BE 150/Bi 250 Spring 2014

Systems Biology
Instructors Michael Elowitz (Bi/BE/APh) Richard Murray (CDS/BE) Lectures: MWF 11-12, 200 BRD	Teaching Assistants Victoria Hsiao (BE) Vipul Singhal (CNS) Recitation: Fr 11-12, location TBD
This is the course homepage for BE 150/Bi 250 for Spring 2014. This page contains all of the information about the material that will be covered in the class, as well as links to the homeworks and information about the course projects and grading.

WARNING: This page is still under construction. This banner will be removed when things are finalized.

Lecture Schedule

There will be 2-3 one-hour lectures each week, as well as occasional one-hour tutorials, recitations or journal club.

Week	Date	Topic	Reading	Homework
1	31 Mar 2 Apr MBE/RMM	Course overview, gene circuit dynamics Principles in systems biology Core processes in cells Modeling transcription, translation and regulation using ODEs Negative auto-regulation Recitation section: 5 Apr MATLAB and SimBiology Tutorial Useful MATLAB commands: useful_matlab.m SimBiology example: rec1_pos_regdemo.sbproj MATLAB/ode45 example: pos_reg_main.m, pos_reg.m	Bi 250b: Alon, Ch 1: Introduction Alon, Ch 2: Transcription networks : basic concepts Alon, Ch 3: Autoregulation : a network motif BE 150: BFS Ch 1: Introductory Concepts (skim) BFS Ch 2: Modeling of Core Processes Section 2.1: Modeling Techniques (skim) Sections 2.2-2.3: transcription and translation, transcriptional regulation Papers discussed in lecture: Negative Autoregulation Speeds the Response Times of Transcription Networks, Nitzan Rosenfeld, Michael B. Elowitz and Uri Alon, J. Mol. Biol. 323: 785–793, 2002. Engineering stability in gene networks by autoregulation, Attila Becskei & Luis Serrano, Nature, 405:590-593, 2000. Rate of environmental change determines stress response specificity, Jonathan W. Young, James C. W. Locke, Michael B. Elowitz, PNAS, 110:4140-4145, 2013.	HW1
2	7 Apr 11 Apr* RMM	Circuit motifs Feedforward loops (FFLs) Phosphorylation cascades (?) Two-component signaling systems (?) Sequestration and 'futile cycles' for ultrasensitivty Positive feedback for toggle switches, hysteresis and irreversibility Cytokine mediated Population response Recitation (9 Apr): sample problems MATLAB/curve fitting tool example: cftools_example.m	Bi 250b: Alon, Ch 4: The feed-forward loop network motif Alon, Ch 6: Network motifs in developmental, signal transduction, and neuronal networks BE 150: BFS Ch 2: Modeling of Core Processes Section 2.4: post-transcriptional regulation Section 2.5: cellular subsystems Papers discussed in lecture: Design principles of cell circuits with paradoxical components, Hart, Antebi, Mayo, Friedman, Alon, PNAS, 109 (21) 8346-8351 2012.	HW2 I1FFL.sbproj
3	14 Apr+ 16 Apr+ MBE?	Robustness Chemotaxis and perfect adaptation Fold change detection, robust linear amplifiers Controls analysis of robustness Oxygen Homeostasis via Cosubstrate competition Recitation (1 Feb): sensitivity analysis Demo of sensitivity analysis and how to add events in simbio: I1FFL_sens_event_demo.sbproj Demo of how to use compartments within one model: multiple_compartments.sbproj	Alon, Ch 7: Robustness of protein circuits : the example of bacterial chemotaxis BE 150: BFS Ch 3: Sec 3.3 (Robustness) and Sec 3.6 (Bifurcations) BFS Sec 5.2: Bacterial chemotaxis Papers discussed in lecture: Maintenance of Mitochondrial Oxygen Homeostasis by Cosubstrate Compensation, Kueh HY, Niethammer P., Mitchison TJ. Biophys J, 104 (6) 1338-1348 2013. H. Kitano, Biological robustness, Nat Rev Genet, vol. 5, no. 11, pp. 826–837, Nov. 2004. N. Barkai and S. Leibler, Robustness in simple biochemical networks, Nature, vol. 387, no. 6636, pp. 913–917, Jun. 1997. (optional) C. V. Rao, J. R. Kirby, and A. P. Arkin, Design and diversity in bacterial chemotaxis: a comparative study in Escherichia coli and Bacillus subtilis, PLoS Biol, vol. 2, no. 2, p. E49, Feb. 2004. BE150: (optional) O. Shoval, L. Goentoro, Y. Hart, A. Mayo, E. Sontag, and U. Alon, Fold-change detection and scalar symmetry of sensory input fields, Proceedings of the National Academy of Sciences, vol. 107, no. 36, pp. 15995–16000, Sep. 2010.	HW4
4	21 Apr 23 Apr+ MBE?	Guest lecture: Joe Markson Biological clocks: how to produce oscillations in cells Plant clocks/circadian rhythm Synthetic oscillators (repressilator, phosphorylation oscillator, dual-feedback oscillator (? is the dual feedback osc the same as the relaxation oscilltor) Circadian clocks in cyanobacteria April 25: Course Project Assignments	BE 150: BFS Ch 3: Analysis of Dynamic Behavior Sections 3.5: Oscillatory Behavior Papers discussed in lecture: Robust, Tunable Biological Oscillations from Interlinked Positive and Negative Feedback Loops, Tsai, Choi, Ma, Pomerening, Tang and Ferrell. Science Signaling, 321(5885): 126, 2008 A synthetic oscillatory network of transcriptional regulators, Elowitz and Leibler. Nature, 403:335-338, 2000. A fast, robust and tunable synthetic gene oscillator, Stricker, et al.. Nature, 456:516-519, 2008. Ordered Phosphorylation Governs Oscillation of a Three-Protein Circadian Clock, Rust MJ, Markson JS, Lane WS, Fisher DS, O'Shea EK. Science, 218 (5851) 809-812 2007.	HW3 dde.m
5	28 Apr 30 Apr RMM	Noise Random processes Intrinsic and extrinsic noise Stochastic modeling: master equation, SSA	Stochastic Gene Expression in a Single Cell, Michael B. Elowitz, Arnold J. Levine, Eric D. Siggia and Peter S. Swain. Science, 297(5584):1183-1186, 2002. Stochastic protein expression in individual cells at the single molecule level, Long Cai, Nir Friedman and X. Sunney Xie. Nature, 440:358-362, 2006. BE 150: BFS Ch 4: Stochastic behavior App B: Probability and random processes (optional)	HW5
6	5 May* 7 May* RMM	Burstiness in gene expression and signalling Birth-death processes	Dynamics of the p53-Mdm2 feedback loop in individual cells, Galit Lahav et al. Nature Genetics, 36:147-150, 2004. Frequency-modulated nuclear localization bursts coordinate gene regulation, Long Cai, Chiraj K. Dalal and Michael B. Elowitz. Nature 455:485-490, 2008. Single-cell NF-kB dynamics reveal digital activation and analogue information processing, S. Tay et al. Nature, 466(7303):267-271, 2010 An excitable gene regulatory circuit induces transient cellular differentiation, Suel GM, Gracia-Ojalvo J, Liberman LM, Elowitz, MB. Nature, 440:545-550 2006 Tunability and Noise Dependence in Differentiation Dynamics, Suel GM, Kulkarni RP, Dworkin J, Gracia-Ojalvo J, Elowitz, MB. Science, 315(5819): 1716-1719 2007
	9 May	Course project discussion with TAs
7	12 May 14 May MBE	Guest Lecture: Sandy Nandagopal & Joe Markson Patterning Morphogenesis Robust morphagen gradient Proportionality and scaling Lateral inhibition Notch-delta	Alon, Ch 8: Robust Patterning in Development Elucidating mechanisms underlying robustness of morphogen gradients, Avigdor Eldar, Ben-Zion Shilo and Naama Barkai. Curr Opin Genet Dev., 14(4):435-439, 2004. Scaling of morphogen gradients by an expansion-repression integral feedback control, Danny Ben-Zvia and Naama Barkai. PNAS, 107(15):6924-6929, 2010. Pattern formation by lateral inhibition with feedback: a mathematical model of delta-notch intercellular signalling, Collier et al. Journal of theoretical biology (1996) vol. 183 (4) pp. 429-46. Cis-interactions between Notch and Delta generate mutually exclusive signalling states, Sprinzak et al. Nature (2010) vol. 465 (7294) pp. 86-90	HW6 NotchDeltaGui.m NotchDeltaGui2.m
8	19 May 21 May MBE	Project presentations
9	28 May+ 30 May*	Project presentations

Course Description

BE 150/Bi 250b is a jointly taught class that shares lectures but has different reading material and homework assignments. Students in BE 150 are expected to have a more quantitative background and the course material includes a combination of analytical and conceptual tools. Students in Bi 250b are expected to have more knowledge of basic biological processes and the course material focuses on the principles and tools for understanding biological processes and systems.

BE 150: Quantitative studies of cellular and developmental systems in biology, including the architecture of specific genetic circuits controlling microbial behaviors and multicellular development in model organisms. Specific topics include chemotaxis, multistability and differentiation, biological oscillations, stochastic effects in circuit operation, as well as higher-level circuit properties such as robustness. Organization of transcriptional and protein-protein interaction networks at the genomic scale. Topics are approached from experimental, theoretical and computational perspectives.

Bi 250b: The class will focus on quantitative studies of cellular and developmental systems in biology. It will examine the architecture of specific genetic circuits controlling microbial behaviors and multicellular development in model organisms. The course will approach most topics from both experimental and theoretical/computational perspectives. Specific topics include chemotaxis, multistability and differentiation, biological oscillations, stochastic effects in circuit operation, as well as higher-level circuit properties such as robustness. The course will also consider the organization of transcriptional and protein-protein interaction networks at the genomic scale.

Textbook

The primary text for the BE 150 and Bi 250b is

[Alon]

U. Alon, An Introduction to Systems Biology: Design Principles of Biological Circuits, CRC Press, 2006.

Students in BE 150 should also obtain the following notes (freely downloadable from the web):

[BFS]

D. Del Vecchio and R. M. Murray, Biomolecular Feedback Systems (available online) Note: these notes are being written and will be updated during the course The public version is missing some copyrighted figures. These are available in the class version. Class version (Caltech access only, 5 Jan 2013): TOC, Ch 1, Ch 2, Ch 3, Ch 4, Sec 5.2, App B, Refs

The following additional texts and notes may be useful for some students:

[Klipp]	Edda Klipp, Wolfram Liebermeister, Christoph Wierling, Axel Kowald, Hans Lehrach, Ralf Herwig, Systems biology: A textbook. Wiley, 2009.
[Strogatz]	Steven Strogatz, Nonlinear Dynamics And Chaos: With Applications To Physics, Biology, Chemistry, And Engineering. Westview Press, 2001.

Course project

All students enrolled in the course will be expected to participate in a course project, which will be assigned after the fourth week of class. Course projects will generally consist of reviewing one or more papers on a topic that makes use principles and tools discussed in the course. Each project will be undertaking by two students (nominally one from BE 150, one from Bi 250). Topic suggestions are posted here. Students can also propose their own topic of student by preparing a 1-2 page proposal and submitting this to the instructors no later than 4 Feb for consideration.

Course project timeline:

• 1 Feb (Fri): course projects posted on home page and announced in class
• 4 Feb (Mon): course project preferences due
• 6 Feb (Wed): project assignments available
• 20 Feb (Wed): discussion of course projects with TAs and others
• 4-13 Mar: course project presentations. 15-20 minutes per project + 5-10 minutes questions.

Course preference instructions

• Each student should send e-mail no later than 4 Feb (Mon) with the following information
  • Course: (BE 150/Bi 250b/Audit)
  • Up to three project preferences (use titles from project listings)
  • Optional preferred partner (both students should e-mail identical preferences)
• Students will work in pairs, with most teams consisting of a BE 150 student and a Bi 250b student
• To propose your own project, please e-mail a 1-2 page proposal in addition to at least two project preferences selected from the list of course projects

Grading

The final grade will be based on biweekly homework sets (75%) and a course project (25%). The homework will be due in class approximately one week after they are assigned. Late homework will not be accepted without prior permission from the instructor. The lowest homework score you receive will be dropped in computing your homework average. The class project will be assigned and the end of the 5th week of instruction and project presentations will be scheduled for the last two weeks of class.

Collaboration Policy

Collaboration on homework assignments and the course project is encouraged. You may consult outside reference materials, other students, the TA, or the instructor. Use of solutions from previous years in the course is not allowed. All solutions that are handed in should reflect your understanding of the subject matter at the time of writing. Your course project presentation to properly acknowledge all source materials.