Difference between revisions of "BE 150/Bi 250 Spring 2014"
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* Victoria Hsiao (BE)  * Victoria Hsiao (BE)  
* Vipul Singhal (CNS)  * Vipul Singhal (CNS)  
* Recitation: Fr 1112, location  * Recitation: Fr 1112, location ANN107  
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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.  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.  
There is also a forum for students to ask questions, and can be accessed [https://piazza.com/caltech/spring2014/be150bi250b/home here]. You will need to create a Piazza account to enroll.  
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* Useful MATLAB commands: [http://www.cds.caltech.edu/~murray/courses/be150/sp14/matlab/useful_matlab.m useful_matlab.m]  * Useful MATLAB commands: [http://www.cds.caltech.edu/~murray/courses/be150/sp14/matlab/useful_matlab.m useful_matlab.m]  
* SimBiology example: [http://www.cds.caltech.edu/~murray/courses/be150/sp14/matlab/rec1_pos_regdemo.sbproj Simbiology Project File]  * SimBiology example: [http://www.cds.caltech.edu/~murray/courses/be150/sp14/matlab/rec1_pos_regdemo.sbproj Simbiology Project File]  
* MATLAB/ode45 example: [http://www.cds.caltech.edu/~murray/courses/be150/sp14/matlab/pos_reg_main.m pos_reg_main.m]  * MATLAB/ode45 example: [http://www.cds.caltech.edu/~murray/courses/be150/sp14/matlab/pos_reg_main.m pos_reg_main.m] and [http://www.cds.caltech.edu/~murray/courses/be150/sp14/matlab/pos_reg.m pos_reg.m]  
* [http://www.mathworks.com/help/simbio/gs/simbiologycommandlinetutorial.html Simbiology Tutorial]  * [http://www.mathworks.com/help/simbio/gs/simbiologycommandlinetutorial.html Simbiology Tutorial]  
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[http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw1.pdf HW1]  [http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw1.pdf HW1]  
[http://www.cds.caltech.edu/~murray/courses/be150/sp14/matlab/pplane8.m pplane8 (Needed for Problem 2)]  
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'''2'''  '''2'''  
 7 Apr <br> 9 Apr   7 Apr <br> 9 Apr+ <br> MBE  
 Circuit motifs   Circuit motifs  
*Feedforward loops enable temporal filtering and pulse generation  *Feedforward loops enable temporal filtering and pulse generation  
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** Section 2.4: posttranscriptional regulation  ** Section 2.4: posttranscriptional regulation  
** Section 2.5: cellular subsystems  ** Section 2.5: cellular subsystems  
Papers discussed in lecture:  
* [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.  
* [http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.0050229 Quantitative Characteristics of Gene Regulation by Small RNA] Levine et al. "PLOS Biology" 2007  
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* [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> 83468351 2012.  * [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> 83468351 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.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.  
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[http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw2.pdf HW2]  
{{be150sp14 matlabI1FFL.sbproj}}  
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*Bifunctional kinases can generate ideal linear amplifiers with robustness to component concentrations  *Bifunctional kinases can generate ideal linear amplifiers with robustness to component concentrations  
*Cosubstrate compensation provides oxygen homeostasis across a broad range of oxygen levels (Kueh)  *Cosubstrate compensation provides oxygen homeostasis across a broad range of oxygen levels (Kueh)  
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Recitation (1 Feb): sensitivity analysis  Recitation (1 Feb): sensitivity analysis  
*Demo of sensitivity analysis and how to add events in simbio: {{be150sp14 matlabI1FFL_sens_event_demo.sbproj}}  *Demo of sensitivity analysis and how to add events in simbio: {{be150sp14 matlabI1FFL_sens_event_demo.sbproj}}  
*Demo of how to use compartments within one model: {{be150sp14 matlabmultiple_compartments.sbproj}}  *Demo of how to use compartments within one model: {{be150sp14 matlabmultiple_compartments.sbproj}}  
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* Alon, Ch 7: Robustness of protein circuits : the example of bacterial chemotaxis  * Alon, Ch 7: Robustness of protein circuits : the example of bacterial chemotaxis  
BE 150:  BE 150:  
* {{be150 pdfsp14caltech/bfsclassdynamics_31Mar14.pdfBFS Ch 3}}: Sec 3.  * {{be150 pdfsp14caltech/bfsclasscoreproc_31Mar14.pdfBFS Ch 2}}: Sec 2.4: Posttranscriptional regulation  
* {{be150 pdfsp14caltech/bfsclassdynamics_31Mar14.pdfBFS Ch 3}}: Sec 3.2 (Robustness)  
* {{be150 pdfsp14caltech/bfsclasschemotaxis_31Mar14.pdfBFS Sec 5.2}}: Bacterial chemotaxis  * {{be150 pdfsp14caltech/bfsclasschemotaxis_31Mar14.pdfBFS 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> 13381348 2013.  
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Papers discussed in lecture:  Papers discussed in lecture:  
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[http://www.cds.caltech.edu/~murray/courses/be150/sp14/  [http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw3.pdf HW3]  
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* {{be150 pdfsp14caltech/bfsclassdynamics_31Mar14.pdfBFS Ch 3}}: Analysis of Dynamic Behavior  * {{be150 pdfsp14caltech/bfsclassdynamics_31Mar14.pdfBFS Ch 3}}: Analysis of Dynamic Behavior  
** Sections 3.5: Oscillatory 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'', 403:335338, 2000.  
* [http://www.nature.com/nature/journal/v456/n7221/full/nature07389.html A fast, robust and tunable synthetic gene oscillator], Stricker, ''et al.''. ''Nature'', 456:516519, 2008.  
* [http://www.sciencedirect.com/science/article/pii/S0092867413014189 Circadian control of global gene expression by the cyanobacterial master regulator RpaA], Markson JS, et al. Cell, 2013 Dec 5;155(6):1396408.  
* [http://www.sciencemag.org/content/318/5851/809.short Ordered phosphorylation governs oscillation of a threeprotein circadian clock.] Rust et al. Science, 318(5851), 809–812. 2007.  
* [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810098/ The molecular clockwork of a proteinbased circadian oscillator.] Markson, J. S., & O'Shea, E. K. (2009). FEBS Letters, 583(24), 3938–3947.  
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Papers discussed in lecture:  Papers discussed in lecture:  
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[http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw4.pdf HW4]  
* {{be150sp14 matlabdde.m}}  
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[http://www.cds.caltech.edu/~murray/courses/be150/sp14/  [http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw4.pdf HW4]  
* {{be150sp14 matlabdde.m}}  * {{be150sp14 matlabdde.m}}  
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* Variability can be controlled by altering burst parameters  * Variability can be controlled by altering burst parameters  
    
* [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):11831186, 2002.  * [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):11831186, 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'', 440:358362, 2006.  * [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'', 440:358362, 2006.  
* [http://www.nature.com/ng/journal/v40/n12/pdf/ng.281.pdf Regulatory Activity Revealed by Dynamic Correlations in Gene Expression Noise] Mary J. Dunlop, Robert Sidney Cox, Joseph H. Levine, Richard M. Murray, and Michael B. Elowitz. Nat Genet. Dec 2008; 40(12): 1493–1498.  
BE 150:  BE 150:  
* {{be150 pdfsp14caltech/bfsclassstochastic_31Mar14.pdfBFS Ch 4}}: Stochastic behavior  * {{be150 pdfsp14caltech/bfsclassstochastic_31Mar14.pdfBFS Ch 4}}: Stochastic behavior  
* {{be150 pdfsp14caltech/bfsclassrandom_05Jan13.pdfApp B}}: Probability and random processes (optional)  * {{be150 pdfsp14caltech/bfsclassrandom_05Jan13.pdfApp B}}: Probability and random processes (optional)  
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[http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw5.pdf HW5]  
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[http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw5.pdf HW5]  [http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw5.pdf HW5]  
>  
<![http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw6.pdf HW6]  
[http://www.cds.caltech.edu/~murray/courses/be150/sp14/matlab/NotchDeltaGui.m NotchDeltaGui.m]  
[http://www.cds.caltech.edu/~murray/courses/be150/sp14/matlab/NotchDeltaGui2.m NotchDeltaGui2.m]  
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'''6'''  '''6'''  
 5 May   5 May <br> 7 May* <br> RMM  
   Patterning  
* Selfenhanced degradation makes morphogen gradients robust to variation in morphogen production rates.  
*  * Shuttling mechanisms enable morphogenbased patterning systems to scale with tissue size.  
*  
    
* Alon, Ch 8: Robust Patterning in Development  
* [http://www.nature.com/nature/journal/v419/n6904/pdf/nature01061.pdf Robustness of the BMP morphogen gradient in Drosophila embryonic patterning], Eldar et al. Nature 419, 304308 (19 September 2002)  
* [http://ac.elscdn.com/S1534580703002922/1s2.0S1534580703002922main.pdf?_tid=4155dfe4d48111e3835900000aacb360&acdnat=1399313916_fc28c2a5c2eee01a7821157a8df44aee SelfEnhanced Ligand Degradation Underlies Robustness of Morphogen Gradients], Avigdor Eldar, Dalia Rosin, BenZion Shilo, and Naama Barkai. Developmental Cell, Vol. 5, 635–646, October, 2003  
* [http://www.pnas.org/content/107/15/6924.short Scaling of morphogen gradients by an expansionrepression integral feedback control], Danny BenZvia and Naama Barkai. ''PNAS'', 107(15):69246929, 2010.  
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* [http://  * [http://linkinghub.elsevier.com/retrieve/pii/S0959437X04000887 Elucidating mechanisms underlying robustness of morphogen gradients], Avigdor Eldar, BenZion Shilo and Naama Barkai. ''Curr Opin Genet Dev.'', 14(4):435439, 2004.  
* [http://www.  * [http://www.ncbi.nlm.nih.gov/pubmed/9015458 Pattern formation by lateral inhibition with feedback: a mathematical model of deltanotch intercellular signalling], Collier et al. Journal of theoretical biology (1996) vol. 183 (4) pp. 42946.  
* [http://www.  * [http://www.ncbi.nlm.nih.gov/pubmed/20418862 Cisinteractions between Notch and Delta generate mutually exclusive signalling states], Sprinzak et al. Nature (2010) vol. 465 (7294) pp. 8690  
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'''7'''  '''7'''  
 12 May <br> 14 May <br>   12 May <br> 14 May <br> RMM  
   Engineered circuits  
* Current approaches for analysis and design of engineered biocircuits + limitations  
*  * Tools for analyzing/designing biocircuits to predict limiting effects  
*    
  * {{be150 pdfsp14caltech/bfsclassdynamics_31Mar14.pdfBFS Ch 3}}: Sec 3.2 (sensitivity analysis)  
*  * {{be150 pdfsp14caltech/bfsclasscomponents_31Mar14.pdfBFS Ch 5}}: Biological Circuit Components  
* {{be150 pdfsp14caltech/bfsclassinterconnection_31Mar14.pdfBFS Ch 6}}: Interconnecting Components  
* {{be150 pdfsp14caltech/bfsclasstradeoffs_31Mar14.pdfBFS Ch 7}}: Design Tradeoffs  
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*  [http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw6.pdf HW6]  
*  
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'''8'''  '''8'''  
 19 May <br> 21 May <br> MBE   19 May <br> 21 May <br> MBE  
   ''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 noisedependent mechanism that enables probabilistic control of transient, stereotyped differentiation events  
* Pulsing can enable dynamic multiplexing (example: p53)  
  
* [http://www.sciencedirect.com/science/article/pii/S0092867403003465 Development of Genetic Circuitry Exhibiting Toggle Switch or Oscillatory Behavior in Escherichia coli], Mariette R. Atkinson ''et al''. ''Cell'', Volume 113, Issue 5, 30 May 2003, Pages 597–607  
* [http://www.nature.com/nature/journal/v455/n7212/full/nature07292.html Frequencymodulated nuclear localization bursts coordinate gene regulation], Long Cai, Chiraj K. Dalal and Michael B. Elowitz. Nature 455:485490, 2008.  
* [http://www.nature.com/nature/journal/v446/n7136/full/nature05685.html Antibiotic interactions that select against resistance.], Remy Chait ''et al''. ''Nature'', 2007 Apr 5;446(7136):66871.  
* [http://www.nature.com/ng/journal/v37/n1/abs/ng1489.html Modular epistasis in yeast metabolism.], Daniel Segrè ''et al''. ''Nature Genetics'', 37, 77  83 (2004) .  
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* [http://www.nature.com/ng/journal/v36/n2/full/ng1293.html Dynamics of the p53Mdm2 feedback loop in individual cells], Galit Lahav ''et al''. ''Nature Genetics'', 36:147150, 2004.  
* [http://www.nature.com/nature/journal/v455/n7212/full/nature07292.html Frequencymodulated nuclear localization bursts coordinate gene regulation], Long Cai, Chiraj K. Dalal and Michael B. Elowitz. Nature 455:485490, 2008.  
* [http://www.nature.com/nature/journal/v466/n7303/full/nature09145.html Singlecell NFkB dynamics reveal digital activation and analogue information processing], S. Tay ''et al''. ''Nature'', 466(7303):267271, 2010  
* [http://www.nature.com/nature/journal/v440/n7083/abs/nature04588.html An excitable gene regulatory circuit induces transient cellular differentiation], Suel GM, GraciaOjalvo J, Liberman LM, Elowitz, MB. ''Nature'', 440:545550 2006  
* [http://www.sciencemag.org/content/315/5819/1716.abstract Tunability and Noise Dependence in Differentiation Dynamics], Suel GM, Kulkarni RP, Dworkin J, GraciaOjalvo J, Elowitz, MB. ''Science'', 315(5819): 17161719 2007  
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'''9'''  '''9'''  
   29 May <br> 30 May <br> 2 Jun  
 colspan=3  Project presentations   colspan=3  [[BE 150/Bi 250 Spring 2014, Project presentation scheduleProject presentations]]  
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Latest revision as of 21:10, 21 May 2014
Systems Biology  
Instructors

Teaching Assistants


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. There is also a forum for students to ask questions, and can be accessed here. You will need to create a Piazza account to enroll. 
Lecture Schedule
There will be 23 onehour lectures each week, as well as occasional onehour tutorials, recitations or journal club.
Week  Date  Topic  Reading  Homework 
1 
31 Mar 2 Apr MBE/RMM 
Course overview, gene circuit dynamics
Recitation section: 4 Apr

Bi 250b:
BE 150: 

2 
7 Apr 9 Apr+ MBE 
Circuit motifs
Recitation (11 Apr): sample problems

Bi 250b:
BE 150:
Papers discussed in lecture:



14 Apr+ 16 Apr+ 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:

BE 150:
Papers discussed in lecture:


4 
21 Apr 23 Apr+ MBE 
Guest lecture: Joe Markson
Clocklike oscillations can be implemented in cells:
April 25: Course Project Assignments 
BE 150:
Papers discussed in lecture:


5 
28 Apr 30 Apr RMM 
Stochasticity, or ‘noise’ is ubiquitous in genetic circuits:

BE 150: 

6 
5 May 7 May* RMM 
Patterning

 
9 May 
Course project discussion with TAs  
7 
12 May 14 May RMM 
Engineered circuits


8 
19 May 21 May MBE 
Stochastic pulsing provides multiple functions in cells, similar to the role of oscillatory signals in engineering

 
9 
29 May 30 May 2 Jun 
Project presentations 
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 higherlevel circuit properties such as robustness. Organization of transcriptional and proteinprotein 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 higherlevel circuit properties such as robustness. The course will also consider the organization of transcriptional and proteinprotein 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) 
The following additional texts and notes may be useful for some students:
[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. 
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 here. Students can also propose their own topic of student by preparing a 12 page proposal and submitting this to the instructors no later than 4 Feb for consideration.
Course project timeline:
 1 Feb (Fri): 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
 413 Mar: course project presentations. 1520 minutes per project + 510 minutes questions.
Course preference instructions
 Each student should send email no later than 4 Feb (Mon) with the following information
 Course: (BE 150/Bi 250b/Audit)
 Up to three project preferences (use titles from project listings)
 Optional preferred partner (both students should email identical preferences)
 Students will work in pairs, with most teams consisting of a BE 150 student and a Bi 250b student
 To propose your own project, please email a 12 page proposal in addition to at least two project preferences selected from the list of course projects
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.