Bulletin of the American Physical Society
2006 APS March Meeting
Monday–Friday, March 13–17, 2006; Baltimore, MD
Session R28: Focus Session: Biological Networks: Structure, Dynamics and Function |
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Sponsoring Units: DBP Chair: Chao Tang, University of California, San Francisco Room: Baltimore Convention Center 325 |
Wednesday, March 15, 2006 2:30PM - 3:06PM |
R28.00001: Unraveling Biological Design Principles Using Engineering Methods: The Heat Shock Response as a Case Study Invited Speaker: The bacterial heat shock response refers to the mechanism by which bacteria react to a sudden increase in the ambient temperature. The consequences of such an unmediated temperature increase at the cellular level is the unfolding, misfolding, or aggregation of cell proteins, which threatens the life of the cell. To combat such effects, cells have evolved an intricate set of feedback and feedforward mechanisms. In this talk, we present a mathematical model that describes the core functionality of these mechanisms. We illustrate how such a model provides valuable insight, explaining dynamic phenomena exhibited by wild type and mutant heat shock responses, corroborating experimental data and guiding novel biological experiments. Furthermore, we demonstrate, through the careful control analysis of the model, several design principles that appear to have shaped the feedback structure of the heat shock system. Specifically, we itemize the roles of the various feedback strategies and demonstrate their necessity in achieving performance objectives such as efficiency, robustness, stability, good transient response, and noise rejection in the presence of limited cellular energies and materials. Examined from this perspective, the heat shock model can be decomposed, both conceptually and mathematically, into functional modules. These modules possess the characteristics of more familiar modular structures: sensors, actuators and controllers present in a typical technological control system. We finally point to various theoretical research challenges inspired by the heat shock response system, and discuss the crucial relevance of these challenges in the modeling and analysis of many classes of systems that are likely to arise in the study of gene regulatory networks. [Preview Abstract] |
Wednesday, March 15, 2006 3:06PM - 3:18PM |
R28.00002: Network growth models and genetic regulatory networks Joshua Socolar, David Foster, Stuart Kauffman We study a class of growth algorithms for directed graphs that are candidate models for the evolution of genetic regulatory networks. The algorithms involve partial duplication of nodes and their links, together with innovation of new links, allowing for the possibility that input and output links from a newly created node may have different probabilities of survival. We find some counterintuitive trends as parameters are varied, including the broadening of indegree distribution when the probability for retaining input links is decreased. We also find that both the scaling of transcription factors with genome size and the measured degree distributions for genes in yeast can be reproduced by the growth algorithm if and only if a special seed is used to initiate the process. [Preview Abstract] |
Wednesday, March 15, 2006 3:18PM - 3:30PM |
R28.00003: Bistability of the naturally induced lactose utilization system of Escherichia coli Jelena Stajic, Michael Wall In the absence of the preferred sugar glucose, lactose utilization machinery in the bacterium E. coli is activated. The genetic circuit responsible for this response, lac operon, has been observed to exhibit bistability when induced by an artificial inducer, TMG. Here we investigate conditions under which bistability might be observed in response to lactose. The aim of our study is to establish whether the natural system exhibits bistability, as is often assumed despite the lack of experimental support. [Preview Abstract] |
Wednesday, March 15, 2006 3:30PM - 3:42PM |
R28.00004: Origins of sloppiness in biological models. Joshua Waterfall, Fergal Casey, Ryan Gutenkunst, Kevin Brown, Christopher Myers, James Sethna Models of biological networks such as those involved in signal transduction, development, and the cell cycle routinely contain dozens of parameters. Even if high quality data on the dynamics of every form of every chemical species were available for such networks, some parameter combinations would be orders of magnitude more constrained than other combinations -- a feature we term sloppiness. In order to understand this shared, possibly universal, behavior we turn to mathematically well-defined classes of models -- multiple linear regression, sums of polynomials and sums of exponentials. The origins of sloppiness turn out to have nothing to do with how much data is available or how many parameters a model has, but are instead the scale of description at which a model is constructed and how the parameters of the model map to the data. Thus describing a cloud of points by a plane, the core of linear regression, is not sloppy while describing complex biological networks by the biochemical reactions, just as fitting sums of exponentials or polynomials, is unavoidably sloppy. [Preview Abstract] |
Wednesday, March 15, 2006 3:42PM - 3:54PM |
R28.00005: Function Constrains Topology. Chao Tang, Wenzhe Ma, Qi Ouyang In the biological world, intimate relations between function and form are well established on the macroscopic and the microscopic scales. However, on the ``mesoscopic'' scales, to what extend the function of a system and the organization of its parts are related? In this talk, I will present a case study of the segmentation polarity gene network in Drosophila. The function of this network is to stabilize the segmentation pattern of gene expression during the development. We found that although there are numerous networks which can perform the function, the requirement for the function to be robust severely constrains the network's topology. The network selected by nature is among the most robust topological classes. Furthermore, I will show that the knowledge of viable topologies can be used to help identify ``missing'' links in the network. [Preview Abstract] |
Wednesday, March 15, 2006 3:54PM - 4:06PM |
R28.00006: Stability tuned: An analysis of a gene network with counteracting feedback loops Murat Acar, Attila Becskei, Alexander van Oudenaarden On induction of cell differentiation, distinct cell phenotypes are encoded by complex genetic networks. Here we explore the key parameters that determine the stability of cellular memory by using the yeast galactose-signalling network as a model system. This network contains multiple nested feedback loops. Of the two positive feedback loops, only the loop mediated by the signal transducer Gal3p is able to generate two stable expression states with a persistent memory of previous galactose consumption states. A negative feedback through the inhibitor Gal80p reduces the strength of the core positive feedback. Despite this, a constitutive increase in the Gal80p concentration tunes the system from having destabilized memory to having persistent memory. A model reveals that fluctuations are trapped more efficiently at higher Gal80p concentrations. Indeed, the rate at which single cells randomly switch back and forth between expression states was reduced. These observations provide a quantitative understanding of the stability and reversibility of cellular differentiation states. (For more information: Nature 435, 228-232 (2005)). [Preview Abstract] |
Wednesday, March 15, 2006 4:06PM - 4:18PM |
R28.00007: Parameters of the proteome evolution from the distribution of sequence identities of paralogous proteins Koon-Kiu Yan, Jacob Axelsen, Sergei Maslov The evolution of the full repertoire of proteins encoded in a given genome is driven by gene duplications, deletions and modifications of amino-acid sequences of already existing proteins. The information about relative rates and other intrinsic parameters of these three basic processes is contained in the distribution of sequence identities of pairs of paralogous proteins. We introduced a simple mathematical framework that allows one to extract some of this hidden information. It was then applied to the proteome-wide set of paralogous proteins in H. pylori, E. coli, S. cerevisiae, C. elegans, D. melanogaster and H. sapiens. We estimated the stationary per-gene deletion and duplication rates, the distribution of amino-acid substitution rate of these organisms. The validity of our mathematical framework was further confirmed by numerical simulations of a simple evolutionary model of a fixed-size proteome. [Preview Abstract] |
Wednesday, March 15, 2006 4:18PM - 4:54PM |
R28.00008: Differentiation at the single cell level: slow, noisy, and out of control Invited Speaker: Transient differentiation allows genetically identical cells to generate dynamical phenotypic diversity in a homogeneous environment. In Bacillus subtilis, competence is a transient state associated with the capability for DNA uptake from the environment. Individual genes and proteins underlying differentiation into the competent state have been elucidated, but it is unclear how these genes interact dynamically in individual cells to control both entry into competence and return to vegetative growth. Here we show that transient differentiation can be understood in terms of excitable behavior of the underlying genetic circuit. Using quantitative fluorescence time-lapse microscopy, we directly observed the activities of multiple circuit components simultaneously in individual cells. We analyzed the resulting data in terms of a mathematical model. A core module containing positive and negative feedback loops controls both entry into, and exit from, the competent state. Reengineering the competence network to bypass the negative feedback loop specifically blocks exit from competence converting the excitable system into a bistable one. These results show that a simple genetic circuit combines stochastic and deterministic elements to support transient differentiation through excitability. [Preview Abstract] |
Wednesday, March 15, 2006 4:54PM - 5:06PM |
R28.00009: The Structure of Parasites in Food Webs Christopher Warren, Mercedes Pascual, Kevin Lafferty, Armand Kuris Using the recent food web data, we investigate how parasites are connected to the rest of the web and see how they differ from random connection. To model these differences in a simple static model, we explore several approaches to extending the highly successful niche model to include parasites. [Preview Abstract] |
Wednesday, March 15, 2006 5:06PM - 5:18PM |
R28.00010: Quantitative study of gene regulation mediated by small RNA Erel Levine, Thomas Kuhlman, Zhongge Zhang, Terence Hwa The role of small regulatory RNAs (sRNA) in controlling many pathways in bacteria has been highlighted in recent years. Small RNAs have been found in regulating the response of \textit{E. Coli} to various stress conditions, frequently by destabilizing the mRNA molecules of their target. Here we describe quantitatively the unique properties of this mode of regulation. We characterize - both theoretically and experimentally - the expression of a sRNA-regulated reporter, under different regulatory signals and genetic backgrounds. Our analysis predicts the existence of two regimes of gene expression, separated by a sharp transition: When the transcription rate of the sRNA exceeds that of its targets, we expect very low level of protein synthesis, with fluctuations strongly suppressed. However, when the sRNA transcription rate becomes lower than that of its target, a proportional fraction of target transcripts are expected to be stable, leading to protein expression. In the context of stress response, our results suggest a ``stress-relief'' mechanism, where gradual response is evoked only once a ``tolerance threshold'' is exceeded. We also characterized an intriguing \textit{coupling} effect between the mRNA levels of different genes, arising from their shared regulatory sRNA. Such coupling may be used by the cell to create a hierarchy of responses to changes in regulatory signals. [Preview Abstract] |
Wednesday, March 15, 2006 5:18PM - 5:30PM |
R28.00011: Quantitative Dissection of a Bacterial Promoter: Cooperativity, Sensitivity, and Combinatorial Control Thomas Kuhlman, Zhongge Zhang, Milton Saier, Terence Hwa \textit{E. coli's lac} promoter offers a possibility of confronting system-level properties of transcriptional regulation with the known biochemistry of the molecular constituents and their mutual interactions. We repeated a previous study [Setty et al, PNAS 100: 7702-7 (2003)] by removing several extraneous factors which modulated expression of the \textit{lac} promoter. Through characterization of the promoter activity for key mutants and using thermodynamic modeling, we account for the control of the \textit{lac} promoter in terms of known interactions. We reveal how the sensitive response to inducers arises from the accumulation of several weakly cooperative interactions, and depict how the activator CRP plays a dual role as the enhancer and sensitizer of repression by assisting LacI-mediated DNA looping. [Preview Abstract] |
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