A stochastic model dissects cell states in biological transition processes

Many biological processes, including differentiation, reprogramming, and disease transformations, involve transitions of cells through distinct states. Direct, unbiased investigation of cell states and their transitions is challenging due to several factors, including limitations of single-cell assays. Here we present a stochastic model of cellular transitions that allows underlying single-cell information, including cell-state-specific parameters and rates governing transitions between states, to be estimated from genome-wide, population-averaged time-course data. The key novelty of our approach lies in specifying latent stochastic models at the single-cell level, and then aggregating these models to give a likelihood that links parameters at the single-cell level to observables at the population level. We apply our approach in the context of reprogramming to pluripotency. This yields new insights, including profiles of two intermediate cell states, that are supported by independent single-cell studies. Our model provides a general conceptual framework for the study of cell transitions, including epigenetic transformations

The modern versus extended evolutionary synthesis : sketch of an intra-genomic gene's eye view for the evolutionary-genetic underpinning of epigenetic and developmental evolution

Studying the phenotypic evolution of organisms in terms of populations of genes and genotypes, the Modern Synthesis (MS) conceptualizes biological evolution in terms of 'inter-organismal' interactions among genes sitting in the different individual organisms that constitute a population. It 'black-boxes' the complex 'intra-organismic' molecular and developmental epigenetics mediating between genotypes and phenotypes. To conceptually integrate epigenetics and evo-devo into evolutionary theory, advocates of an Extended Evolutionary Synthesis (EES) argue that the MS's reductive gene-centrism should be abandoned in favor of a more inclusive organism-centered approach. To push the debate to a new level of understanding, we introduce the evolutionary biology of 'intra-genomic conflict' (IGC) to the controversy. This strategy is based on a twofold rationale. First, the field of IGC is both ‘gene-centered’ and 'intra-organismic' and, as such, could build a bridge between the gene-centered MS and the intra-organismic fields of epigenetics and evo-devo. And second, it is increasingly revealed that IGC plays a significant causal role in epigenetic and developmental evolution and even in speciation. Hence, to deal with the ‘discrepancy’ between the ‘gene-centered’ MS and the ‘intra-organismic’ fields of epigenetics and evo-devo, we sketch a conceptual solution in terms of ‘intra-genomic conflict and compromise’ – an ‘intra-genomic gene’s eye view’ that thinks in terms of intra-genomic ‘evolutionarily stable strategies’ (ESSs) among numerous and various DNA regions and elements – to evolutionary-genetically underwrite both epigenetic and developmental evolution, as such questioning the ‘gene-de-centered’ stance put forward by EES-advocates

The Extended (Evolutionary) Synthesis Debate: Where Science Meets Philosophy

Recent debates between proponents of the modern evolutionary synthesis (the standard model in evolutionary biology) and those of a possible extended synthesis are a good example of the fascinating tangle among empirical, theoretical, and conceptual or philosophical matters that is the practice of evolutionary biology. In this essay, we briefly discuss two case studies from this debate, highlighting the relevance of philosophical thinking to evolutionary biologists in the hope of spurring further constructive cross-pollination between the two fields

Allostatic load and preterm birth

Preterm birth is a universal health problem that is one of the largest unmet medical needs contributing to the global burden of disease. Adding to its complexity is that there are no means to predict who is at risk when pregnancy begins or when women will actually deliver. Until these problems are addressed, there will be no interventions to reduce the risk because those who should be treated will not be known. Considerable evidence now exists that chronic life, generational or accumulated stress is a risk factor for preterm delivery in animal models and in women. This wear and tear on the body and mind is called allostatic load. This review explores the evidence that chronic stress contributes to preterm birth and other adverse pregnancy outcomes in animal and human studies. It explores how allostatic load can be used to, firstly, model stress and preterm birth in animal models and, secondly, how it can be used to develop a predictive model to assess relative risk among women in early pregnancy. Once care providers know who is in the highest risk group, interventions can be developed and applied to mitigate their risk

Fitness and entropy production in a cell population dynamics with epigenetic phenotype switching

Motivated by recent understandings in the stochastic natures of gene expression, biochemical signaling, and spontaneous reversible epigenetic switchings, we study a simple deterministic cell population dynamics in which subpopulations grow with different rates and individual cells can bi-directionally switch between a small number of different epigenetic phenotypes. Two theories in the past, the population dynamics and thermodynamics of master equations, separatedly defined two important concepts in mathematical terms: the {\em fitness} in the former and the (non-adiabatic) {\em entropy production} in the latter. Both play important roles in the evolution of the cell population dynamics. The switching sustains the variations among the subpopulation growth thus continuous natural selection. As a form of Price's equation, the fitness increases with ($i$) natural selection through variations and $(ii)$ a positive covariance between the per capita growth and switching, which represents a Lamarchian-like behavior. A negative covariance balances the natural selection in a fitness steady state | "the red queen" scenario. At the same time the growth keeps the proportions of subpopulations away from the "intrinsic" switching equilibrium of individual cells, thus leads to a continous entropy production. A covariance, between the per capita growth rate and the "chemical potential" of subpopulation, counter-acts the entropy production. Analytical results are obtained for the limiting cases of growth dominating switching and vice versa.Comment: 16 page