Drugs and treatments could be precisely tailored to an individual patient by extracting their cellular- and molecular-level information. For this approach to be feasible on a global scale, however, information on complete genomes (DNA), transcriptomes (RNA) and proteomes (all proteins) needs to be obtained quickly and at low cost. Quantum mechanical phenomena could potentially be of value here, because the biological information needs to be decoded at an atomic level and quantum tunnelling has recently been shown to be able to differentiate single nucleobases and amino acids in short sequences. Here, we review the different approaches to using quantum tunnelling for sequencing, highlighting the theoretical background to the method and the experimental capabilities demonstrated to date. We also explore the potential advantages of the approach and the technical challenges that must be addressed to deliver practical quantum sequencing devices.
At a glance
- The diploid genome sequence of an individual human. PLoS Biol. 5, 2113–2144 (2007). et al.
- The complete genome of an individual by massively parallel DNA sequencing. Nature 452, 872–875 (2008). et al.
- A HapMap harvest of insights into the genetics of common disease. J. Clin. Invest. 118, 1590–1605 (2008). , &
- Epigenetic reprogramming in plant and animal development. Science 330, 622–627 (2010). , &
- Genome sequence and analysis of the tuber crop potato. Nature 475, 189–194 (2011). et al.
- Whole-genome sequencing of Oryza brachyantha reveals mechanisms underlying Oryza genome evolution. Nature Commun. 4, 1595 (2013). et al.
- Rapid method for determining sequences in DNA by primed synthesis with DNA-polymerase. J. Mol. Biol. 94, 441–446 (1975). &
- Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001). et al.
- How to get genomes at one ten-thousandth the cost. Nature Biotechnol. 26, 1113–1115 (2008).
- A decade's perspective on DNA sequencing technology. Nature 470, 198–203 (2011).
- High-throughput DNA sequencing — concepts and limitations. Bioessays 32, 524–536 (2010). &
- High-throughput bacterial genome sequencing: an embarrassment of choice, a world of opportunity. Nature Rev. Microbiol. 10, 599–606 (2012). et al.
- Applications of next-generation sequencing technologies — the next generation. Nature Rev. Genet. 11, 31–46 (2010).
- The new paradigm of flow cell sequencing. Genome Res. 18, 839–846 (2008). &
- An integrated semiconductor device enabling non-optical genome sequencing. Nature 475, 348–352 (2011). et al.
- Performance comparison of benchtop high-throughput sequencing platforms. Nature Biotechnol. 30, 434–439 (2012). et al.
- Colloquium: physical approaches to DNA sequencing and detection. Rev. Mod. Phys. 80, 141–165 (2008). &
- The potential and challenges of nanopore sequencing. Nature Biotechnol. 26, 1146–1153 (2008).
A comprehensive review of nanopore-based methods for DNA sequencing.
- Nanopore sensors for nucleic acid analysis. Nature Nanotech. 6, 615–624 (2011).
A comprehensive review of recent advances and challenges in controlling the translocation speed of single DNA molecules through nanopores.
- Characterization of individual polynucleotide molecules using a membrane channel. Proc. Natl Acad. Sci. USA 93, 13770–13773 (1996). , , &
- Modeling the conductance and DNA blockade of solid-state nanopores. Nanotechnology 22, 315101–315105 (2011). , , &
- Directly observing the motion of DNA molecules near solid-state nanopores. ACS Nano 6, 10090–10097 (2012). , , &
- Pressure-controlled motion of single polymers through solid-state nanopores. Nano Lett. 13, 3048–3052 (2013). et al.
- Designed protein pores as components for biosensors. Chem. Biol. 4, 497–505 (1997). et al.
- Solid-state nanopores. Nature Nanotech. 2, 209–215 (2007).
A comprehensive review of recent advances in solid-state nanopores.
- Beyond the gene chip. Bell Labs Tech. J. 10, 5–22 (2005). et al.
- Integrated nanopore sensing platform with sub-microsecond temporal resolution. Nature Methods 9, 487–492 (2012). , , , &
- Topological jamming of spontaneously knotted polyelectrolyte chains driven through a nanopore. Phys. Rev. Lett. 109, 118301 (2012). , &
- Oxford Nanopore announcement sets sequencing sector abuzz. Nature Biotechnol. 30, 295–296 (2012).
- Improved data analysis for the MinION nanopore sequencer. Nature Methods 12, 351–356 (2015).
A demonstration of the feasibility of the MinION sequencer, which is based on biological nanopores.
- A first look at the Oxford Nanopore MinION sequencer. Mol. Ecol. Resour. 14, 1097–1102 (2014). &
- Partial sequencing of a single DNA molecule with a scanning tunnelling microscope. Nature Nanotech. 4, 518–522 (2009). &
- Electronic signature of DNA nucleotides via transverse transport. Nano Lett. 5, 421–424 (2005).
A paper that theoretically shows that quantum tunnelling can differentiate single nucleobases.
- Effect of noise on DNA sequencing via transverse electronic transport. Biophys. J. 97, 1990–1996 (2009). , , &
- Fast DNA sequencing via transverse electronic transport. Nano Lett. 6, 779–782 (2006).
A paper that proposes the quantum sequencing protocol.
- Improving sequencing by tunneling with multiplexing and cross-correlations. J. Comput. Electron. 13, 794–800 (2014). , , &
- Influence of the environment and probes on rapid DNA sequencing via transverse electronic transport. Biophys. J. 93, 2384–2390 (2007). , &
- Controlling DNA translocation through gate modulation of nanopore wall surface charges. ACS Nano 5, 5509–5518 (2011). , , , &
- DNA capture in nanopores for genome sequencing: challenges and opportunities. J. Mater. Chem. 22, 13423–13427 (2012). , , &
- Electrode-embedded nanopores for label-free single-molecule sequencing by electric currents. RSC Adv. 4, 15886–15899 (2014). , &
- Identifying single bases in a DNA oligomer with electron tunnelling. Nature Nanotech. 5, 868–873 (2010).
Proof-of-principle experiments demonstrating the identification of single-base molecules using recognition tunnelling.
- Single-molecule electrical random resequencing of DNA and RNA. Sci. Rep. 2, 501 (2012). et al.
- Base-calling of automated sequencer traces using Phred. II. Error probabilities. Genome Res. 8, 186–194 (1998). &
- Base-calling of automated sequencer traces using Phred. I. Accuracy assessment. Genome Res. 8, 175–185 (1998). , , &
- The accuracy of DNA-sequences — estimating sequence quality. Genomics 14, 89–98 (1992). &
- Quantum properties of atomic-sized conductors. Phys. Rep. 377, 81–279 (2003). , &
- Nanogap detector inside nanofluidic channel for fast real-time label-free DNA analysis. Nano Lett. 8, 1472–1476 (2008). &
- Tunnelling readout of hydrogen-bonding-based recognition. Nature Nanotech. 4, 297–301 (2009). et al.
- Electronic signatures of all four DNA nucleosides in a tunneling gap. Nano Lett. 10, 1070–1075 (2010). et al.
- Fabrication of the gating nanopore device. Appl. Phys. Lett. 95, 123701 (2009). , , &
- DNA tunneling detector embedded in a nanopore. Nano Lett. 11, 279–285 (2011). et al.
- Nanopore integrated nanogaps for DNA detection. Nano Lett. 14, 244–249 (2014). et al.
- Transverse electric field dragging of DNA in a nanochannel. Sci. Rep. 2, 394 (2012). et al.
- Local electrical potential detection of DNA by nanowire–nanopore sensors. Nature Nanotech. 7, 119–125 (2012). , , , &
- Toward sensitive graphene nanoribbon–nanopore devices by preventing electron beam-induced damage. ACS Nano 7, 11283–11289 (2013). , , &
- Detecting the translocation of DNA through a nanopore using graphene nanoribbons. Nature Nanotech. 8, 939–945 (2013). et al.
- Identifying single nucleotides by tunnelling current. Nature Nanotech. 5, 286–290 (2010).
Proof-of-principle experiments that identify single nucleotides via tunnelling currents using nanogap electrodes.
, , &
- Electrical detection of single methylcytosines in a DNA oligomer. J. Am. Chem. Soc. 133, 9124–9128 (2011). et al.
- Next-generation DNA sequencing. Nature Biotechnol. 26, 1135–1145 (2008). &
- Biogenesis of small RNAs in animals. Nature Rev. Mol. Cell Biol. 10, 126–139 (2009). , &
- Electric field effect in atomically thin carbon films. Science 306, 666–669 (2004). et al.
- A roadmap for graphene. Nature 490, 192–200 (2012). et al.
- Two-dimensional atomic crystals. Proc. Natl Acad. Sci. USA 102, 10451–10453 (2005). et al.
- Progress, challenges, and opportunities in two-dimensional materials beyond graphene. ACS Nano 7, 2898–2926 (2013). et al.
- DNA base detection using a single-layer MoS2. ACS Nano 8, 7914–7922 (2014). , &
- Graphene as a subnanometre trans-electrode membrane. Nature 467, 190–193 (2010). et al.
- DNA translocation through graphene nanopores. Nano Lett. 10, 3163–3167 (2010). et al.
- DNA translocation through graphene nanopores. Nano Lett. 10, 2915–2921 (2010). et al.
- Rapid sequencing of individual DNA molecules in graphene nanogaps. Nano Lett. 10, 420–425 (2010).
- Detection of nucleic acids with graphene nanopores: ab initio characterization of a novel sequencing device. Nano Lett. 10, 3237–3242 (2010). , &
- DNA base-specific modulation of microampere transverse edge currents through a metallic graphene nanoribbon with a nanopore. Nano Lett. 12, 50–55 (2012). , &
- Graphene quantum point contact transistor for DNA sensing. Proc. Natl Acad. Sci. USA 110, 16748–16753 (2013). , , &
- Capacitive DNA detection driven by electronic charge fluctuations in a graphene nanopore. Phys. Rev. Appl. 3, 034003 (2015). et al.
- Atomically thin molybdenum disulfide nanopores with high sensitivity for DNA translocation. ACS Nano 8, 2504–2511 (2014). , , &
- Identification of single nucleotides in MoS2 nanopores. Nature Nanotech. 10, 1070–1076 (2015). et al.
- Defensins: antimicrobial peptides of innate immunity. Nature Rev. Immunol. 3, 710–720 (2003).
- Antimicrobial peptides of multicellular organisms. Nature 415, 389–395 (2002).
- Therapeutic potential of venom peptides. Nature Rev. Drug Discov. 2, 790–802 (2003). &
- The co-evolution of host cationic antimicrobial peptides and microbial resistance. Nature Rev. Microbiol. 4, 529–536 (2006). &
- Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide. Nature Rev. Mol. Cell Biol. 8, 101–112 (2007). &
- Antimicrobial and host-defense peptides as new anti-infective therapeutic strategies. Nature Biotechnol. 24, 1551–1557 (2006). &
- Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nature Rev. Microbiol. 3, 238–250 (2005).
- Designing peptide receptor agonists and antagonists. Nature Rev. Drug Discov. 1, 847–858 (2002).
- More than one reason to rethink the use of peptides in vaccine design. Nature Rev. Drug Discov. 6, 404–414 (2007). , &
- Designing antimicrobial peptides: form follows function. Nature Rev. Drug Discov. 11, 37–51 (2012). , , &
- Proteomic analysis of post-translational modifications. Nature Biotechnol. 21, 255–261 (2003). &
- Post-translational modification of p53 in tumorigenesis. Nature Rev. Cancer 4, 793–805 (2004). &
- Post-translational modifications regulate microtubule function. Nature Rev. Mol. Cell Biol. 4, 938–947 (2003). &
- Post-translational modifications regulate the ticking of the circadian clock. Nature Rev. Mol. Cell Biol. 8, 139–148 (2007). &
- Post-translational modifications in the context of therapeutic proteins. Nature Biotechnol. 24, 1241–1252 (2006). &
- Method for determination of the amino acid sequence in peptides. Acta Chem. Scand. 4, 283–293 (1950).
- The ABC's (and XYZ's) of peptide sequencing. Nature Rev. Mol. Cell Biol. 5, 699–711 (2004). &
- Mapping protein post-translational modifications with mass spectrometry. Nature Methods 4, 798–806 (2007). , , &
- Single-molecule spectroscopy of amino acids and peptides by recognition tunnelling. Nature Nanotech. 9, 466–473 (2014).
Proof-of-principle experiments demonstrating the discrimination of amino acid molecules and peptides using recognition tunnelling.
- Detection of post-translational modifications in single peptides using electron tunnelling currents. Nature Nanotech. 9, 835–840 (2014).
Proof-of-principle experiments demonstrating the identification of amino acid molecules and the partial sequencing of peptides via tunnelling currents using nanogap electrodes.
- LIBSVM: a library for support vector machines. ACM Trans. Intell. Syst. Technol. 2, 27 (2011). &
- A tutorial on support vector machines for pattern recognition. Data Min. Knowl. Disc. 2, 121–167 (1998).
- A comparison of methods for multiclass support vector machines. IEEE Trans. Neural Networ. 13, 415–425 (2002). &
- Gene selection for cancer classification using support vector machines. Mach. Learn. 46, 389–422 (2002). , , &
- Least squares support vector machine classifiers. Neural Process. Lett. 9, 293–300 (1999). &
- Knowledge-based analysis of microarray gene expression data by using support vector machines. Proc. Natl Acad. Sci. USA 97, 262–267 (2000). et al.
- Direct growth of graphene/hexagonal boron nitride stacked layers. Nano Lett. 11, 2032–2037 (2011). et al.
- A low-noise solid-state nanopore platform based on a highly insulating substrate. Sci. Rep. 4, 7448 (2014). et al.
- Noise and its reduction in graphene based nanopore devices. Nanotechnology 24, 495503–495509 (2013). , , &
- Twisting and stretching single DNA molecules. Prog. Biophys. Mol. Biol. 74, 115–140 (2000). , , &
- Characterizing and controlling the motion of ssDNA in a solid-state nanopore. Biophys. J. 101, 2214–2222 (2011). , &
- Electrochemical characterization of thin film electrodes toward developing a DNA transistor. Langmuir 26, 19191–19198 (2010). et al.
- Quantized ionic conductance in nanopores. Phys. Rev. Lett. 103, 128102 (2009). , &
- Ionic coulomb blockade in nanopores. J. Phys. Condens. Matter 25, 065101–065105 (2013). &