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.

Electronic modulation of biochemical signal generation

Nature Nanotechnology volume 9, pages 605–610 (2014)Cite this article

Subjects

Abstract

Microelectronic devices that contain biological components are typically used to interrogate biology1,2 rather than control biological function. Patterned assemblies of proteins and cells have, however, been used for in vitro metabolic engineering3,4,5,6,7, where coordinated biochemical pathways allow cell metabolism to be characterized and potentially controlled8 on a chip. Such devices form part of technologies that attempt to recreate animal and human physiological functions on a chip9 and could be used to revolutionize drug development10. These ambitious goals will, however, require new biofabrication methodologies that help connect microelectronics and biological systems11,12 and yield new approaches to device assembly and communication. Here, we report the electrically mediated assembly, interrogation and control of a multi-domain fusion protein that produces a bacterial signalling molecule. The biological system can be electrically tuned using a natural redox molecule, and its biochemical response is shown to provide the signalling cues to drive bacterial population behaviour. We show that the biochemical output of the system correlates with the electrical input charge, which suggests that electrical inputs could be used to control complex on-chip biological processes.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Schematic of the biohybrid device controlled by electronic signals.
Figure 2: Electronically driven HLPT attenuation by natural mediator acetosyringone (AS).
Figure 3: On-chip enzyme activity is linear with input charge.
Figure 4: In situ enzyme attenuation mediates biological signalling.

References

  1. Nivala, J., Marks, D. B. & Akeson, M. Unfoldase-mediated protein translocation through an α-haemolysin nanopore. Nature Biotechnol. 31, 247–250 (2013).

    Article  CAS  Google Scholar 

  2. Moreau, C. J., Dupuis, J. P., Revilloud, J., Arumugam, K. & Vivaudou, M. Coupling ion channels to receptors for biomolecule sensing. Nature Nanotech. 3, 620–625 (2008).

    Article  CAS  Google Scholar 

  3. Mora-Pale, M., Sanchez-Rodriguez, S. P., Linhardt, R. J., Dordick, J. S. & Koffas, M. A. Metabolic engineering and in vitro biosynthesis of phytochemicals and non-natural analogues. Plant Sci. 210, 10–24 (2013).

    Article  CAS  Google Scholar 

  4. Luo, X. et al. Programmable assembly of a metabolic pathway enzyme in a pre-packaged reusable bioMEMS device. Lab Chip 8, 420–430 (2008).

    Article  CAS  Google Scholar 

  5. Jung, G. Y. & Stephanopoulos, G. A functional protein chip for pathway optimization and in vitro metabolic engineering. Science 304, 428–431 (2004).

    Article  Google Scholar 

  6. Lee, M. Y., Park, C. B., Dordick, J. S. & Clark, D. S. Metabolizing enzyme toxicology assay chip (MetaChip) for high-throughput microscale toxicity analyses. Proc. Natl Acad. Sci. USA 102, 983–987 (2005).

    Article  CAS  Google Scholar 

  7. Fernandes, R., Roy, V., Wu, H. C. & Bentley, W. E. Engineered biological nanofactories trigger quorum sensing response in targeted bacteria. Nature Nanotech. 5, 213–217 (2010).

    Article  CAS  Google Scholar 

  8. Esch, M. B., King, T. L. & Shuler, M. L. The role of body-on-a-chip devices in drug and toxicity studies. Annu. Rev. Biomed. Eng. 13, 55–72 (2011).

    Article  CAS  Google Scholar 

  9. Service, R. F. Bioengineering. Lung-on-a-chip breathes new life into drug discovery. Science 338, 731 (2012).

    Article  CAS  Google Scholar 

  10. Huh, D. et al. Reconstituting organ-level lung functions on a chip. Science 328, 1662–1668 (2010).

    Article  CAS  Google Scholar 

  11. Kim, E. et al. Redox-capacitor to connect electrochemistry to redox-biology. Analyst 139, 32–43 (2014).

    Article  CAS  Google Scholar 

  12. Wu, L. Q. & Payne, G. F. Biofabrication: using biological materials and biocatalysts to construct nanostructured assemblies. Trends Biotechnol. 22, 593–599 (2004).

    Article  CAS  Google Scholar 

  13. Yi, H. et al. Biofabrication with chitosan. Biomacromolecules 6, 2881–2894 (2005).

    Article  CAS  Google Scholar 

  14. Schauder, S., Shokat, K., Surette, M. G. & Bassler, B. L. The LuxS family of bacterial autoinducers: biosynthesis of a novel quorum-sensing signal molecule. Mol. Microbiol. 41, 463–476 (2001).

    Article  CAS  Google Scholar 

  15. Hardie, K. R. & Heurlier, K. Establishing bacterial communities by ‘word of mouth’: LuxS and autoinducer 2 in biofilm development. Nature Rev. Microbiol. 6, 635–643 (2008).

    Article  CAS  Google Scholar 

  16. Li, J, et al. Quorum sensing in Escherichia coli is signaled by AI-2/LsrR: effects on small RNA and biofilm architecture. J. Bacteriol. 189, 6011–6020 (2007).

    Article  CAS  Google Scholar 

  17. Wu, H. C. et al. Biofabrication of antibodies and antigens via IgG-binding domain engineered with activatable pentatyrosine pro-tag. Biotechnol. Bioeng. 103, 231–240 (2009).

    Article  CAS  Google Scholar 

  18. Lewandowski, A. T. et al. Protein assembly onto patterned microfabricated devices through enzymatic activation of fusion pro-tag. Biotechnol. Bioeng. 99, 499–507 (2008).

    Article  CAS  Google Scholar 

  19. Clement, J.-L., Gilbert, B. C., Rockenbauer, A. & Tordo, P. Radical damage to proteins studied by EPR spin-trapping techniques. J. Chem Soc. Perkin Trans. 2, 1463–1470 (2001).

    Article  Google Scholar 

  20. Baker, C. J. et al. Induction of redox sensitive extracellular phenolics during plant–bacterial interactions. Physiol. Mol. Plant Pathol. 66, 90–98 (2005).

    Article  CAS  Google Scholar 

  21. Martorana, A . et al. A spectroscopic characterization of a phenolic natural mediator in the laccase biocatalytic reaction. J. Mol. Catal. B 97, 203–208 (2013).

    Article  CAS  Google Scholar 

  22. Hilgers, M. T. & Ludwig, M. L. Crystal structure of the quorum-sensing protein LuxS reveals a catalytic metal site. Proc. Natl Acad. Sci. USA 98, 11169–11174 (2001).

    Article  CAS  Google Scholar 

  23. Lee, J. E., Cornell, K. A., Riscoe, M. K. & Howell, P. L. Structure of E. coli 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase reveals similarity to the purine nucleoside phosphorylases. Structure 9, 941–953 (2001).

    Article  CAS  Google Scholar 

  24. Dykstra, P. H., Roy, V., Byrd, C., Bentley, W. E. & Ghodssi, R. Microfluidic electrochemical sensor array for characterizing protein interactions with various functionalized surfaces. Anal. Chem. 83, 5920–5927 (2011).

    Article  CAS  Google Scholar 

  25. Yung, C. W. et al. Transglutaminase crosslinked gelatin as a tissue engineering scaffold. J. Biomed. Mater. Res. A. 83, 1039–1046 (2007).

    Article  CAS  Google Scholar 

  26. Liu, Y. et al. Biofabrication to build the biology–device interface. Biofabrication 2, 022002 (2010).

    Article  Google Scholar 

  27. Cheng, Y. et al. In situ quantitative visualization and characterization of chitosan electrodeposition with paired sidewall electrodes. Soft Matter 6, 3177–3183 (2010).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank the UMD Fischell Department of Bioengineering Core FACS Facility for assistance with FACS data collection and the UMD Nanocenter for providing workspace and tools for electrode fabrication and ICP-EOS measurements. The authors thank Y. Zhou of the UMD Department of Nutrition and Food Science for help with EPR measurements. Financial support for this work was provided by the Defense Threat Reduction Agency (HDTRA1-13-0037), the National Science Foundation (no. 1160005 to WEB, no. 1264509 to HO Sintim) and the RWD Foundation.

Author information

Authors and Affiliations

  1. Fischell Department of Bioengineering, University of Maryland, College Park, Maryland 20742, USA

    Tanya Gordonov, Gregory F. Payne & William E. Bentley

  2. Institute for Bioscience & Biotechnology Research, University of Maryland, College Park, Maryland 20742, USA

    Tanya Gordonov, Eunkyoung Kim, Gregory F. Payne & William E. Bentley

  3. Institute for Systems Research, University of Maryland, College Park, Maryland 20742, USA

    Yi Cheng, Hadar Ben-Yoav, Reza Ghodssi & Gary Rubloff

  4. Department of Materials Science and Engineering, University of Maryland, College Park, Maryland 20742, USA

    Yi Cheng & Gary Rubloff

  5. Department of Electrical and Computer Engineering, University of Maryland, College Park, Maryland 20742, USA

    Hadar Ben-Yoav & Reza Ghodssi

  6. Division of Analytical Chemistry, Office of Regulatory Science, Center for Food Safety and Applied Nutrition, US Food and Drug Administration, College Park, Maryland 20740, USA

    Jun-Jie Yin

Authors
  1. Tanya Gordonov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eunkyoung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yi Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hadar Ben-Yoav
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Reza Ghodssi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Gary Rubloff
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jun-Jie Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Gregory F. Payne
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. William E. Bentley
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.G., E.K., G.F.P. and W.E.B. developed the concepts and planned and designed the experiments. T.G., E.K., H.B. and Y.C. fabricated components and performed the experiments and data analysis. J.J.Y., G.F.P., W.E.B. and G.R. supervised the work. T.G., E.K., G.F.P. and W.E.B. wrote and edited the manuscript.

Corresponding author

Correspondence to William E. Bentley.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Information (PDF 3042 kb)

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gordonov, T., Kim, E., Cheng, Y. et al. Electronic modulation of biochemical signal generation. Nature Nanotech 9, 605–610 (2014). https://doi.org/10.1038/nnano.2014.151

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nnano.2014.151

This article is cited by

Search

Advanced search

Quick links

Find nanotechnology articles, nanomaterial data and patents all in one place. Visit Nano by Nature Research