(6d) Genome-Scale Models for Systems Biology and Combinatorial Drug Discovery

Research Overview:

In my current position as a Harvard Junior Fellow, I have established an independent research program focused on developing systems biology approaches for multi-omic data integration and drug discovery. As a faculty, I propose to lead a research lab that develops genome-scale approaches that enable model-driven combination therapy and genome engineering – two challenging problems that are high dimensional in nature and have a large search-space of solutions, necessitating a computational approach. Yet solving them can have a tremendous global impact by addressing drug resistance in cancer and infectious diseases, and can enable rational genome design for biotechnology applications. My proposed research builds on my strength in developing innovative methods that reconstruct and model biological networks, such as PROM, ASTRIX, INDIGO and GEMINI. My accomplishments, described below, highlight my ability to successfully secure research funding, execute innovative research projects, establish collaborations with academic labs and biotech startups, and mentor scientists.  (web: http://scholar.harvard.edu/sriram) 

Positions: 

1. 2008 – 2013  PhD (Systems Biology), University of Illinois, Urbana (Advisor: Nathan Price)
2. 2011 – 2013  Visiting Fellow, Institute for Systems Biology, Seattle
3. 2013 –          Junior Fellow and Principal Investigator, Harvard University, Cambridge (Mentor: James J. Collins, MIT)
4. 2013 –          Visiting Fellow, Broad Institute of MIT and Harvard, Cambridge

Successful Proposals: 

1. William Milton Fund, Harvard Medical School (PI)
2. Harvard Junior Fellowship from the Harvard Society of Fellows
3. Robert Emerson Fellowship
4. Howard Hughes Medical Institute (HHMI) International Predoctoral Fellowship

Current and Past Research Accomplishments:

A. Genome-scale Modeling and Drug-discovery:

1. Developed the first integrated framework called PROM (Probabilistic Regulation of Metabolism), for automated integrated modeling of metabolic and regulatory networks at the genome-scale (Chandrasekaran and Price, PNAS 2010).

2. Created the GEMINI (Gene Expression and Metabolism Integrated for Network Inference) algorithm, that integrates data across many published experiments to iteratively test and curate network models to improve their predictive ability (Chandrasekaran and Price, PLOS Computational Biology, 2013). 

3. Developed a new approach called INDIGO (Inferring Nonlinear Drug Interactions using a chemo-Genomic Omnibus), which predicts novel antibiotic combinations with enhanced potency from chemogenomic data (Chandrasekaran et al, in revision)

B. Reverse-engineering and Multi-Omic Data Integration:

1. Designed a new reverse engineering pipeline called ASTRIX (Analyzing Subsets of Transcriptional Regulators Influencing eXpression), to reconstruct the first genome-scale model of a gene regulatory network operating in the brain, and identified regulatory genes that control behavior states in the brain (Chandrasekaran et al PNAS 2011).

2. Integrated analysis of transcriptomic and metabolomics data led to the discovery of a novel metabolic state in the brain of aggressive honeybees that is strikingly similar to a metabolic alteration that occurs in cancer cells called the Warburg Effect. (Chandrasekaran et al, Genes Brain and Behavior, 2015).

3. Currently developing new metabolic models that integrate transcriptomic, epigenomic and metabolomics data to investigate normal and aberrant metabolic states, such as the Warburg Effect, in diverse cancers and in brain disorders (supported by seed funding from the William Milton Fund to S.C). This can lead to metabolic drug targets or adjuvants for combination therapy for cancer and neurological disorders

Peer-reviewed Publications

⁺- Corresponding Author, * - Co-first author

 Research Articles:

1. Chandrasekaran S⁺, Cokol-Cakmak M, Sahin N, Yilancioglu K, Kazan H, Collins J.J⁺ and Cokol M⁺, “Chemical-genetic Inference of Antibiotic Interactions for Combination Therapies” (in revision)
2. Chandrasekaran S*, Rittschof C*, Djukovic D, Gu H, Raftery D, Price N.D, and Robinson G.E, “Aggression is Associated with Aerobic Glycolysis in the Honey Bee Brain", Genes Brain and Behavior, 2015
3. Chandrasekaran S and Price N.D. “Metabolic Constraint-based Refinement of Transcriptional Regulatory Networks”, Plos Computational Biology, 2013. Highlighted in Nature Reviews Genetics
4. Chandrasekaran S, Ament S.A, Eddy J.A, Rodriguez-Zas S.R, Schatz B.R, Price N.D, and Robinson G.E, "Behavior-specific changes in transcriptional modules lead to distinct and predictable neurogenomic states", PNAS, 2011 (Cover Article). Highlighted in PNAS
5. Chandrasekaran S and Price N.D. , "Probabilistic integrative modeling of genome-scale metabolic and regulatory networks in Escherichia coli and Mycobacterium tuberculosis," PNAS, 2010
6. Brooks A.N, Reiss D.J, Allard A, Wu W, Salvanha D.M, Plaisier C, Chandrasekaran S, Pan M, Kaur A, Baliga N.S. “A system‐level model for the microbial regulatory genome”, Molecular Systems Biology, 2014

Review Articles:

1. Chandrasekaran S, “Predicting Phenotype from Genotype through Reconstruction and Integrative Modeling of Metabolic and Regulatory Networks”, Systems and Synthetic Biology: A Systematic Approach,  2014
2. Simeonidis E, Chandrasekaran S, Price N.D. “A guide to integrating transcriptional regulatory and metabolic networks using PROM (Probabilistic Regulation of Metabolism)”, Methods in Molecular Biology: Systems Metabolic Engineering, 2012.
3. Sung J, Wang Y, Chandrasekaran S, Witten DM, and Price N.D, “Molecular signatures from omics data: from chaos to consensus”. Biotechnology Journal, 2012.
4. L.B. Edelman, Chandrasekaran S, and Price N.D. "Systems biology of embryogenesis”, Reproduction, Fertility, and Development, 2010.

Honors and Activities:

1. Elected to the Harvard Society of Fellows, 2013
2. Lemelson MIT Illinois Student Award for innovation - finalist, 2012
3. HHMI International Predoctoral Fellowship, 2011
4. Outstanding Oral Presentation Award, CMBTG Symposium, UIUC, 2010
5. Biophysics Travel Grant Award, 2010
6. Q-Bio Conference Travel Fellowship, 2010 
7. Reviewer for PNAS, Plos One, BMC Systems Biology, Molecular Biosystems, Journal of Theoretical Biology