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Synthetic Biology - Genetic Switch

If you download the NetLogo application, this model is included. You can also Try running it in NetLogo Web

WHAT IS IT?

This a multi-agent model of a genetic circuit in a bacterial cell and is an extension of the GenEvo 1 model. This model shows how biologists can use laboratory techniques to tweak certain aspects of a genetic circuit in order to affect the cell's behavior.

Synthetic biology allows biologists to design and test their own genetic circuits. For example, a biologist could design a genetic circuit that caused a bacterium to glow when it was placed in water with a high lead content. This kind of biological engineering is a new frontier being actively explored by scientists around the globe.

HOW IT WORKS

The genetic circuit modelled here has the following components:

1. promoter with a lac operator – Transcription starts at the promoter if the repressor protein (LacI) is not bound to the lac operator region. The probability of an RNA polymerase binding to the promoter and starting transcription depends on the promoter strength.
2. RBS – A ribosome binding site is downstream to the promoter. The number of proteins produced per transcription depends on the strength of the RBS.
3. lacZ gene – A gene that codes for the LacZ protein
4. a terminator – RNA polymerase separates from the DNA when it reaches this region.
5. RNA polymerases - These are represented by brown blobs in the model. This model does not include mRNAs.
6. LacI repressor proteins - The purple-colored shapes in the model represent a repressor (LacI proteins). They bind to the operator region (see below) of the DNA and do not let RNAP to pass along the gene, thus stopping protein synthesis. When lactose binds to LacI, they form LacI-lactose complexes (shown by a purple shape with a grey dot attached to it). These complexes cannot bind to the operator region of the DNA.
7. ONPG molecules – These are grey pentagons in the model. [ONPG]( https://en.wikipedia.org/wiki/IPTG) is a chemical that mimics lactose. It is normally colorless. ONPG is hydrolyzed by LacZ enzyme to produce yellow color which is used to check for enzyme activity. Typically, [IPTG] (https://en.wikipedia.org/wiki/ONPG), another chemical that mimics lactose, is used with ONPG. For simplicity, we have not incorporated IPTG in this model. In this model, ONPG molecules bind to LacI repressor proteins that changes the shape of LacIs preventing them binding to the operator region of DNA.

The model explicitly incorporates transcription by showing the movement of RNA polymerases across DNA. It implicitly incorporates translation and does not incorporate mRNAs or ribosomes.

A user can select the promoter and RBS strengths, add ONPG (by making 'ONPG?' ON) and run the model. The model simulates interactions between the components of the genetic circuit that results in an emergent cellular behavior. The cellular behavior of interest in this model is LacZ (beta-galactosidase) activity which can be observed in a graph and is also represented in the change in the color of the cell to yellow. Beta-galactosidase cleaves ONPG to produce an intensely yellow colored compound.

HOW TO USE IT

Select the promoter strength and RBS strength using the two choosers.

Press SETUP to initialize the components in the model.

Press GO to run the model.

You can use the RUN EXPERIMENT button to run experiments for a specified time duration (2500 ticks). This is useful for comparing the behavior of the cell in different simulations of the same conditions. You could also use this button to run a timed experiment for different initial conditions (e.g. different promoter and RBS strengths).

‘ONPG?’ is a switch which keeps ONPG concentration constant throughout the simulation. This switch can be used to emulate situations where ONPG concentration in the medium is excess and not a limiting factor.

THINGS TO NOTICE

Run the model with 'ONPG?' switch OFF. Notice the molecular interactions inside the cell - interaction of the LacI protein with the operator - RNAPs binding to promoter - RNAPs moving along the DNA - proteins being generated after an RNAP transcribes the DNA

Observe the same interactions when 'ONPG?' is ON.

Run the model with a set PROMOTER-STRENGTH and RBS-STRENGTH and observe changes in the scaled transcription and translation rates. Also, observe changes in the LacZ activity in the graph as well as in the simulation. Run it multiple times and observe the differences.

THINGS TO TRY

Change the PROMOTER-STRENGTH and RBS-STRENGTH combination and observe the behavior again.

See which combination has the most robust and optimum behavior.

Change the parameter values of LACI-BOND-LEAKAGE, ONPG-DEGRADATION-CHANCE, COMPLEX-SEPARATION-CHANCE, COMPLEX-FORMATION-CHANCE, and LACZ-DEGRADATION-CHANCE. Notice how these changes affects the behavior of the model.

HOW TO CITE

If you mention this model or the NetLogo software in a publication, we ask that you include the citations below.

For the model itself:

• Dabholkar, S. and Wilensky, U. (2016). NetLogo Synthetic Biology - Genetic Switch model. http://ccl.northwestern.edu/netlogo/models/SyntheticBiology-GeneticSwitch. Center for Connected Learning and Computer-Based Modeling, Northwestern University, Evanston, IL.

Please cite the NetLogo software as:

• Wilensky, U. (1999). NetLogo. http://ccl.northwestern.edu/netlogo/. Center for Connected Learning and Computer-Based Modeling, Northwestern University, Evanston, IL.

To cite the GenEvo Systems Biology curriculum as a whole, please use:

• Dabholkar, S. & Wilensky, U. (2016). GenEvo Systems Biology curriculum. http://ccl.northwestern.edu/curriculum/genevo/. Center for Connected Learning and Computer-Based Modeling, Northwestern University, Evanston, IL.

COPYRIGHT AND LICENSE

Copyright 2016 Uri Wilensky.

This work is licensed under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License. To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-sa/3.0/ or send a letter to Creative Commons, 559 Nathan Abbott Way, Stanford, California 94305, USA.

Commercial licenses are also available. To inquire about commercial licenses, please contact Uri Wilensky at uri@northwestern.edu.

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