Rapid Response to Biological Agents
National Challenge
Terrorism has altered our nation's priorities. These threats can adversely impact national security, including our health, the environment, and our nation's economy. The Rapid Response to Biological Agents Focus Area is addressing a need for biomarker-based detection systems for field surveillance and early detection of potential biothreats in an environmental setting. The scientific challenges lie in identifying biosignatures based upon molecular mechanisms of toxicity that could pinpoint internal dose and predict effects presymptomatically, rather than relying on external measures of exposure or observed symptoms that may present late in the disease progression. Use of biomarkers will provide early warning of environmental exposure to biological agents, and serve as a means for quickly assessing impacts and selecting appropriate countermeasures. Employing biomarkers could also facilitate triage of potentially exposed populations to ascertain levels of exposure; speed and guide actions to quarantine those affected; and/or enable effective communication by providing measurable assurances following the release of infectious or toxic substances.
PNNL's Integrative Approach
The hypothesis: A combination of proteins and/or metabolites in non-invasive biological samples can be identified and used to rapidly detect exposure and response to bioagents in an environmental setting. To test this hypothesis, the Focus Area will develop novel screening techniques, discover metabolite and protein signatures, and monitor biosignatures in live cells in real-time to identify biomarkers that predict cellular response to bioagent exposure and that lead to non-invasive, highly sensitive sensors and prognostic tools that identify bioterrorist and naturally occurring events. An important objective is to work in media that are readily accessible and less invasive than drawing blood samples (e.g., saliva, breath). The goal is to predict the response of individuals to biological agents in order to conduct environmental surveillance, gather intelligence on dissemination of infectious agents and to discriminate between the truly affected and the worried well during an exposure event.
Projects
PNNL's integrative approach will be demonstrated through projects that utilize a common pathogen model, Francisella novicida. While Francisella novicida is a mouse pathogen, rather than a human pathogen, it is a close relative of Francisella tularensis, cited as a pathogen of concern on agency lists of potential biological weapons. The Focus Area has developed a partnership with the University of Washington where PNNL will have access to animals being exposed to Francisella novicida, information generated on associated mechanisms of action identified, and samples from exposure trials. Proteins, peptides, volatile organics and various metabolites produced in response to exposure to the model pathogen will be identified. The integrated analytical approach will improve biosignature discovery capabilities through the discrimination of specific biomarkers, validation of biomarkers through reagent and platform development, and design of new statistical and computational methods for analyzing large sets of high dimensional data. Mass spectrometry instrumentation and experience will be used in sample analysis and identification of molecules uniquely produced in exposed treatments versus controls. In tracking location and prevalence of biomarkers in vivo and in real-time, capabilities and instrumentation including the 1H slow-MAS NMR and FTIR will be implemented. Integrating biosignature data derived from the same organism (Francisella novicida), but generated by different analytical techniques, will be the focus to providing a more complete understanding of the human response and which combination of biomarkers provide the best, early indicators of exposure.
Specific capabilities are being developed as part of the following projects:
- Characterization of Ex-vivo and In-vivo 1H-NMR Biosignatures of Respiratory Exposure to Model Systems
- Detecting Biomarkers in High-dimensional Data in the Presence of Unobserved Confounding Variables
- Discovery of Novel Volatile Organic Metabolic Signatures for Early Immune Response or Inflammatory Conditions
- Early, Validated Biomarkers of Infectious Diseases in Humans
- Protein and Peptide Markers of Infection
- Sensor Platforms for Biomarkers of Response to Biological Agents: Immuno-PCR Bead Assays for Detecting Early Biomarkers
- Sensor Platforms for Biomarkers of Response to Biological Agents: Nanoparticle Immunoassays for Detecting Protein Biomarkers
Focus Area Point of Contact: Joel Pounds