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Summary

We are developing methods, technology, and theories to enable the efficient detection, characterization, and identification of biological molecules.  Our focus is primarily on addressing next generation health care applications using advanced single-molecule detection techniques. Recent efforts are directed to the identification of RNA and proteins at low copy number, and the physical characterization of metallo-nanoparticles at low concentration.  Realization of these new measurement tools could prove useful for personalized medicine applications, early cancer detection, and developing drugs against infectious bacteria and other forms of disease.

    Description

    Single molecule mass Spectrometry (Image courtesy of Jeffrey Aarons)

    Figure 1. Single Molecule "Mass Spectrometry".  The size and amount of charged adsorbed onto a single molecule is measured by the degree it reduces the flow of ions through a nanometer-scale pore.

    Every person is unique, and that holds true for how each of us respond to therapeutic drugs. Pharmaceutical and health care industries currently lack measurement tools to determine whether such treatments will be effective, harm or even cause the death of individual patients. To help address this issue in part, we pioneered and developed an electronic nanopore-based method for single molecule metrology. The technology is currently being used to sequence DNA at the single molecule limit, and will hopefully prove useful to rapidly identify thousands of different proteins in blood. In addition to aiding the next generation of personalized health care applications, these methods should also provide insight into fundamental cellular properties, which could lead to understanding the molecular basis of disease.

    We also seek to help resolve a long-outstanding problem of determining the structures of membrane proteins, which is crucial for the cost-efficient development of pharmaceutical therapeutic agents.

    Major Accomplishments

    2016

    • Post-doctoral fellow Jessica Ettedgui developed a method to physically characterize individual metallo-nanoparticles at concentrations far below those used in conventional assays.  The method can even discriminate between isomers of certain particles.
    • Post-doctoral fellow Jacob Forstater developed a time domain-based analytical theory for analyzing single molecule data.

    2015

    • Developed a novel method to detect and physically characterize single metallic nanoparticles
    • Showed the ability to electronically discriminate between different neurotransmitters
    • Released software for single molecule state detection (highly relevant for DNA sequencing apps)

    2014

    • Developed a method, based on physics and circuit theory, to discriminate between subtly different molecules
    • Presented Keynote/Plenary opening lecture at the 2014 International High Performance Liquid Chromatography Conference
    • Submitted several provisional patent applications for a process to identify individual proteins

    2013

    • Demonstrated the ability to rapidly heat single molecules and measure their response to temperature jumps; a technology that will support many applications including discriminating between subtly different molecules, understanding the mechanism of protein folding, etc.
    • Demonstrated experimentally a potential mechanism by which anthrax toxins kill cells
    • Critically evaluated a proposed DNA sequencing technology

    Nanopore-based DNA Sequencing-by-Synthesis Technology.
    Figure 3. Nanopore-based DNA Sequencing-by-Synthesis Technology. In collaboration with Columbia University, we demonstrated initial proof of concept for separating polymer tags that uniquely represent the 4 different DNA bases. Our collaboration has been extended to include a small company.

    NIST's concept for a portable Point of Care device for personalized medical applications.
    Figure 2. NIST's concept for a portable Point of Care device for personalized medical applications. The ability to simultaneously quantitate thousands of different types of protein in blood will dramatically change disease detection and management, as did the electronic blood glucose meter late last century.
    Technical Goals:

    • develop the measurement science required to address next generation health care applications
    • determine the mechanisms by which bacteria infect and kill cells
    • develop new methods to determine membrane protein structure
    Created September 23, 2014, Updated April 5, 2019