The University of Colorado was recently awarded a cooperative agreement worth up to $14.6 million from the Defense Advanced Research Projects Agency (DARPA) to develop a new technological system to rapidly determine how drugs and biological or chemical agents affect human cells.
The project, called the Subcellular Pan-Omics for the Advanced Rapid Threat Assessment (SPARTA) will be conducted by an interdisciplinary CU-Boulder team led by Research Assistant Professor William Old of the chemistry and biochemistry department.
DARPA, an arm of the U.S. Department of Defense, wants to better understand the biochemical mechanisms at work during cellular exposures to biological or chemical agents to help prevent mortality during potential conflicts. The research also is expected to lead to new broad-scale techniques to analyze cellular processes to wide societal benefit.
"We believe the technology developed under this program will go far beyond military and commercial applications," said SPARTA Program Manager Emina Begovic. "We envision powerful applications of these new tools in a biomedical setting. Understanding how cells are affected by bacterial infection, for example, could lead to the development of new treatments."
"Traditionally it takes decades to figure out how drugs affect an organism's biology," says Old. "Our goal is to rapidly speed up the process, identifying how these compounds work, in weeks. This could lower the barriers to developing effective drugs that have minimal side effects."
Old's team will comprehensively measure all major classes of biomolecules that respond to any cellular treatment or biological signal within milliseconds to days. This will help to determine the key molecular events that mediate cellular responses. The team is developing new microfluidic devices to control and manipulate individual cell components to obtain subcellular resolution that will provide new insights into the functions of individual organelles and proteins within cells.
One example that illustrates the complexities of the project is the nerve gas, sarin, which causes a malfunction in a key cellular enzyme used to control muscles, resulting in their overstimulation.
"We know this drug causes negative effects in multiple signaling pathways," said Tristan McClure-Begley, a pharmacologist and analytical chemist working on the SPARTA team. "But what we lack a comprehensive understanding of the mechanisms that lead to long-term systemic damage in individuals the survive exposure."
The Jennie Smoly Caruthers Biotechnology Building already houses seven mass spectrometers in the Proteomics and Mass Spectrometry Core Facility directed by Old. These powerful instruments can identify the molecular components of a cell by measuring the mass of different molecules. The mass spectrometers are used for a range of projects, from identifying biomarkers for Alzheimer's disease to finding the mechanisms of drug resistance in metastatic melanoma. Under the DARPA contract, Old's facility will install to additional next-generation mass spectrometers at a cost of $2.2 million, which will also be used by scientists, students and local biotechnology companies who use the spectrometry facility.
SPARTA team members include Professor of Chemistry and Biochemistry and BioFrontiers Associate Director, Natalie Ahn; Associate Professor Michael Stowell of the molecular, cellular and developmental biology department; Professor Y.C. Lee of the mechanical engineering department; and Associate Professor Xuedong Liu of the chemistry and biochemistry department. The team also includes Associate Professor Nichole Reisdorph of the University of Colorado School of Medicine and National Jewish Health in Denver.