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Synthetic two-way communication between mammalian cells

Nature Biotechnology volume 30, pages 991–996 (2012)Cite this article

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Abstract

The design of synthetic biology–inspired control devices enabling entire mammalian cells to receive, process and transfer metabolic information and so communicate with each other via synthetic multichannel networks may provide new insight into the organization of multicellular organisms and future clinical interventions1. Here we describe communication networks that orchestrate behavior in individual mammalian cells in response to cell-to-cell metabolic signals. We engineered sender, processor and receiver cells that interact with each other in ways that resemble natural intercellular communication networks such as multistep information processing cascades, feed-forward–based signaling loops, and two-way communication. The engineered two-way communication devices mimicking natural control systems in the development of vertebrate extremities2 and vasculature3,4,5 was used to program temporal permeability in vascular endothelial cell layers. These synthetic multicellular communication systems may inspire future therapies or tissue engineering strategies.

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Figure 1: Design and validation of L-tryptophan sender and receiver cell modules.
Figure 2: Validation of sender and receiver cell interactions.
Figure 3: Design and validation of L-tryptophan sender and receiver cell modules in bioreactors and in mice.
Figure 4: Validation and implementation of a two-way communication device.

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References

  1. Weber, W., Daoud-El Baba, M. & Fussenegger, M. Synthetic ecosystems based on airborne inter- and intrakingdom communication. Proc. Natl. Acad. Sci. USA 104, 10435–10440 (2007).

    Article  CAS  Google Scholar 

  2. Freeman, M. Feedback control of intercellular signalling in development. Nature 408, 313–319 (2000).

    Article  CAS  Google Scholar 

  3. Thurston, G. et al. Leakage-resistant blood vessels in mice transgenically overexpressing angiopoietin-1. Science 286, 2511–2514 (1999).

    Article  CAS  Google Scholar 

  4. Thurston, G. Complementary actions of VEGF and angiopoietin-1 on blood vessel growth and leakage. J. Anat. 200, 575–580 (2002).

    Article  CAS  Google Scholar 

  5. Lee, S.W., Kim, W.J., Jun, H.O., Choi, Y.K. & Kim, K.W. Angiopoietin-1 reduces vascular endothelial growth factor-induced brain endothelial permeability via upregulation of ZO-2. Int. J. Mol. Med. 23, 279–284 (2009).

    CAS  PubMed  Google Scholar 

  6. Guido, N.J. et al. A bottom-up approach to gene regulation. Nature 439, 856–860 (2006).

    Article  CAS  Google Scholar 

  7. Gardner, T.S., Cantor, C.R. & Collins, J.J. Construction of a genetic toggle switch in Escherichia coli. Nature 403, 339–342 (2000).

    Article  CAS  Google Scholar 

  8. Kramer, B.P. et al. An engineered epigenetic transgene switch in mammalian cells. Nat. Biotechnol. 22, 867–870 (2004).

    Article  CAS  Google Scholar 

  9. Auslander, S., Auslander, D., Muller, M., Wieland, M. & Fussenegger, M. Programmable single-cell mammalian biocomputers. Nature 487, 123–127 (2012).

    Article  Google Scholar 

  10. Danino, T., Mondragon-Palomino, O., Tsimring, L. & Hasty, J. A synchronized quorum of genetic clocks. Nature 463, 326–330 (2010).

    Article  CAS  Google Scholar 

  11. Weber, W. et al. A synthetic time-delay circuit in mammalian cells and mice. Proc. Natl. Acad. Sci. USA 104, 2643–2648 (2007).

    Article  CAS  Google Scholar 

  12. Friedland, A.E. et al. Synthetic gene networks that count. Science 324, 1199–1202 (2009).

    Article  CAS  Google Scholar 

  13. Tigges, M., Marquez-Lago, T.T., Stelling, J. & Fussenegger, M. A tunable synthetic mammalian oscillator. Nature 457, 309–312 (2009).

    Article  CAS  Google Scholar 

  14. Weber, W. et al. A synthetic mammalian gene circuit reveals antituberculosis compounds. Proc. Natl. Acad. Sci. USA 105, 9994–9998 (2008).

    Article  CAS  Google Scholar 

  15. Weber, W. & Fussenegger, M. Emerging biomedical applications of synthetic biology. Nat. Rev. Genet. 13, 21–35 (2012).

    Article  CAS  Google Scholar 

  16. Kemmer, C. et al. Self-sufficient control of urate homeostasis in mice by a synthetic circuit. Nat. Biotechnol. 28, 355–360 (2010).

    Article  CAS  Google Scholar 

  17. Ye, H., Daoud-El Baba, M., Peng, R.W. & Fussenegger, M. A synthetic optogenetic transcription device enhances blood-glucose homeostasis in mice. Science 332, 1565–1568 (2011).

    Article  CAS  Google Scholar 

  18. Miki, T. et al. ATP-sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat. Neurosci. 4, 507–512 (2001).

    Article  CAS  Google Scholar 

  19. Yarilina, A., Park-Min, K.H., Antoniv, T., Hu, X. & Ivashkiv, L.B. TNF activates an IRF1-dependent autocrine loop leading to sustained expression of chemokines and STAT1-dependent type I interferon-response genes. Nat. Immunol. 9, 378–387 (2008).

    Article  CAS  Google Scholar 

  20. Tamsir, A., Tabor, J.J. & Voigt, C.A. Robust multicellular computing using genetically encoded NOR gates and chemical 'wires'. Nature 469, 212–215 (2011).

    Article  CAS  Google Scholar 

  21. Regot, S. et al. Distributed biological computation with multicellular engineered networks. Nature 469, 207–211 (2011).

    Article  CAS  Google Scholar 

  22. Chen, M.T. & Weiss, R. Artificial cell-cell communication in yeast Saccharomyces cerevisiae using signaling elements from Arabidopsis thaliana. Nat. Biotechnol. 23, 1551–1555 (2005).

    Article  CAS  Google Scholar 

  23. Shou, W., Ram, S. & Vilar, J.M. Synthetic cooperation in engineered yeast populations. Proc. Natl. Acad. Sci. USA 104, 1877–1882 (2007).

    Article  CAS  Google Scholar 

  24. Basu, S., Gerchman, Y., Collins, C.H., Arnold, F.H. & Weiss, R. A synthetic multicellular system for programmed pattern formation. Nature 434, 1130–1134 (2005).

    Article  CAS  Google Scholar 

  25. Basu, S., Mehreja, R., Thiberge, S., Chen, M.T. & Weiss, R. Spatiotemporal control of gene expression with pulse-generating networks. Proc. Natl. Acad. Sci. USA 101, 6355–6360 (2004).

    Article  CAS  Google Scholar 

  26. Hartman, S.C. & Mulligan, R.C. Two dominant-acting selectable markers for gene transfer studies in mammalian cells. Proc. Natl. Acad. Sci. USA 85, 8047–8051 (1988).

    Article  CAS  Google Scholar 

  27. Akers, J.C. & Tan, M. Molecular mechanism of tryptophan-dependent transcriptional regulation in Chlamydia trachomatis. J. Bacteriol. 188, 4236–4243 (2006).

    Article  CAS  Google Scholar 

  28. Weber, W. et al. Gas-inducible transgene expression in mammalian cells and mice. Nat. Biotechnol. 22, 1440–1444 (2004).

    Article  CAS  Google Scholar 

  29. Schlatter, S., Rimann, M., Kelm, J. & Fussenegger, M. SAMY, a novel mammalian reporter gene derived from Bacillus stearothermophilus alpha-amylase. Gene 282, 19–31 (2002).

    Article  CAS  Google Scholar 

  30. Lee, S.W. et al. SSeCKS regulates angiogenesis and tight junction formation in blood-brain barrier. Nat. Med. 9, 900–906 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank M. Tan (pMT1182), M. Ehrbar (pVEGF165pcDNA3), G.Y. Koh (pAng-1) and K. Frei (EA.hy926 cells) for providing reagents and D. Grasso for critical comments on the manuscript. This work was supported by the Swiss National Science Foundation (grant no. 31003A0-126022) and in part by the EC Framework 7 (Persist). Work of W.W. is supported by the Excellence Initiative of the German Federal and State Governments (EXC 294).

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Authors and Affiliations

  1. Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland

    William Bacchus, Moritz Lang, Wilfried Weber, Jörg Stelling & Martin Fussenegger

  2. Département Génie Biologique, Institut Universitaire de Technologie, IUTA, Villeurbanne Cedex, France

    Marie Daoud El-Baba

  3. Faculty of Biology and Centre for Biological Signalling Studies (BIOSS), Albert-Ludwigs-Universität Freiburg, Freiburg, Germany

    Wilfried Weber

  4. Swiss Institute of Bioinformatics, ETH Zurich, Zurich, Switzerland

    Jörg Stelling

  5. Faculty of Science, University of Basel, Basel, Switzerland

    Martin Fussenegger

Authors
  1. William Bacchus
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  3. Marie Daoud El-Baba
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  4. Wilfried Weber
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  5. Jörg Stelling
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Contributions

W.B., M.L., W.W., J.S. and M.F. designed the project, analyzed results and wrote the manuscript. W.B. and M.D.E.-B. performed the experimental work. M.L. and J.S. designed and analyzed the mathematical model and performed the simulations.

Corresponding authors

Correspondence to Jörg Stelling or Martin Fussenegger.

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The authors declare no competing financial interests.

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Supplementary Model, Supplementary Figures 1–19, Supplementary Table 1 and Supplementary Assembly (PDF 1058 kb)

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Bacchus, W., Lang, M., El-Baba, M. et al. Synthetic two-way communication between mammalian cells. Nat Biotechnol 30, 991–996 (2012). https://doi.org/10.1038/nbt.2351

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