BE 150/Bi 250b Winter 2012

Systems Biology
Instructors Michael Elowitz (Bi/BE/APh) Richard Murray (CDS/BE) Lectures: MWF 11-12, 200 Broad (tentative)	Teaching Assistants Emzo de los Santos Vanessa Jonsson

Course Description

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.

Announcements

• 19 Nov 2011: added TAs; updated schedule
• 2 Oct 2011: web page creation

Textbook

The primary text for the course (available via the online bookstore) is

[Alon]

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

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.
[BFS]	D. Del Vecchio and R. M. Murray, Biomolecular Feedback Systems. Available online at http://www.cds.caltech.edu/~murray/amwiki/BFS. Class version (Caltech access only): TOC, Ch 1, Ch 2, Ch 3, Ch 5, Refs
[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. In addition, if your score on the final is higher than the weighted average of your homework and final, your final will be used to determine your course grade.

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.

Lecture Schedule

Week	Date	Topic	Reading	Homework
1	4 Jan MBE/RMM	Course overview Principles in systems biology Recitation sections (TAs): Ordinary differential equations
2	9 Jan 11 Jan+ MBE	Gene circuit dynamics Core processes in cells Modeling transcription, translation and regulation using ODEs Negative auto-regulation Recitation sections (TAs): MATLAB tutorial	Alon, Ch 2: Transcription networks : basic concepts BFS, Ch 2: Modeling of Core Processes Alon, Ch 3: Autoregulation : a network motif
3	16 Jan* 18 Jan* RMM	Circuit motifs Finding "motifs" Feedforward loops (FFLs) SIMS and multi-output FFLs	Alon, Ch 4: The feed-forward loop network motif Alon, Ch 5: Temporal programs and the global structure of transcription networks Alon, Ch 6: Network motifs in developmental, signal transduction, and neuronal networks
4	23 Jan 25 Jan RMM	Biological clocks: how to produce oscillations in cells Synthetic oscillators (repressilator, dual-feedback oscillator) Circadian clocks in cyanobacteria Optional: plant clocks/circadian rhythm Background slides on modeling and stability Modeling of core processes Dynamics and stability in ODEs	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.
5	30 Jan 1 Feb RMM	Robustness Chemotaxis and perfect adaptation Controls analysis of robustness	Alon, Ch 7: Robustness of protein circuits : the example of bacterial chemotaxis BFS, Sec 5.4: Bacterial chemotaxis Robust perfect adaptation in bacterial chemotaxis through integral feedback control, Tau-Mu Yi, Yun Huang, Melvin I. Simon and John Doyle. PNAS, 97(9):4649-4653, 2000.	HW4 Solutions
6 Feb* 8 Feb MBE	Noise Random processes Intrinsic and extrinsic noise Stochastic modeling Probabilistic differentiation (?)	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.	HW5 Solutions
7	13 Feb+ 15 Feb MBK/MBE	Modeling of complex biological networks (MBK) Dynamic signal coding PWM FM NFkB example	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
8	20 FebX 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.
9	27 Feb 29 Feb*+ MBE/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
10	5 Mar 7 Mar MBE	Epistasis and modularity Flux balance analysis and yeast metabolism Antibiotic interactions Principle of monochroniticity (?)	Modular epistasis in yeast metabolism, Daniel Segrè, Alexander DeLuna, George M Church and Roy Kishony. Nature Genetics, 37:77-83, 2004.