Fun GCAT (Functional Genomic and Computational Assessment of Threats)

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1 Fun GCAT (Functional Genomic and Computational Assessment of Threats) John Julias, Ph.D. Program Manager Intelligence Advanced Research Projects Activity (IARPA)

2 Fun GCAT seeks to significantly advance our biosecurity capabilities OVERALL GOAL Improve our analytical capabilities in order to detect and prevent both accidental and intentional biological threats OVERALL APPROACH Develop enhancements to assess DNA screening ( ex. synthesis orders); provide improved capabilities to analyze and characterize the function and threat potential of both natural and manmade unknown genetic sequences; and develop new methods to experimentally characterize novel sequences 2

3 Overview Thrust 1: Computational tools for better screening of DNA sequences Thrust 2: Experimental approaches for determining function Sequence Information (e.g., origin, function, threat) FUTURE STATE Fun GCAT advancements CURRENT STATE Sequence Length Current methods for DNA sequence analysis require a trade-off between time, accuracy, and sequence length. Fun GCAT seeks to improve the ability to screen shorter sequences while maintaining accuracy and decreasing the time needed for analysis. Advances in the analysis of how biological molecules interact with each other and their hosts will allow the development of better models to characterize unknown sequences, understand their functions, and reduce the risks of creation of a threat. 3

4 THRUST 1 (Computational) APPROACHES Optimize and integrate currently available bioinformatics tools and databases using machine learning Leverage high-throughput modeling statistics Use ensemble and Bayesian fusion approaches to derive overall predictions on sequence characteristics TARGET DELIVERABLE Source code for a computational pipeline that automatically evaluates DNA sequences and reports sequence origin (taxa), functional information, and threat level Significant reduction in the length of DNA sequences whose threat potential can be evaluated PERFORMERS Battelle Memorial Institute Virginia Tech Signature Sciences SRI 4

5 THRUST 2 (Experimental) APPROACHES High-throughput methods to evaluate sequence function and threat Automatable methods to evaluate sequence function and threat Characterization of unknown functions TARGET DELIVERABLE Significant advancements in the experimental characterization of genetic sequence function Model systems to validate the characterization of genetic elements Apply tools to DNA sequences of concern to determine function of novel genetic elements for threat determination PERFORMERS Church Lab (Harvard) Silver Lab (Harvard) SRI 5

6 Church Lab Overview Aim 1: Screen purified polypeptides with a cell-type-specific cell-culture assay system to evaluate toxicity Aim 2: Improve substrates for evaluating toxicity Aim 3: For sequences that generate toxicity beyond a certain threshold, perform a high-throughput assay to detect their interactions with host proteins 6

7 Church Lab Overview Goal: Advance the ability to safely and rapidly test the toxicity and mechanism of action of toxins Approach: AIM 1 AIM 2 AIM 3 Develop bio-contained and encrypted expression systems to safely express DNA sequences of toxins Create cell-type-specific cellculture assays to evaluate toxicity Develop a high-throughput and - content automated approach to detect toxin/host protein interaction inside a single cell Complete Pipeline: 7

8 Silver Lab Overview Aim 1: A method to deliver viral proteins into mammalian cells and test effects on viral growth Aim 2: Testing viral proteins in insect cells Aim 3: Apply high-throughput cellbased drug-screening assays to test for viral gene function Goal: screen 950 viral genes to look for effects 8

9 Silver Lab Overview Goal: Develop rapid tests for viral genes that suppress host defenses Approach: AIM 1 AIM 2 AIM 3 Develop a wellrepresented panel of 1000 viral genes to test Develop yeastmammalian cell fusion systems for identifying viral genes that suppress host defenses Develop yeastinsect cell fusion system for identifying viral genes that suppress host defenses AIM 4 AIM 5 Develop assays for measuring viral gene impact on innate immune system pathways Develop an automated unbiased cell phenotype characterization approach using Cell Paint High-content cell-based screening 9

10 Cells Convey Information Through Networks 10

11 Takeaways Fun GCAT extends the ability to predict and experimentally determine gene function and host responses ECHO captures host-derived epigenetic signatures of exposure Success in both programs requires advances in data generation and analysis Determining the specificity of functional activities or epigenetic signatures will define program utility See powerful results in the application of neural networks for biothreat classification 11

12 Advice Develop a strong team Reach across organizations to compile the right expertise Stay on the path to success focus on the endpoint Risk mitigation and backup plans are key Develop internal waypoints that lead to milestones Have an internal validation plan Stay agile Team/re-team to adapt to new data, approaches, etc. 12