International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi
School of Medicine, New York, United States
Regional Centre for Biotechnology, Faridabad, Haryana
Since my school days, I had always been interested in life sciences. I used to get fascinated by biology and different biological processes. I did Bachelor of Science in Botany Honors from University of Delhi. My teachers were always supportive of my curiosity to science and encouraged me in every possible way. After completing my Bachelor degree, I joined Department of Genetics, University of Delhi for my Master degree. This was a very crucial stage of my scientific carrier. I studied the basics of genes, genetic variation, and heredity of different organisms. It was the time when I inclined towards the microbes and microbial genetics. Microbes are microscopic organisms that are found all around us and even inside our bodies. They include a range of organism including bacteria, viruses, algae, archaea, and protozoa. Among these, bacteria fascinated me the most and especially pathogenic bacteria. Pathogenic bacteria serve as a constant threat to human health and survival. Despite having a large repertoire of antibiotics, which are very effective against most bacterial infections, we always have the antibiotic-resistant bacterial strains.
After completing my M.Sc. in Genetics, I joined the Ph.D. program at International Center for Genetic Engineering and Biotechnology, New Delhi. As part of my Ph.D. work, I proposed the synthesis and selection of codon-shuffled de novo proteins that bind to a selected Mycobacterium tuberculosis (M. tuberculosis) protein target, the histone-like protein HupB, believed to be essential for mycobacterial growth. Using a versatile bacterial two-hybrid system that entailed utilization of HupB and various codon- shuffled protein libraries as bait and prey, respectively, we were able to identify proteins that bound strongly to HupB. One of the protein binders was expressed in Mycobacterium smegmatis and was shown to appreciably affect growth in the exponential phase, a period wherein HupB is selectively expressed. Next, I targeted secretory proteins of M. tuberculosis recognized to be involved in the virulence, proliferation, and pathogenesis of the pathogen. We isolated peptides bound to the virulence determinant protein Esat6, noting that all were less than fifty amino acids in length. We confirmed their binding with in vivo and in vitro examinations.
For my postdoctoral work, I choose the laboratory of Prof. Richard P. Novick at New York University School of Medicine. The Novick lab studies the pathobiology and molecular genetics of Staphylococcus aureus (S. aureus). In Novick’s lab, I started working on a remarkable family of phage-inducible chromosomal islands known as staphylococcal pathogenicity islands (SaPIs). These islands, often carry unique toxin genes, move readily between strains, mediate the transfer of unlinked chromosomal genes and interfere with the reproduction of the very phages they parasitize.
I have identified and characterized the diverse mechanisms by which SaPIs interfere with bacteriophage reproduction. One mechanism involves a SaPI-encoded protein that directly and specifically interferes with phage DNA packaging by blocking the phage terminase small subunit (TerSP). Another strategy involves interference with phage reproduction by the diversion of the vast majority of virion proteins to the formation of SaPI-specific small infectious particles. The third mechanism is unique in that it targets the promoter of late phage gene transcription, which is responsible for the production of virion and lysis proteins. These three entirely unrelated phage interference mechanisms represent a remarkable example of convergent evolution.
It is interesting to compare SaPI-mediated interference mechanisms with an entirely different phage-interference mechanism that of the clustered regularly interspaced short palindromic repeats (CRISPRs), which blocks phage propagation completely by degrading incoming phage DNA and thus blocks all phage-mediated horizontal gene transfer (HGT). In contrast, SaPIs interfere substantially with phage reproduction, however, they do not interfere completely with it and therefore do not have the downside of CRISPR system. Because the SaPIs are extremely common, with most strains harboring at least one, whereas the CRISPRs are extremely rare in S. aureus, it could be argued that the SaPIs have won that particular evolutionary contest.
The next stage of my carrier was to start my own S. aureus laboratory to carry forward my work to dissect out complicated virulence regulation and adaptation of this highly successful pathogen. I started looking for various funding opportunities to work in India. Finally, I decided to apply for Wellcome Trust/DBT India Alliance fellowship. The whole application and screening process of India Alliance fellowship is thorough and highly competitive. It provided me an extraordinary experience in grant writing and management. Overall, this prestigious fellowship allowed me a perfect start and sufficient funding for my research carrier in India. I joined Regional Centre for Biotechnology (RCB), Faridabad, in December 2016 as Wellcome Trust/DBT intermediate fellow.