Nonequilibrium Statistical Mechanics of Dividing Cell Populations

We present and study a model for the nonequilibrium statistical mechanics of protein distributions in a proliferating cell population. Our model describes how the total protein variation is shaped by two processes: variation in protein production internal to the cells and variation in division and inheritance at the population level. It enables us to assess the contribution of each of these components separately. We find that, even if production is deterministic, cell division can generate a large variation in protein distribution. In this limit we solve exactly a special case and draw an analogy between protein distribution along cell generations and stress distribution in layers of granular material. At the other limit of extremely noisy protein production, we find that the population structure restrains variation and that the details of division do not affect the tail of the distribution

From cellular properties to population asymptotics in the Population Balance Equation

Proliferating cell populations at steady state growth often exhibit broad protein distributions with exponential tails. The sources of this variation and its universality are of much theoretical interest. Here we address the problem by asymptotic analysis of the Population Balance Equation. We show that the steady state distribution tail is determined by a combination of protein production and cell division and is insensitive to other model details. Under general conditions this tail is exponential with a dependence on parameters consistent with experiment. We discuss the conditions for this effect to be dominant over other sources of variation and the relation to experiments.Comment: Exact solution of Eq. 9 is adde

Identifying Dynamic Regulation with Adversarial Surrogates

Homeostasis, the ability to maintain a stable internal environment in the face of perturbations, is essential for the functioning of living systems. Given observations of a system, or even a detailed model of one, it is both valuable and extremely challenging to extract the control objectives of the homeostatic mechanisms. Lacking a clear separation between plant and controller, frameworks such as inverse optimal control and inverse reinforcement learning are unable to identify the homeostatic mechanisms. A recently developed data-driven algorithm, Identifying Regulation with Adversarial Surrogates (IRAS), detects highly regulated or conserved quantities as the solution of a min-max optimization scheme that automates classical surrogate data methods. Yet, the definition of homeostasis as regulation within narrow limits is too strict for biological systems which show sustained oscillations such as circadian rhythms. In this work, we introduce Identifying Dynamic Regulation with Adversarial Surrogates (IDRAS), a generalization of the IRAS algorithm, capable of identifying control objectives that are regulated with respect to a dynamical reference value. We test the algorithm on simulation data from realistic biological models and benchmark physical systems, demonstrating excellent empirical results

Visual detection of time-varying signals: opposing biases and their timescales

Human visual perception is a complex, dynamic and fluctuating process. In addition to the incoming visual stimulus, it is affected by many other factors including temporal context, both external and internal to the observer. In this study we investigate the dynamic properties of psychophysical responses to a continuous stream of visual near-threshold detection tasks. We manipulate the incoming signals to have temporal structures with various characteristic timescales. Responses of human observers to these signals are analyzed using tools that highlight their dynamical features as well. We find that two opposing biases shape perception, and operate over distinct timescales. Positive recency appears over short times, e.g. consecutive trials. Adaptation, entailing an increased probability of changed response, reflects trends over longer times. Analysis of psychometric curves conditioned on various temporal events reveals that the balance between the two biases can shift depending on their interplay with the temporal properties of the input signal. A simple mathematical model reproduces the experimental data in all stimulus regimes. Taken together, our results support the view that visual response fluctuations reflect complex internal dynamics, possibly related to higher cognitive processes.Comment: Number of pages: 31 Number of figures: 2

Single-cell protein dynamics reproduce universal fluctuations in cell populations

Protein variability in single cells has been studied extensively in populations, but little is known about temporal protein fluctuations in a single cell over extended times. We present here traces of protein copy number measured in individual bacteria over multiple generations and investigate their statistical properties, comparing them to previously measured population snapshots. We find that temporal fluctuations in individual traces exhibit the same universal features as those previously observed in populations. Scaled fluctuations around the mean of each trace exhibit the same universal distribution shape as found in populations measured under a wide range of conditions and in two distinct microorganisms. Additionally, the mean and variance of the traces over time obey the same quadratic relation. Analyzing the temporal features of the protein traces in individual cells, reveals that within a cell cycle protein content increases as an exponential function with a rate that varies from cycle to cycle. This leads to a compact description of the protein trace as a 3-variable stochastic process - the exponential rate, the cell-cycle duration and the value at the cycle start - sampled once each cell cycle. This compact description is sufficient to preserve the universal statistical properties of the protein fluctuations, namely, the protein distribution shape and the quadratic relationship between variance and mean. Our results show that the protein distribution shape is insensitive to sub-cycle intracellular microscopic details and reflects global cellular properties that fluctuate between generations

Excitability Constraints on Voltage-Gated Sodium Channels

We study how functional constraints bound and shape evolution through an analysis of mammalian voltage-gated sodium channels. The primary function of sodium channels is to allow the propagation of action potentials. Since Hodgkin and Huxley, mathematical models have suggested that sodium channel properties need to be tightly constrained for an action potential to propagate. There are nine mammalian genes encoding voltage-gated sodium channels, many of which are more than ≈90% identical by sequence. This sequence similarity presumably corresponds to similarity of function, consistent with the idea that these properties must be tightly constrained. However, the multiplicity of genes encoding sodium channels raises the question: why are there so many? We demonstrate that the simplest theoretical constraints bounding sodium channel diversity—the requirements of membrane excitability and the uniqueness of the resting potential—act directly on constraining sodium channel properties. We compare the predicted constraints with functional data on mammalian sodium channel properties collected from the literature, including 172 different sets of measurements from 40 publications, wild-type and mutant, under a variety of conditions. The data from all channel types, including mutants, obeys the excitability constraint; on the other hand, channels expressed in muscle tend to obey the constraint of a unique resting potential, while channels expressed in neuronal tissue do not. The excitability properties alone distinguish the nine sodium channels into four different groups that are consistent with phylogenetic analysis. Our calculations suggest interpretations for the functional differences between these groups

Individuality and slow dynamics in bacterial growth homeostasis

Microbial growth and division are fundamental processes relevant to many areas of life science. Of particular interest are homeostasis mechanisms, which buffer growth and division from accumulating fluctuations over multiple cycles. These mechanisms operate within single cells, possibly extending over several division cycles. However, all experimental studies to date have relied on measurements pooled from many distinct cells. Here, we disentangle long-term measured traces of individual cells from one another, revealing subtle differences between temporal and pooled statistics. By analyzing correlations along up to hundreds of generations, we find that the parameter describing effective cell-size homeostasis strength varies significantly among cells. At the same time, we find an invariant cell size which acts as an attractor to all individual traces, albeit with different effective attractive forces. Despite the common attractor, each cell maintains a distinct average size over its finite lifetime with suppressed temporal fluctuations around it, and equilibration to the global average size is surprisingly slow (> 150 cell cycles). To demonstrate a possible source of variable homeostasis strength, we construct a mathematical model relying on intracellular interactions, which integrates measured properties of cell size with those of highly expressed proteins. Effective homeostasis strength is then influenced by interactions and by noise levels, and generally varies among cells. A predictable and measurable consequence of variable homeostasis strength appears as distinct oscillatory patterns in cell size and protein content over many generations. We discuss the implications of our results to understanding mechanisms controlling division in single cells and their characteristic timescalesComment: In press with PNAS. 50 pages, including supplementary informatio