What basic mechanisms underlie development and how can we manipulate, disrupt, or correct them? I propose to study the collective behavior of Dictyostelium discoideum - a classic model organism for cell-cell signaling - focusing on how single-cell dynamics influence and give rise to the behavior of the aggregate. During starvation, Dictyostelium cells periodically secrete the chemoattractant cAMP, inducing production of cAMP in other cells. The result is a wavelike signal relay, and, ultimately, cellular aggregation. This transition from single-celled to multicellular life provides an ideal system to utilize my background in condensed matter physics to address a fundamental question in biology. At Princeton, I will collaborate closely with Thomas Gregor's lab, which developed the first FRET reporter of intracellular cAMP concentration. Their quantitative experiments provide a unique opportunity to connect the behavior of individual cells with the consequent fate of the population. The guidance of my mentor Ned Wingreen, an expert in bacterial chemotaxis, gradient sensing, and cell-cell communication, will be an invaluable resource. Through analysis of quantitative single-cell experiments, I have developed a model of the single-cell response to extracellular cAMP. My preliminary studies indicate that each cell behaves as an excitable system (a prime example is a spiking neuron). I will extend this model to study collective spatial dynamics mediated by diffusion of cAMP. In preliminary studies, I considered a "mean-field" situation, as in a well-mixed perfusion chamber, finding an intriguing dynamical quorum-sensing transition. To include spatial dynamics, I will first construct a model of spatial gradient sensing - unifying the concepts of excitability, adaptation, and directional sensing - guided by microfluidics-based experiments performed by the Gregor Lab. With this model, I will quantitatively reproduce aggregation through simulations of chemotactic cells. I will compare aggregation fidelity, measured by the size and spatial distribution of mound centers, against other chemotaxis mechanisms lacking excitable dynamics. I will then explore ways to disrupt faithful aggregation and make predictions for the behavior of various Dictyostelium mutants that can be tested in the Gregor Lab. Answering the questions in this proposal requires the right balance between using my background in condensed matter physics theory and engaging with the details of a complex biological system. The proposed project is therefore ideal for my transition to become an independent researcher working in the field of quantitative biology-it will allow me to use my established skills and to develop new ones. The environment at Princeton, both due to the guidance of my mentors, Professors Ned Wingreen and Thomas Gregor, and the greater community of quantitative biologists, provides an ideal setting to develop into an effective independent investigator.

Public Health Relevance

Understanding how modifications of single cells alter population-level dynamics may lead to new ideas for drugs and therapies. My findings are likely to be applicable to systems related to Dictyostelium, e.g. neutrophils migrating collectively withi lymph nodes or self-organized tissue migration during embryogenesis. In summary, I propose to use insights into cellular dynamics to reprogram macroscopic behaviors, which are best controlled at molecular and cellular levels.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Mentored Quantitative Research Career Development Award (K25)
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Modeling and Analysis of Biological Systems Study Section (MABS)
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Maas, Stefan
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Princeton University
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Schwab, David J; Nemenman, Ilya; Mehta, Pankaj (2014) Zipf's law and criticality in multivariate data without fine-tuning. Phys Rev Lett 113:068102
Bitbol, Anne-Florence; Schwab, David J (2014) Quantifying the role of population subdivision in evolution on rugged fitness landscapes. PLoS Comput Biol 10:e1003778