1. Platforms to combat emerging viruses: (A) Viral neutralization and stopping viral entry: Our adaptive  immune system evolves antibodies in real time to combat threats associated with invading pathogens. Inspired by how our adaptive immune system evolves antibodies, we are developing novel laboratory evolution platforms for evolving antibodies targeting emerging zoonotic pathogens. Such antibody evolution approaches are expected to provide a platform for evolving human antibodies targeting epitopes on viruses, drug resistant bacteria and cancer. We are also developing single B-cell sequencing platforms and are using the enriched antibody sequences as evolutionary starting points. Our observations could also inform vaccine design and diagnostics. (B) Targeting viral replication: During the course of evolution, viruses evolved to have an RNA cap structure that is chemically identical to the host mRNAs; essentially viruses mimic their genomes or transcripts as host mRNAs. These viral RNA cap structures are necessary for viral replication, translation and immune evasion. We are developing synthetic biology approaches to understand the molecular details of these essential viral enzymes. Further we are using a directed evolution to target these enzymes to systematically engineer attenuated variants and study the implication of these attenuated variants on viral pathogenesis. We are also using medicinal chemistry approaches to develop novel antivirals selectively targeting viral RNA capping enzymes over human RNA capping enzymes. We are expanding these approaches to combat human and animal viruses. 

2. Directed endosymbiosis for evolutionary studies and synthetic biology: Endosymbiotic theory suggests that mitochondria and chloroplasts evolved from free-living prokaryotes which entered the host cell and were retained as endosymbionts; however, there is a minimal understanding of chloroplast evolved from cyanobacterial endosymbionts. We are developing synthetic model systems to study chloroplast evolution by generating cyanobacterial endosymbionts within eukaryotic cells. Our studies focus on studying various stages of chloroplast evolution including but not limited to (i) cyanobacterial endosymbiont genome minimization, (ii) engineer cyanobacterial endosymbionts to secrete photosynthetic end-products, (iii) develop strategies to facilitate protein exchange between the endosymbiont and host and (iv) mutation-based evolution and selection. These studies are expected to provide molecular details into the evolution of structure/function of complex organelles in eukaryotic cells. Further, these studies are providing us with a roadmap to build synthetic endosymbiotic systems for various synthetic biology applications. Synthetic Biology applications: Engineering genetically tractable yeast/cyanobacteria endosymbiosis will be to generate "photosynthetic yeasts". This platform will couples the biosynthetic and biocatalytic potential of yeast to the photosynthetic ability of cyanobacteria; essentially the cyanobacterial endosymbionts will act as artificial chloroplasts for yeast cells. This platform will allow us harnessing light and photosynthesis to biosynthesize high value molecules like natural products, biofuels among others.

3. Engineering selectivity in targeting cancer: We are combining synthetic biology, synthetic chemistry and material science to develop fundamentally novel, modular platforms for selectively targeting cancers with defined biomarkers. We are using principles of directed evolution and biomolecule delivery platforms to engineer novel biologics that specifically target cancers where the biomarkers are well characterized.