Angad P. Mehta

Evolution serves as a powerful inspiration for synthetic biology. We use evolutionary observations to design synthetic biology approaches for answering fundamental molecular question in biological systems or for developing novel translational platforms for human health. Key areas in the lab include:

1. Directed evolution and synthetic immunology 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 continuous directed evolution platforms for evolving human antibodies and biologics targeting emerging pathogens (viruses, drug resistant bacteria) and cancer. To identify new starting points for antibody evolution, we are also developing single B cell sequencing approaches to obtain antibody sequences from zoonotic host reservoirs. Our studies could inform biologics development, 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 organelles in eukaryotic cells. Synthetic Biology applications: These studies are providing us with a roadmap to build synthetic endosymbiotic systems for various 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.