Difference between revisions of "BE 150/Bi 250b project ideas, Winter 2013"

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=== Digit patterning (MBE) ===
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{| style="float: right"
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|-
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| align=right | [[BE 150/Bi 250b Winter 2013|Course home]]
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|}
  
* Paper: Hox Genes Regulate Digit Patterning by Controlling the Wavelength of a Turing-Type Mechanism by Sheth and Marco, et al, Science Dec 2012
+
This page contains a list of course project ideas for BE 150/Bi 250b, Winter 2013. 
  
* Idea: build a reaction diffusion model to replicate the results in the paper, showing how multiple digit patterns can be generated in mice. Show how to tune the number of digits on the hand by progressively removing copies of a hox gene.  Discuss this as evidence for a turing type patterning process (with modeling).
+
== Project Presentation Schedule ==
 +
* Each group will have '''15 minutes''' to present
 +
* 1-2 minutes of questions while the next group is setting up
 +
<br>
  
=== Scaling of embryonic patterning (MBE) ===
+
{| width=100% border=1
 +
|-
 +
! Day
 +
! Project
 +
! Presenters
 +
|-
 +
| Fri, 8 Mar || Robustness and tunability comparison for synthetic oscillators || NB, PH
 +
|-
 +
| Fri, 8 Mar || Fold-change detection || MA, AB
 +
|-
 +
| Fri, 8 Mar || Robustness and loading effects in MAPK cascades || KC, TH
 +
|-
 +
| colspan=3 |
 +
|-
 +
| Mon, 11 Mar || Scaling of embryonic patterning || KB, KHH
 +
|-
 +
| Mon, 11 Mar ||Quorum sensing‐mediated control of bacterial metabolism || SB
 +
|-
 +
| Mon, 11 Mar || Fold-change detection || JP, SS
 +
|-
 +
| colspan=3 |
 +
|-
 +
| Wed, 13 Mar || Feedback loops operating at different time scales || KK, SS
 +
|-
 +
| Wed, 13 Mar || The advantage of bet-hedging || SS, CW
 +
|-
 +
| Wed, 13 Mar || Digit patterning || KS, YW
 +
|}
  
* Paper: Scaling of embryonic patterning based on phase-gradient encoding by Lauschke and Tsiairis et al, Nature Jan 2013.
+
== Project Signup Information ==
 +
{{righttoc}}
  
* Idea: paper shows an ex vivo model of the presomitic mesoderm wave propagation system for simile patterning, ie they cut some of these cells out from the mouse embryo and show that they can still make segments similar to in vivo. They then use the system to show that there is scaling of number and size of segments with overall explant size.
+
'''Instructions:'''
 +
{{BE 150 project instructions, Winter 2013}}
  
=== Robustness and tunability comparison for synthetic oscillators (RMM) ===
+
=== Digit patterning ===
  
* Papers: Elowitz and Leibler, Stricker et al, Danino et al, Nimfa 2004
+
* [http://www.sciencemag.org/content/338/6113/1476 Hox Genes Regulate Digit Patterning by Controlling the Wavelength of a Turing-Type Mechanism] by Sheth and Marco, et al, Science Dec 2012
  
* Idea: put together models of different types of oscillators in E. coli using consistent parameters.  Explore parameter sensitivity, noise attenuation and behavioral diversity in each and comment on the relevant robustness and tunability processes.
+
Idea: build a reaction diffusion model to replicate the results in the paper, showing how multiple digit patterns can be generated in mice. Show how to tune the number of digits on the hand by progressively removing copies of a hox gene.  Discuss this as evidence for a turing type patterning process (with modeling).
  
=== Robustness and loading effects in MAPK cascades (RMM) ===
+
Note: This is a pretty difficult project.  You should probably only select it if you already know about reaction diffusion models (we will cover this in Weeks 7-8)
  
* Papers: TBD
+
=== Scaling of embryonic patterning  ===
  
* Idea: In class we showed that one of the advantages of a two component signaling system and multi-stage MAPK cascades is that you can get higher input/output gain. Another potential benefit of such constructs may be the robustness to downstream loads as well as insensitivity to noise and parameters. Construct models of a set of different signalling mechanisms and explore some of these tradeoffs.
+
* [http://www.nature.com/nature/journal/v493/n7430/full/nature11804.html Scaling of embryonic patterning based on phase-gradient encoding] by Lauschke and Tsiairis et al, Nature, Jan 2013.
  
=== Feedback loops operating at different time scales (EDLS) ===
+
Idea: this paper shows an ''ex vivo'' model of the presomitic mesoderm wave propagation system for simile patterning, ie they cut some of these cells out from the mouse embryo and show that they can still make segments similar to in vivo. They then use the system to show that there is scaling of number and size of segments with overall explant size.  Reproduce the model used in the paper and explore the application of the principles that we covered in class to provide some insight into this behavior.
  
* Paper: Bacterial virulence proteins as tools to rewire kinase pathways in yeast and immune cells. Ping Wei*, Wilson W. Wong*, Jason S. Park, Ethan E. Corcoran, Sergio G. Peisajovich, James J. Onuffer, Arthur Weiss, Wendell A. Lim.  Nature 488, 384–388 (2012)
+
Note: this problem will require some iteration with the instructors to make the goals more concrete.
  
* Idea: Explore feedback loops operating on different time scales and look at the effect of this on pulses with different frequencies. Need to flesh this out a bit more but you can do a bunch of things like looking what happens if you combine the feedback loops, or looking at the entire frequency response curve or doing sensitivity analysis on the different parameters. The model in the paper was built off from:
+
=== Robustness and tunability comparison for synthetic oscillators  ===
  
** Zi, Z., Liebermeister, W. & Klipp, E. A quantitative study of the Hog1 MAPK response to fluctuating osmotic stress in Saccharomyces cerevisiae. PloS one 5, e9522 (2010).
+
* [http://www.nature.com/nature/journal/v403/n6767/full/403335a0.html A synthetic oscillatory network of transcriptional regulators], M. B. Elowitz and S. Leibler,. ''Nature'', 403(6767):335–338, 2000.
 +
* [http://www.cell.com/retrieve/pii/S0092867403003465 Development of Genetic Circuitry Exhibiting Toggle Switch or Oscillatory Behavior in Escherichia coli], M. R. Atkinson, M. A. Savageau, J. T. Myers, and A. J. Ninfa.  ''Cell'', 113(5):597–607, 2003.
 +
* [http://www.nature.com/nature/journal/v456/n7221/full/nature07389.html A fast, robust and tunable synthetic gene oscillator], J. Stricker, S. Cookson, M. R. Bennett, W. H. Mather, L. S. Tsimring, and J. Hasty.  ''Nature'', 456( 7221):516–519, 2008.
  
=== Utilization of a conserved resource (EDLS) ===
+
Idea: put together models of different types of oscillators in ''E. coli'' using a consistent set parameters. Explore parameter sensitivity, noise attenuation and behavioral diversity in each and comment on the relevant robustness and tunability of each circuit.  Answer, once and for all, the question of whether the repressilator is robust or fragile.
* Like Dan's ACC paper
+
  
=== Asymmetric positive feedback (VH) ===
+
=== Robustness and loading effects in MAPK cascades ===
* Paper: http://www.nature.com/msb/journal/v8/n1/full/msb201210.html
+
* Idea: Positive feedback is one of the central components of biological circuits. In this paper by Ratushny et al, they analyze the effects of having asymmetrical positive feedback loops, in which only one of the molecules in a heterodimer is self-upregulates. In the paper, they mention a number of biological systems with this circuit motif. Choose one of the examples which is not demonstrated in the paper with which to perform a thorough analysis. Model the system to include additional features other than the ASSURE system and compare that to a model in which there is symmetrical upregulation. How does this affect the behavior of your system? What implications does it have for the organism as a whole?
+
  
=== Propose you own project (RMM) ===
+
* [http://www.pnas.org/content/78/11/6840.abstract An amplified sensitivity arising from covalent modification in biological systems], Goldbeter and D.E.Koshland, ''Proceedings of the National Academy of Sciences'', 78(11): 6840–6844, 1981.
 +
* [http://www.pnas.org/content/93/19/10078.abstract Ultra sensitivity in the mitogen-activated protein kinase cascade], C.Y. Huang and J.E.Ferrell. ''Proceedingsof the National Academy of Sciences'', 93(19):10078–10083,1996.
 +
 
 +
In class we showed that one of the advantages of a two component signaling system and multi-stage MAPK cascades is that you can get higher input/output gain.  Another potential benefit of such constructs may be the robustness to downstream loads as well as insensitivity to noise and parameters.  Construct models of a set of different signalling mechanisms and explore some of these tradeoffs.
 +
 
 +
=== Feedback loops operating at different time scales ===
 +
 
 +
* [http://www.nature.com/nature/journal/v488/n7411/full/nature11259.html Bacterial virulence proteins as tools to rewire kinase pathways in yeast and immune cells], P Wei, WW Wong*, JS Park, EE Corcoran, SG Peisajovich, JJ Onuffer, A Weiss, WA Lim.  Nature 488, 384–388 (2012)
 +
 
 +
Explore feedback loops operating on different time scales and look at the effect of this on pulses with different frequencies. Possible extensions to the model can include: effect of multiple feedback loops, looking at the entire frequency response curve or doing sensitivity analysis on the different parameters.
 +
<!-- Not sure why this is here (RMM, 31 Jan 2013)
 +
* Zi, Z., Liebermeister, W. & Klipp, E. A quantitative study of the Hog1 MAPK response to fluctuating osmotic stress in Saccharomyces cerevisiae. PloS one 5, e9522 (2010).
 +
-->
 +
 
 +
=== Utilization of a conserved resource  ===
 +
* [http://www.nature.com/msb/journal/v7/n1/full/msb201194.html Queueing up for enzymatic processing: correlated signaling through coupled degradation], NA Cookson, WH Mather, T Danino, O Mondragon-Palomino, RJ Williams, LS Tsimring and J Hasty. Molecular Systems Biology 7:561
 +
* [http://www.cds.caltech.edu/~murray/preprints/snm13-acc_s.pdf Biomolecular resource utilization in elementary cell-free gene circuits], D Siegal-Gaskins, V Noireaux, RM Murray ACC 2013 (submitted)
 +
 
 +
The papers above show correlations between seemingly independent outputs because of crosstalk due to limitations of a shared resource. Explore this in more detail or look at another limited shared resource.
 +
 
 +
Note: If you choose this project, you might find it useful to talk to Dan Siegal-Gaskins, a postdoc in Richard Murray's group, for possible extensions/modeling ideas.
 +
 
 +
=== Robustness in KaiABC oscillations due to a slow binding step ===
 +
* [http://www.pnas.org/content/110/3/1124.full.pdf?with-ds=yes Robust and tunable circadian rhythms from differentially sensitive catalytic domains], C Phong, JS Markson, CM Wilhoite and MJ Rust. PNAS 110(3):1124-9 (2013)
 +
 
 +
The oscillations of the KaiABC cycle are known to be robust to the ATP/ADP ratio, even if ATP is a substrate for KaiC. Experimentally the researchers in the paper found found that this might be due to the ATPase activity of the CI domain (which is slow compared to everything else). They built a model to explore this which added slow binding steps to the existing model. Modify their model and use an alternate mechanism for delay ( such as explicit time delay in the differential equation), calculate sensitivities for the period for both models or potentially model a simpler, synthetic circuit that has this feature and also demonstrates invariance to substrate input.
 +
 
 +
=== Asymmetric positive feedback ===
 +
* [http://www.nature.com/msb/journal/v8/n1/full/msb201210.html Asymmetric positive feedback loops reliably control biological responses] Alexander V Ratushny, Ramsey A Saleem, Katherine Sitko, Stephen A Ramsey & John D Aitchison,Molecular Systems Biology 8 Article number: 577
 +
* [http://www.sciencemag.org/content/310/5747/496 Interlinked fast and slow positive feedback loops drive reliable cell decisions.] Brandman O, Ferrell JE Jr, Li R, Meyer T (2005) Interlinked fast and slow positive feedback loops drive reliable cell decisions. Science 310: 496–498
 +
 
 +
Idea: Positive feedback is one of the central components of biological circuits. In this paper by Ratushny et al, they analyze the effects of having asymmetrical positive feedback loops, in which only one of the molecules in a heterodimer is self-upregulates. In the paper, they mention a number of biological systems with this circuit motif. Choose one of the examples which is not demonstrated in the paper with which to perform a thorough analysis. Model the system to include additional features other than the ASSURE system and compare that to a model in which there is symmetrical upregulation. How does this affect the behavior of your system? What implications does it have for the organism as a whole?
 +
 
 +
=== Fold-change detection ===
 +
 
 +
* [http://www.cell.com/molecular-cell/abstract/S1097-2765(09)00858-2 Evidence that Fold-Change, and Not Absolute Level, of β-Catenin Dictates Wnt Signaling], Goentoro and Kirschner, ''Molecular Cell'', 2009.
 +
 
 +
Idea: This paper shows how the Wnt signaling system produces a robust fold-change in levels of beta-catenin, an intracellular signal conveying molecule,  even though the absolute levels of beta-catenin can fluctuate.  Discuss the modeling approach used in the paper, explain fold-change detection, and compare to other fold change detection systems that may be more familiar, such as Weber's law.
 +
 
 +
=== The advantage of bet-hedging ===
 +
 
 +
* [http://www.genetics.org.clsproxy.library.caltech.edu/content/167/1/523.long Stochastic Gene Expression in Fluctuating Environments], M. Thattai and A. van Oudenarden. ''Genetics'', 167(1):523–530, 2004.
 +
* [http://www.sciencemag.org/content/309/5743/2075.full Phenotypic Diversity, Population Growth, and Information in Fluctuating Environments], E. Kussell.  ''Science'', 309(5743):2075–2078, 2005.
 +
 
 +
Idea: Bacteria have been suggested to use "bet-hedging" in environments that change in unpredictable ways. Bet-hedging systems allow cells to switch randomly among different fates, that may have different fitness levels in any given environment. Read one or both of the following papers and explain how it analyzes the relative cost and benefits of bet-hedging and under what circumstances bet-hedging is advantageous. Think of some interesting examples in any system where one would or would not expect a bet-hedging strategy to evolve.
 +
 
 +
For extra fun, explain the "Kelly betting" strategy (1956) that can be applied to horse racing and investing (http://en.wikipedia.org/wiki/Kelly_criterion) and whether and how it might relate to bacterial behavior.
 +
 
 +
=== Propose you own project ===
  
 
Guidelines: propose a project that involves reading a set of papers in the literature and performing some modeling and analysis to propose a testable hypothesis about the behavior of the system you investigate.  Your writeup should include a list of 1-3 papers along with a short (1-2 sentence summary of their main results), followed by a 1-2 paragraph description of the question you propose to explore.  All proposals must be submitted by a 2 person team, ideally with one student in Bi 250b and one student in BE 150.
 
Guidelines: propose a project that involves reading a set of papers in the literature and performing some modeling and analysis to propose a testable hypothesis about the behavior of the system you investigate.  Your writeup should include a list of 1-3 papers along with a short (1-2 sentence summary of their main results), followed by a 1-2 paragraph description of the question you propose to explore.  All proposals must be submitted by a 2 person team, ideally with one student in Bi 250b and one student in BE 150.

Latest revision as of 17:53, 8 March 2013

Course home

This page contains a list of course project ideas for BE 150/Bi 250b, Winter 2013.

Project Presentation Schedule

  • Each group will have 15 minutes to present
  • 1-2 minutes of questions while the next group is setting up


Day Project Presenters
Fri, 8 Mar Robustness and tunability comparison for synthetic oscillators NB, PH
Fri, 8 Mar Fold-change detection MA, AB
Fri, 8 Mar Robustness and loading effects in MAPK cascades KC, TH
Mon, 11 Mar Scaling of embryonic patterning KB, KHH
Mon, 11 Mar Quorum sensing‐mediated control of bacterial metabolism SB
Mon, 11 Mar Fold-change detection JP, SS
Wed, 13 Mar Feedback loops operating at different time scales KK, SS
Wed, 13 Mar The advantage of bet-hedging SS, CW
Wed, 13 Mar Digit patterning KS, YW

Project Signup Information

Instructions:

  • Each student should send e-mail 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 e-mail 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 e-mail a 1-2 page proposal in addition to at least two project preferences selected from the list of course projects

Digit patterning

Idea: build a reaction diffusion model to replicate the results in the paper, showing how multiple digit patterns can be generated in mice. Show how to tune the number of digits on the hand by progressively removing copies of a hox gene. Discuss this as evidence for a turing type patterning process (with modeling).

Note: This is a pretty difficult project. You should probably only select it if you already know about reaction diffusion models (we will cover this in Weeks 7-8)

Scaling of embryonic patterning

Idea: this paper shows an ex vivo model of the presomitic mesoderm wave propagation system for simile patterning, ie they cut some of these cells out from the mouse embryo and show that they can still make segments similar to in vivo. They then use the system to show that there is scaling of number and size of segments with overall explant size. Reproduce the model used in the paper and explore the application of the principles that we covered in class to provide some insight into this behavior.

Note: this problem will require some iteration with the instructors to make the goals more concrete.

Robustness and tunability comparison for synthetic oscillators

Idea: put together models of different types of oscillators in E. coli using a consistent set parameters. Explore parameter sensitivity, noise attenuation and behavioral diversity in each and comment on the relevant robustness and tunability of each circuit. Answer, once and for all, the question of whether the repressilator is robust or fragile.

Robustness and loading effects in MAPK cascades

In class we showed that one of the advantages of a two component signaling system and multi-stage MAPK cascades is that you can get higher input/output gain. Another potential benefit of such constructs may be the robustness to downstream loads as well as insensitivity to noise and parameters. Construct models of a set of different signalling mechanisms and explore some of these tradeoffs.

Feedback loops operating at different time scales

Explore feedback loops operating on different time scales and look at the effect of this on pulses with different frequencies. Possible extensions to the model can include: effect of multiple feedback loops, looking at the entire frequency response curve or doing sensitivity analysis on the different parameters.

Utilization of a conserved resource

The papers above show correlations between seemingly independent outputs because of crosstalk due to limitations of a shared resource. Explore this in more detail or look at another limited shared resource.

Note: If you choose this project, you might find it useful to talk to Dan Siegal-Gaskins, a postdoc in Richard Murray's group, for possible extensions/modeling ideas.

Robustness in KaiABC oscillations due to a slow binding step

The oscillations of the KaiABC cycle are known to be robust to the ATP/ADP ratio, even if ATP is a substrate for KaiC. Experimentally the researchers in the paper found found that this might be due to the ATPase activity of the CI domain (which is slow compared to everything else). They built a model to explore this which added slow binding steps to the existing model. Modify their model and use an alternate mechanism for delay ( such as explicit time delay in the differential equation), calculate sensitivities for the period for both models or potentially model a simpler, synthetic circuit that has this feature and also demonstrates invariance to substrate input.

Asymmetric positive feedback

Idea: Positive feedback is one of the central components of biological circuits. In this paper by Ratushny et al, they analyze the effects of having asymmetrical positive feedback loops, in which only one of the molecules in a heterodimer is self-upregulates. In the paper, they mention a number of biological systems with this circuit motif. Choose one of the examples which is not demonstrated in the paper with which to perform a thorough analysis. Model the system to include additional features other than the ASSURE system and compare that to a model in which there is symmetrical upregulation. How does this affect the behavior of your system? What implications does it have for the organism as a whole?

Fold-change detection

Idea: This paper shows how the Wnt signaling system produces a robust fold-change in levels of beta-catenin, an intracellular signal conveying molecule, even though the absolute levels of beta-catenin can fluctuate. Discuss the modeling approach used in the paper, explain fold-change detection, and compare to other fold change detection systems that may be more familiar, such as Weber's law.

The advantage of bet-hedging

Idea: Bacteria have been suggested to use "bet-hedging" in environments that change in unpredictable ways. Bet-hedging systems allow cells to switch randomly among different fates, that may have different fitness levels in any given environment. Read one or both of the following papers and explain how it analyzes the relative cost and benefits of bet-hedging and under what circumstances bet-hedging is advantageous. Think of some interesting examples in any system where one would or would not expect a bet-hedging strategy to evolve.

For extra fun, explain the "Kelly betting" strategy (1956) that can be applied to horse racing and investing (http://en.wikipedia.org/wiki/Kelly_criterion) and whether and how it might relate to bacterial behavior.

Propose you own project

Guidelines: propose a project that involves reading a set of papers in the literature and performing some modeling and analysis to propose a testable hypothesis about the behavior of the system you investigate. Your writeup should include a list of 1-3 papers along with a short (1-2 sentence summary of their main results), followed by a 1-2 paragraph description of the question you propose to explore. All proposals must be submitted by a 2 person team, ideally with one student in Bi 250b and one student in BE 150.