Tunable synthetic phenotypic diversification on Waddington's landscape through autonomous signaling

Ryoji Sekine, Masayuki Yamamura, Shotaro Ayukawa, Kana Ishimatsu, Satoru Akama, Masahiro Takinoue, Masami Hagiya, Daisuke Kiga*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)


Phenotypic diversification of cells is crucial for developmental and regenerative processes in multicellular organisms. The diversification concept is described as the motion of marbles rolling down Waddington's landscape, in which the number of stable states changes as development proceeds. In contrast to this simple concept, the complexity of natural biomolecular processes prevents comprehension of their design principles. We have constructed, in Escherichia coli, a synthetic circuit with just four genes, which programs cells to autonomously diversify as the motion on the landscape through cell-cell communication. The circuit design was based on the combination of a bistable toggle switch with an intercellular signaling system. The cells with the circuit diversified into two distinct cell states, "high" and "low," in vivo and in silico, when all of the cells started from the low state. The synthetic diversification was affected by not only the shape of the landscape determined by the circuit design, which includes the synthesis rate of the signaling molecule, but also the number of cells in the experiments. This cell-number dependency is reminiscent of the "community effect": The fates of developing cells are determined by their number. Our synthetic circuit could be a model system for studying diversification and differentiation in higher organisms. Prospectively, further integrations of our circuit with different cellular functions will provide unique tools for directing cell fates on the population level in tissue engineering.

Original languageEnglish
Pages (from-to)17969-17973
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
Publication statusPublished - 2011 Nov 1
Externally publishedYes


  • Biological engineering
  • Mathematical modeling
  • Synthetic biology

ASJC Scopus subject areas

  • General


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