Follow @IARPAnewsBio-Intelligence Chips (BIC) Program
The human adaptive immune system is known to carry a long-term memory of its exposure to antigens, i.e., molecules derived from the chemical constituents of pathogenic organisms and viruses. Human immune memory resides in T and B memory cells (lymphocytes), and also in plasma cells that secrete circulating antibodies into the bloodstream directed against specific antigens. Vaccines, which are designed to provoke lasting responses that can lead to disease resistance, purposefully stimulate the adaptive immune system. Immune memory can be extremely long-lived. Certain forms of persistent response have already been well established through biomedical research, while other forms remain less well characterized at the present.
IARPA is interested in the human physiological changes resulting from chemical, radiological and biological exposures reflected in omni-omic signatures(REF: 1), i.e., immunological, transcriptional, genomic, proteomic, metabolomic, epigenetic and microbiomic characteristics. BIC envisions developing an understanding of how such exposures present within an array of biological functions can be used to build a biological response signature.
The goal of the BIC program is to develop portable Lab-on-a-Chip (LOC) platforms that provide simultaneous read-out and analysis of omni-omic signatures. The BIC program will be a multiple phase program that will develop revolutionary biotechnology for lab-on-a-chip platforms to determine the exposure status of an individual to a suite of pathogens and toxins of interest. Further, the BIC program will develop integrated LOCs that can determine exposures to industrial chemicals, toxins, and radiological materials. LOCs that can detect and identify proteins, DNA, miRNA, siRNA, and small molecules such as certain pharmaceutical agents, nerve agents and toxic industrial chemicals simultaneously are therefore important to the BIC program. Analyses should be done with high reliability and based on the collection of a small (microliters) blood sample, or secretory sample (saliva or urine specimen). Multiple methods of detection such as Surface Enhanced Raman Spectroscopy (SERS), nano-resonators, molecular beacons, ion mobility, fluorescence, or other ultra-sensitive read-out modalities should be considered for orthogonal identification of analytes.
The BIC program will develop hardware and bioassays and methods to gather bio-intelligence in the field. The BIC program will require aggressive research and advancements in LOC technologies (e.g., digital microfluidics) and omni-omic signature identification and correlation. The LOC platforms should be able to provide end-to-end sample processing from sample in to analyzed output in less than 10 minutes in a handheld device.
At a minimum the LOC platforms will require sample clean-up and pre-processing, automated operation, potential for single molecule detection, orthogonal multi-analyte detection modalities to minimize false alarm rates, and automated analysis/reporting output. Omni-omic signature databases will need to be developed that provide statistical relevance, minimize false positives, and provide confidence factors from correlated data.
The vision of the BIC program is to develop revolutionary technologies for omni-omic detection and analysis that provide answers to the following questions, among others:
1) What information can be gathered about human exposure to dangerous chemicals, radiological materials, and/or biological pathogens by examining an individual’s omni-omic signature?
2) Can we determine the exposure history (temporal) of an individual based on assessment of his or her omni-omic signature?
3) Algorithms: Is it possible to differentiate between vaccination and natural exposure to a biological pathogen using an omni-omic approach?
4) Bio-Assay Design: What are the absolute or potential show-stoppers (e.g., cross-reactivity of epitopes) for developing a rapid (< 10 min), lab-on-a-chip, multiplex assay that relies on binding interactions between receptor molecules (probes) and their corresponding epitopes/glycotopes exposed on the analyte? What means might be developed to overcome such show-stoppers?
5) Bio-Assay Design: What are the key challenges with bioinformatics tools presently available for epitope (conformational and linear) and glycotope predictions? Using the present tools, how long might it take to design reliable probes for newly discovered organisms at the strain level? What technologies/methods might be developed to decrease the design time?
6) Automation: What are the challenges associated with developing a reconfigurable digital microfluidic chip that can be programmed to assay for a specific bioagent of interest on the fly?
7) Sample pre-processing: Given that protein extraction efficiency is typically 40% on-chip, what are some scalable methods that would enable achieving close to 100% extraction efficiency (similar to macro-scale extraction)?
8) Sample pre-processing: What is the best separation resolution that on-chip techniques can accomplish rapidly?
9) Detection: How does functionalization chemistry affect detection limit in pre-processed and raw blood, saliva, urine for a model protein? How important is the surface density and orientation of the receptor molecule? From a QA/QC perspective, are these parameters variable enough such that measurements of both (surface density and orientation) for specification-compliance would be necessary?
10) Detection: If the input analyte concentration is very low and one needs to ensure that each analyte is released after capture, how would one reverse the binding of an analyte? Can this or has this been done at the level of a single molecule within a single droplet or vesicle?
11) Detection: Several types of resonators have enhanced zones versus dead zones in which sensing are not possible. This suggests that patterned or directed functionalization of receptor molecules on resonators would be beneficial. What are some of the promising ways to perform patterned or directed functionalization en masse? Upon functionalization, are resonator qualities degraded?
12) To preserve a small biological sample on-chip for later analysis, what preservatives are readily available for preserving proteins in non-refrigerated environments? What is their period of reliability? Do new preservatives need to be developed?
The BIC program aims to provide innovative contributions in the following areas: 1) real human sample clean-up and pre-processing, 2) bioassay development, 3) digital microfluidic controls, 4) rapid detection and readout of at least one bioassay, and 5) information processing and correlation.
Collaborative efforts and teaming among potential performers are strongly encouraged. It is anticipated that teams will be multidisciplinary with capabilities including, but not limited to, lab-on-a-chip design, bioassay development, diagnostic instrumentation/equipment design, bio-technology, and immunology. Team members should complement each other’s technical expertise and resources.
IARPA anticipates that universities and companies from around the world will participate in this program.
