BE 150/Bi 250b Winter 2013

Systems Biology
Instructors Michael Elowitz (Bi/BE/APh) Richard Murray (CDS/BE) Lectures: MWF 10-11, 200 BRD	Teaching Assistants Emzo de los Santos Victoria Hsiao Recitation: Fr 10-11, location TBD
This is the course homepage for BE 150/Bi 250b for Winter 2013. 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.

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	7 Jan 9 Jan+ 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: 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	HW1
2	13 Jan 15 Jan MBE	Circuit motifs Feedforward loops (FFLs) Phosphorylation cascades Two-component signaling systems Sequestration for ultrasensitivty Recitation (17 Jan): 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	HW2 I1FFL.sbproj
3	21 Jan 23 Jan* 25 Jan RMM	Biological clocks: how to produce oscillations in cells Plant clocks/circadian rhythm Synthetic oscillators (repressilator, dual-feedback oscillator) Circadian clocks in cyanobacteria No recitation	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. BE 150: BFS Ch 3: Analysis of Dynamic Behavior Sections 3.5: Oscillatory Behavior	HW3 dde.m
4	28 Jan 30 Jan RMM	Robustness Chemotaxis and perfect adaptation Fold change detection Controls analysis of robustness 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 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. BE 150: BFS, Ch 3: Sec 3.3 (Robustness) and Sec 3.6 (Bifurcations) BFS, Sec 5.2: Bacterial chemotaxis (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
	1 Feb	Course projects posted. 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
5	4 Feb 6 Feb MBE	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 BFS, App B: Probability and random processes (optional)	HW5
6	11 Feb 13 Feb+ MBE	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
	15 Feb+*	Course project discussion with TAs
7	18 Feb 20 Feb 22 Feb* 25 Feb RMM	Patterning Morphogenesis Robust morphagen gradient Proportionality and scaling	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.	HW6 NotchDeltaGui.m NotchDeltaGui2.m
8	27 Feb 1 Mar RMM	Fine grain patterns Lateral inhibition Notch-delta	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
9	4 Mar 6 Mar 8 Mar	Project presentations
10	11 Mar 13 Mar	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.