{{HTDB paper
| authors = Victoria Hsiao, Yutaka Hori, Paul W.K. Rothemund, Richard M. Murray
| title = A population-based temporal logic gate for timing and recording chemical events
| source = Molecular Systems Biology (Accepted, In press)
| year = 2016
| type = Molecular Systems Biology article
| funding = ICB
| url = TBD
| abstract =
Engineered bacterial sensors have potential applications in human health monitoring, environmental chemical detection, and materials biosynthesis. While such bacterial devices have long been engineered to differentiate between combinations of inputs, their potential to process signal timing and duration has been overlooked. In this work, we present a two-input temporal logic gate that can sense and record the order of the inputs, the timing between inputs, and the duration of input pulses. Our temporal logic gate design relies on unidirectional DNA recombination mediated by bacteriophage integrases to detect and encode sequences of input events. For an E. coli strain engineered to contain our temporal logic gate, we compare predictions of Markov model simulations with laboratory measurements of final population distributions for both step and pulse inputs. Although single cells were engineered to have digital outputs, stochastic noise created heterogeneous single-cell responses that translated into analog population responses. Furthermore, when single-cell genetic states were aggregated into population-level distributions, these distributions contained unique information not encoded in individual cells. Thus, final differentiated sub-populations could be used to deduce order, timing, and duration of transient chemical events.

| flags =
| tag = hsi+16-MSB
| id = 2016n
}}

'''Preprints'''

BioRxiv DOI: [http://biorxiv.org/content/early/2015/10/27/029967| 10.1101/029967]

Posted: 27 Oct 2015

2014-04-24T19:02:40Z

Vhsiao: /* Lecture Schedule */

{| width=100%
|-
| colspan=3 align=center |
Systems Biology__NOTOC__
|- valign=top
|
'''Instructors'''
* Michael Elowitz (Bi/BE/APh)
* Richard Murray (CDS/BE)
* Lectures: MWF 11-12, 200 BRD
|
'''Teaching Assistants'''
* Victoria Hsiao (BE)
* Vipul Singhal (CNS)
* Recitation: Fr 11-12, location ANN107
| rowspan=2 width=20% align=right |
__TOC__
|-
| colspan=2 |
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.
|}

=== Lecture Schedule ===
There will be 2-3 one-hour lectures each week, as well as occasional one-hour tutorials, recitations or journal club.
{| width=100% border=1 cellpadding=5
|-
| '''Week'''
| '''Date'''
| width=40% | '''Topic'''
| width=40% | '''Reading'''
| '''Homework'''
|- valign=top
|- valign=top
|
'''1'''
| 31 Mar 2 Apr 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: [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]
* 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/simbiology-command-line-tutorial.html Simbiology Tutorial]

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

BE 150:
* {{be150 pdf|sp14|caltech/bfs-class-intro_31Mar14.pdf|BFS Ch 1}}: Introductory Concepts (skim)
* {{be150 pdf|sp14|caltech/bfs-class-coreproc_31Mar14.pdf|BFS Ch 2}}: Modeling of Core Processes
** Section 2.1: Modeling Techniques (skim)
** Sections 2.2-2.3: transcription and translation, transcriptional regulation

|

[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)]

|- valign=top
|

'''2'''
| 7 Apr 9 Apr+ MBE
| 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 (11 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|sp14|caltech/bfs-class-coreproc_31Mar14.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.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


|
[http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw2.pdf HW2]
{{be150-sp14 matlab|I1FFL.sbproj}}

|- valign=top
|

'''3'''
| 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:''
*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 compensation provides oxygen homeostasis across a broad range of oxygen levels (Kueh)

|
* Alon, Ch 7: Robustness of protein circuits : the example of bacterial chemotaxis
BE 150:
* {{be150 pdf|sp14|caltech/bfs-class-coreproc_31Mar14.pdf|BFS Ch 2}}: Sec 2.4: Post-transcriptional regulation
* {{be150 pdf|sp14|caltech/bfs-class-dynamics_31Mar14.pdf|BFS Ch 3}}: Sec 3.2 (Robustness)
* {{be150 pdf|sp14|caltech/bfs-class-chemotaxis_31Mar14.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'', 104 (6) 1338-1348 2013.


|

[http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw3.pdf HW3]

|- valign=top
|

'''4'''
| 21 Apr 23 Apr+ 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
|

BE 150:
* {{be150 pdf|sp14|caltech/bfs-class-dynamics_31Mar14.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.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):1396-408.
* [http://www.sciencemag.org/content/318/5851/809.short Ordered phosphorylation governs oscillation of a three-protein 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 protein-based circadian oscillator. Markson, J. S., & O'Shea, E. K. (2009). FEBS Letters, 583(24), 3938–3947.


|
[http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw4.pdf HW4]
* {{be150-sp14 matlab|dde.m}}

|- valign=top
|

'''5'''
| 28 Apr 30 Apr 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
|

BE 150:
* {{be150 pdf|sp14|caltech/bfs-class-stochastic_31Mar14.pdf|BFS Ch 4}}: Stochastic behavior
* {{be150 pdf|sp14|caltech/bfs-class-random_05Jan13.pdf|App B}}: Probability and random processes (optional)
| rowspan=2 |

|- valign=top
|

'''6'''
| 5 May* 7 May* 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)
|

|-
|
| 9 May 
| colspan=3 | Course project discussion with TAs

|- valign=top
|

'''7'''
| 12 May 14 May MBE
| Guest Lecture: Sandy Nandagopal & Joe Markson
Patterning
* Self-enhanced degradation makes morphogen gradients robust to variation in morphogen production rates.
* Shuttling mechanisms enable morphogen-based patterning systems to scale with tissue size.
|
* Alon, Ch 8: Robust Patterning in Development

| rowspan=2 |

|- valign=top
|

'''8'''
| 19 May 21 May MBE
| colspan=3 | Project presentations
|- valign=top
|

'''9'''
| 28 May+ 30 May* 
| colspan=3 | 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 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
{|
|- valign=top
| align=right |  [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):
{|
|- valign=top
| align=right |  [BFS] 
| 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}}
|}

The following additional texts and notes may be useful for some students:
{|
|- valign=top
|- valign=top
| align=right |  [Klipp] 
| Edda Klipp, Wolfram Liebermeister, Christoph Wierling, Axel Kowald, Hans Lehrach, Ralf Herwig, ''Systems biology: A textbook''. Wiley, 2009.
|- valign=top
| align=right |  [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 [[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]]

BE 150/Bi 250 Spring 2014

2014-04-24T18:56:57Z

Vhsiao: /* Lecture Schedule */

{| width=100%
|-
| colspan=3 align=center |
Systems Biology__NOTOC__
|- valign=top
|
'''Instructors'''
* Michael Elowitz (Bi/BE/APh)
* Richard Murray (CDS/BE)
* Lectures: MWF 11-12, 200 BRD
|
'''Teaching Assistants'''
* Victoria Hsiao (BE)
* Vipul Singhal (CNS)
* Recitation: Fr 11-12, location ANN107
| rowspan=2 width=20% align=right |
__TOC__
|-
| colspan=2 |
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.
|}

=== Lecture Schedule ===
There will be 2-3 one-hour lectures each week, as well as occasional one-hour tutorials, recitations or journal club.
{| width=100% border=1 cellpadding=5
|-
| '''Week'''
| '''Date'''
| width=40% | '''Topic'''
| width=40% | '''Reading'''
| '''Homework'''
|- valign=top
|- valign=top
|
'''1'''
| 31 Mar 2 Apr 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: [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]
* 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/simbiology-command-line-tutorial.html Simbiology Tutorial]

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

BE 150:
* {{be150 pdf|sp14|caltech/bfs-class-intro_31Mar14.pdf|BFS Ch 1}}: Introductory Concepts (skim)
* {{be150 pdf|sp14|caltech/bfs-class-coreproc_31Mar14.pdf|BFS Ch 2}}: Modeling of Core Processes
** Section 2.1: Modeling Techniques (skim)
** Sections 2.2-2.3: transcription and translation, transcriptional regulation

|

[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)]

|- valign=top
|

'''2'''
| 7 Apr 9 Apr+ MBE
| 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 (11 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|sp14|caltech/bfs-class-coreproc_31Mar14.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.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


|
[http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw2.pdf HW2]
{{be150-sp14 matlab|I1FFL.sbproj}}

|- valign=top
|

'''3'''
| 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:''
*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 compensation provides oxygen homeostasis across a broad range of oxygen levels (Kueh)

|
* Alon, Ch 7: Robustness of protein circuits : the example of bacterial chemotaxis
BE 150:
* {{be150 pdf|sp14|caltech/bfs-class-coreproc_31Mar14.pdf|BFS Ch 2}}: Sec 2.4: Post-transcriptional regulation
* {{be150 pdf|sp14|caltech/bfs-class-dynamics_31Mar14.pdf|BFS Ch 3}}: Sec 3.2 (Robustness)
* {{be150 pdf|sp14|caltech/bfs-class-chemotaxis_31Mar14.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'', 104 (6) 1338-1348 2013.


|

[http://www.cds.caltech.edu/~murray/courses/be150/sp14/hw3.pdf HW3]

|- valign=top
|

'''4'''
| 21 Apr 23 Apr+ 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
|

BE 150:
* {{be150 pdf|sp14|caltech/bfs-class-dynamics_31Mar14.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.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):1396-408.
* [http://www.sciencemag.org/content/318/5851/809.short Ordered phosphorylation governs oscillation of a three-protein 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 protein-based circadian oscillator. Markson, J. S., & O'Shea, E. K. (2009). FEBS Letters, 583(24), 3938–3947.


|

|- valign=top
|

'''5'''
| 28 Apr 30 Apr 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
|

BE 150:
* {{be150 pdf|sp14|caltech/bfs-class-stochastic_31Mar14.pdf|BFS Ch 4}}: Stochastic behavior
* {{be150 pdf|sp14|caltech/bfs-class-random_05Jan13.pdf|App B}}: Probability and random processes (optional)
| rowspan=2 |

|- valign=top
|

'''6'''
| 5 May* 7 May* 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)
|

|-
|
| 9 May 
| colspan=3 | Course project discussion with TAs

|- valign=top
|

'''7'''
| 12 May 14 May MBE
| Guest Lecture: Sandy Nandagopal & Joe Markson
Patterning
* Self-enhanced degradation makes morphogen gradients robust to variation in morphogen production rates.
* Shuttling mechanisms enable morphogen-based patterning systems to scale with tissue size.
|
* Alon, Ch 8: Robust Patterning in Development

| rowspan=2 |

|- valign=top
|

'''8'''
| 19 May 21 May MBE
| colspan=3 | Project presentations
|- valign=top
|

'''9'''
| 28 May+ 30 May* 
| colspan=3 | 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 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
{|
|- valign=top
| align=right |  [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):
{|
|- valign=top
| align=right |  [BFS] 
| 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}}
|}

The following additional texts and notes may be useful for some students:
{|
|- valign=top
|- valign=top
| align=right |  [Klipp] 
| Edda Klipp, Wolfram Liebermeister, Christoph Wierling, Axel Kowald, Hans Lehrach, Ralf Herwig, ''Systems biology: A textbook''. Wiley, 2009.
|- valign=top
| align=right |  [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 [[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]]