Nanobiotechnology

Electronics revolutionized biological research twice in the past century. The ability to make precise and quantitative high-impedance measurements in live cells made it possible to understand the molecular basis of nerve activity and to observe single biological molecules in action. The Nanobiotechnology Project’s goal is to combine electronic and optical metrologies to help address the next generation of problems in cell biology research and for critical applications in health sciences and homeland security. The methods under development are designed to provide a better understanding of complex dynamic processes in cells, to determine the structure of membrane proteins, and to detect and quantify a wide range of biological molecules.

The reductionist paradigm, which has brought about spectacular gains in our understanding of physical and chemical systems, has been applied to biology and culminated with the sequencing of the entire human genome. While powerful, this approach has not provided a complete understanding of biological systems.

The new Systems Biology approach suggests that theability to simultaneously detect, quantify, and characterize biological molecules is needed to understand how cells work. That capability will require a significant breakthrough in metrology because a human cell can express in excess of 30,000 different proteins and other biomarkers. In addition, cells’ and tissues’ behavior is time-dependent.

Electronics has the potential to address these challenging measurement issues because semiconductor devices can be miniaturized, are scaleable, make use of systems integration, and have the appropriate dynamic and temporal ranges. Techniques that hold promise, and that are just emerging from the fields of bioelectronics and biophysics, include nanotransducers (nanopores, nanowires), single molecule optical characterization, and manipulation and isolation approaches (including dielectrophoresis, laser tweezers, and microfluidics). These and related techniques must be further advanced and validated, so that measurements of complex molecular interactions with single molecule sensitivity can be made available to researchers and the healthcare community. Towards that goal, we are developing tools for biomarker metrology.

For example, we have shown that single nanopores can used to identify, quantify, and characterize ions, RNA, DNA, proteins, and toxins. We have also demonstrated proof-of-concept for a highly sensitive conductance-based method for aqueous-based mass spectrometry and more recently increased the mass resolution. 

In collaboration with scientists in the NCNR, CSTL, and elsewhere we are also developing methods for determining the structure of integral membrane proteins, which are both the principal targets of health-related therapeutic agents. Electronic measurements are being used to verify that the proteins are fully functional. This capability is a significant achievement in structural biology research.

• Developed a method that combines electronic measurements and neutron reflectometry to determine the structure of fully functional membrane proteins
• Initiated protein structural studies that combine fluorescence and neutron scattering measurements
• Estimated the diameter of the anthrax toxin that punches holes in cells
• Determined how two anthrax toxins interact with each other
• Extracting intact single mitochondria from cells for disease studies
• Improved the resolution for our innovative conductance-based single molecule mass spectrometry method