Abstract: Biological systems often display sudden, radical shifts in their state in response to small changes in the environment. Such """"""""""""""""tipping points"""""""""""""""" include disease outbreaks, the collapse of populations, and cellular differentiation. Given that many of these tipping points have huge health implications-either positive or negative-it is essential that we develop an increased understanding of these transitions. Although a complete understanding requires detailed knowledge of the system, recent progress in the theory of nonlinear dynamics argues that there are generic early warning indicators preceding such tipping points. In particular, theory predicts that fluctuations of the system should become larger and slower as the tipping point is approached, potentially signaling dramatic changes in the biological system. Here we propose to measure these early warning indicators experimentally, first at the level of the population before sudden collapse and next within individual cells before a change in cell state. We will start by using laboratory microbial populations that display catastrophic collapse in deteriorating environments. The primary model system will be budding yeast, which cooperatively breakdown the sugar sucrose. The cooperative nature of this growth means that in each environment there is a critical population size required for population survival;in response to a deteriorating environment the population therefore collapses suddenly. However, by measuring the day-to-day fluctuations in the population size we have observed both an increase in the size and timescale of the fluctuations as the tipping point approaches. To our knowledge, this preliminary work is the first experimental measurement of these early warning indicators in a population that displays catastrophic collapse. Now that we have demonstrated the feasibility of the approach, we will measure these early warning indicators in different deteriorating environments, in the presence of """"""""""""""""cheater"""""""""""""""" cells (that don't contribute to breaking down the sugar), and in laboratory ecosystems containing more than one species. We will also study population fluctuations before collapse in spatially extended populations;this coupling between neighboring regions is expected to obscure some early warning indicators, but may also cause spatial patterns to emerge before the tipping point. Finally, we will move to the level of the cell and explore whether it is possible to experimentally observe these early warning indicators before a phenotypic switch, initially in sugar utilization. Theory predicts that gene expression will become more variable before important cellular transitions such as differentiation. In addition, the timescale of fluctuations of the key proteins involved in the genetic circuit should increase before the switch. The experiments described in this proposal represent a unique opportunity to explore the universal signatures of biological systems before sudden transitions. Public Health Relevance: Biological systems can experience sudden """"""""tipping points"""""""" such as a disease outbreak, population collapse, cellular differentiation, or cancer metastasis. As many of these transitions have profound implications for human health, there would be extreme value in being able to determine in advance when such transitions are about to take place. Here we propose to study possible early warning indicators of impending tipping points that are based upon the fluctuations of the biological system.

National Institute of Health (NIH)
National Institute on Aging (NIA)
NIH Director’s New Innovator Awards (DP2)
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Special Emphasis Panel (ZGM1-NDIA-C (01))
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Velazquez, Jose M
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Limdi, Anurag; Pérez-Escudero, Alfonso; Li, Aming et al. (2018) Asymmetric migration decreases stability but increases resilience in a heterogeneous metapopulation. Nat Commun 9:2969
Rindi, Luca; Bello, Martina Dal; Dai, Lei et al. (2017) Direct observation of increasing recovery length before collapse of a marine benthic ecosystem. Nat Ecol Evol 1:153
Ratzke, Christoph; Gore, Jeff (2016) Self-organized patchiness facilitates survival in a cooperatively growing Bacillus subtilis population. Nat Microbiol 1:16022
Gandhi, Saurabh R; Yurtsev, Eugene Anatoly; Korolev, Kirill S et al. (2016) Range expansions transition from pulled to pushed waves as growth becomes more cooperative in an experimental microbial population. Proc Natl Acad Sci U S A 113:6922-7
Hoek, Tim A; Axelrod, Kevin; Biancalani, Tommaso et al. (2016) Resource Availability Modulates the Cooperative and Competitive Nature of a Microbial Cross-Feeding Mutualism. PLoS Biol 14:e1002540
Dai, Lei; Korolev, Kirill S; Gore, Jeff (2015) Relation between stability and resilience determines the performance of early warning signals under different environmental drivers. Proc Natl Acad Sci U S A 112:10056-61
Chen, Andrew; Sanchez, Alvaro; Dai, Lei et al. (2014) Dynamics of a producer-freeloader ecosystem on the brink of collapse. Nat Commun 5:3713
Korolev, Kirill S; Xavier, Joao B; Gore, Jeff (2014) Turning ecology and evolution against cancer. Nat Rev Cancer 14:371-80
Sanchez, Alvaro; Gore, Jeff (2013) feedback between population and evolutionary dynamics determines the fate of social microbial populations. PLoS Biol 11:e1001547
Datta, Manoshi Sen; Korolev, Kirill S; Cvijovic, Ivana et al. (2013) Range expansion promotes cooperation in an experimental microbial metapopulation. Proc Natl Acad Sci U S A 110:7354-9

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