1 Introduction to Biological Modeling Steve Andrews Brent lab, Basic Sciences Division, FHCRC Lecture 1: Introduction Sept. 22, 2010.

Slides:



Advertisements
Similar presentations
7 Steps to a Logical Process
Advertisements

Receptor clustering and signal processing in E.coli Chemotaxis Ref.1----TRENDS in Microbiology Vol.12 No.12 December 2004 Ref.2----PNAS Vol. 102 No. 48.
Bacterial motility, chemotaxis Lengeler et al. Chapter 20, p Global regulatory networks and signal transduction pathways.
5/10/2015Yang Yang, Candidacy Seminar1 Near-Perfect Adaptation in Bacterial Chemotaxis Yang Yang and Sima Setayeshgar Department of Physics Indiana University,
Chemotaxis and Motility in E. coli Examples of Biochemical and Genetic Networks Background Chemotaxis- signal transduction network Flagella gene expression.
Cartoon modeling of proteins Fred Howell and Dan Mossop ANC Informatics.
Combinatorial Synthesis of Genetic Networks Guet et. al. Andrew Goodrich Charles Feng.
Signal transduction in bacterial chemotaxis Lengeler et al. pp
Sept 25 Biochemical Networks Chemotaxis and Motility in E. coli Examples of Biochemical and Genetic Networks Background Chemotaxis- signal transduction.
Marcus Tindall Centre for Mathematical Biology Mathematical Institute St Giles’ Oxford. PESB, Manchester, 2007.
Chemotaxis: Another go Chrisantha Fernando Systems Biology Centre Birmingham University Chrisantha Fernando Systems Biology Centre Birmingham University.
SCB : 1 Department of Computer Science Simulation and Complexity SCB : Simulating Complex Biosystems Susan Stepney Department of Computer Science Leo Caves.
Modeling the chemosensing system of E. coli
Systems Biology Biological Sequence Analysis
Indiana University Bloomington, IN Junguk Hur Computational Omics Lab School of Informatics Differential location analysis A novel approach to detecting.
Systems Biology Biological Sequence Analysis
Bacterial Chemotaxis Dr. Chrisantha Fernando Systems Biology Centre University of Birmingham, UK March 2007 Dr. Chrisantha Fernando Systems Biology Centre.
Introduction to molecular networks Sushmita Roy BMI/CS 576 Nov 6 th, 2014.
Triangulation of network metaphors The Royal Netherlands Academy of Arts and Sciences Iina Hellsten & Andrea Scharnhorst Networked Research and Digital.
Shankar Subramaniam University of California at San Diego Data to Biology.
Cell Signaling Networks From the Bottom Up Anthony M.L. Liekens BioModeling and BioInformatics Anthony M.L. Liekens BioModeling and BioInformatics.
1 Dynamics and Control of Biological Systems Chapter 24 addresses a variety of analysis problems in the field of biosystems: Systems Biology Gene Regulation.
E. coli exhibits an important behavioral response known as chemotaxis - motion toward desirable chemicals (usually nutrients) and away from harmful ones.
Bacterial chemotaxis lecture 2 Manipulation & Modeling Genetic manipulation of the system to test the robustness model Explaining Ultrasensitivity and.
AMATH 382: Computational Modeling of Cellular Systems Dynamic modelling of biochemical, genetic, and neural networks Introductory Lecture, Jan. 6, 2014.
The chemotaxis network is able to extract once the input signal varies slower relative to the response time of the chemotaxis network. Under an input signal.
Agent-based modelling of epithelial cells An example of rule formulation and extension Dr Dawn Walker, University of Sheffield, UK.
Overview of next five lectures: How is directional motility accomplished at the single cell level? An emphasis on experimental approaches for testing models.
Robustness in protein circuits: adaptation in bacterial chemotaxis 1 Information in Biology 2008 Oren Shoval.
Graphical Rule-Based Modeling of Signal-Transduction Systems
1 Stochasticity and robustness Steve Andrews Brent lab, Basic Sciences Division, FHCRC Lecture 5 of Introduction to Biological Modeling Oct. 20, 2010.
NY Times Molecular Sciences Institute Started in 1996 by Dr. Syndey Brenner (2002 Nobel Prize winner). Opened in Berkeley in Roger Brent,
Bioinformatics MEDC601 Lecture by Brad Windle Ph# Office: Massey Cancer Center, Goodwin Labs Room 319 Web site for lecture:
March 8, 2007March APS Meeting, Denver, CO1 Near-Perfect Adaptation in Bacterial Chemotaxis Yang Yang and Sima Setayeshgar Department of Physics Indiana.
1 Introduction to Biological Modeling Steve Andrews Brent lab, Basic Sciences Division, FHCRC Lecture 2: Modeling dynamics Sept. 29, 2010.
Optimal Strategy in E. coli Chemotaxis: An Information Theoretic Approach Lin Wang and Sima Setayeshgar Department of Physics, Indiana University, Bloomington,
Fig 7.1. Fig 7.2 The bacteria flagella motor [source: Berg HC, Ann. Rev. Biochem 2003] Fig 7.3.
L17. Robustness in bacterial chemotaxis response
Introduction to biological molecular networks
12/24/2015Yang Yang, Candidacy Seminar1 Near-Perfect Adaptation in Bacterial Chemotaxis Yang Yang and Sima Setayeshgar Department of Physics Indiana University,
1/2/2016Yang Yang, Candidacy Seminar1 Near-Perfect Adaptation in Bacterial Chemotaxis Yang Yang and Sima Setayeshgar Department of Physics Indiana University,
Optimal Strategy in E. coli Chemotaxis: An Information Theoretic Approach Lin Wang and Sima Setayeshgar Department of Physics, Indiana University, Bloomington,
Microbiology and Molecular Biology for Engineers IGEM, 20 June 2006.
Lin Wang Advisor: Sima Setayeshgar. Motivation: Information Processing in Biological Systems Chemical signaling cascade is the most fundamental information.
MA354 Math Modeling Introduction. Outline A. Three Course Objectives 1. Model literacy: understanding a typical model description 2. Model Analysis 3.
In-silico Implementation of Bacterial Chemotaxis Lin Wang Advisor: Sima Setayeshgar.
Approach…  START with a fine-tuned model of chemotaxis network that:  reproduces key features of experiments (adaptation times to small and large ramps,
The chemotaxis network is able to extract as much as information possible once the input signal varies slower relative to the response time of the chemotaxis.
BCB 570 Spring Signal Transduction Julie Dickerson Electrical and Computer Engineering.
BT8118 – Adv. Topics in Systems Biology
Advanced Aspects of Chemotactic Mechanisms:
Near-Perfect Adaptation in Bacterial Chemotaxis
Introduction to Biology
Bacterial Chemotaxis Bacteria swim toward attractants and away from repellents. Their motion is a biased random walk due to control of tumbling frequency.
The chemotaxis network of E. coli
Module 2: Robustness in Biochemical Signaling Networks
Bacterial Chemotaxis Bacteria swim toward attractants and away from repellents. Their motion is a biased random walk due to control of tumbling frequency.
AMATH 882: Computational Modeling of Cellular Systems
Near-Perfect Adaptation in Bacterial Chemotaxis
Yang Yang & Sima Setayeshgar
Fundamental Constraints on the Abundances of Chemotaxis Proteins
Mechanism of chemotaxis in E
Near-Perfect Adaptation in Bacterial Chemotaxis
Computational Biology
Toshinori Namba, Masatoshi Nishikawa, Tatsuo Shibata 
Near-Perfect Adaptation in Bacterial Chemotaxis
Simulating cell biology
Robustness of Cellular Functions
Model of the change in receptor structure on engagement of the ligand IFN-γ. Model of the change in receptor structure on engagement of the ligand IFN-γ.
Presentation transcript:

1 Introduction to Biological Modeling Steve Andrews Brent lab, Basic Sciences Division, FHCRC Lecture 1: Introduction Sept. 22, 2010

2 About me Background: experimental chemical physics Changed to computational biology in 2001 Focusing on spatial simulations of cellular systems Joined Hutch last year office: Weintraub B

3 About you You are...Your divisions are... Backgrounds include: genetics, proteomics, epidemiology, molecular biology, biochemistry, etc. ~ 25% of you have modeling experience

4 About you You are...Your divisions are... Backgrounds include: genetics, proteomics, epidemiology, molecular biology, biochemistry, etc. ~ 25% of you have modeling experience Please ask questions and share your knowledge in this class!

5 About this class Introduction to Biological Modeling Broad Scope dynamics metabolism gene networks stochasticity development mechanics cancer primary focus is systems within cells (not tissues, physiology, epidemiology, ecology...) today’s class (not statistics, bioinformatics,...)

6 Why model biology? Example: E. coli chemotaxis Typical modeling progression

7 A cell is like a clock closed compartment, complex internal machinery, does interesting things Credits: guardian.co.uk, January 8, 2009;

8 Make a simplified model system... Credits:

9... experiment on it... Credits: Edyta Zielinska, The Scientist 21: 36, 2007;

10... and summarize what we know Cartoons convey basic concepts, but we still don’t fully understand Credits: Wikipedia, public domain;

11 To understand, we need to create a model that: is precise accounts for the important facts ignores the unimportant facts allows us to explore the system dynamics... and build an understanding We don’t truly understand until we can make accurate predictions

12 A clock model Pendulum period: Gear ratio: This model is a hypothesis that allows quantitative predictions Credits:

13 Why model biology? Example: E. coli chemotaxis Typical modeling progression

14 E. coli swimming E. coli cells “run” and “tumble” run (CCW rotation) tumble (CW rotation) Credits: Alberts, Bray, Lewis, Raff, Roberts, and Watson, Molecular Biology of the Cell, 3rd ed. Garland Publishing, 1993.

15 E. coli chemotaxis If attractant concentration increases, cells run longer If attractant concentration decreases, cells tumble sooner no attractant unbiased random walk with attractant biased random walk Credit: Alberts, Bray, Lewis, Raff, Roberts, and Watson, Molecular Biology of the Cell, 3rd ed. Garland Publishing, 1993.

16 E. coli chemotaxis signal transduction Signal transduction causing tumble 1.Tar (receptor) activates CheA 2.CheA autophosphorylates 3.CheA phosphorylates CheY 4.CheYp diffuses and binds to motor 5.Motor switches to CW, causing tumble 6.CheZ dephosphorylates CheY Attractant binding decreases activities, suppressing tumbles Credit: Andrews and Arkin, Curr. Biol. 16:R523, 2006.

17 First chemotaxis signal transduction model Simple model: only addressed phospho-relay (no adaptation) no spatial, stochastic, or allostery detail 8 proteins, 18 reactions many guessed parameters Bray, Bourret, and Simon, 1993 Credit: Bray, Bourret, Simon, Mol. Biol. Cell 4:469, 1993.

18 Model predictions vs. mutant data 47 comparisons: 33 agreed, 8 differed, 6 had no experimental data

19 Quantitative model exploration Credit: Bray, Bourret, Simon, Mol. Biol. Cell 4:469, Dose-response curve for motor bias after adding different amounts of ligand Ni 2+ (repellent) model based on experimental network has too low gain modified model has more accurate gain tumble run

20 Model summary Successes agreed with most mutant data qualitative trends agree with experiment Failures failed for some mutant data some parameters had to be way off from experiment insufficient sensitivity and gain Conclusions pathway is basically correct sensitivity and gain are wrong

21 Why model biology? How was modeling used to better understand E. coli chemotaxis?

22 Why model biology? Create a precise description of the system focus on important aspects highlight poorly understood aspects a description that we can communicate Explore the system test hypotheses make predictions build intuition identify poorly understood aspects

23 E. coli adaptation Credit: Segall, Block, Berg, Proc. Natl. Acad. Sci. USA 83:8987, no attractantadd attractant10 s later fraction of time running run tumble

24 E. coli chemotaxis signal transduction Signal transduction to tumble 1.Tar activates CheA 2.CheA autophosphorylates 3.CheA phosphorylates CheY 4.CheYp diffuses and binds to motor 5.Motor switches to CW -> tumble 6.CheZ dephosphorylates CheY Attractant binding decreases activities, suppressing tumbles Adaptation 1.CheR methylates Tar 2.CheA phosphorylates CheB 3.CheBp demethylates Tar Methyl groups bound to Tar increase signaling activity Credit: Andrews and Arkin, Curr. Biol. 16:R523, 2006.

25 Modeling adaptation Barkai and Leibler, 1997 Postulated: CheB only demethylates active receptors Specific results: 1.perfect adaptation 2.adaptation robust to variable protein concentrations General results: 1.Robustness may be common in biology 2.Robustness can arise from network architecture Credit: Barkai and Leibler, Nature, 387:913, 1997.

26 Model for gain and sensitivity Bray, Levin, and Morton-Firth, 1998 Postulate: receptor activity spreads in the cluster Credit:Maddock and Shapiro, Science, 259:1717, 1993; Bray, Levin, and Morton-Firth, Nature 393:85, Experimental result receptors cluster at poles (Maddock and Shapiro, 1993) Problem Experimental aspartate detection range: 2 nM to 100 mM. From receptor K D, detection range: 220 nM to 0.7 mM. black = active receptor white = inactive receptor x = ligand no spreading spreading

27 Model for gain and sensitivity Specific results Clustering leads to: increased sensitivity early saturation Prediction some receptors are clustered, and some unclustered clustering decreases with adaptation to high attractant General results Many proteins form extended complexes; perhaps they have similar purposes. Credit: Alberts, Bray, Lewis, Raff, Roberts, and Watson, Molecular Biology of the Cell, 3rd ed. Garland Publishing, 1993.

28 Spatial chemotaxis model Credits: Lipkow and Odde, Cell and Molecular Bioengineering, 1:84, Lipkow and Odde, 2008 Made spatial chemotaxis model Included CheY-CheZ interactions CheA CheY position in cell concentration Results some localization + different diffusion coefficients can create intracellular gradients

29 Chemotaxis summary Basic network determined First semi-accurate model Exact adaptation solved Dynamic range addressed Protein localization studied Good review Tindall et al., Bulletin of Mathematical Biology, 70:1525, 2008.

30 A new understanding of E. coli Credit: Andrews and Arkin, Curr. Biol. 16:R523, 2006; Bray, Science 229:1189, 2003; Bray, personal communication.

31 Why model biology? Example: E. coli chemotaxis Typical modeling progression

32 Modeling progression Basic network determined First semi-accurate model Exact adaptation solved Dynamic range addressed Protein localization studied several models, mostly wrong initial pretty good model solving model problems further refinement and exploration

33 More modeling progression Initial models simple low accuracy core network specific Later models detailed good accuracy large network general System is mapped out Too complex for qualitative reasoning

34 Class details class web page on LibGuide: lists class topics, readings, homework Registration Textbook: Systems Biology by Klipp et al. (at library or $85 from Amazon)

35 Homework Things to think about What aspects of your research are ready for modeling? What might you learn from it? Reading Tyson, Chen, and Novak “Sniffers, buzzers, toggles, and blinkers: dynamics of regulatory and signaling pathways in the cell” Current Opinion in Cell Biology 15: , (link will be on the LibGuides page,

36 Workflow for building a model