The war on terror has been much like aiming at a moving target. However, an alliance of researchers is currently working on a project that could lead to a new tool for defense from biological and chemical threat agents. The project called SPARTAN (Single Protein Actuation by Real-Time Transduction of Affinity in Nanospace) aims to control the function of an isolated protein molecule by detecting and changing its shape in real time. Such advanced control of single proteins will significantly improve scientific understanding of the relationship between protein structure and function, and will create a new paradigm for sensors that employ real-time control of a protein’s conformation and biological activity.
The Defense Advanced Research Projects Agency (DARPA) is funding phase one of the project with $1.3 million because such a capability will provide the foundation for a new class of advanced sensors for the detection of chemical and biological weapons.
Scientists at the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE) are heading up the SPARTAN project and The University of Tennessee Space Institute’s Center for Laser Applications is playing a vital role in the yearlong research project. “Professor Lloyd Davis, Principal Investigator at UTSI, is a pioneer of single-molecule spectroscopy and his work was instrumental in winning this highly competitive project,” said UTSI Professor William Hofmeister, Director of the Center for Laser Applications. The DARPA project builds upon Davis’s ongoing research funded by the National Institutes of Health to develop highly sensitive multi-wavelength microscopes for bio-imaging. Others at UTSI who will contribute to the research include Professors Bruce Bomar and William Hofmeister, Shaun Li, Paul Shen, Peter Sikorski and Yelena White, and graduate students Isaac Lescano and Will Robinson.
“In the area of chemical and biological agent sensors, the controllable protein is the equivalent of the transistor in microelectronics,” said John Wikswo, Gordon A. Cain University Professor at Vanderbilt and director of the project. “The single transistor was a technical breakthrough, but its true potential was not realized until millions of transistors were combined on individual microcircuits,” Wikswo said. “Similarly, the true potential of controllable proteins will be realized when we can combine them into large arrays that can be dynamically tuned to respond to a wide variety of different agents.”
While the idea of controlling individual proteins may seem futuristic, most of the underlying tools already exist. For some time, scientists have known that a protein’s shape determines its function. Today, our understanding of the relationship between protein structure, conformational dynamics and function is growing dramatically. Combine this with a number of other recent developments – the capability to design and fabricate tailored proteins, the ability to use optical spectroscopy to monitor the shape of individual proteins, plus assorted advances in nanophotonics, biophotonics, micro- and nano-fluidics and modern control theory – and the result could be an important new national resource, according to Professor Davis.
The interdisciplinary SPARTAN project brings together researchers from Vanderbilt, the University of Tennessee Space Institute, the University of Texas at Austin, the University of Wisconsin-Madison, the University of Tennessee Knoxville, and Oak Ridge National Laboratory.
Vanderbilt University researchers have developed the capability to isolate and manipulate individual proteins within microfluidic and nanofluidic devices and to use nature to sort through billions of different protein possibilities to find those that bind most strongly under given conditions.
University of Tennessee Space Institute researchers have developed custom single-molecule microscopes with multi-color lasers and advanced control electronics and a laser nano-machining capability that can produce novel nanoscale platforms for the single-protein experiments.
Researchers at the University of Tennessee Knoxville have expertise in state-of-the-art control theory.
Oak Ridge National Laboratory researchers provide expertise and unique facilities for fabrication, characterization and imaging of nanoscale features to be used in the research.
University of Texas at Austin researchers have created highly efficient antibodies to anthrax-related biomolecules that will be used as the target proteins for initial demonstrations, have developed the means to insert organic chemicals in specific locations within proteins and have developed computer models for predicting the properties of such engineered proteins.
University of Wisconsin-Madison researchers have synthesized a class of organic chemicals that can be specifically attached to proteins and cause them to reversibly change shape when exposed to light of different colors.
The goal of the first phase of the project is to prove that it is possible to reversibly control the conformation of a single protein in real time. In the second phase, researchers will attempt to incorporate real-time control of protein conformation into novel technologies for the detection of chemical or biological threat agents.
Further information can be found at www.darpa.mil/dso/thrust/biosci/cpc.htm.