View source for BE 150/Bi 250 Spring 2014

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<font color='blue' size='+2'>Systems Biology</font>__NOTOC__
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'''Instructors'''
* Michael Elowitz (Bi/BE/APh)
* Richard Murray (CDS/BE)
* Lectures: MWF 11-12, 200 BRD
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'''Teaching Assistants'''
* Victoria Hsiao (BE)
* Vipul Singhal (CNS)
* Recitation: Fr 11-12, location TBD
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__TOC__
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This is the course homepage for BE 150/Bi 250 for Spring 2014.  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.
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{{warning|This page is still under construction.  This banner will be removed when things are finalized.}}

=== Lecture Schedule ===
There will be 2-3 one-hour lectures each week, as well as occasional one-hour tutorials, recitations or journal club.
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| '''Week'''
| '''Date'''
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| width=40% | '''Reading'''
| '''Homework'''
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'''1'''
| 31&nbsp;Mar <br> 2 Apr <br> MBE/RMM
| Course overview, gene circuit dynamics
* Introduction to the course
* Rate equations enable analysis of gene regulation circuits
* Degradation rates control response times in simple open-loop gene regulation
* Autoregulatory feedback loops modulate the response times of genetic circuits, limit variability, and can enable rate-responsive systems
* Cooperative responses can enable switch-like regulation and bistability
* Circuit motifs can help identify functional modules in complex circuits
Recitation section: 4 Apr
* [[Media:MatlabTutorial.pdf|MATLAB]] and [[Media:SimbiologyTutorial.pdf|SimBiology]] Tutorial
* Useful MATLAB commands: [[Media:Useful_matlab.m.zip|Useful Matlab Commands]]
* SimBiology example: [[Media:Rec1_pos_regdemo.sbproj.zip|Simbiology Project Pos Reg]]
* MATLAB/ode45 example: [[Media:ODE45_model_pos_reg.zip|ODE45 pos reg model]]
* [http://www.mathworks.com/help/simbio/gs/simbiology-command-line-tutorial.html Simbiology Tutorial]

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Bi 250b:
* Alon, Ch 1: Introduction
* Alon, Ch 2: Transcription networks : basic concepts
* Alon, Ch 3: Autoregulation : a network motif

BE 150:
* {{be150 pdf|wi13|caltech/bfs-class-intro_05Jan13.pdf|BFS Ch 1}}: Introductory Concepts (skim)
* {{be150 pdf|wi13|caltech/bfs-class-coreproc_05Jan13.pdf|BFS Ch 2}}: Modeling of Core Processes
** Section 2.1: Modeling Techniques (skim)
** Sections 2.2-2.3: transcription and translation, transcriptional regulation
<!--
Papers discussed in lecture:
* [http://www.sciencedirect.com/science/article/pii/S0022283602009944# Negative Autoregulation Speeds the Response Times of Transcription Networks], Nitzan Rosenfeld, Michael B. Elowitz and Uri Alon, ''J. Mol. Biol.'' <b>323</b>: 785–793, 2002.
* [http://www.nature.com/nature/journal/v405/n6786/full/405590a0.html Engineering stability in gene networks by autoregulation], Attila Becskei & Luis Serrano, ''Nature'', <b>405</b>:590-593, 2000.
* [http://www.pnas.org/content/110/10/4140.full Rate of environmental change determines stress response specificity], Jonathan W. Young, James C. W. Locke, Michael B. Elowitz, ''PNAS'', <b>110</b>:4140-4145, 2013.


* [http://www.nature.com/nature/journal/v403/n6767/abs/403339a0.html Construction of a genetic toggle switch in <i>Escherichia coli </i>], Gardner TS, Cantor CR, Collins JJ. ''Nature'', <b>403</b>:339-342, 2000.
* [http://www.nature.com/nature/journal/v426/n6965/abs/nature02089.html A positive-feedback-based bistable 'memory module' that governs a cell fate decision], Xiong and Ferrell. ''Nature'', <b>426</b>:460-465, 2003.
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'''2'''
| 7 Apr <br> 11 Apr* <br> RMM
| Circuit motifs
*Feed-forward loops enable temporal filtering and pulse generation
*‘Futile cycles’ generate zero-order ultrasensitivity (phospho-switches)
*Multi-gene positive feedback loops can enable toggle switch behaviors
*Positive feedback can generate hysteresis and irreversibility - example: Xenopus oocyte maturation
*Paradoxical regulation by cytokines could enable regulation of a population response
Recitation (9 Apr): sample problems
* MATLAB/curve fitting tool example: {{be150-sp14 matlab|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:
* {{be150 pdf|wi13|caltech/bfs-class-coreproc_05Jan13.pdf|BFS Ch 2}}: Modeling of Core Processes
** Section 2.4: post-transcriptional regulation
** Section 2.5: cellular subsystems
<!--
Papers discussed in lecture:
* [http://www.pnas.org/content/109/21/8346.short Design principles of cell circuits with paradoxical components], Hart, Antebi, Mayo, Friedman, Alon, ''PNAS'', <b>109 (21) </b> 8346-8351 2012.

* [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC349147/?tool=pmcentrez 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.
* [http://www.nature.com/msb/journal/v5/n1/full/msb200930.html Protein sequestration generates a flexible ultrasensitive response in a genetic network], N. E. Buchler and F. R. Cross.  ''Molecular Systems Biology'', 5:272, 2009.
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'''3'''
| 14 Apr+<br> 16&nbsp;Apr+ <br> MBE
| Robustness
''Critical features of genetic circuits may be robust to variation in their own components, and the principle of robustness can be used to select identify likely circuit architectures:''
*In the bacterial chemotaxis circuit, perfect adaptation is robust to fluctuations in key cellular components
*Bifunctional kinases can generate ideal linear amplifiers with robustness to component concentrations
*Cosubstrate competition provides oxygen homeostasis across a broad range of oxygen levels (Kueh)
Recitation (1 Feb): sensitivity analysis
*Demo of sensitivity analysis and how to add events in simbio: {{be150-sp14 matlab|I1FFL_sens_event_demo.sbproj}}
*Demo of how to use compartments within one model: {{be150-sp14 matlab|multiple_compartments.sbproj}}

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* Alon, Ch 7: Robustness of protein circuits : the example of bacterial chemotaxis
BE 150:
* {{be150 pdf|wi13|caltech/bfs-class-dynamics_05Jan13.pdf|BFS Ch 3}}: Sec 3.3 (Robustness) and Sec 3.6 (Bifurcations)
* {{be150 pdf|wi13|caltech/bfs-class-chemotaxis_05Jan13.pdf|BFS Sec 5.2}}: Bacterial chemotaxis
<!--
Papers discussed in lecture:
* [http://www.sciencedirect.com/science/article/pii/S0006349513001355 Maintenance of Mitochondrial Oxygen Homeostasis by Cosubstrate Compensation], Kueh HY, Niethammer P., Mitchison TJ. ''Biophys J'', <b> 104 (6)</b> 1338-1348 2013. 
* H. Kitano, [http://www.ncbi.nlm.nih.gov/pubmed/15520792 Biological robustness], Nat Rev Genet, vol. 5, no. 11, pp. 826–837, Nov. 2004.
* N. Barkai and S. Leibler, [http://www.ncbi.nlm.nih.gov/pubmed/9202124 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, [http://www.ncbi.nlm.nih.gov/pubmed/14966542 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.
BE150:
* (optional) O. Shoval, L. Goentoro, Y. Hart, A. Mayo, E. Sontag, and U. Alon, [http://www.pnas.org/content/107/36/15995.long 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.
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'''4'''
| 21 Apr <br> 23 Apr+ <br> MBE
| Guest lecture: Joe Markson
''Clock-like oscillations can be implemented in cells:''
* Delayed negative feedback can enable clock-like oscillations in individual cells (Repressilator)
* Combined positive/negative feedback enables relaxation oscillation whose period and amplitude can be tuned independently
* A simple three-protein system can generate accurate clock-like oscillations of phosphorylation state
April 25: Course Project Assignments
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BE 150:
* {{be150 pdf|sp14|caltech/bfs-class-dynamics_05Jan13.pdf|BFS Ch 3}}: Analysis of Dynamic Behavior
** Sections 3.5: Oscillatory Behavior
<!--
Papers discussed in lecture:
* [http://stke.sciencemag.org/cgi/content/full/sci;321/5885/126 Robust, Tunable Biological Oscillations from Interlinked Positive and Negative Feedback Loops], Tsai, Choi, Ma, Pomerening, Tang and Ferrell. ''Science Signaling'', 321(5885): 126, 2008
* [http://www.nature.com/nature/journal/v403/n6767/full/403335a0.html A synthetic oscillatory network of transcriptional regulators], Elowitz and Leibler. ''Nature'', 403:335-338, 2000.
* [http://www.nature.com/nature/journal/v456/n7221/full/nature07389.html A fast, robust and tunable synthetic gene oscillator], Stricker, ''et al.''.  ''Nature'',  456:516-519, 2008.
* [http://www.sciencemag.org/content/318/5851/809 Ordered Phosphorylation Governs Oscillation of a Three-Protein Circadian Clock], Rust MJ, Markson JS, Lane WS, Fisher DS, O'Shea EK. ''Science'', <b> 218 (5851)</b> 809-812 2007. 
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'''5'''
| 28 Apr <br> 30 Apr <br> RMM
| ''Stochasticity, or ‘noise’  is ubiquitous in genetic circuits:''
* Intrinsic noise (stochasticity) in gene expression limits the accuracy of gene regulation
* Variability can be controlled by altering burst parameters
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<!--
* [http://www.sciencemag.org/content/297/5584/1183 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.
* [http://www.nature.com/nature/journal/v440/n7082/full/nature04599.html Stochastic protein expression in individual cells at the single molecule level], Long Cai, Nir Friedman and X. Sunney Xie.  ''Nature'', 440:358-362, 2006.
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BE 150:
* {{be150 pdf|wi13|caltech/bfs-class-stochastic_05Jan13.pdf|BFS Ch 4}}: Stochastic behavior
* {{be150 pdf|wi13|caltech/bfs-class-random_05Jan13.pdf|App B}}: Probability and random processes (optional)
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'''6'''
| 5 May* <br> 7 May* <br> RMM
| ''Stochastic pulsing provides multiple functions in cells, similar to the role of oscillatory signals in engineering''
* Frequency modulation coordinates the responses of diverse genetic targets (example: yeast stress response)
* Excitability is a noise-dependent mechanism that enables probabilistic control of transient, stereotyped differentiation events
* Pulsing can enable dynamic multiplexing (example: p53)
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<!--
* [http://www.nature.com/ng/journal/v36/n2/full/ng1293.html Dynamics of the p53-Mdm2 feedback loop in individual cells], Galit Lahav ''et al''.  ''Nature Genetics'',  36:147-150, 2004.
* [http://www.nature.com/nature/journal/v455/n7212/full/nature07292.html Frequency-modulated nuclear localization bursts coordinate gene regulation], Long Cai, Chiraj K. Dalal and Michael B. Elowitz.  Nature 455:485-490, 2008.
* [http://www.nature.com/nature/journal/v466/n7303/full/nature09145.html Single-cell NF-kB dynamics reveal digital activation and analogue information processing], S. Tay ''et al''.  ''Nature'', 466(7303):267-271, 2010
* [http://www.nature.com/nature/journal/v440/n7083/abs/nature04588.html An excitable gene regulatory circuit induces transient cellular differentiation], Suel GM, Gracia-Ojalvo J, Liberman LM, Elowitz, MB.  ''Nature'', 440:545-550 2006
* [http://www.sciencemag.org/content/315/5819/1716.abstract Tunability and Noise Dependence in Differentiation Dynamics], Suel GM, Kulkarni RP, Dworkin J, Gracia-Ojalvo J, Elowitz, MB.  ''Science'', 315(5819): 1716-1719 2007
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| 9&nbsp;May<br>
| colspan=3 | Course project discussion with TAs

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'''7'''
| 12 May <br> 14 May <br> MBE 
| Guest Lecture: Sandy Nandagopal & Joe Markson
Patterning
* Cis inhibition can enforce heterotypic signaling (example: The Notch signaling pathway)
* Morphogen
* Shuttling can enable robust scaling (example BMP signaling)
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* Alon, Ch 8: Robust Patterning in Development
<!--
* [http://linkinghub.elsevier.com/retrieve/pii/S0959437X04000887 Elucidating mechanisms underlying robustness of morphogen gradients], Avigdor Eldar, Ben-Zion Shilo and Naama Barkai. ''Curr Opin Genet Dev.'', 14(4):435-439, 2004.
* [http://www.pnas.org/content/107/15/6924.short Scaling of morphogen gradients by an expansion-repression integral feedback control], Danny Ben-Zvia and Naama Barkai.  ''PNAS'',  107(15):6924-6929, 2010.
* [http://www.ncbi.nlm.nih.gov/pubmed/9015458 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.
* [http://www.ncbi.nlm.nih.gov/pubmed/20418862 Cis-interactions between Notch and Delta generate mutually exclusive signalling states], Sprinzak et al. Nature (2010) vol. 465 (7294) pp. 86-90
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'''8'''
| 19 May <br> 21 May <br> MBE
| colspan=3 | Project presentations
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'''9'''
|  28 May+ <br> 30 May* <br>
| colspan=3 | Project presentations
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<br>

=== 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
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| align=right | &nbsp;[Alon]&nbsp;
| U. Alon, ''An Introduction to Systems Biology: Design Principles of Biological Circuits'', CRC Press, 2006.
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Students in BE 150 should also obtain the following notes (freely downloadable from the web):
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| align=right | &nbsp;[BFS]&nbsp;
| D. Del Vecchio and R. M. Murray, ''[[http:www.cds.caltech.edu/~murray/amwiki/BFS|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): {{be150 pdf|wi13|caltech/bfs-class-frontmatter_05Jan13.pdf|TOC}}, {{be150 pdf|wi13|caltech/bfs-class-intro_05Jan13.pdf|Ch 1}}, {{be150 pdf|wi13|caltech/bfs-class-coreproc_05Jan13.pdf|Ch 2}},  {{be150 pdf|wi13|caltech/bfs-class-dynamics_05Jan13.pdf|Ch 3}},  {{be150 pdf|wi13|caltech/bfs-class-stochastic_05Jan13.pdf|Ch 4}}, {{be150 pdf|wi13|caltech/bfs-class-chemotaxis_05Jan13.pdf|Sec 5.2}}, {{be150 pdf|wi13|caltech/bfs-class-random_05Jan13.pdf|App B}}, {{be150 pdf|wi13|caltech/bfs-class-backmatter_05Jan13.pdf|Refs}}
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The following additional texts and notes may be useful for some students:
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| align=right | &nbsp;[Klipp]&nbsp;
| Edda Klipp, Wolfram Liebermeister, Christoph Wierling, Axel Kowald, Hans Lehrach, Ralf Herwig, ''Systems biology: A textbook''.  Wiley, 2009.
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| align=right | &nbsp;[Strogatz]&nbsp;
| Steven Strogatz, ''Nonlinear Dynamics And Chaos: With Applications To Physics, Biology, Chemistry, And Engineering''.  Westview Press, 2001.
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=== 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 [[BE 150/Bi 250b project ideas, Winter 2013|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): [[BE 150/Bi 250b project ideas, Winter 2013|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
{{BE 150 project instructions, Winter 2013}}

=== 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.

[[Category:Courses]]