oscillations. However, many biological oscillators also have a positive feedback loop, raising the question of what advantages the extra loop imparts. Through computational studies, we show that it is generally difficult to adjust a negative feedback oscillator's frequency without compromising its amplitude, whereas with positive-plus-negative feedback, one can achieve a widely tunable frequency and near-constant amplitude. This tunability makes the latter design suitable for biological rhythms like heartbeats and cell cycles that need to provide a constant output over a range of frequencies. Positive-plus-negative oscillators also appear to be more robust and easier to evolve, rationalizing why they are found in contexts where an adjustable frequency is unimportant.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Anaphase-Promoting Complex-Cyclosome
  • Animals
  • Biological Clocks*
  • Biological Evolution
  • CDC2 Protein Kinase / metabolism*
  • Cell Cycle*
  • Cell Division
  • Circadian Rhythm
  • Cyclin B / biosynthesis
  • Cyclin B / metabolism
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / metabolism
  • Feedback, Physiological*
  • Interphase
  • Models, Biological
  • Monte Carlo Method
  • Ubiquitin-Protein Ligase Complexes / metabolism
  • Xenopus Proteins / metabolism
  • Xenopus laevis


  • Cyclin B
  • Xenopus Proteins
  • Ubiquitin-Protein Ligase Complexes
  • Anaphase-Promoting Complex-Cyclosome
  • CDC2 Protein Kinase