Note: Front Cover -- Phenotypic Switching -- Copyright Page -- Contents -- List of contributors -- Preface -- Introduction -- Background: Lamarck and Darwin -- Woltereck and the reaction norm -- Waddington, canalization and genetic assimilation -- Behavior -- the Baldwin effect -- Domestication -- Developmental noise -- Phenotypic noise and phenotypic plasticity -- Cancer -- Summing up -- Acknowledgments -- Summaries of contributions -- Acknowledgments -- 1 The fundamentals of phenotypic plasticity -- Introduction -- Phenotypic plasticity at an intracellular level: macromolecules, pathways, and organelles -- Phenotypic plasticity at a cellular level: Implications in development, homeostasis, and disease -- Phenotypic plasticity at the organismal level -- Conclusion -- Acknowledgment -- References -- 2 Rethinking the role of chance in the explanation of cell differentiation -- Introduction -- Noise in gene expression: a descriptive analysis -- What, actually, is noise? -- From noise to chance as explanatory -- Chance in immunology: an example to follow -- A positive view of chance: main features and theoretical advantages -- Three reasons for biological explanations in terms of chance -- Conclusion: Chance and the reductionism/antireductionism debate -- Acknowledgments -- References -- 3 Random walk across the epigenetic landscape -- Concepts -- Historical origins -- The epigenetic landscape -- A new conceptual framework -- Putting together the pieces of the puzzle to build a new operative model -- Conclusion -- Acknowledgments -- References -- 4 Manoeuvring protein functions and functional levels by structural excursions -- Moonlighting proteins -- Functional switch mediated by protein-protein interactions -- Modulation of protein function by oligomerization -- Influence of domain association on protein function. , Modulation of protein function by posttranslational modifications -- Silent mutation tunes gene function -- Synonymous mutations dictate gene splicing -- Synonymous mutations regulate folding of mRNA secondary structure -- Synonymous mutations impair the interactions of mRNA with RNA-binding proteins and miRNAs -- Synonymous mutations modulate cotranslational folding -- Conclusion -- Acknowledgments -- Abbreviations -- References -- 5 Prion-mediated phenotypic diversity in fungi -- Introduction -- Prion formation and loss -- Prion propagation and transmission in the fungal cell -- Prion-mediated phenotypes -- [PSI+]/Sup35: regulating the decoding of stop codons and more -- [MOT3+]/Mot3: controlling multicellularity in response to environmental triggers -- [SWI+]/Swi1: an impact on global transcriptional regulation -- [GAR+]/Pma1/Std1: broadening the choice of sugars -- Conformational diversity generates phenotypic diversity -- Concluding remarks -- Acknowledgments -- References -- 6 Bistability in virus-host interaction networks underlies the success of hepatitis C treatments -- Introduction -- Bistability in the interferon signaling network -- Interferons and HCV infection -- HCV induces bistability in the interferon signaling network -- Phenotypic heterogeneity in interferon responsiveness -- Phenotypic heterogeneity, viral kinetics, and treatment outcomes -- Interferon-based treatment outcome -- Leveraging endogenous interferon responsiveness to improve DAA treatments -- Potential considerations and strategies for optimizing DAA treatments -- Mutational pathways of resistance to DAA-based treatments -- Posttreatment cure -- Natural outcomes of HCV infection -- Concluding remarks -- Acknowledgments -- References -- 7 Quantifying Waddington landscapes, paths, and kinetics of cell fate decision making of differentiation/development -- Introduction. , Potential and flux landscape theory of cell fate decision of differentiation and reprograming -- Potential and flux as the driving force for stem cell differentiation and development -- Optimal paths for quantifying the differentiation/development and reprograming processes -- Kinetic rates of differentiation/development and reprograming cell fate decision-making processes -- Quantifying Waddington landscape and paths for differentiation/development -- Gene regulatory motif circuit determining the differentiation -- Cell fate decision for differentiation and reprograming through regulations -- Quantified Waddington landscape and paths for development/differentiation -- Epigenetics, heterogeneity, and plasticity -- Identifying key factors of cell fate decision making in differentiation/development -- Discussions on critical issues of cell fate decision making of differentiation and development -- Cell fate decision-making dynamics of differentiation/development is not only determined by the landscape but also by the c... -- The differences of the original Waddington landscape and quantified landscape for cell fate decision making in differentiat... -- Origins of the bifurcations and phase transitions of cell fate decision making of differentiation/development -- Time arrow and mechanism of irreversibility originating from the curl flux breaking the detailed balance -- Heterogeneity from epigenetics -- Quantifications of transition states, speed, and optimal paths of cell fate decision making of differentiation and reprogra... -- Transition states or intermediate states? -- Discrete paths versus continuous paths -- Acknowledgment -- References -- 8 The physics of cell fate -- Introduction -- The "physical laws" of cell fate dynamics -- Statistical mechanics of cell state dynamics -- Universality in cell biology -- Critique and outlook -- Conclusions. , References -- 9 Disentangling the environmentally induced and stochastic developmental components of phenotypic variation -- Introduction -- Considerations on phenotypic, genetic, environmentally induced, and stochastic developmental variations -- Occurrence of environmentally induced variation and stochastic developmental variation in the kingdoms of life -- Determination of stochastic developmental variation in laboratory experiments -- Disentangling genetic variation, environmentally induced variation, and stochastic developmental variation in the laboratory -- Disentangling genetic variation, environmentally induced variation, and stochastic developmental variation in field studies -- Disentangling genetic variation plus environmentally induced variation from stochastic developmental variation by mathemati... -- Identification of the molecular mechanisms underlying environmentally induced variation and stochastic developmental variation -- The marbled crayfish as a promising model for investigating the nongenetic components of phenotypic variation -- Conclusions -- Acknowledgments -- References -- 10 The evolution of cell differentiation in animals: biomolecular condensates as amplification hubs of inherent cell functions -- Introduction -- Metazoan-specific modes of transcriptional regulation -- Beta-catenin, Grainyhead-like and the role of multicellularity in the evolution of differentiation -- Inherent cell functions in the origin of differentiation -- Conclusion: Prolific cell differentiation as a metazoan evolutionary innovation -- Abbreviations -- References -- 11 Phenotypic switching and its evolutionary consequences -- Evolution and the principle of inheritance -- Molecular basis and examples of epigenetically determined phenotypic switching -- Evolutionary consequences of phenotypic switching -- Acknowledgments -- References. , 12 Cell-state organization by exploratory sloppy dynamics -- Introduction -- Experimental approach: cell adaptation to an unforeseen challenge -- Implications of the yeast adaptation experiments -- The exploratory dynamics of cell-state organization -- The living cell as a sloppy dynamical system -- Summary and open issues -- Acknowledgments -- References -- 13 Emergence of metabolic heterogeneity in cell populations: lessons from budding yeast -- Introduction: cell state heterogeneity in isogenic microbial populations -- Metabolic heterogeneity and spatial organization within yeast colonies -- The idea of a threshold, controlling resource -- General considerations on the manifestation of multiple cellular states at the population level -- Case 1: When growth is much faster than switching, such that one can ignore the latter -- Case 2: When switching is much faster than growth, such that one can ignore the latter -- Case 3: Both switching and growth have to be taken into account -- Cell-state heterogeneity of yeast in a well-mixed chemostat -- Discussion -- Acknowledgments -- Appendix -- Case 1: When growth is much faster than switching, such that one can ignore the latter -- Case 2: When switching is much faster than growth, such that one can ignore the latter -- Case 3: Both switching and growth have to be taken into account -- References -- 14 Stochastic phenotypic switching in endothelial cell heterogeneity -- Introduction -- From genes to phenotypic plasticity -- Biological noise meets phenotypic plasticity -- Biological noise in developmental plasticity -- Biological noise in response to environmental change -- Stochastic phenotype switching and cellular memory -- Is biological noise-mediated heterogeneity adaptive? -- Noise-mediated endothelial cell heterogeneity in vivo -- Dynamic heterogeneity of vWF expression in vivo. , Dynamic vWF mosaicism in vitro is driven by biological noise.