BE 150/Bi 250b Winter 2012

Systems Biology
Instructors Michael Elowitz (Bi/BE/APh) Richard Murray (CDS/BE) Lectures: MWF 10-11, 101 Kerckhoff	Teaching Assistants Emzo de los Santos Vanessa Jonsson

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.

Announcements

• 0 Jan 2012: updated copy of BFS, Ch 2 has been posted
• 4 Jan 2012: course mailing list created; sign up at https://utils.its.caltech.edu/mailman/listinfo/be150-students
• 4 Jan 2012: course time and location have been updated
• 11 Dec 2011: updated syllabus (should be final now)
• 19 Nov 2011: added TAs; updated schedule
• 2 Oct 2011: web page creation

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, 18 Jan 2012): TOC, Ch 1, Ch 2, Ch 3, 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.

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	4 Jan 6 Jan+ MBE/RMM	Course overview Principles in systems biology Recitation section: MATLAB tutorial (optional) Matlab Tutorial	Bi 250b: Alon, Ch 1: Introduction BE 150: BFS, Ch 1: Introductory Concepts BFS, Ch 2: Modeling of Core Processes Section 2.1: Modeling Techniques
2	9 Jan 11 Jan+ MBE	Gene circuit dynamics Core processes in cells Modeling transcription, translation and regulation using ODEs Negative auto-regulation	Bi 250b: Alon, Ch 2: Transcription networks : basic concepts Alon, Ch 3: Autoregulation : a network motif BE 150: BFS, Ch 2: Modeling of Core Processes Sections 2.2-2.3: transcription and translation, transcriptional regulation Papers discussed in lecture: Construction of a genetic toggle switch in Escherichia coli , Gardner TS, Cantor CR, Collins JJ. Nature, 403:339-342, 2000. A positive-feedback-based bistable 'memory module' that governs a cell fate decision, Xiong and Ferrell. Nature, 426:460-465, 2003.	BEHW1 BIOHW1 lacIOpenMain.m lacIClosedMain.m lacIOpen.m lacIClosed.m toggleMain.m toggle.m posFeedMain.m posFeed.m
3	16 Jan 18 Jan* 20 Jan* RMM	Circuit motifs Feedforward loops (FFLs) Phosphorylation cascades Two-component signaling systems Sequestration for ultrasensitivty	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-transcriptoinal regulation Section 2.5: cellular subsystems Papers discussed in lecture: An amplified sensitivity arising from covalent modification in biological systems, Goldbeter A, Koshland DE. Proc. Natl. Acad. Sci. U.S.A., 78 (11): 6840–4, 1981. Protein sequestration generates a flexible ultrasensitive response in a genetic network, N. E. Buchler and F. R. Cross. Molecular Systems Biology, 5:272, 2009.	HW #2
4	23 Jan 25 Jan MBE	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.	HW #3
5	30 Jan 1 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 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.	HW #4
6	6 Feb* 8 Feb RMM	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.	HW #5
7	13 Feb+ 15 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
8	20 Feb 22 Feb 24 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
9	27 Feb 29 Feb*+ MBK	Modeling of complex biological networks (Mary Kennedy)	A Dynamic Model of Interactions of Ca2+, Calmodulin, and Catalytic Subunits of Ca2+/Calmodulin-Dependent Protein Kinase II. Pepke, S., Kinzer-Ursem, T., Mihalas, S., and Kennedy, M.B. (2010). PLoS Comput Biol 6, e1000675. Fast Monte Carlo simulation methods for biological reaction-diffusion systems in solution and on surfaces. Kerr, R.A., Bartol, T.M., Kaminsky, B., Dittrich, M., Chang, J.-C.J., Baden, S.B., Sejnowski, T.J., and Stiles, J.R. (2008). SIAM Journal on Scientific Computing 30, 3126-3149. Complexity of calcium signaling in synaptic spines. Franks, K.M., and Sejnowski, T.J. (2002). Bioessays 24, 1130-1144.
10	5 Mar 7 Mar MBE	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