Team:Edinburgh/Modelling

From 2010.igem.org

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   <ul>
   <ul>
   <li><a href="https://2010.igem.org/Team:Edinburgh/Project/Protocol">the protocol</a></li>
   <li><a href="https://2010.igem.org/Team:Edinburgh/Project/Protocol">the protocol</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Project/BioBricks">submitted parts</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/BioBricks#Genomic">submitted parts</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Project/Results">results</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Results#Genomic">results</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Project/Future">future work</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Project/Future">the future</a></li>
   <li><a href="https://2010.igem.org/Team:Edinburgh/Project/References">references</a></li>
   <li><a href="https://2010.igem.org/Team:Edinburgh/Project/References">references</a></li>
   </ul>
   </ul>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial" class="dir">bacterial BRIDGEs</a>
  <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial" class="dir">bacterial BRIDGEs</a>
   <ul>
   <ul>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Core_repressilator">the repressilator</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Core_repressilator">the project</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Red_light_producer">red light</a></li>
   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Red_light_sensor">red sensor</a></li>
   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Red_light_sensor">red sensor</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Red_light_producer">red producer</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Blue_light_producer">blue light</a></li>
   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Blue_light_sensor">blue sensor</a></li>
   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Blue_light_sensor">blue sensor</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Blue_light_producer">blue producer</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Green_light_producer">green light</a></li>
   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Green_light_sensor">green sensor</a></li>
   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Green_light_sensor">green sensor</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Green_light_producer">green producer</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/BioBricks#Bacterial">submitted parts</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/BioBricks">submitted parts</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Results#Bacterial">results</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Results">results</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Future">the future</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/Future">future work</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/References">references</a></li>
   <li><a href="https://2010.igem.org/Team:Edinburgh/Bacterial/References">references</a></li>
   </ul>
   </ul>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling" class="dir">modelling BRIDGEs</a>
  <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling" class="dir">modelling BRIDGEs</a>
   <ul>
   <ul>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling">the model</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling/Kappa">kappa</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling">results</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling/Genomic">the genomic model</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling">future work</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling/Bacterial">the bacterial model</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling">references</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling/Signalling">the signalling model</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling/Tools">tools</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Results#Modelling">results</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling/Future">the future</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Modelling/References">references</a></li>
   </ul>
   </ul>
  </li>
  </li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Human" class="dir">human BRIDGEs</a>
  <li><a href="https://2010.igem.org/Team:Edinburgh/Human" class="dir">human BRIDGEs</a>
   <ul>
   <ul>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Human">human aspects</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Human/Communication">communication of science</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Human">results</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Human/Branding">iGEM survey</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Human">future work</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Human/Conversations">conversations</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Human">references</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Human/Epic">the epic</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Human/FutureApps">future applications</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Results#Human">further thoughts</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Human/References">references</a></li>
   </ul>
   </ul>
  </li>
  </li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook" class="dir">lab notes&nbsp;&nbsp;&nbsp;</a>
  <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook" class="dir">lab notes&nbsp;&nbsp;&nbsp;</a>
   <ul>
   <ul>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook">collaboration</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook/Collaboration">collaboration</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook">BRIDGE</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook/Attribution">attribution</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook">red light</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook/BRIDGE">BRIDGE</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook">red sensor</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook/Red_light_producer">red light</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook">blue light</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook/Red_light_sensor">red sensor</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook">blue sensor</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook/Blue_light_producer">blue light</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook">safety</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook/Blue_light_sensor">blue sensor</a></li>
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   <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook/Green_light_producer">green light</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook/Green_light_sensor">green sensor</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook/Modelling">modelling</a></li>
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  <li><a href="https://2010.igem.org/Team:Edinburgh/Notebook/Safety">safety</a></li>
   <li><a href="http://www.openwetware.org/wiki/French_Lab">protocols</a></li>
   <li><a href="http://www.openwetware.org/wiki/French_Lab">protocols</a></li>
   </ul>
   </ul>
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<a name="Overview" id="Overview"></a><h2>Overview: The Kappa modelling language</h2>
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<a name="Introduction" id="Introduction"></a><h2>Modelling BRIDGEs</h2>
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<br>
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<p>An <b>integral</b> part of the engineering <b>approach</b> to biology is the use of modelling <b>techniques</b> that attempt to <b>predict</b> and <b>understand</b> the behaviour of complex biological systems before they are actually fabricated. One of the greatest advantages of models is that they can present an <b>abstract picture</b> of the activity of a part or device long before the actual biology - limited by the time needed for <b>protocols</b> such as PCR and transformation - can. Furthermore, they can help to <b>simplify</b> the mind-boggling amount and complexity of data and interactions involved into a more <b>concise</b> form with some measure of <b>predictive</b> ability.</p>
 +
<p>On the other hand, modelling remains very much a <b>guessing game</b>. <b>Abstractions and assumptions</b> are made at every stage of the process, and even then the finished model will fail to capture all the intricacies of working in biology: interference between various parts and devices, the host not always being a benevolent chassis, and so forth. The extraction of meaningful biological data upon which to base the model, for example kinetic rate parameters, is an extremely time-consuming <b>process</b>, fraught with difficulty and inaccuracy .</p>
 +
<p>Hence, biological modelling can be considered to be a little bit of a <b>black art</b>. If you're good, it will give you an answer; if you're very good, it might even be close to the truth.</p>
 +
<p>Still, in order to effect in the future the <b>rational design and engineering</b> of biological systems, <b>advances</b> in modelling techniques remain crucial. As happened in chemistry in the 1940s and 1950s, <b>capturing</b> the enormous complexity of such processes in a way useful for <b>applications</b> can lead to the establishment of new and useful <b>disciplines</b>. It is our fervent hope that this section of our project has made at least some small <b>progress</b> in this direction.</p><br>
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<p>In order to model the core repressilator system and its attached signal transduction pathways, we are using a stochastic, agent- and rule-based language called Kappa.<p>
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<a name="Project" id="Project"></a><h2>Our Project</h2>
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<center><br><br><p><img src="https://static.igem.org/mediawiki/2010/5/5c/Ed10-Agent.jpg" /></p><br><br></center>
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<p>In Kappa, biological entities such as proteins, DNA, and RNA are represented as agents, which are essentially named sets of sites that can be used to hold state or bind and interact with other agents. The example shown shows how a promoter BioBrick can be represented within Kappa – as a three-agent-long piece of DNA, connected via upstream and downstream sites, with binding sites for transcription factors and RNA polymerase, and a type site to keep track of its Registry code.</p>
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<center><br><br><p><img src="https://static.igem.org/mediawiki/2010/9/9e/Ed10-Rule.JPG" /></p><br><br></center>
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<p>Interactions are represented by rules in the form of precondition and effect, with an associated rate of reaction that governs how frequently the interaction occurs. The example shown describes a repressor binding to an open binding site upon a promoter; note the preconditions that both promoter and repressor binding sites must be empty beforehand, and the effect that they are now bound together. In this case, the reaction is reversible; that is, there are both forward and backward reaction rates associated with binding and dissociation of the repressor upon the promoter. By combining agents with an appropriate set of rules and rates, a Kappa model can be used to simulate systems of varying complexity, from a simple MAPK cascade to the oscillating rhythm of a circadian clock.</p>
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<p>Our primary <b>goal</b> was to ensure that all of our <b>endeavours</b> in the wet lab had a corresponding modelling element, including but not limited to a <a href="https://2010.igem.org/Team:Edinburgh/Modelling/Genomic">model for simulating the BRIDGE protocol</a>, <a href="https://2010.igem.org/Team:Edinburgh/Modelling/Bacterial#Repressilator">a model for the core repressilator system</a>, <a href="https://2010.igem.org/Team:Edinburgh/Modelling/Bacterial">a model for each of the light sensor pathways and how they responded to stimulation by light of the appropriate wavelength</a>, and <a href="https://2010.igem.org/Team:Edinburgh/Modelling/Signalling">a model for attempting to simulate a colony communicating as one via light</a>.</p>
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<p>On the other hand, we didn't want to model just for the sake of modelling; in our opinion, modelling should always have a clear <b>objective</b>, aiding and adding to the biology in some way. For example, by <b>highlighting</b> possible problems or inefficiencies in the biological systems in question, or by <b>testing</b> two separate designs against one another to determine which of them would be more efficient in achieving the desired outcome, we would be able to <b>solve</b> theoretical conundrums and <b>help</b> our wet-lab team to eliminate unnecessary time and work. Although the time and feasibility constraints of the project and the setbacks we suffered along the way meant that this was not always possible, work continued throughout on <b>refining</b> and <b>rebuilding</b> the model to flexibly <b>adapt</b> to the continually evolving needs of our system.</p><br>
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<center><br><br><p><img src="https://static.igem.org/mediawiki/2010/9/92/Ed10-V2Results.png" /></p><br><br></center>
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<a name="Content" id="Content"></a><h2>Table of Contents</h2>
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<p>The results of the simulation shown track the discrete counts of lambda-cI (red), TetR (blue), and LacI (yellow) in a slightly-modified version of the Elowitz repressilator described previously, for one particular stochastic trajectory (obviously, different runs of the simulation will generate different results, some more variable than others). The modification made was the addition of a red luciferase BioBrick linked to a lacI promoter; high amounts of lacI repress the production of the red luciferase, but as soon as the concentration of lacI falls, the amount of red luciferase in the system rises, as expected. Ultimately, we wish to be able to simulate and study the effects of various perturbations upon the functionality of the repressilator, with the aim of aiding in the understanding, characterisation, and possibly even the design of the system itself..</p>
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<p>For more information regarding Kappa and the basics of the language, please see the following resources:</p>
 
<ul>
<ul>
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  <li><a href="http://www.kappalanguage.org/">The Kappa Language</a></li>
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  <li>
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  <li><a href="http://rulebase.org/">RuleBase</a></li>
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<a href="https://2010.igem.org/Team:Edinburgh/Modelling/Kappa">An introduction to our primary technique, the Kappa biological modelling language.</a>
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  <li><a href="http://www.macteria.co.uk/kappaIntro/introduction.html">An Introductory Kappa Tutorial</a></li>
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</li>
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  <li><a href="http://www.macteria.co.uk/circClock/introduction.html">Modelling the Mammalian Circadian Clock</a></li>
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  <li>
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<a href="https://2010.igem.org/Team:Edinburgh/Modelling/Genomic">Modelling the BRIDGE protocol in Kappa.</a>
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</li>
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  <li>
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<a href="https://2010.igem.org/Team:Edinburgh/Modelling/Bacterial">Modelling the individual light sensing pathways and their integration into a repressilator system in Kappa.</a>
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</li>
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<li>
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<a href="https://2010.igem.org/Team:Edinburgh/Modelling/Signalling">Modelling the intercellular signalling processes.</a>
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</li>
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<a href="https://2010.igem.org/Team:Edinburgh/Modelling/Tools">Some of the tools that we used during the modelling process, and an explanation for them.</a>
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</li>
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<li>
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<a href="https://2010.igem.org/Team:Edinburgh/Results#Modelling">A summary of what we achieved through the construction and analysis of our models.</a>
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<a href="https://2010.igem.org/Team:Edinburgh/Modelling/Future">Our vision of the future of the modelling process, and where we would like to go next.</a>
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</li>
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<li>
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<a href="https://2010.igem.org/Team:Edinburgh/Modelling/References">References used throughout the section.</a><br>
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</li>
</ul>
</ul>
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<span style="color:ivory;">Throughout this wiki there are words in <b>bold</b> that indicate a relevance to <b>human aspects</b>. It will become obvious that <b>human aspects</b> are a part of almost everything in <b>iGEM</b>.</span>
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Latest revision as of 15:13, 8 January 2011







Modelling BRIDGEs


An integral part of the engineering approach to biology is the use of modelling techniques that attempt to predict and understand the behaviour of complex biological systems before they are actually fabricated. One of the greatest advantages of models is that they can present an abstract picture of the activity of a part or device long before the actual biology - limited by the time needed for protocols such as PCR and transformation - can. Furthermore, they can help to simplify the mind-boggling amount and complexity of data and interactions involved into a more concise form with some measure of predictive ability.

On the other hand, modelling remains very much a guessing game. Abstractions and assumptions are made at every stage of the process, and even then the finished model will fail to capture all the intricacies of working in biology: interference between various parts and devices, the host not always being a benevolent chassis, and so forth. The extraction of meaningful biological data upon which to base the model, for example kinetic rate parameters, is an extremely time-consuming process, fraught with difficulty and inaccuracy .

Hence, biological modelling can be considered to be a little bit of a black art. If you're good, it will give you an answer; if you're very good, it might even be close to the truth.

Still, in order to effect in the future the rational design and engineering of biological systems, advances in modelling techniques remain crucial. As happened in chemistry in the 1940s and 1950s, capturing the enormous complexity of such processes in a way useful for applications can lead to the establishment of new and useful disciplines. It is our fervent hope that this section of our project has made at least some small progress in this direction.



Our Project


Our primary goal was to ensure that all of our endeavours in the wet lab had a corresponding modelling element, including but not limited to a model for simulating the BRIDGE protocol, a model for the core repressilator system, a model for each of the light sensor pathways and how they responded to stimulation by light of the appropriate wavelength, and a model for attempting to simulate a colony communicating as one via light.

On the other hand, we didn't want to model just for the sake of modelling; in our opinion, modelling should always have a clear objective, aiding and adding to the biology in some way. For example, by highlighting possible problems or inefficiencies in the biological systems in question, or by testing two separate designs against one another to determine which of them would be more efficient in achieving the desired outcome, we would be able to solve theoretical conundrums and help our wet-lab team to eliminate unnecessary time and work. Although the time and feasibility constraints of the project and the setbacks we suffered along the way meant that this was not always possible, work continued throughout on refining and rebuilding the model to flexibly adapt to the continually evolving needs of our system.



Table of Contents





Throughout this wiki there are words in bold that indicate a relevance to human aspects. It will become obvious that human aspects are a part of almost everything in iGEM.