Biological systems, from our bodies to cellular regulatory networks, are built of modules. And modules of modules, a hierarchy.
This is great news! It means reductionism is in, sort of, as long as we carefully chop the biological system at its joints. We understand the modules in isolation, and put them together to figure out how the whole system works. Right?
Well. This is yet to work for drug discovery (see “ Eroom’s law” for the extent of their troubles). The problem is, when these modules are wired together, they create a system which is strongly dependent on its microenvironment and history. A registry of modules (and their behaviors) is not sufficient to decipher their coordinated response. We need to understand the laws that govern this coordination. Assuming they exist.
If and when we uncover general rules that link regulatory modules into hierarchies, we may then be in a position to understand cellular regulation one module at a time, at every level of the hierarchy.
The central goal of my research program is to uncover the principles of coordination between cellular phenotypes at multiple scales of organization, and build predictive models of this coordination in health and disease. To this end, I pursue four complementary lines of inquiry:
- Computational modeling of coupled biological circuits, each of which drive small-scale phenotypic switches. The goal is to predict the emergent, complex coordination of biological phenotypes. This work focuses on a) modeling regulatory networks that drive cellular life and death processes, and their breakdown in cancer, and b) modeling mammalian stem cell states and their crosstalk with the cell cycle. Several generations of College of Wooster Independent Study students have been involved in this effort, and their work is showcased here!
- Development of theoretical measures, computational tools, and visualization techniques to aid dy- namical modeling of multi-scale, hierarchically organized phenotypes (difficult for most biology/ BCMB IS students; but potential collaborative opportunity for physics majors).
- Developing a predictive, dynamic computational model of the epigenetic state of individual gene promoters (pursued by an NIH-funded Postdoctoral Fellow & IS students)
- Measuring, modeling, and predicting the behavior of noise driven mosaic heterogeneity of the endothelium in vitro and in vivo (NIH-funded collaboration with William Aird at the BIDMC).
- Featured in a video about the 25th Krakow Conference on Endothelium: https://www.youtube.com/watch?v=v_RY-lr55eE
- H. Sizek, A. Hamel, D. Deritei, S. Campbell, E. Ravasz Regan, Boolean model of growth signaling, cell cycle and apoptosis predicts the molecular mechanism of aberrant cell cycle progression driven by hyperactive PI3K. PLoS Computational Biology 15(3): e1006402, 2019.
- Wade A, Lin CH, Kurkul C, Ravasz Regan E, Johnson RM, Combined toxicity of insecticides and fungicides applied to California almond orchards to honey bee larvae and adults. Insects, 10(1), 20, 2019.
- Venkatraman L, Ravasz Regan E, Bentley K, Time to Decide? Dynamical Analysis Predicts Partial Tip/Stalk Patterning States Arise during Angiogenesis, PLOS One, 11(11): e0166489, 2016.
- D. Deritei, W. C. Aird, M.M. Ercsey-Ravasz, E. Ravasz Regan, Principles of dynamical modularity in biological regulatory networks, Scientific Reports, 6:21957, 2016.
- L. Yuan, G.C. Chan, D. Beeler, L. Janes, K.C. Spokes, H. Dharaneeswaran, A. Mojiri, W. Adams, T. Sciuto, G. Garcia-Cardena, G. Molema, P. Kang, N. Jahroudi, P. Marsden, A. Dvorak, E. Ravasz Regan, W.C. Aird, A role of stochastic phenotype switching in generating mosaic endothelial cell heterogeneity, Nature Communications, 7:10160, 2016.
- H. Dharaneeswaran, R. Abid, L. Yuan, D. Dupuis, D. Beeler, KC Spokes, L. Janes, T. Sciuto, P. Kang, SC. Jaminet, A. Dvorak, M.A. Grant, E. Ravasz Regan, W. C. Aird, FoxO1-mediated Activation of Akt plays a critical role in vascular homeostasis, Circulation Research CIRCRESAHA.115.303227, 2014.
- Katie Bentley, Andrew Philippides, Erzsébet Ravasz Regan, Do Endothelial Cells Dream of Eclectic Shape?, Developlental Cell, 29:146-158, 2014.
- Katie Bentley, Kyle I. Harrington, Erzsébet Ravasz Regan, Can active perception generate bistability? Heterogeneous collective dynamics and vascular patterning, ALIFE 14: The Fourteenth International Conference on the Synthesis and Simulation of Living Systems 14, 328-335, 2014.
- Carmen Priolo, Saumyadipta Pyne, Joshua Rose, Erzsébet Ravasz Regan, Giorgia Zadra, Cornelia Photopoulos, Stefano Cacciatore, Denise Schultz, Natalia Scaglia, Jonathan McDunn, Angelo M. De Marzo, Massimo Loda, AKT1 and MYC Induce Distinctive Metabolic Fingerprints in Human Prostate Cancer, Cancer Research 74, 7198-204, 2014.
- Dávid Deritei, Zsolt Lázár, István Papp, Ferenc Járai-Szabó, Robert Sumi, Levente Varga, Erzsébet Ravasz Regan, Mária-Magdolna Ercsey-Ravasz, Community detection by graph Voronoi diagrams, New Journal of Physics 16, 063007, 2014; Video Abstract.
Research experience – endothelial biology & systems biology:
- Organizing princliples of dynamical modularity in biological regulation. Endothelial cells are great examples of complex functional coordination. This cell type displays extraordinary functional heterogeneity across the vasculature, a result of context-dependent, combinatorial use of a sizable functional arsenal. Deciphering how this coordination occurs remains problematic, in spite of detailed knowledge about individual functions. The central questions driving my research revolve around this problem:
- Are there general principles that govern coordination between regulatory modules?
- Can we use such principles to build a theoretical foundation for modeling multi-module regulatory systems?
- Is there a critical type of modularity that is key to deciphering a cell’s higher-level responses?
We have recently defined dynamical modules as robust, multistable regulatory switches. Using this definition, we propose three general principles that characterize coordination between these regulatory modules. We are in the process of developing appropriate quantitative measures in order to test their validity in Boolean regulatory networks. We have built a dynamically modular model of the mammalian cell cycle, and showed that this biological model obeys the three principles, while its randomized counterparts do not. We are now extending the cell cycle model with an apoptotic and DNA damage switch, them build the module responsible for growth factor signaling and cellular growth, an input module of the cell cycle engine in our current model.
- Biological noise-driven dynamic mosaic heterogeneity and functional bet hedging in vivo. We have found a novel adaptive strategy used by endothelial cells to increase their phenotypic plasticity and protect tissues from sudden environmental change. Briefly, the endothelium of healthy organs can exploit biological noise to generate a spatially heterogeneous, slowly flickering mosaic of Willebrand factor (vWF)-positive and -negative cells. These dynamic mosaics only appear in specific organs and vascular beds, such as heart capillaries. Their absence damages heart capillary endothelial cells and neighboring cardiomyocytes, but does not affect other vessels. Our data point to a novel, tissue-specific strategy for homeostasis.
- Bistability in endothelial morphogenesis. In a recent Developmental Cell review I coauthored with Dr. Katie Bentley, we explored the parallels between endothelial morphogenesis and the core principles of adaptive systems robotics. In a subsequent paper we showed that sensorimotor feedback can generate bistability in single endothelial cells sensing VEGF gradients at the angiogenic front. This bistability pre-patterns the vascular front to some extent even before lateral inhibition sets the pattern of tip/stalk phenotypes, and can significantly speed the formation of their physiological salt-and-pepper pattern.
- Role of the Akt -| FoxO1 -> Akt negative feedback in endothelial life and death. The FoxO1 transcription factor is expressed by most mammalian cells and it affects multiple cellular functions such as cell cycle, apoptosis, oxidative stress response, DNA repair, metabolism, aging and differentiation. Consequently, FoxO1 has been implicated in diseases as diverse as cancer, diabetes, muscle atrophy or Parkinson’s disease, but its effects are cell-type specific and often paradoxical. FoxO1 promotes cell cycle arrest and/or apoptosis in many cell types, but it’s presence in the endothelium is required for embryonic vascular development. We have recently shown that endothelial FoxO1 is both necessary and sufficient for embryonic development. Mechanistically, FoxO1 feeds back to up-regulate the activity of its repressor AKT, and the downstream AKT target mTORC1. Loss of endothelial FoxO1 thus causes G1 arrest. Conversely, overexpression of FoxO1 induces both AKT and mTORC1 in endothelial cells, and promotes mTORC1-mediated cell growth. Excess FoxO1 nonetheless fails to increase proliferation, as it also induces G2 arrest. In contract, the FoxO1-AKT feedback does not induce mTORC1 in nonvascular cells. Pharmacological elevation of FoxO1 may thus promote quiescence and ROS resistance in some tissues, but carries the risk of damaging the vasculature.
- Metabolite profiling in Akt- and Myc-overexpressing prostate cancer.
- Genome-wide transcriptional profiling of phenotypic drift in freshly isolated endothelial cells.
- Genome-wide transcriptional profiling of multi-potent mouse and rat brain arachnoid cells.
- Identification of transcription factor binding sites.