Nature 457, 309-312 (15 January 2009) | doi:10.1038/nature07616; Received 26 July 2008; Accepted 4 November 2008

A tunable synthetic mammalian oscillator

Marcel Tigges1, Tatiana T. Marquez-Lago1,2,3, Jörg Stelling1,2,3 & Martin Fussenegger1

  1. Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland
  2. Institute of Computational Science and,
  3. Swiss Institute of Bioinformatics, ETH Zurich, CH-8092 Zurich, Switzerland

Correspondence to: Jörg Stelling1,2,3Martin Fussenegger1 Correspondence and requests for materials should be addressed to M.F. (Email: fussenegger@bsse.ethz.ch) or J.S. (Email: joerg.stelling@bsse.ethz.ch).

Autonomous and self-sustained oscillator circuits mediating the periodic induction of specific target genes are minimal genetic time-keeping devices found in the central and peripheral circadian clocks1, 2. They have attracted significant attention because of their intriguing dynamics and their importance in controlling critical repair3, metabolic4 and signalling pathways5. The precise molecular mechanism and expression dynamics of this mammalian circadian clock are still not fully understood. Here we describe a synthetic mammalian oscillator based on an auto-regulated sense–antisense transcription control circuit encoding a positive and a time-delayed negative feedback loop, enabling autonomous, self-sustained and tunable oscillatory gene expression. After detailed systems design with experimental analyses and mathematical modelling, we monitored oscillating concentrations of green fluorescent protein with tunable frequency and amplitude by time-lapse microscopy in real time in individual Chinese hamster ovary cells. The synthetic mammalian clock may provide an insight into the dynamics of natural periodic processes and foster advances in the design of prosthetic networks in future gene and cell therapies.


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