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Register a new userEffect of noise in intelligent cellular decision making
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Similar to intelligent multicellular neural networks controlling human brains, even single cells surprisingly are able to make intelligent decisions to classify several external stimuli or to associate them. This happens because of the fact that gene regulatory networks can perform as perceptrons, simple intelligent schemes known from studies on Artificial Intelligence. We study the role of genetic noise in intelligent decision making at the genetic level and show that noise can play a constructive role helping cells to make a proper decision. We show this using the example of a simple genetic classifier able to classify two external stimuli.
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We present the epithelial-to-mesenchymal transition (EMT) from two perspectives: experimental/technological and theoretical. We review the state of the current understanding of the regulatory networks that underlie EMT in three physiological contexts: embryonic development, wound healing, and metastasis. We describe the existing experimental systems and manipulations used to better understand the molecular participants and factors that influence EMT and metastasis. We review the mathematical models of the regulatory networks involved in EMT, with a particular emphasis on the network motifs (such as coupled feedback loops) that can generate intermediate hybrid states between the epithelial and mesenchymal states. Ultimately, the understanding gained about these networks should be translated into methods to control phenotypic outcomes, especially in the context of cancer therapeutic strategies. We present emerging theories of how to drive the dynamics of a network toward a desired dynamical attractor (e.g. an epithelial cell state) and emerging synthetic biology technologies to monitor and control the state of cells.
Cell functional diversity is a significant determinant on how biological processes unfold. Most accounts of diversity involve a search for sequence or expression differences. Perhaps there are more subtle mechanisms at work. Using the metaphor of information processing and decision-making might provide a clearer view of these subtleties. Understanding adaptive and transformative processes (such as cellular reprogramming) as a series of simple decisions allows us to use a technique called cellular signal detection theory (cellular SDT) to detect potential bias in mechanisms that favor one outcome over another. We can apply method of detecting cellular reprogramming bias to cellular reprogramming and other complex molecular processes. To demonstrate scope of this method, we will critically examine differences between cell phenotypes reprogrammed to muscle fiber and neuron phenotypes. In cases where the signature of phenotypic bias is cryptic, signatures of genomic bias (pre-existing and induced) may provide an alternative. The examination of these alternates will be explored using data from a series of fibroblast cell lines before cellular reprogramming (pre-existing) and differences between fractions of cellular RNA for individual genes after drug treatment (induced). In conclusion, the usefulness and limitations of this method and associated analogies will be discussed.
The work reported here aims to address the effects of time-dependent parameters and stochasticity on decision-making in biological systems. We achieve this by extending previous studies that resorted to simple normal forms. Yet, we focus primarily on the issue of the systems sensitivity to initial conditions in the presence of different noise distributions. In addition, we assess the impact of two-way sweeping through the critical region of a canonical Pitchfork bifurcation with a constant external asymmetry. The parallel with decision-making in bio-circuits is performed on this simple system since it is equivalent in its available states and dynamics to more complex genetic circuits. Overall, we verify that rate-dependent effects are specific to particular initial conditions. Information processing for each starting state is affected by the balance between sweeping speed through critical regions, and the type of fluctuations added. For a heavy-tail noise, forward-reverse dynamic bifurcations are more efficient in processing the information contained in external signals, when compared to the system relying on escape dynamics, if it starts at an attractor not favoured by the asymmetry and, in conjunction, if the sweeping amplitude is large.
Cellular signaling involves the transmission of environmental information through cascades of stochastic biochemical reactions, inevitably introducing noise that compromises signal fidelity. Each stage of the cascade often takes the form of a kinase-phosphatase push-pull network, a basic unit of signaling pathways whose malfunction is linked with a host of cancers. We show this ubiquitous enzymatic network motif effectively behaves as a Wiener-Kolmogorov (WK) optimal noise filter. Using concepts from umbral calculus, we generalize the linear WK theory, originally introduced in the context of communication and control engineering, to take nonlinear signal transduction and discrete molecule populations into account. This allows us to derive rigorous constraints for efficient noise reduction in this biochemical system. Our mathematical formalism yields bounds on filter performance in cases important to cellular function---like ultrasensitive response to stimuli. We highlight features of the system relevant for optimizing filter efficiency, encoded in a single, measurable, dimensionless parameter. Our theory, which describes noise control in a large class of signal transduction networks, is also useful both for the design of synthetic biochemical signaling pathways, and the manipulation of pathways through experimental probes like oscillatory input.
Stem cells can precisely and robustly undergo cellular differentiation and lineage commitment, referred to as stemness. However, how the gene network underlying stemness regulation reliably specifies cell fates is not well understood. To address this question, we applied a recently developed computational method, Random Circuit Perturbation (RACIPE), to a nine-component gene regulatory network (GRN) governing stemness, from which we identified fifteen robust gene states. Among them, four out of the five most probable gene states exhibit gene expression patterns observed in single mouse embryonic cells at 32-cell and 64-cell stages. These gene states can be robustly predicted by the stemness GRN but not by randomiz
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