Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Distributed biological computation with multicellular engineered networks

Nature volume 469, pages 207–211 (2011)Cite this article

Subjects

Abstract

Ongoing efforts within synthetic and systems biology have been directed towards the building of artificial computational devices1 using engineered biological units as basic building blocks2,3. Such efforts, inspired in the standard design of electronic circuits4,5,6,7, are limited by the difficulties arising from wiring the basic computational units (logic gates) through the appropriate connections, each one to be implemented by a different molecule. Here, we show that there is a logically different form of implementing complex Boolean logic computations that reduces wiring constraints thanks to a redundant distribution of the desired output among engineered cells. A practical implementation is presented using a library of engineered yeast cells, which can be combined in multiple ways. Each construct defines a logic function and combining cells and their connections allow building more complex synthetic devices. As a proof of principle, we have implemented many logic functions by using just a few engineered cells. Of note, small modifications and combination of those cells allowed for implementing more complex circuits such as a multiplexer or a 1-bit adder with carry, showing the great potential for re-utilization of small parts of the circuit. Our results support the approach of using cellular consortia as an efficient way of engineering complex tasks not easily solvable using single-cell implementations.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Figure 1: Basic engineered cells (cell types).
Figure 2: In vivo analyses of engineered cells.
Figure 3: Engineered cells to implement different logic gates in vivo.
Figure 4: Design and in vivo implementation of a multiplexer (MUX2to1) and 1-bit adder with carry.

References

  1. Bashor, C. J. & Horwitz, A. A. Peisajovich, S. G., & Lim, W. A. Rewiring cells: synthetic biology as a tool to interrogate the organizational principles of living. Ann. Rev. Biophys. 39, 515–537 (2010)

    CAS  Article  Google Scholar 

  2. Amos, M. Cellular Computing (Oxford University Press, 2004)

    MATH  Google Scholar 

  3. Andrianantoandro, E., Basu, S., Karig, D. & Weiss, R. Synthetic biology: new engineering rules for an emerging discipline. Mol. Syst. Biol. 2, E1–E14 (2006)

    Article  Google Scholar 

  4. Bray, D. Protein molecules as computational elements in living cells. Nature 376, 307–312 (1995)

    ADS  CAS  Article  Google Scholar 

  5. Hjelmfelt, A., Weinbeger, E. D. & Ross, J. Chemical implementation of neural networks and Turing machines. Proc. Natl Acad. Sci. USA 88, 10983–10987 (1991)

    ADS  CAS  Article  Google Scholar 

  6. McAdams, H. H. & Shapiro, L. Circuit simulation of genetic circuits. Science 269, 650–656 (1995)

    ADS  CAS  Article  Google Scholar 

  7. Arkin, A. & Ross, J. Computational functions in biochemical reaction networks. Biophys. J. 67, 560–578 (1994)

    ADS  CAS  Article  Google Scholar 

  8. Elowitz, M. B. & Leibler, S. A synthetic oscillatory network of transcriptional regulators. Nature 403, 335–338 (2000)

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  10. Becskei, A. & Serrano, L. Engineering stability in gene networks by autoregulation. Nature 405, 590–593 (2000)

    ADS  CAS  Article  Google Scholar 

  11. Voigt, C. A. Genetic parts to program bacteria. Curr. Opin. Biotechnol. 17, 548–557 (2006)

    CAS  Article  Google Scholar 

  12. Kramer, B. P., Fischer, C. & Fussenegger, M. BioLogic gates enable logical transcription control in mammalian cells. Biotechnol. Bioeng. 87, 478–484 (2004)

    CAS  Article  Google Scholar 

  13. Win, M. N. & Smolke, C. D. Higher-order cellular information processing with synthetic RNA devices. Science 322, 456–460 (2008)

    ADS  CAS  Article  Google Scholar 

  14. Greber, D. & Fussenegger, M. An engineered mammalian band-pass network. Nucleic Acids Res. 38, e174 (2010)

    Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  16. Rinaudo, K. et al. A universal RNAi-based logic evaluator that operates in mammalian cells. Nature Biotechnol. 25, 795–801 (2007)

    CAS  Article  Google Scholar 

  17. Purnick, P. E. M. & Weiss, R. The second wave of synthetic biology: from modules to systems. Nature Rev. Mol. Cell Biol. 10, 410–422 (2009)

    CAS  Article  Google Scholar 

  18. Brenner, K., You, L. & Arnold, F. H. Engineering microbial consortia: a new frontier in synthetic biology. Trends Biotechnol. 26, 483–489 (2008)

    CAS  Article  Google Scholar 

  19. Brenner, K., Karig, D. K., Weiss, R. & Arnold, F. H. Engineered bidirectional communication mediates a consensus in a microbial biofilm consortium. Proc. Natl Acad. Sci. USA 104, 17300–17304 (2007)

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  21. You, L., Cox, R. S., III, Weiss, R. & Arnold, F. H. Programmed population control by cell-cell communication and regulated killing. Nature 428, 868–871 (2004)

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

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

    ADS  CAS  Article  Google Scholar 

  24. Balagaddé, F. K. et al. A synthetic Escherichia coli predator–prey ecosystem. Mol. Syst. Biol. 4, 187 (2008)

    Article  Google Scholar 

  25. Lucks, J. B., Qi, L., Whitaker, W. R. & Arkin, A. P. Toward scalable parts families for predictable design of biological circuits. Curr. Opin. Microbiol. 11, 567–573 (2008)

    Article  Google Scholar 

  26. Chin, J. W. Programming and engineering biological networks. Curr. Opin. Struct. Biol. 16, 551–556 (2006)

    CAS  Article  Google Scholar 

  27. Rao, C. V., Wolf, D. M. & Arkin, A. P. Control, exploitation and tolerance of intracellular noise. Nature 420, 231–237 (2002)

    ADS  CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank L. Subirana and S. Ovejas for technical support and S. Pellet and M. Peter for their help in setting up the microfluidics platform, and K. Kuchler for the FUS1-mCherry construct. S.R. is recipient of a FPU fellowship (Spanish Government). This work was supported by grants from the James McDonnell Foundation to R.S., the MICINN (BIO2009-07762 and FIS2009-12365); Consolider Ingenio 2010 programme (grant CSD2007-0015), from the ESF (ERAS-CT-2003-980409) FP6 as part of a EURYI scheme award (http://www.esf.org/euryi) to F.P. and the CELLCOMPUT (FP6) project to F.P., R.S. and S.H., and FP7 UNICELLSYS grant (#201142) to F.P. and S.H., and The Santa Fe Institute to R.S.; F.P. and R.S. laboratories are also supported by the Fundación Marcelino Botín (FMB). F.P. is recipient of an ICREA Acadèmia (Generalitat de Catalunya).

Author information

Author notes

  1. Sergi Regot and Javier Macia: These authors contributed equally to this work.

Authors and Affiliations

  1. Cell signaling unit, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), Barcelona, E-08003, Spain

    Sergi Regot, Núria Conde, Tom Peeters, Eulàlia de Nadal & Francesc Posas

  2. ICREA-Complex Systems Laboratory, Universitat Pompeu Fabra (UPF), Barcelona, E-08003, Spain

    Javier Macia, Núria Conde & Ricard Solé

  3. Department of Cell and Molecular Biology/Microbiology, University of Gothenburg, Box 462, 40530 Gothenburg, Sweden,

    Kentaro Furukawa, Jimmy Kjellén & Stefan Hohmann

  4. Santa Fe Institute, Santa Fe, 87501, New Mexico, USA

    Ricard Solé

  5. Institut de Biologia Evolutiva, CSIC-UPF, Passeig Maritim de la Barceloneta, 37-49, 08003 Barcelona, Spain ,

    Ricard Solé

Authors
  1. Sergi Regot
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Javier Macia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Núria Conde
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kentaro Furukawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jimmy Kjellén
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tom Peeters
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stefan Hohmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eulàlia de Nadal
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Francesc Posas
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ricard Solé
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors shared all the phases of the work. J.M. and R.S. developed the theoretical background for multicellular computing. Circuits were designed by S.R., J.M., N.C., E.N., F.P. and R.S.; S.R., N.C., K.F., J.K. and T.P. did the experimental designs. J.M., F.P., E.N., S.H. and R.S. wrote the paper.

Corresponding authors

Correspondence to Francesc Posas or Ricard Solé.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Methods and Data, Supplementary Tables 1-2 and additional references. (PDF 282 kb)

Supplementary Figures

This file contains Supplementary Figures 1-11 with legends. (PDF 2028 kb)

Supplementary Data

This file contains Supplementary Dataset 2 (PDF 3170 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Regot, S., Macia, J., Conde, N. et al. Distributed biological computation with multicellular engineered networks. Nature 469, 207–211 (2011). https://doi.org/10.1038/nature09679

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09679

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing