BE 150/Bi 250b Winter 2013

Systems Biology
Instructors Michael Elowitz (Bi/BE/APh) Richard Murray (CDS/BE) Lectures: MW 10-11, location TBD	Teaching Assistants Emzo de los Santos TBD Recitation: Fr 10-11, location TBD

Lecture Schedule

There will be two 1-hour lectures each week, as well as a 1-hour recitation section.

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 Recitation section: MATLAB tutorial (optional) Matlab Tutorial	Bi 250b: Alon, Ch 1: Introduction Alon, Ch 2: Transcription networks : basic concepts BE 150: BFS, Ch 1: Introductory Concepts BFS, Ch 2: Modeling of Core Processes Section 2.1: Modeling Techniques Sections 2.2-2.3: transcription and translation, transcriptional regulation	HW1
2	13 Jan 15 Jan MBE	Circuit motifs Negative auto-regulation Feedforward loops (FFLs) Phosphorylation cascades Two-component signaling systems Sequestration for ultrasensitivty	Bi 250b: Alon, Ch 3: Autoregulation : a network motif 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-transcriptoinal regulation Section 2.5: cellular subsystems	HW 2
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	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. Cyanobacterial clock, a stable phase oscillator with negligible intercellular coupling, M. Amdaoud, M. Vallade, C. Weiss-Schaber, and I. Mihalcescu. Proc Natl Acad Sci, 104(17):7051–7056, 2007. BE 150: BFS, Ch 3: Analysis of Dynamic Behavior Sections 3.5: Oscillatory Behavior	HW 3
4	28 Jan 30 Feb RMM	Robustness Chemotaxis and perfect adaptation Fold change detection Controls analysis of robustness	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.	HW 4
5	4 Feb* 8 Feb MBE	Noise Random processes Intrinsic and extrinsic noise Stochastic modeling: master equation, SSA	BFS, Ch 4 and App C 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 C: Probability and random processes (optional)	HW 5
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	HW 6
7	18 Feb 20 Feb 22 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.	HW 7
8	25 Feb 27 Feb 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	HW 8
9	4 Mar 6 Mar MBE	Special topics
9	11 Mar 13 Mar RMM	Special topics

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 at http://www.cds.caltech.edu/~murray/amwiki/BFS. Note: these notes are being written and will be updated during the course Class version (Caltech access only, 29 Jan 2012): TOC, Ch 1, Ch 2, Ch 3, Ch 4, Sec 5.2, App C, Refs

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

[FBS]	K. J. Astrom and R. M. Murray, Feedback Systems. Available online at http://www.cds.caltech.edu/~murray/amwiki.
[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.

Grading

The final grade will be based on biweekly homework sets. The homework will be due in class 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.

Collaboration Policy

Collaboration on homework assignments 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.