We use synthetic biology and synthetic chemistry to study fundamental cellular chemistry and develop novel therapeutic strategies. Following are the key areas of research in the lab:
1. Platforms to combat emerging pathogens:
Emerging pathogenic RNA viruses: It has become imperative to develop novel therapeutics to tackle emerging RNA virus pathogens including coronaviruses like SARS-CoV-2.In order to develop novel strategies to combat RNA viruses, we are targeting an essential but relatively less explored target in RNA virus replication , translation and propagation, i.e., viral genome encoded RNA capping enzymes. We are using synthetic approaches to understand the molecular details of these essential viral enzymes. Further we are using a combination of synthetic chemistry and synthetic biology to target these enzymes with a view to develop live attenuated vaccine platforms and antiviral agents. We are expanding this approach to combat existing pathogenic RNA viruses like coronaviruses, Ebola virus and Zika virus, as well as other emerging RNA virus pathogens.
Drug-resistant bacteria: Antibiotics have been effectively used for decades to treat bacterial infections. However, the emergence of multidrug resistant bacteria has posed a significant challenge to develop new antibiotics. While several ongoing efforts focus on developing new antibiotics, the National Vaccine Advisory Committee has also suggested developing vaccines to combat antibiotic resistant bacteria. To this end, we are developing live attenuated bacterial vaccine candidates by using a combination of small-molecule synthesis, directed evolution and metabolic engineering.
2. Directed endosymbiosis for evolutionary studies and synthetic biology:
Chloroplasts are the key photosynthetic organelles in plants and green algal cells, and thereby an integral part of the global ecosystem. 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 model systems (Figure 1) to study chloroplast evolution by generating cyanobacterial endosymbionts within eukaryotic cells. Our studies focus on recapitulating 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. To the best of our knowledge, such an experimental recapitulation of chloroplast evolution starting from cyanobacterial endosymbionts has not been reported before. These studies are expected to provide insights into the evolution of structure/function of complex organelles in eukaryotic cells. Further, we plan on expanding this platform for various biomedical applications.
Biosynthesis and Metabolic engineering using “photosynthetic yeasts”: There is a huge need to develop sustainable platforms for production of high value molecules like Taxol, Artemisinin amongst others. Several semi-synthesis platforms are being developed for this purpose. We will investigate if we can utilize our genetically tractable yeast/cyanobacteria endosymbiotic platform to synthesize these molecules using photosynthesis. Our platform 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 our expertise in synthetic biology and synthetic chemistry to develop fundamentally novel, modular platforms to engineer selectivity in targeting cancers. 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.