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DNA-based communication in populations of synthetic protocells

Abstract

Developing molecular communication platforms based on orthogonal communication channels is a crucial step towards engineering artificial multicellular systems. Here, we present a general and scalable platform entitled ‘biomolecular implementation of protocellular communication’ (BIO-PC) to engineer distributed multichannel molecular communication between populations of non-lipid semipermeable microcapsules. Our method leverages the modularity and scalability of enzyme-free DNA strand-displacement circuits to develop protocellular consortia that can sense, process and respond to DNA-based messages. We engineer a rich variety of biochemical communication devices capable of cascaded amplification, bidirectional communication and distributed computational operations. Encapsulating DNA strand-displacement circuits further allows their use in concentrated serum where non-compartmentalized DNA circuits cannot operate. BIO-PC enables reliable execution of distributed DNA-based molecular programs in biologically relevant environments and opens new directions in DNA computing and minimal cell technology.

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Fig. 1: Design elements for BIO-PC.
Fig. 2: Signalling cascade between protocell populations using non-enzymatic DNA signal amplification.
Fig. 3: Three-layer amplified signalling cascade.
Fig. 4: Protocellular negative feedback loop.
Fig. 5: Compartmentalized DNA-based Boolean logic circuits.
Fig. 6: Compartmentalized DNA reaction networks in 50% FBS.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank G. Seelig, W. Mulder and L. Cronin for helpful discussions. This work was supported by the European Research Council (ERC project no. 677313 BioCircuit), the ERC Advanced Grant Scheme (EC-2016-ADG 740235) and a Marie Curie Individual Fellowship, an NWO-VIDI grant from the Netherlands Organisation for Scientific Research (NWO, 723.016.003), funding from the Ministry of Education, Culture and Science (Gravity programmes 024.001.035 and 024.003.013) and BrisSynBio (BB/L01386X/1).

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Contributions

A.J. designed the study, performed experiments, analysed the data and wrote the manuscript. S.Y., B.B. and P.P. performed experiments and analysed the data. A.v.d.L. and A.J. designed and fabricated the microfluidic chip. N.D. and A.P. performed computational experiments. B.V.V.S.P.K. and S.M. provided key reagents and provided critical input for the initial experiments. T.F.A.d.G. conceived, designed and supervised the study, analysed the data and wrote the manuscript. S.M. revised the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Tom F. A. de Greef.

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The authors declare no competing interests.

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Journal peer review information Nature Nanotechnology thanks Friedrich Simmel and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary information

Supplementary Methods, Figures 1–14, Notes, Tables 1–6 and References.

Supplementary Video 1

Diffusion of a fluorescently labelled input DNA strand into protocells and activation of a fluorescent DNA gate complex.

Supplementary Video 2

Activation of the two-layer signalling cascade.

Supplementary Video 3

Negative feedback loop in two populations.

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Joesaar, A., Yang, S., Bögels, B. et al. DNA-based communication in populations of synthetic protocells. Nat. Nanotechnol. 14, 369–378 (2019). https://doi.org/10.1038/s41565-019-0399-9

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