We propose to demonstrate proof-of-principle single DNA base discrimination by harnessing the one-atom thickness and electrical properties of newly emerging 2D materials (as thin as the separation between nucleotides). A direct readout of the DNA sequence may be possible by measuring the modulation of the current flowing through a single-layer novel 2D nanoribbon (NR) FET, beyond graphene, induced by each base in a single-stranded DNA molecule as it passes through a nanopore (NP) in that NR. This geometry is anticipated to exhibit large electrical current changes for each nucleotide base due to the unique electrostatic potential associated with each nucleotide. These potentials modulate the charge density in the narrow 2D FET NR, altering the corresponding NR current levels. The major benefit of this approach is that can NR may produce large currents, potentially enabling measurements at high speed. This approach is newer and high-risk, compared to ionic-current-based sequencing, and it is tremendously exciting because signal levels ~ A or higher are predicted, towards multiplexed high-bandwidth sequencing. This approach particularly addresses the three key obstacles to nanopore-based sequencing: 1) our approach circumvents the need to slow down DNA motion through the pore, 2) the predicted differences in electronic current for each base are large enough that we anticipate the signal-to-noise ratio will be large enough for base discrimination, even at this native speed, and 3) the sequence readout method is compatible with multiplexed detection. Important feasibility tests have already been realized in our group, but this project is still exploratory and suitable for the R21. Previous efforts in the community, involved pioneering carbon nanotube-NP FETs (e.g.,Golovchenko?s lab) and more recently, graphene-NP FETs by Drndic, Radenovic, and Dekker labs. Despite these results, due to the performance of measured graphene NR-NP FETs even when sub-10-nm-width, probably due to lack of significant bandgap, and the hydrophobicity of graphene, here we focus on a more promising, newer class of single-atom thin materials as candidate 2D channels. These NRs have tunable bandgaps and are more hydrophilic and include: 2D metal dichalcogenides (MoS2, WS2) and phosphorene. We previously tested 20 ? 200 nm wide single- layer graphene NRs with NPs carrying up to 10 A in 1 mM to 1M KCl solution at bandwidths as high as 100 MHz. We also developed a way to drill NPs without lowering the 2D NR conductance and observed correlated NR and ionic signals during dsDNA translocation. We anticipate that single-base resolution may be achievable at currently reported DNA translocation speeds (106 bases/s). This eliminates the need for custom high-speed ultralow noise electronics, as many off-the-shelf photodiode amplifiers for fiber-optics are designed for these current and bandwidth ranges. Illustration: The ACS Nano Cover Art from 2016 illustrating phosphorene (a 2D sheet of phosphorous atoms) nanoribbons (and nanopores) developed in Drndic lab, to be tested in this work, in addition to 2D metal dichalcogenides NR FETs.

Public Health Relevance

This research aims to achieve much faster and lower-cost DNA sequencing with the development of nanometer-sized electronic sensors constructed from atomically-thin, 2D sheets of semiconducting materials with tunable bandgaps, including metal dichalcogenides and phosphorene. It will enable major improvements in the understanding, diagnosis, treatment and prevention of disease, by allowing us to determine the underlying genetic causes and symptoms, detect these rapidly and accurately in patients, and treat them appropriately.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZHG1)
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Smith, Michael
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University of Pennsylvania
Schools of Arts and Sciences
United States
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