Bi/BE 250c Winter 2011

Systems Biology
Instructors Michael Elowitz (Bi/BE) Richard Murray (CDS/BE) Lectures: Tu/Th, 1-2:30 pm, 151 Braun	Teaching Assistants Vanessa Jonsson Fiona Chandra

Course Description

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

• 24 Oct 2010: 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:

[BFS]	D. Del Vecchio and R. M. Murray, Biomolecular Feedback Systems. Available online at http://www.cds.caltech.edu/~murray/amwiki/BFS.
[Klipp]	Edda Klipp, Wolfram Liebermeister, Christoph Wierling, Axel Kowald, Hans Lehrach, Ralf Herwig, Systems biology: a textbook. Wiley, 2009.

Lecture Schedule

Week	Date	Topic	Reading	Homework
1	4 Jan 6 Jan	Course overview; gene circuit dynamics Core processes in cells Modeling transcription, translation and regulation using ODEs Negative auto-regulation Recitation section(s): Ordinary differential equations MATLAB tutorial	Alon, Ch 2: Transcription networks : basic concepts BFS, Ch 2: Modeling of Core Processes Alon, Ch 3: Autoregulation : a network motif
2	11 Jan 13 Jan	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
3	18 Jan? 20 Jan	Biological clocks: how to produce oscillations in cells Synthetic oscillators (repressilator, dual-feedback oscillator) Circadian clocks in cyanobacteria Optional: plant clocks/circadian rhythm	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.
4	25 Jan 27 Jan	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.
5	1 Feb* 3 Feb	Noise Random processes Intrinsic and extrinsic noise Stochastic modeling	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.
6	8 Feb* 10 Feb	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
7	15 Feb 17 Feb	Patterning Morphogenesis Robust morphagen gradient Proportionality and scaling	Alon, Ch 8: Robust Patterning in Development
8	22 Feb 24 Feb	Fine grain patterns Lateral inhibition Notch-delta
9	1 Mar 3 Mar	Epistasis and modulatory (Keasling) - ???
10	8 Mar

Grading

The final grade will be based on homework and a final exam:

• Homework (75%) - There will be 9 one-week problem sets, due in class one week after they are assigned. Late homework will not be accepted without prior permission from the instructor.
• Final exam (25%) - The final will be handed out the last day of class and is due back at the end of finals week. Open book, time limit to be decided (likely N hours over a 4-8N hour period).

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 should reflect your understanding of the subject matter at the time of writing.

No collaboration is allowed on the final exam.