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Distributed biological computation with multicellular engineered networks

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.

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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.

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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).

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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.

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The authors declare no competing financial interests.

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Supplementary Information

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

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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

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