University of Minnesota
Department of Biomedical Engineering
http://www1.umn.edu/bme
612-624-4507

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Brenda Ogle

Casim Sarkar

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Molecular Cell Engineering

Our laboratory uses the tools of biomolecular engineering, synthetic biology, and systems biology for two purposes: 1) to elucidate fundamental biological design principles that underlie cellular decision making and 2) to design new molecular and cellular therapeutics for diseases ranging from diabetes to cancer. We couple methods from experimental disciplines such as molecular biology, protein biochemistry, microbiology, and mammalian cell biology with computational modeling and engineering analyses to develop quantitative and predictive frameworks for the biological processes that we interrogate and design.

Elucidating biological design principles in cellular decision making

The inherent complexity and our incomplete understanding of native cell signaling networks often obfuscate the core biological design principles that govern how cells make decisions. A complementary approach to 'top-down' dissection of complex, natural signaling pathways is 'bottom-up' construction, analysis, and perturbation of minimal, well-defined signaling modules. We are applying both systems biology and synthetic biology approaches to elucidate mechanisms of signal processing and multimodal decision making in stem and progenitor cells. Through these studies we are uncovering novel modes of regulation in these natural systems, which in turn inform design strategies for rationally engineering cell behavior.

Designing new molecular and cellular therapeutics

The creation of novel molecular and cellular reagents for specific biomedical or biotechnological applications can often benefit from a quantitative, holistic perspective in order to maximize the utility of these products. We are using such systems-level approaches to overcome clinical challenges ranging from oral delivery of therapeutic proteins to eradication of tumors. When a system is sufficiently well characterized, we can employ modeling to elucidate mechanisms and design criteria; when the critical bottlenecks are less easily identified, directed evolution approaches can often be used to achieve the desired result and the outcomes of these selections can retrospectively provide deeper insight into the limitations that existed in the original system.

Selected Honors and Awards

2011-2016 - CAREER Award, National Science Foundation

2008-2012 - Scientist Development Grant, American Heart Association

2003-2005 - NRSA Postdoctoral Fellowship, National Institutes of Health

1997 - Graduate Fellowship, Howard Hughes Medical Institute (declined)

1997 - Graduate Fellowship, National Science Foundation (declined)

1997 - Graduate Fellowship, Whitaker Foundation (declined)

1997-2002 - Graduate Fellowship, Fannie and John Hertz Foundation (accepted)

Selected Publications

N.A. Shah, M. Levesque, A. Raj, and C.A. Sarkar. "Robust hematopoietic progenitor cell commitment in the presence of a conflicting cue." Journal of Cell Science, 128:3009-3017 (2015).

I. Dodevski, G.C. Markou, and C.A. Sarkar. "Conceptual and methodological advances in cell-free directed evolution." Current Opinion in Structural Biology, 33:1-7 (2015).

N.A. Shah and C.A. Sarkar. "Computationally guided design of robust gene circuits." Methods in Molecular Biology, 1244:167-178 (2015).

D.T.W. Ng and C.A. Sarkar. "NP-Sticky: a web server for optimizing DNA ligation with non-palindromic sticky ends." Journal of Molecular Biology, 426:1861-1869 (2014).

M.S. Magaraci, A. Veerakumar, P. Qiao, A. Amurthur, J.Y. Lee, J.S. Miller, M. Goulian, and C.A. Sarkar. "Engineering Escherichia coli for light-activated cytolysis of mammalian cells." ACS Synthetic Biology, 3:944-948 (2014).

H.M. Mehta, M. Futami, T. Glaubach, Q. Yang, D.W. Lee, J.R. Andolina, Z. Whichard, M. Quinn, H. Lu, W.-M. Kao, B. Przychodzen, C.A. Sarkar, A. Minella, J.P. Maciejewski, and S.J. Corey. "Alternatively spliced, truncated GCSF receptor promotes leukemogenic properties and sensitivity to JAK inhibition." Leukemia, 28:1041-1051 (2014).

C.A. Sarkar. "Concentrating (on) native proteins to control cell fate." Science, 341:1349-1351 (2013).

P.A. Barendt, N.A. Shah, G.A. Barendt, P.A. Kothari, and C.A. Sarkar. "Evidence for context-dependent complementarity of non-Shine-Dalgarno ribosome binding sites to Escherichia coli rRNA." ACS Chemical Biology, 8:958-966 (2013).

P.A. Barendt, D.T.W. Ng, C.N. McQuade, and C.A. Sarkar. "Streamlined protocol for mRNA display." ACS Combinatorial Science, 15:77–81 (2013).

D.T.W. Ng and C.A. Sarkar. "Engineering signal peptides for enhanced protein secretion from Lactococcus lactis." Applied and Environmental Microbiology, 79:347-356 (2013).

S.T. Jung, W. Kelton, T.H. Kang, D.T.W. Ng, J.T. Andersen, I. Sandlie, C.A. Sarkar, and G. Georgiou. "Effective phagocytosis of low Her2 tumor cell lines with engineered, aglycosylated IgG displaying high FcγRIIa affinity and selectivity." ACS Chemical Biology, 8:368-375 (2013).

D.T.W. Ng and C.A. Sarkar. "Model-guided ligation strategy for optimal assembly of DNA libraries." Protein Engineering, Design, and Selection, 25:669-678 (2012).

P.A. Barendt, N.A. Shah, G.A. Barendt, and C.A. Sarkar. "Broad-specificity mRNA-rRNA complementarity in efficient protein translation." PLOS Genetics, 8:e1002598 (2012).

S. Palani and C.A. Sarkar. "Transient noise amplification and gene expression synchronization in a bistable mammalian cell-fate switch." Cell Reports, 1:215-224 (2012).

E.C. O'Shaughnessy and C.A. Sarkar. "Analyzing and engineering cell signaling modules with synthetic biology." Current Opinion in Biotechnology, 23:785-790 (2012).

N.A. Shah and C.A. Sarkar. "Robust network topologies for generating switch-like cellular responses." PLOS Computational Biology, 7:e1002085 (2011).

S. Palani and C.A. Sarkar. "Synthetic conversion of a graded receptor signal into a tunable, reversible switch." Molecular Systems Biology, 7:480 (2011).

D.T.W. Ng and C.A. Sarkar. "Nisin-inducible secretion of a biologically active single-chain insulin analog by Lactococcus lactis NZ9000." Biotechnology and Bioengineering, 108:1987-1996 (2011).

E.C. O'Shaughnessy, S. Palani, J.J. Collins, and C.A. Sarkar. "Tunable signal processing in synthetic MAP kinase cascades." Cell, 144:119-131 (2011).