Biological Robustness in Complex Settings (BRICS)

Transcription

1 Biological Robustness in Complex Settings (BRICS) Justin Gallivan, Ph.D. Program Manager Biological Technologies Office Briefing Prepared for the National Academy of Sciences Future of Biological Products Committee Washington, DC July 25, 2016 Distribution Statement A (Approved for Public Release, Distribution Unlimited)

2 BRICS Will Develop Enabling Technologies Monitoring Water Quality Enhancing Resistance to Infection Sensing Chemicals Preventing Equipment Corrosion Providing On-site Bioproduction Distribution Statement A (Approved for Public Release, Distribution Unlimited) 2

3 Biological Robustness in Complex Settings (BRICS) Distribution Statement A (Approved for Public Release, Distribution Unlimited) 3

4 Program Plan, Technical Milestones & Deliverables Phase I (6 months) Prototype Phase II (12 months) Scale-up/Optimize Phase III (12 months) Demo Phase IV (18 months) Integration/App TA 1 Robustness Design methods for creating a self-organizing multispecies consortium. Demonstrate control of 2- species community. Expand Phase I work to a 5- species community. Engineer metabolic networks that divide labor between multiple species in a community of at least 5 species. TA 2 Stability Design a new genetic system that results in reduced tolerance to point mutations. Demonstrate stability in stressful conditions. Expand Phase I work to a 5- species community. Demonstrate the ability to maintain pure genotypes in a multi-species culture for 1000 generations. Solve a DoDrelevant problem as described in the second BAA TA 3 Safety Design methods for sensing physical and functional properties of communities. Demonstrate override mechanisms with simple reporter system Expand Phase I work to include intracellular monitoring. Demonstrate kinetics of override mechanism. Demonstrate complete growth arrest within 2 hrs and for up to 7 days after triggering override mechanism. Kick off 05/15 Today Next Decision 11/16 Next BAA estimated 04/17 Phase I Phase II Phase III Distribution Statement A (Approved for Public Release, Distribution Unlimited) 4

5 Four Approaches to Building Communities Natural Synthetic UT-Austin MIT Harvard Caltech 1. Top-down Engineering 2. Middle-in Engineering 3. Bottom-up Engineering 4. Synthetic Assembly Start with an existing community and develop methods for engineering in desired functions, safety, and stability. Start with a model for predicting potential symbiotic interactions between species, mix, and allow community to evolve. Engineer symbiotic relationships into domesticated strains to force a group of microbes to co-exist as a community. Physically manipulate and constrain growth of individual species, so that communities can be assembled from building blocks. Major Challenge: introducing new genes and circuits into undomesticated species Major Challenge: predicting evolutionary dynamics of the community Major Challenge: Engineering relationships between species that do not naturally live together Major Challenge: Balancing physical separation with the need to share metabolites and biosynthetic precursors Distribution Statement A (Approved for Public Release, Distribution Unlimited) 5

6 Team Harvard: Living biosensors that report and treat gastrointestinal infections PI: Pam Silver A robust, stable, and safe synthetic community of commensal gut bacteria that detects chemical signatures of pathogenic microbes. Stable colonization of synthetic community in mouse colon Signal amplification from proximal species to most abundant species Closed-loop control of in-situ therapeutic production Distribution Statement A (Approved for Public Release, Distribution Unlimited) 6

7 Team MIT: Modifying the gut microbiome to allow an animal to survive on a naturally indigestible food source PI: Tim Lu A gut microbiome engineered with synthetic metabolic pathways that enable an animal to extract energy from an indigestible source cellulose degradation community Distribution Statement A (Approved for Public Release, Distribution Unlimited) 7

8 PI: Nancy Moran Team UT-Austin: Controlling behavior of an animal through the gut microbiome Demonstration of engineering a microbiome to safely and stably control individual and collective animal behavior. Engineered for biosynthesis of neuropeptides or neurotransmitters Passed from bee to bee BGM: a community of only 8 species that lives in the bee hindgut Distribution Statement A (Approved for Public Release, Distribution Unlimited) 8

9 Team Caltech: Performing incompatible reactions through physical encapsulation PI: Rustem Ismagilov BioFARMs: Biologically Functional Assemblies of Robust Microenvironments One-pot synthesis of Brillinta : Distribution Statement A (Approved for Public Release, Distribution Unlimited) 9

10 Development of Supporting Technology Columbia University: Overlapping-ORFs algorithm MIT: In situ microbiome engineering Universal gene expression system GOI is stabilized by linkage with essential gene Engineered integrative conjugative elements LBNL: Community interaction modeling BCM: Community analytics Time-series data Principal component analysis Euclidean distance Network model Distribution Statement A (Approved for Public Release, Distribution Unlimited) 10

11 Distribution Statement A (Approved for Public Release, Distribution Unlimited) 11