DOCSLIB.ORG

Building Biological Memory by Linking Positive Feedback Loops

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Building Biological Memory by Linking Positive Feedback Loops Building biological memory by linking positive feedback loops Dong-Eun Changa, Shelly Leunga, Mariette R. Atkinsona, Aaron Reiflera, Daniel Forgerb, and Alexander J. Ninfaa,1 aDepartment of Biological Chemistry, University of Michigan Medical School; and bDepartment of Mathematics and Center for Computational Medicine and Biology, University of Michigan, Ann Arbor, MI 48109 Edited by Clyde A. Hutchison III, The J. Craig Venter Institute, San Diego, CA, and approved November 20, 2009 (received for review July 23, 2009) A common topology found in many bistable genetic systems is two transcriptional promoter to the concentration of activator protein interacting positive feedback loops. Here we explore how this must display a kinetic order or sensitivity greater than one (8, 10– relatively simple topology can allow bistability over a large range 12). If these minimal requirements are met, bistability may be of cellular conditions. On the basis of theoretical arguments, we anticipated to occur under some environmental conditions. predict that nonlinear interactions between two positive feedback An important example of a bistable genetic system consisting of loops can produce an ultrasensitive response that increases the a single positive feedback loop was provided by the work of range of cellular conditions at which bistability is observed. This Novick and Weiner, who studied the so-called “preinduction ef- prediction was experimentally tested by constructing a synthetic fect” of the lacZYA operon in Escherichia coli (13). The lac op- genetic circuit in Escherichia coli containing two well-characterized eron preinduction effect is observed when the operon is induced positive feedback loops, linked in a coherent fashion. The concerted by nonphysiological xenobiotic inducers, known as gratuitous in- action of both positive feedback loops resulted in bistable behavior ducers, that are not metabolized by the cell but can bind to the over a broad range of inducer concentrations; when either of the LacI repressor protein and cause it to release the lac operator feedback loops was removed, the range of inducer concentrations DNA. The preinduction effect refers to the observation that a at which the system exhibited bistability was decreased by an order higher concentration of gratuitous inducer was required for the of magnitude. Furthermore, bistability of the system could be induction of naive (uninduced) cells than was required to main- tuned by altering growth conditions that regulate the contribution tain preinduced cells in the fully induced state. At certain con- of one of the feedback loops. Our theoretical and experimental centrations of inducer, known as the maintenance concentrations, work shows how linked positive feedback loops may produce the naive cells remained uninduced, and previously induced cells re- robust bistable responses required in cellular networks that regu- mained in the induced state, indefinitely (13). Even when cultures late development, the cell cycle, and many other cellular responses. showed an intermediate level of induction, the lacZYA operon was either fully on or fully off in the individual cells (13, 14). Al- bistability | genetic network | synthetic biology | ultrasensitivity | hysteresis though the original lacZYA operon preinduction effect experi- ments were performed using a chemostat and with TMG as the istable genetic systems display a discontinuity of expression inducer, we show in the supporting information that the effect can Bstates, where two distinct stable steady states are obtained be demonstrated using standard flask-grown cultures and with without the presence of stable intermediate steady states. The IPTG as the inducer (Fig. S1). Mathematical modeling has con- previous history of the system determines which stable steady firmed the mechanism of bistability in the lacZYA operon and state is occupied. One of the important problems in systems confirmed the role of both positive feedback and high sensitivity biology is to understand how genetic bistability is established and (14–17). This system remains the most well-characterized and regulated. This is because bistable genetic switches play an widely used example of cellular bistability. important role in a variety of cellular processes, such as cellular The lacZYA operon preinduction effect is due to the positive oscillators, progression through the eukaryotic cell cycle, and the feedback of the lacY product, galactoside permease, on its own development of differentiated cell and tissue types in organisms expression (13, 18). This permease allows the gratuitous inducer ranging from the temperate bacteriophage to the human (1–7). to enter into the cell. When cells lack the galactoside permease, Many previous studies have focused on whether a given circuit as in the naive state, a high concentration of gratuitous inducer is topology has the capacity to display bistability for some range of required for induction. However, upon induction of the operon, environmental conditions (e.g., refs. 8–10). Although the possi- the cells come to acquire many molecules of the galactoside bility of bistable behavior is important, it is also important that the permease that can bring about further internalization of the in- range of environmental conditions at which it occurs be large ducer (positive feedback). The presence of permease protein GENETICS enough to achieve practical control of biological processes. Here, molecules allows the induced cells to maintain a high intracellular we focus upon identification and manipulation of the parameters concentration of the inducer, even when the extracellular con- that control the range of environmental conditions at which bis- centration is low. As expected, the lac preinduction effect is tablity is obtained for systems known to be capable of bistability. eliminated upon mutation of the lacY gene (18). Furthermore, We use the methods of synthetic biology to create model ex- the preinduction effect is minimized under conditions where the perimental systems to address the functions of multiple positive function of the LacY protein is down-regulated (19). Inhibition of feedback loops in bistability. Theoretical studies have argued that the minimal requirements for genetic bistability are twofold. First, there must be some type Author contributions: D.-E.C., D.F., and A.J.N. designed research; D.-E.C., S.L., A.R., and of positive feedback controlling gene expression. Examples of D.F. performed research; M.R.A. contributed new reagents/analytic tools; D.-E.C., S.L., positive feedback are when an activator protein drives its own D.F., and A.J.N. analyzed data; and D.-E.C., D.F., and A.J.N. wrote the paper. expression or when an even number of linked negative regulatory The authors declare no conflict of interest. steps are present, such as when a repressor blocks the expression This article is a PNAS Direct Submission. of a repressor of its own expression. Second, the kinetic order or Freely available online through the PNAS open access option. sensitivity of the system to the positive feedback element must be 1To whom correspondence should be addressed. E-mail: [email protected]. – high (8, 10 12). For example, in the simple case where a tran- This article contains supporting information online at www.pnas.org/cgi/content/full/ scriptional activator drives its own expression, the response of the 0908314107/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.0908314107 PNAS | January 5, 2010 | vol. 107 | no. 1 | 175–180 Downloaded by guest on October 3, 2021 the LacY permease activity occurs when the PTS component and Results glc signal-transduction protein EIIA is present in its un- A Graphic Analysis of the Problem. To understand the factors phosphorylated state and binds to LacY (20). This occurs when controlling the range of bistability of the activator module of the the cell is grown in the presence of PTS sugars, such as glucose, Atkinson et al. oscillator, we use rate-balance plots following the and, to lesser extents, when the cell is grown in the presence of work of Ferrell and Xiong (10, 11). In this method, the rates of other substrates that exert catabolite repression (21). Thus, the activator production and decay are plotted as a function of ac- lac preinduction effect was not discernible in glucose-grown cells tivator concentration. Because activator has no direct effect on (Fig. S1). Even in succinate-grown cells, the lac preinduction its own decay, we expect activator decay to be a simple linear effect was a fairly weak bistability; in an experiment using IPTG function of activator concentration (Fig. 1). Conversely, bio- as the inducer, the range of inducer concentrations at which chemical studies of the activation of transcription by the NRI ∼ P fl bistability was observed was narrow [about 4-fold in ask-grown activator indicated a high kinetic order and an S-shaped re- fl fi cells (Fig. S1)]. Indeed, in ask-grown cells, it was dif cult to sponse (25) (Fig. 1). Steady states are possible only where the demonstrate a maintenance concentration of IPTG (Fig. S1). curves for production rate of activator and decay rate of activator In nature, simple bistable systems with a single positive feed- intersect (Fig. 1). A key feature of the genetic toggle switch used back loop are rarely encountered; instead, natural systems are in our studies is that activator and repressor compete for the complex and contain multiple feedback loops that could be promoter that drives transcription of the activator structural
Load more

Recommended publications
  • Bistability Dynamics in Structured Ecological Models
    CHAPTER 3 Bistability Dynamics in Structured Ecological Models Jifa Jiang1 and Junping Shi2,3 1Department of Mathematics, Shanghai Normal University, Shanghai 200092, P.R.China [email protected] 2Department of Mathematics, College of William and Mary, Williamsburg, VA 23185, USA [email protected] 3School of Mathematics, Harbin Normal University, Harbin, Heilongjiang 150080, P.R.China Abstract. Alternative stable states exist in many important ecosystems, and gradual change of the environment can lead to dramatic regime shift in these systems (Beisner et.al. (2003), May (1977), Klausmeier (1999), Rietkerk et.al. (2004), and Scheffer et.al. (2001)). Exam- ples have been observed in the desertification of Sahara region, shift in Caribbean coral reefs, and the shallow lake eutrophication (Carpenter et.al. (1999), Scheffer et.al. (2003), and Scheffer et.al. (2001)). It is well-known that a social-economical system is sustain- able if the life-support ecosystem is resilient (Holling (1973) and Folke et.al. (2004)). Here resilience is a measure of the magnitude of disturbances that can be absorbed before a system centered at one locally stable equilibrium flips to another. Mathematical mod- els have been established to explain the phenomena of bistability and hysteresis, which provide qualitative and quantitative information for ecosystem managements and policy making (Carpenter et.al. (1999) and Peters et.al. (2004)). However most of these models of catastrophic shifts are non-spatial ones. A theory for spatially extensive, heterogeneous ecosystems is needed for sustainable management and recovery strategies, which requires a good understanding of the relation between system feedback and spatial scales (Folke et.al.
    [Show full text]
  • Analysis of Performance and Robustness of Biological Switches: Local Tools for Non-Local Dynamical Phenomena
    Analysis of performance and robustness of biological switches: local tools for non-local dynamical phenomena. PhD thesis of Laura Trotta Supervised by Pr. Rodolphe Sepulchre Co-supervised by Pr. Eric Bullinger Faculty of Applied Sciences Department of Electrical Engineering and Computer Science The present dissertation has been evaluated by the jury members Pr. V. Seutin, Chair, University of Liège Pr. R. Sepulchre, Advisor, University of Liège Pr. E. Bullinger, Co-advisor, University of Liège Pr. P. Geurts, University of Liège Pr. G-B. Stan, Imperial College London (UK) Pr. B. Gutkin, Ecole normale supérieure de Paris (France) Pr. J-A. Sepulchre, Université de Nice Sophia Antipolis (France) The research described in the present dissertation was financially sup- ported by the Belgian Network DYSCO (Dynamical Systems, Control, and Optimization), funded by the Interuniversity Attraction Poles Pro- gramme initiated by the Belgian Science Policy Office. Copyright c 2013 Laura Trotta Abstract Biological switches are frequently encountered in mathematical model- ing of biological systems because binary decisions are at the core of many cellular processes. A bistable switch presents two stable steady-states, each of them corresponding to a distinct decision. These two decisions are assumed to result from the interactions between biochemical effec- tors at the molecular level. Because these molecular interactions are particularly complex, involving many effectors, mathematical models of biological switches are often high dimensional and nonlinear. Therefore, an analysis of these systems is challenging. In this dissertation, we try to identify principles and tools to study the performance and robustness of biological switches. Our first contribution is to highlight the dynamical nature of these switches.
    [Show full text]
  • Bistable Biochemical Switching and the Control of the Events of the Cell Cycle*
    Oncogene (1997) 15, 317 ± 325 1997 Stockton Press All rights reserved 0950 ± 9232/97 $12.00 Bistable biochemical switching and the control of the events of the cell cycle* CD Thron 5 Barrymore Road, Hanover, New Hampshire 03755, USA Some of the events of the cell cycle appear to be development (Edelstein, 1971; Seelig and Denzel, 1972; triggered by a bistable mechanism. A bistable biochem- Meinhart, 1982; Murray, 1989). Biochemical switches ical system can respond to a small, slow signal and is of the simple types considered here have been described carried by positive feedback from one stable steady state and discussed by Edelstein-Keshet (1988) and Murray directly to another, in an all-or-none manner. Slow or (1989). Lewis et al. (1977) have particularly stressed subthreshold stimuli do not cause accommodation or loss that other types of biochemical switch do not show of excitability. Switching is not readily reversible by true thresholds of discontinuity, and do not provide removing the stimulus, i.e. there is hysteresis: reversal either the sharpness or the irrevocability of bistable generally requires a stronger, opposite stimulus. Bio- switches. Bistable switching is typically caused by a chemically, bistable biochemical switching requires change in a rate constant or other parameter which positive feedback, and mechanisms for stabilizing the changes the biochemical dynamics and destabilizes the system against premature activation and for destabiliza- current stable state, and thereby forces the system to tion in response to a biological signal. Three bistable bio- go to the alternate stable state. A change of steady chemical models, all suggested by reported experimental state may alternatively be caused by addition of observations, are described and analysed.
    [Show full text]
  • BAX and SMAC Regulate Bistable Properties of the Apoptotic Caspase
    bioRxiv preprint doi: https://doi.org/10.1101/867663; this version posted December 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. BAX and SMAC Regulate Bistable Properties of the Apoptotic Caspase System Stephanie McKenna1, Lucía García-Gutiérrez1, David Matallanas1,2*, Dirk Fey1,2* (*corresponding and senior authors) 1 Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland 2 School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland e-mail: David Matallanas: [email protected] Dirk Fey: [email protected] Running Title: BAX and SMAC control apoptotic bi-stability. Key words: apoptosis, IAP, Diablo, SMAC, BAX, mechanistic model, bistability. 1 bioRxiv preprint doi: https://doi.org/10.1101/867663; this version posted December 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Abstract The initiation of apoptosis is a core mechanism in cellular biology by which organisms control the removal of damaged or unnecessary cells. The irreversible activation of caspases is essential for apoptosis, and mathematical models have demonstrated that the process is tightly regulated by positive feedback and a bistable switch. BAX and SMAC are often dysregulated in diseases such as cancer or neurodegeneration and are two key regulators that interact with the caspase system generating the apoptotic switch.
    [Show full text]
  • Of Differential Negative Resistance
    On the “mystery” of differential negative resistance Sebastian Popescu, Erzilia Lozneanu and Mircea Sanduloviciu Department of Plasma Physics Complexity Science Group Al. I. Cuza University 6600 Iasi, Romania [email protected] Investigating the causes of the nonlinear behavior of a gaseous conductor we identified the presence of two states of the complex space charge configuration self-assembled in front of the anode. These states correspond to two levels of self-organization from which the first one is related to spatial pattern whereas the second one to spatiotemporal pattern. Their emergence through two kinds of instabilities produced for two critical distances from thermodynamic equilibrium is emphasized in the current voltage characteristic as an S-shaped, respectively Z-shaped bistability. Their presence attributes to the gaseous conductor the ability to work as an S-shaped, respectively an N-shaped negative differential resistance. 1. Introduction Many physical, chemical or biological systems driven away from thermodynamical equilibrium may give birth to a rich variety of patterns displaying strong structural and dynamical resemblances. The study of these nonlinear structures reveals many interesting features as multiplicities of states, hysteresis, oscillations and eventually chaos. In a characteristic in which a response parameter of the analyzed system is represented as a function of a control parameter, the multiplicity of states (e.g. bistabilities) is intimately related to the hysteresis phenomenon proving that the system has memory [1]. Informative for the genuine origin of the memory effect are experimental investigations recently performed on gaseous conductors [2,3]. Thus, when the gaseous conductor (plasma) is gradually driven away from the thermodynamic equilibrium the system reveals two different bistable regions (bifurcations) that successively appear in the form of an S-shaped, respectively an N-shaped negative differential resistance (NDR).
    [Show full text]
  • Chapter 3 One-Dimensional Systems
    Chapter 3 One-Dimensional Systems In this chapter we describe geometrical methods of analysis of one-dimensional dynam- ical systems, i.e., systems having only one variable. An example of such a system is the space-clamped membrane having Ohmic leak current IL ˙ C V = ¡gL(V ¡ EL) : (3.1) Here the membrane voltage V is a time-dependent variable, and the capacitance C, leak conductance gL and leak reverse potential EL are constant parameters described in the previous chapter. We use this and other one-dimensional neural models to introduce and illustrate the most important concepts of dynamical system theory: equilibrium, stability, attractor, phase portrait, and bifurcation. 3.1 Electrophysiological Examples The Hodgkin-Huxley description of dynamics of membrane potential and voltage-gated conductances can be reduced to a one-dimensional system when all transmembrane conductances have fast kinetics. For the sake of illustration, let us consider a space- clamped membrane having leak current and a fast voltage-gated current Ifast having only one gating variable p, Leak I I z }| L { z }|fast { ˙ C V = ¡ gL(V ¡ EL) ¡ g p (V ¡ E) (3.2) p˙ = (p1(V ) ¡ p)=¿(V ) (3.3) with dimensionless parameters C = 1, gL = 1, and g = 1. Suppose that the gating kinetic (3.3) is much faster than the voltage kinetic (3.2), which means that the voltage- sensitive time constant ¿(V ) is very small, i.e. ¿(V ) ¿ 1, in the entire biophysical voltage range. Then, the gating process may be treated as being instantaneous, and the asymptotic value p = p1(V ) may be used
    [Show full text]
  • Dynamic Bistable Switches Enhance Robustness and Accuracy of Cell Cycle Transitions
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.11.246017; this version posted August 11, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Dynamic bistable switches enhance robustness and accuracy of cell cycle transitions Jan Rombouts1, Lendert Gelens1*, 1 Laboratory of Dynamics in Biological Systems, Department of Cellular and Molecular Medicine, University of Leuven (KU Leuven), B-3000 Leuven, Belgium *[email protected] Abstract Bistability is a common mechanism to ensure robust and irreversible cell cycle transitions. Whenever biological parameters or external conditions change such that a threshold is crossed, the system abruptly switches between different cell cycle states. Experimental studies indicate that the shape of the bistable response curve changes dynamically in time. Here, we show how such a dynamically changing bistable switch can provide a cell with better control over the timing of cell cycle transitions. Moreover, cell cycle oscillations built on bistable switches are more robust when the bistability is modulated in time. Our results are not specific to cell cycle models and may apply to other bistable systems in which the bistable response curve is time-dependent. Author summary Many systems in nature show bistability, which means they can evolve to one of two stable steady states under exactly the same conditions. Which state they evolve to depends on where the system comes from. Such bistability underlies the switching behavior that is essential for cells to progress in the cell division cycle.
    [Show full text]
  • Bistability in ODE and Boolean Models
    Bistability in ODE and Boolean models Elena Dimitrova School of Mathematical and Statistical Sciences Clemson University http://edimit.people.clemson.edu/ Algebraic Biology E. Dimitrova (Clemson) Bistability in ODE and Boolean models Algebraic Biology 1 / 28 Bistability A system is bistable if it has two stable steady-states separated by an unstable state. From Wikipedia. 1 y y The threshold ODE: y “ ´ry 1 ´ M 1 ´ T . In the threshold model for population growth, there are three steady-states,` ˘` 0 ă T 㢠M: M “ carrying capacity (stable), T “ extinction threshold (unstable), 0 “ extinct (stable). E. Dimitrova (Clemson) Bistability in ODE and Boolean models Algebraic Biology 2 / 28 Types of bistability The lac operon exhibits bistability. The expression level of the lac operon genes are either almost zero (\basal levels"), or very high (thousands of times higher). There's no \inbetween" state. The exact level depends on the concentration of intracellular lactose. Let's denote this parameter by p. Now, let's \tune" this parameter. The result might look like the graph on the left. This is reversible bistability. In other situations, it may be irreversible (at right). E. Dimitrova (Clemson) Bistability in ODE and Boolean models Algebraic Biology 3 / 28 Hysteresis For reversible bistability, the up-threshold L2 of p is higher than the down-threshold L1 of p. This is hysteresis: a dependence of a state on its current state and past state. Thermostat example Consider a home thermostat. If the temperature is T ă 18 (e.g., in winter), the heat is on. If the temperature is T ¡ 23 (e.g., in summer), the AC is on.
    [Show full text]
  • Tristable and Astable Multivibrators and Chaos Generator
    Nonlinear Nanophotonic Circuitry: Tristable and Astable Multivibrators and Chaos Generator Pujuan Ma1,2, Lei Gao1,#, Pavel Ginzburg3,4, and Roman E. Noskov3,4,§ 1School of Physical Science and Technology & Jiangsu Key Laboratory of Thin Film of Soochow University, Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215006, China. 2 Shandong Provincial Engineering and Technical Center of Light Manipulations & Shandong Provincial Key Laboratory of Optics and Photonic Device, School of Physics and Electronics, Shandong Normal University, Jinan 250014, China 3 Department of Electrical Engineering, Tel Aviv University, Ramat Aviv, Tel Aviv 69978, Israel 4 Light-Matter Interaction Centre, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978, Israel #e-mail: [email protected] §e-mail: [email protected] Keywords: bistability, switching, modulation instability, Kerr-type nonlinearity, optical nanoantenna Abstract: The concept of lumped optical nanoelements (or metactronics), wherein nanometer- scale structures act as nanoinductors, nanocapacitors and nanoresistors, has attracted a great deal of attention as a simple toolbox for engineering different nanophotonic devices in analogy with microelectronics. While recent studies of the topic have been predominantly focused on linear functionalities, nonlinear dynamics in microelectronic devices plays a crucial role and provides a majority of functions, employed in modern applications. Here, we extend the metactronics paradigm and add nonlinear dynamical modalities to those nanophotonic devices that have never been associated with optical nanoantennas. Specifically, we show that nonlinear dimer nanoantennae can operate in the regimes of tristable and astable multivibrators as well as chaos generators. The physical mechanism behind these modalities relies on the Kerr-type nonlinearity of nanoparticles in the dimer enhanced by a dipolar localized surface plasmon resonance.
    [Show full text]
  • Exploring Robustness of Bistability in Prototypical Positive Feedback Loops
    Exploring Robustness of Bistability in Prototypical Positive Feedback Loops Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Amirhossein Hajihosseini aus Tehran, Iran Basel, 2015 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch This work is licenced under the agreement Attribution Non-Commercial No Derivatives - 3.0 Switzerland (CC BY-NC-ND 3.0 CH). The complete text may be reviewed here: creativecommons.org/licenses/by-nc-nd/3.0/ch/deed.en Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Attila Becskei und Prof. Ruedi Stoop Basel, den 8. Dezember 2015 Prof. Dr. Jörg Schibler Dekan Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 3.0 Schweiz (CC BY-NC-ND 3.0 CH) Sie dürfen: Teilen - den Inhalt kopieren, verbreiten und zugänglich machen Unter den folgenden Bedingungen: Namensnennung − Sie müssen den Namen des Autors/Rechteinhabers in der von ihm festgelegten Weise nennen. Keine kommerzielle Nutzung − Sie dürfen diesen Inhalt nicht für kom- merzielle Zwecke nutzen. Keine Bearbeitung erlaubt − Sie dürfen diesen Inhalt nicht bearbeiten, abwandeln oder in anderer Weise verändern. Wobei gilt: • Verzichtserklärung − Jede der vorgenannten Bedingungen kann aufgehoben werden, sofern Sie die ausdrückliche Einwilligung des Rechteinhabers dazu erhal- ten. • Public Domain (gemeinfreie oder nicht-schützbare Inhalte) − Soweit das Werk, der Inhalt oder
    [Show full text]
  • Role of Feedback and Dynamics in a Gene Regulatory Network
    Role of feedback and dynamics in a gene regulatory network Thesis by Ophelia S. Venturelli In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 2013 (Defended May 30, 2013) ii c 2013 Ophelia S. Venturelli All Rights Reserved iii Acknowledgements I am very fortunate to have had the opportunity of attending Caltech for graduate school. I ap- preciate many unique characteristics of Caltech including an intimate community where I can walk around campus and recognize many familiar faces, a relaxed yet challenging and stimulating intellec- tual environment and the absence of barriers for interdisciplinary research. I also had the privilege of spending almost two years at UCSF during my graduate studies. UCSF is a cutting-edge and exciting place to work and I have learned a tremendous amount during my tenure at UCSF. I would like to especially thank my advisor Richard Murray for his guidance, support and for allowing me the freedom to explore interesting scientific questions. Richard has an incredible positive energy and enthusiasm that has reinforced my motivation about science over the years. By working with Richard, I have learned a quantitative and rigorous reasoning about biological systems. I have enjoyed interacting with members of the Murray group and appreciate their diverse backgrounds in math, computer science, engineering and biology. I am most grateful to Hana El-Samad, who has been a second advisor to me, for the opportunity to pursue exciting research projects in her lab and for supporting my research. Hana is very detail- oriented and meticulous about scientific research and as a consequence I think my approach to scientific problems and writing has significantly improved.
    [Show full text]
  • Measuring and Modeling Apoptosis in Single Cells
    Leading Edge Review Measuring and Modeling Apoptosis in Single Cells Sabrina L. Spencer1,2 and Peter K. Sorger1,* 1Center for Cell Decision Processes, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA 2Present address: Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA *Correspondence: [email protected] DOI 10.1016/j.cell.2011.03.002 Cell death plays an essential role in the development of tissues and organisms, the etiology of disease, and the responses of cells to therapeutic drugs. Here we review progress made over the last decade in using mathematical models and quantitative, often single-cell, data to study apoptosis. We discuss the delay that follows exposure of cells to prodeath stimuli, control of mitochondrial outer membrane permeabilization, switch-like activation of effector caspases, and variability in the timing and probability of death from one cell to the next. Finally, we discuss challenges facing the fields of biochemical modeling and systems pharmacology. Introduction receptors, primarily members of the tumor necrosis factor Apoptosis is a form of programmed cell death involving receptor (TNFR) family (Kaufmann and Earnshaw, 2000). caspases, specialized cysteine proteases found in animal cells Receptor binding by TNF family ligands activates caspase- as inactive proenzymes (Fuentes-Prior and Salvesen, 2004). dependent pathways that are quite well understood in molecular Dramatic progress has been made in recent years in identifying terms. In general, extrinsic apoptosis has received more atten- and determining the biochemical activities and cellular functions tion than intrinsic apoptosis from investigators seeking to of biomolecules that regulate apoptosis and carry out its proteo- develop mathematical models, but extrinsic and intrinsic lytic program.
    [Show full text]