The behavior, adaptability, and survival of organisms, including pathogens or immune system components, depend critically upon the capability to formulate appropriate responses, at different time scales, to fluctuating temporal patterns of environmental cues such as ligand concentrations or stresses. Traditionally, mathematical studies have focused on constant environments and steady-state behaviors, not on naturally occurring signals and transient behavior. The ultimate goal of this work is to investigate, both theoretically and experimentally, the characteristics of biological responses to time-varying signaling and what information is encoded in them. The primary focus will be on the study of invariance with respect to sensory symmetries, with an initial emphasis on fold-change-detection (FCD), a property that confers signaling systems robustness to scale uncertainty. Recent molecular cell biology studies have experimentally discovered FCD behavior in prokaryotic chemotaxis pathways, allowing responses to broad ranges of chemoattractant concentrations, and in the eukaryotic epidermal growth factor ERK and the Wnt signaling pathways, allowing robustness of behavior in the face of large variations in protein abundances.
One aim of this work is to develop new, and to significantly expand existing, theory of FCD and other symmetries.
This aim will involve foundational work in areas of mathematics ranging from control theory to group representations. Broader significance will include new insights in nonlinear dynamics and systems biology, as the properties studied are emergent synthetic behaviors, not explainable easily from the properties of individual chemicals in isolation. A complementary aim is to develop an experimental platform to study transient behaviors, particularly in chemotaxis. New experimental tools will be established, based on microfluidic technology and on molecular level analysis of intracellular signaling (FRET), to afford unprecedented spatiotemporal control of stimuli during measurements and to allow the effective testing of mathematical predictions. Broader significance will be in fostering the development of new microfluidic technology of wide applicability in biology and biomedical engineering.

Public Health Relevance

Chemotaxis plays a key role in bacterial motion, as well as in embryonic morphogenesis, tissue organization, tumor angiogenesis, and wound healing. Activity of the ERK pathway controls cell proliferation, differentiation, and apoptosis. The Wnt signaling pathway plays a role in embryonic patterning and stem cell homeostasis, and its disregulation has been linked to colorectal cancer and hepatocellular carcinoma.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZGM1-CBCB-5 (BM))
Program Officer
Gindhart, Joseph G
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Rutgers University
Biostatistics & Other Math Sci
Schools of Arts and Sciences
New Brunswick
United States
Zip Code
Zarai, Yoram; Margaliot, Michael; Sontag, Eduardo D et al. (2018) Controllability Analysis and Control Synthesis for the Ribosome Flow Model. IEEE/ACM Trans Comput Biol Bioinform 15:1351-1364
Barish, Syndi; Ochs, Michael F; Sontag, Eduardo D et al. (2017) Evaluating optimal therapy robustness by virtual expansion of a sample population, with a case study in cancer immunotherapy. Proc Natl Acad Sci U S A 114:E6277-E6286
Menolascina, Filippo; Rusconi, Roberto; Fernandez, Vicente I et al. (2017) Logarithmic sensing in Bacillus subtilis aerotaxis. NPJ Syst Biol Appl 3:16036
Sontag, Eduardo D (2017) A Dynamic Model of Immune Responses to Antigen Presentation Predicts Different Regions of Tumor or Pathogen Elimination. Cell Syst 4:231-241.e11
Yang, Lu; Dolan, Elliott M; Tan, Sophia K et al. (2017) Computation-Guided Design of a Stimulus-Responsive Multienzyme Supramolecular Assembly. Chembiochem 18:2000-2006
Leitner, Lucia M; Wilson, Rebecca J; Yan, Zhen et al. (2017) Reactive Oxygen Species/Nitric Oxide Mediated Inter-Organ Communication in Skeletal Muscle Wasting Diseases. Antioxid Redox Signal 26:700-717
Son, Kwangmin; Menolascina, Filippo; Stocker, Roman (2016) Speed-dependent chemotactic precision in marine bacteria. Proc Natl Acad Sci U S A 113:8624-9
Ascensao, Joao A; Datta, Pratik; Hancioglu, Baris et al. (2016) Non-monotonic Response to Monotonic Stimulus: Regulation of Glyoxylate Shunt Gene-Expression Dynamics in Mycobacterium tuberculosis. PLoS Comput Biol 12:e1004741
Shah, Ami B; Rejniak, Katarzyna A; Gevertz, Jana L (2016) Limiting the development of anti-cancer drug resistance in a spatial model of micrometastases. Math Biosci Eng 13:1185-1206
Kang, Taek; Moore, Richard; Li, Yi et al. (2015) Discriminating direct and indirect connectivities in biological networks. Proc Natl Acad Sci U S A 112:12893-8

Showing the most recent 10 out of 27 publications