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  • Subject area(s): Engineering
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  • Published on: 7th September 2019
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Being the most abundant living entities on earth, microorganisms are the fundamental aspect of our life. Whether bacterial, viral or eukaryotic in nature, microorganisms impact our life in many ways by influencing the dynamics and functions of every niche in which they inhabit. With their diverse metabolic repertoire, so as to their vast range of activities certainly learning microbial system is a challenging and simultaneously very fascinating field of work.

Currently, I am a Postdoctoral Research Fellow at the School of Engineering and Applied Sciences (SEAS) at Harvard University. At Prof Dave Weitz Lab, I am exploring drop based microfluidic system for various biological applications. In research, I have the same basic philosophy as teaching; that is, in order to understand a complex biological problem we need to gain the ability to think critically and analyze the problems with scientific methods for the logical conclusions. Based on my background and achievements (as described below), I believe, that I am an outstanding researcher in my specialty.

In response to different environmental stimuli, cells and microbes differentiate, proliferate and interact and also regulate its dynamic functionality by protein secretion, gene expression (including that by small-RNAs) and sometime secreting bio-compounds. To address problems at the forefront of human health and sustainability, my long term research goal is to understand how different environmental stimuli influence the functions and adaptations of microbes; using new technologies how we can explore the functionality of pathogens and pathogen causing human diseases; how efficiently we can utilize these understanding to develop new therapeutics.

The research spans at several scales (liters to picoliters), and for many environmental compartments (soil, sediments and clinical samples). Besides microbiological, genetical, biochemical and statistical methods, global tools such as genomics, transcriptomics, proteomics and metabolomics are the instrumental of my research. In typical in-vivo animal models and in-vitro test tube experiments, the result we receive is the average outcome of interactions of millions of cells populations whereas drop based microfluidics technique (pico or nanoliter scale) gives us the opportunity to reveal the functional and genetic contribution of individual cells. This microfluidic device is the instrumental in developing next generation, sophisticated point-of-care devices for health monitoring and for single cell genomics analysis.

Research Accomplishments

• My graduate research (2005-2010) at Kalyani University, India was focused on marine actinobacteria producing novel antibiotics and enzymes. This work was done in collaboration with Jadavpur University, India. I was one who has carried out the first systematic study of marine actinobacteria in the largest mangrove forest of the World, “Sundarban” and established the relationship between distributions of marine actinobacteria, its antagonistic behavior with the physico-chemical characteristics of sediment soil (Mitra et al.2008). The study gave me the idea how distributions and functions of actinobacteria were related with the soil environmental conditions. The potentialities of the strains to synthesize antimicrobials were evaluated against a broad spectrum of gram-positive, gram-negative bacteria, yeast and fungi. The potent strains were identified with polyphasic approach involving 16S rDNA, biochemical and morphological characteristics (Mitra et al. 2011). A new species Streptomyces sundarbansensis sp. nov. (Arumugam et al. 2011, joint co- first author) was reported. We also published that the strain produces 2-allyloxyphenol, first time reported as a natural product (Arumugam et al. 2011). I learned functions of microorganism depend on nutritional availability and every species has its unique requirement to maximize its functions or in other words, different species utilizes systems nutrition in different way for its optimum activity. Thus to maximize production of potential antimicrobials, the strains were studied under various environmental conditions including wide range of pH, high temperature and salinity (Mitra et al. 2011). This approach was used to optimize for the production of polyhydroxybutyrate by Haloarcula marismortui using vinasse, a byproduct of sugar industry (Pramanik et al. 2012).

• During postdoctoral research at Max-Planck Institute for Extra-terrestrial Physics (MPE) and Klinikum Schwabing (08/2011 – 09/2013), I used cold atmospheric plasma (CAP)-generated reactive species, charged particles, and photons as physical stimuli for therapeutic purposes (Mitra et al. 2012, Isbary et al. 2012). Plasma, which is most abundant form of universe, can be generated at room temperature. We used CAP as antibacterial agent to kill ‘the world’s toughest bacterium, Deinococcus radiodurans (Maisch et al, 2012). This study was carried out in collaboration with Regensburg University Hospital, Germany. For the inactivation of surface –borne microorganisms and simultaneously to increase germination of seed specimen, CAP was optimized (Mitra et al. 2014).  It was the first report where surface microbes were managed without compromising seed’s health. We also evaluated the safety standard of CAP where human skin is targeted (Isbery et al. 2013). The molecular mechanisms underlying the interactions between cold atmospheric plasma (CAP) and living cells (bacteria, spore, epithelial cells)  (Mitra et al., 2014; Isbary et al. 2013, Klämpfl et al. 2014) were studied.

• In the first phase of postdoctoral research (09/2013 – current) at Harvard University I worked at Quantitative System Biology Lab and studied how host interact with different microbes in presence of different environmental stimuli, using C. elegans as model system. During worm development, bacteria mainly serve as a source of food and act as commensals or symbionts but as worms’ ages, bacteria proliferate within the gut and become detrimental to the host. I studied interactions of worm and microbes (E. coli, Pseudomonas sp., Salmonella sp., and Lactobacillus sp.) and the collective avoidance behavior of worms. The research at Levine lab provided me a conceptual framework on how distinctive characteristics of ecological and genetic phenomena of different microbes influence the host physiology. The manuscript is under preparation.

• Presently, in the Experimental Soft Condensed Matter Group, I am using droplet microfluidics technique to encapsulate microbes and cells into millions of isolated picoliter and nanoliter-sized biological microenvironments to investigate the effect of different environmental stimuli. It helps us to understand the variability and dynamic nature of important biological phenomena at single cell or population level over a real-time. Moreover these drops can also be detected and sorted in a high-throughput fashion based on fluorescence measurement, ultraviolet –visible spectroscopy or electrochemical detection methods. Currently we are trying to screen targeted antibodies directly from B-cell activation, which can avoid traditional hybridoma fusion step and provide a platform for the naturally –selected antibody repertoire of immunized animals. Since it can screen ~4×107 drops or cells per hour and the reaction volume is in picoliter scale, the technology can significantly reduces time, cost and labor. First experiments on tnf-induced B-cells showed promising results and we are applying this technology to cure various diseases, including AIDS and Cancer.

In another project we are working on Persister cells which are antibiotic- tolerant and a major obstacle of clinical diagnosis and infections treatment. Since these persister cells represent a small fraction (less than 1 %) of the population, which is difficult to detect, we are using drop based microfluidics platform to directly visualize this rare phenomena.

Future Research Plan

With a goal to develop therapies or interventions that can directly or demonstrably contribute to reduce or eliminate health disparities, I would like to explore consequences of environmental stimuli on microbes in the field of species interactions; microbial metabolites; integration of pathogen -host biology and development of new therapeutics. My future research plans are following,

Species communication and interactions

In typical lab conditions bacteria grow in media that are rich in nutrients. In nature, they coexist with other microbes, forms communities; communicate, compete and cooperate for stability to withstand dynamic environments. Genomics shows that many microorganisms contain biosynthetic gene clusters for specialized metabolites that only expressed in presence of other metabolites such as exoenzymes, siderophores or virulence factors secreted from other microbes. It is interesting to know how the secreted metabolites act as common goods and make the decision to grow and secrete metabolites from other kind of bacteria. How the communications between bacteria are taking place? It will help to develop strategies to stimulate the expression of such gene clusters for the specialized metabolites that are not know yet. Measuring, monitoring and managing the relative contributions of these common goods on survival, evolution and functions of microbes will provide us better chance to handle and manipulate industrially and medically relevant microbial communities.

Space pathogenicity:

Space environment differs drastically from life on Earth. With a numbers of successful space missions in the recent past, there is a growing concern about the microbiological implications of long- term space travel and habitations. In addition to microorganisms that may already exist in space, cosmonauts will carry microbial life forms with them from Earth. In space, these organisms may react in unexpected ways to the environmental conditions that exist in reduced gravity or in the closed environment of a spacecraft. As a result, the microbiology of the space environment and its impact on human health has long been a concern. Molecular systems level understanding about the effect of microgravity and space ionizing radiation on human disease pathways and pathogenesis will highlight this research.

Single-cell genomics and micro- environment study of host and pathogens

Cells, the basic units of biology varied broadly in structure and functions. The genes it expresses, the molecules it produces, the functions it performs differs in presence of pathogenic infections. Thus transcriptional profiling of healthy and diseased cell populations at single-cell resolution will give a fundamental understanding of the consequences of host pathogen interactions.

Also to develop therapeutic strategies

• Performing next generation sequencing to identify genomic pathogenic signatures in complex clinical environment

• Performing studies to improve understanding of the biology of pathogens at single cell level

• Elucidating the interactions of pathogens with the host and the environment

• Creating models to capture multi-omic data (or data from genomics, proteomics, and metabolomics) to build interaction networks are important.

It will help us to know how pathogens interact and subvert a host’s immune response develop the knowledge to create new environmental detectors, medical diagnostics systems, therapeutics and vaccines to encounter natural or human made outbreaks.

Personalized immune tools

Pathogens could be virus or bacteria are known to contribute diseases either directly via the expression of their protein products or indirectly via chronic inflammation. In sudden pathogenic outbreak or in cancer, we need personalized -point of care therapeutic strategies for a robust immune response in a cost effective way. For that, I am interested to develop methods for fast analyzing and characterizing pathogens in clinical samples and tissues. The infected tissue may consist of different families of cells, varying in genetic and phenotypic conditions that may influence tumor or disease growth and development as well as resistance to therapeutics. Understanding how heterogeneous diseased cells are and how they will react functionally will improve our strategies for clinical management. High throughput single cell analysis of infected cells has open up to treat diseases in a personalized way. In long run I would like to extend my research also to characterize multiple aspects of antigen-specific B cells, how the repertoires of B cells develop and change in response to infection or interventions like vaccines.

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