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.

  • Progress
  • Published:

Stochastic sensors inspired by biology

Nature volume 413, pages 226–230 (2001)Cite this article

Abstract

Sensory systems use a variety of membrane-bound receptors, including responsive ion channels, to discriminate between a multitude of stimuli. Here we describe how engineered membrane pores can be used to make rapid and sensitive biosensors with potential applications that range from the detection of biological warfare agents to pharmaceutical screening. Notably, use of the engineered pores in stochastic sensing, a single-molecule detection technology, reveals the identity of an analyte as well as its concentration.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Detection of a variety of analytes by stochastic sensing.
Figure 2: Lipid bilayer arrays: fact and fantasy.

Similar content being viewed by others

References

  1. Hladky, S. B. & Haydon, D. A. Discreteness of conductance change in biomolecular lipid membranes in the presence of certain antibiotics. Nature 225, 451–453 (1970).

    Article  ADS  CAS  Google Scholar 

  2. Bayley, H., Braha, O. & Gu, L.-Q. Stochastic sensing with protein pores. Adv. Mater. 12, 139–142 (2000).

    Article  CAS  Google Scholar 

  3. Bayley, H. & Martin, C. R. Resistive-pulse sensing: from microbes to molecules. Chem. Rev. 100, 2575–2594 (2000).

    Article  CAS  Google Scholar 

  4. Hume, R. I., Role, L. W. & Fischbach, G. D. Acetylcholine release from growth cones detected with patches of acetylcholine receptor-rich membranes. Nature 305, 632–634 (1983).

    Article  ADS  CAS  Google Scholar 

  5. Young, S. H. & Poo, M. Spontaneous release of transmitter from growth cones of embryonic cells. Nature 305, 634–637 (1983).

    Article  ADS  CAS  Google Scholar 

  6. Braha, O. et al. Designed protein pores as components for biosensors. Chem. Biol. 4, 497–505 (1997).

    Article  CAS  Google Scholar 

  7. Trivedi, B. & Kramer, R. H. Real-time patch cram detection of intracellular cGMP reveals long-term suppression of responses to NO and muscarinic agents. Neuron 21, 895–906 (1998).

    Article  CAS  Google Scholar 

  8. Cheley, S., Braha, O., Lu, X., Conlan, S. & Bayley, H. A functional protein pore with a “retro” transmembrane domain. Protein Sci. 8, 1257–1267 (1999).

    Article  CAS  Google Scholar 

  9. Braha, O. et al. Simultaneous stochastic sensing of divalent metal ions. Nature Biotechnol. 17, 1005–1007 (2000).

    Article  Google Scholar 

  10. Gu, L.-Q., Braha, O., Conlan, S., Cheley, S. & Bayley, H. Stochastic sensing of organic analytes by a pore-forming protein containing a molecular adapter. Nature 398, 686–690 (1999).

    Article  ADS  CAS  Google Scholar 

  11. Sanchez-Quesada, J., Ghadiri, M. R., Bayley, H. & Braha, O. Cyclic peptides as molecular adapters for a pore-forming protein. J. Am. Chem. Soc. 122, 11758–11766 (2000).

    Article  Google Scholar 

  12. Gu, L.-Q., Cheley, S. & Bayley, H. Capture of a single molecule in a nanocavity. Science 291, 636–640 (2001).

    Article  ADS  CAS  Google Scholar 

  13. Kasianowicz, J. J., Brandin, E., Branton, D. & Deamer, D. W. Characterization of individual polynucleotide molecules using a membrane channel. Proc. Natl Acad. Sci. USA 93, 13770–13773 (1996).

    Article  ADS  CAS  Google Scholar 

  14. Akeson, M., Branton, D., Kasianowicz, J. J., Brandin, E. & Deamer, D. W. Microsecond time-scale discrimination among polycytidylic acid, polyadenylic acid and polyuridylic acid as homopolymers or as segments within single RNA molecules. Biophys. J. 77, 3227–3233 (1999).

    Article  CAS  Google Scholar 

  15. Meller, A., Nivon, L., Brandin, E., Golovchenko, J. & Branton, D. Rapid nanopore discrimination between single polynucleotide molecules. Proc. Natl Acad. Sci. USA 97, 1079–1084 (2000).

    Article  ADS  CAS  Google Scholar 

  16. Henrickson, S. E., Misakian, M., Robertson, B. & Kasianowicz, J. J. Driven DNA transport into an asymmetric nanometer-scale pore. Phys. Rev. Lett. 85, 3057–3060 (2000).

    Article  ADS  CAS  Google Scholar 

  17. Deamer, D. W. & Akeson, M. Nanopores and nucleic acids: prospects for ultrarapid sequencing. Trends Biotechnol. 18, 147–151 (2000).

    Article  CAS  Google Scholar 

  18. Bezrukov, S. M. Ion channels as molecular Coulter counters to probe metabolite transport. J. Membr. Biol. 174, 1–13 (2000).

    Article  CAS  Google Scholar 

  19. Vercoutere, W. et al. Rapid discrimination among individual DNA hairpin molecules at single-nucleotide resolution using an ion channel. Nature Biotechnol. 19, 248–252 (2001).

    Article  CAS  Google Scholar 

  20. Howorka, S., Cheley, S. & Bayley, H. Sequence-specific detection of individual DNA strands using engineered nanopores. Nature Biotechnol. 19, 636–639 (2001).

    Article  CAS  Google Scholar 

  21. Movileanu, L., Howorka, S., Braha, O. & Bayley, H. Detecting protein analytes that modulate transmembrane movement of a polymer chain within a single protein pore. Nature Biotechnol. 18, 1091–1095 (2000).

    Article  CAS  Google Scholar 

  22. Hirn, R., Bayerl, T. M., Rädler, J. O. & Sackmann, E. Collective membrane motions of high and low amplitude, studied by dynamic light scattering and micro-interferometry. Faraday Disc. 111, 17–30 (1998).

    Article  ADS  CAS  Google Scholar 

  23. Schmidt, C., Mayer, M. & Vogel, H. A chip-based biosensor for the functional analysis of single ion channels. Angew. Chem. Int. Edn Engl. 39, 3137–3140 (2000).

    Article  CAS  Google Scholar 

  24. McGeoch, J. E. M., McGeoch, M. W., Carter, D. J. D., Shuman, R. F. & Guidotti, G. Biological-to-electronic interface with pores of ATP synthase subunit c in silicon nitride barrier. Med. Biol. Eng. Comput. 38, 113–119 (2000).

    Article  CAS  Google Scholar 

  25. Sackmann, E. Supported membranes: scientific and practical applications. Science 271, 43–48 (1996).

    Article  ADS  CAS  Google Scholar 

  26. Sackmann, E. & Tanaka, M. Supported membranes on soft polymer cushions: fabrication, characterization and applications. Trends Biotechnol. 18, 58–64 (2000).

    Article  CAS  Google Scholar 

  27. Glazier, S. A. et al. Reconstitution of the pore-forming toxin α-hemolysin in phospholipid/18-octadecyl-1-thiahexa(ethylene oxide) and phospholipid/n-octadecanethiol supported bilayer membranes. Langmuir 16, 10428–10435 (2000).

    Article  CAS  Google Scholar 

  28. Cornell, B. A. et al. A biosensor that uses ion-channel switches. Nature 387, 580–583 (1997).

    Article  ADS  CAS  Google Scholar 

  29. Stora, T., Lakey, J. H. & Vogel, H. Ion-channel gating in transmembrane receptor proteins: functional activity in tethered lipid membranes. Angew. Chem. Int. Edn Engl. 38, 389–392 (1999).

    Article  CAS  Google Scholar 

  30. Lucas, S. W. & Harding, M. M. Detection of DNA vnia an ion channel switch biosensor. Analyt. Biochem. 282, 70–79 (2000).

    Article  Google Scholar 

  31. Straub, B., Meyer, E. & Fromherz, P. Recombinant maxi-K channels on transistor, a prototype of iono-electronic interfacing. Nature Biotechnol. 19, 121–124 (2001).

    Article  CAS  Google Scholar 

  32. Wiegand, G., Neumaier, K. R. & Sackmann, E. Fast impedance spectroscopy: general aspects and performance study for single ion channel measurements. Rev. Sci. Instrum. 71, 2309–2320 (2000).

    Article  ADS  CAS  Google Scholar 

  33. Tonucci, R. J., Justus, B. L., Campillo, A. J. & Ford, C. E. Nanochannel array glass. Science 258, 783–785 (1992).

    Article  ADS  CAS  Google Scholar 

  34. Jirage, K. B., Hulteen, J. C. & Martin, C. R. Nanotubule-based molecular-filtration membranes. Science 278, 655–658 (1997).

    Article  ADS  CAS  Google Scholar 

  35. Schuster, B., Pum, D., Braha, O., Bayley, H. & Sleytr, U. B. Self-assembled α-hemolysin pores in an S-layer supported lipid bilayer. Biochim. Biophys. Acta 1370, 280–288 (1998).

    Article  CAS  Google Scholar 

  36. Schuster, B. et al. S-layer ultrafiltration membranes: a new support for stabilizing functionalized lipid membranes. Langmuir 17, 499–503 (2001).

    Article  CAS  Google Scholar 

  37. Ide, T. & Yanagida, T. An artificial lipid bilayer formed on an agarose-coated glass for simultaneous electrical and optical measurement of single ion channels. Biochem. Biophys. Res. Commun. 265, 595–599 (1999).

    Article  CAS  Google Scholar 

  38. Boxer, S. G. Molecular transport and organization in supported bilayer membranes. Curr. Opin. Chem. Biol. 4, 704–709 (2000).

    Article  CAS  Google Scholar 

  39. Cremer, P. S. & Yang, T. Creating spatially addressed arrays of planar supported fluid phospholipid membranes. J. Am. Chem. Soc. 121, 8130–8131 (1999).

    Article  CAS  Google Scholar 

  40. Yang, T., Simanek, E. E. & Cremer, P. S. Creating addressable aqueous microcompartments above solid supported bilayers using lithographically patterned PDMS molds. Analyt. Chem. 72, 2587–2589 (2000).

    Article  CAS  Google Scholar 

  41. Figeys, D. & Pinto, D. Lab-on-a-chip: a revolution in biological and medical sciences. Analyt. Chem. 72, 330A–335A (2000).

    Article  CAS  Google Scholar 

  42. Yang, T., Jung, S., Mao, H. & Cremer, P. S. Fabrication of phospholipid bilayer-coated microchannels for on-chip immunoassays. Analyt. Chem. 73, 165–169 (2001).

    Article  CAS  Google Scholar 

  43. Dickinson, T. A., White, J., Kauer, J. S. & Walt, D. R. A chemical-detecting system based on a cross-reactive optical sensor array. Nature 382, 687–700 (1996).

    Article  ADS  Google Scholar 

  44. Kodadek, T. Protein microarrays: prospects and problems. Chem. Biol. 8, 105–115 (2001).

    Article  CAS  Google Scholar 

  45. Borman, S. Multivalency: strength in numbers. Chem. Eng. News 48–53 (9 October 2000).

  46. Kramer, R. H. Patch cramming: monitoring intracellular messengers in intact cells with membrane patches containing detector ion channels. Neuron 4, 335–341 (1990).

    Article  CAS  Google Scholar 

  47. Hulteen, J. C., Jirage, K. B. & Martin, C. R. Introducing chemical transport selectivity into gold nanotubule membranes. J. Am. Chem. Soc. 120, 6603–6604 (1998).

    Article  CAS  Google Scholar 

  48. Sun, L. & Crooks, R. M. Single carbon nanotube membranes: a well-defined model for studying mass transport through nanoporous materials. J. Am. Chem. Soc. 122, 12340–12345 (2000).

    Article  CAS  Google Scholar 

  49. Li, J. et al. Ion beam sculpting on the nanoscale. Nature 412, 166–169 (2001).

    Article  ADS  CAS  Google Scholar 

  50. Weiss, S. Fluorescence spectroscopy of single biomolecules. Science 283, 1676–1683 (1999).

    Article  ADS  CAS  Google Scholar 

  51. Xie, X. S. & Lu, H. P. Single-molecule enzymology. J. Biol. Chem. 274, 15967–15970 (1999).

    Article  CAS  Google Scholar 

  52. Mehta, A. D., Rief, M., Spudich, J. A., Smith, D. A. & Simmons, R. M. Single-molecule biomechanics with optical methods. Science 283, 1689–1695 (1999).

    Article  ADS  CAS  Google Scholar 

  53. Fisher, T. E. et al. Single molecule force spectroscopy of modular proteins in the nervous system. Neuron 27, 435–446 (2000).

    Article  CAS  Google Scholar 

  54. Ball, P. Life's lessons in design. Nature 409, 413–416 (2001).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

The investigation of stochastic sensors in the Bayley laboratory has been supported by DARPA, DOE, NIH, ONR and the Texas Advanced Technology Program. The development of membrane arrays in the Cremer laboratory has been supported by ONR, ARO, ACS-PRF, 3M Corporation and the Texas Advanced Technology Program. We thank the members of our laboratories for their energetic pursuit of these projects, and D. Deamer and J. Kauer for comments on the manuscript.

Author information

Authors and Affiliations

  1. Department of Medical Biochemistry & Genetics, The Texas A&M University System Health Science Center, College Station, Texas, 77843-1114, USA

    Hagan Bayley

  2. Department of Chemistry, Texas A&M University, College Station, Texas, 77843-3255, USA

    Hagan Bayley & Paul S. Cremer

  3. Center for Integrated Microchemical Systems, Texas A&M University, College Station, Texas, 77843-3255, USA

    Hagan Bayley & Paul S. Cremer

Authors
  1. Hagan Bayley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul S. Cremer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hagan Bayley.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bayley, H., Cremer, P. Stochastic sensors inspired by biology. Nature 413, 226–230 (2001). https://doi.org/10.1038/35093038

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/35093038

This article is cited by

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