Team:KULeuven/Project

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== Dr. Coli,  the bacterial drug delivery system ==
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!style="text-align:center; background-color:#003E81; border-width:0px; padding:3px;"|[[Team:KULeuven/Project|<font color="#ffffff">The Project</font>]]
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Our team’s project is Dr. Coli, an ''E. coli'' bacterium that produces a drug when and where it is needed in the human body. It does this in an intelligent way, such that the drug production meets the individual patient’s needs. And when the patient is cured, Dr. Coli eliminates itself from the body. To achieve this, a molecular timer registers the time since the last disease signal sensed. Then after a certain time, Dr. Coli self-destructs. However, when the disease flares up again – above a certain noise level - the timer is reset and new drug is produced. Finally, the timer will not start counting during the production of Dr. Coli, thanks to its disease-memory.
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[[Image:kulbanner.jpg|960px]]
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Dr. Coli thus has several advantages over classical drugs, and, if proven successful, could have many medical applications. One example could be the delivery of a vasoactive intestinal peptide as a potential treatment for Crohn's disease.
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=Project brainstorm=
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== Favourite previous iGEM projects ==
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Within the time frame of the iGEM competition, we aim at delivering a proof of concept of Dr. Coli. For the input and output of the system, i.e. sensing the disease signal and producing the appropriate amount of drug, we use a dummy system. The most important assets of our proof of concept are the different control mechanisms. Since these are very much dependent on kinetic and other constants, Dr. Coli heavily relies on proper [https://2008.igem.org/Team:KULeuven/Model/Overview modeling].
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<br>
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==Essential aspects of Dr. Coli==
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'''Maarten Breckpot'''
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===Dr. Coli delivers drugs ''in situ''===
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<div class="floatleft">[[Image:pictogram_input.png|40px]]
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[[Image:pictogram_output.png|40px]]</div>
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Dr. Coli produces a drug when it senses a certain disease signal in the human body. In our project, we replaced the input disease marker by a dummy [https://2008.igem.org/Team:KULeuven/Project/Input input] of anhydrotetracyclin. The proportional [https://2008.igem.org/Team:KULeuven/Project/Output output] drug production is mimicked with a fluorescent protein.
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'''Nathalie Busschaert'''
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===Dr. Coli self-destructs===
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<div class="floatleft">[[Image:pictogram_filter.png|40px]]
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[[Image:pictogram_inverter.png|40px]]</div>
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<div class="floatleft">[[Image:logo_reset.jpg|40px]]
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[[Image:pictogram_celldeath.png|40px]]</div>
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When the patient is cured, Dr. Coli is no longer needed and will eliminate itself from its host. Therefore, we placed an [https://2008.igem.org/Team:KULeuven/Project/Inverter inverter], a [https://2008.igem.org/Team:KULeuven/Project/Inverter molecular timer] and a [https://2008.igem.org/Team:KULeuven/Project/CellDeath cell death] mechanism in cascade. When no input signal is present, the inverter initiates the molecular timer, eventually leading to cell death. Upon renewed presence of the disease signal, the molecular timer is [https://2008.igem.org/Team:KULeuven/Project/Reset reset]. A [https://2008.igem.org/Team:KULeuven/Project/Filter filter], finally, ensures that the timer is not reset when only “noisy” disease signals  are sensed.
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'''Jonas Demeulemeester'''
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===Dr. Coli in production===
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* [http://parts.mit.edu/igem07/index.php/Ljubljana Virotrap Ljubljana 2007]
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[[Image:pictogram_memory.png|40px|left]]
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* [http://parts.mit.edu/igem07/index.php/Princeton RNAi enhanced logic circuit Princeton 2007]
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* Other nice parts/devices:
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** Caltech: Riboswitch design for targeted cell death/molecular sensor
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** Cambridge: Inducible bigger pore protein for E.coli
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** Harvard: Quorum-sensing & targeting!
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** Melbourne: Red/blue light responsive system through chimeric photoreceptors-kinases
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** Peking U: λ-based bistable switch = very powerful
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** UCSF: compartmentalization! Rewired MAPK cascade signaling through scaffolds ≅ circuit board   
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<br> 
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'''Andim Doldurucu'''
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To enable the production of Dr. Coli without it self-destructing, we included a [https://2008.igem.org/Team:KULeuven/Project/Memory memory] device. This is a stable switch that is activated by the first input signal. Only from then on, the clock can start ticking towards cell death.
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'''Jan Mertens'''
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* [http://parts.mit.edu/igem07/index.php/Ljubljana Virotrap Ljubljana 2007]
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* [http://parts.mit.edu/igem07/index.php/Berkeley_UC Bactoblood]
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'''Benjamien Moeyaert'''
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* [http://openwetware.org/wiki/IGEM:Harvard/2006/DNA_nanostructures Harvard 20006: nanostructured DNA containers]
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* [http://parts.mit.edu/igem07/index.php/Berkeley_UC Bactoblood]
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'''Stefanie Roberfroid'''
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* [http://parts.mit.edu/igem07/index.php/Cambridge Bacteria Online]
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* [http://parts.mit.edu/igem07/index.php/Berkeley_UC Bactoblood]
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* [http://parts.mit.edu/igem07/index.php/Princeton RNAi enhanced logic circuit]
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* some other nice ideas
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** [http://parts.mit.edu/igem07/index.php/Edinburgh Self-flavouring yoghurt]
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** Detection of metals: [http://parts.mit.edu/igem07/index.php/Brown Lead], [http://parts.mit.edu/igem07/index.php/Saint_Petersburg Copper]
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'''Hanne Tytgat'''
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* [http://parts.mit.edu/igem07/index.php/Berkeley_UC Bactoblood]
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* [http://parts.mit.edu/igem07/index.php/MIT Sensing & removing Hg ions - MIT 2007]
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* [http://parts.mit.edu/igem07/index.php/Imperial/Infector_Detector/Introduction Infector detector]
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'''Elke Van Assche'''
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* [http://parts.mit.edu/wiki/index.php/MIT_2006 Eau d'E.coli MIT 2006]
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* [http://parts.mit.edu/igem07/index.php/Berkeley_UC Bactoblood Berkeley UC 2007]
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* [http://parts.mit.edu/igem07/index.php/Princeton RNAi enhanced logic circuit Princeton 2007]
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'''Nick Van Damme'''
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* [http://parts.mit.edu/igem07/index.php/Davidson_Missouri_W Bacterial Computer]
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--> idea: solve a nice mathematical problem
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*  several electronical/biological components to build an entire complex combinational logic system
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** [http://parts.mit.edu/igem07/index.php/USTC Extensible Logic Circuit in Bacteria]: both components and linking
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** [http://parts.mit.edu/igem07/index.php/Valencia Comparator]
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** [http://parts.mit.edu/igem07/index.php/Bologna Schmitt trigger]
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--> idea: build an integrator to solve your own ODE's, also build a differentiator to make a PID-controller
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'''Antoine Vandermeersch'''
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*[http://parts2.mit.edu/wiki/index.php/University_of_Texas_2006 Texas 2006: Edge Detector]
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*[http://parts.mit.edu/igem07/index.php/Rice/Project_B:_Quorumtaxis Rice 2007: Quorumtaxis]
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*[http://parts.mit.edu/igem07/index.php/Berkeley_LBL Berkeley LBL 2007: Solar Bacter]
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'''Dries Vercruysse'''
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'''Sigrid De Keersmaecker'''
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* [http://parts.mit.edu/igem07/index.php/MIT Sensing & removing Hg ions - MIT 2007]
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* [http://parts.mit.edu/igem07/index.php/Edinburgh Self-flavouring yoghurt - Edinburgh 2007]
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* [http://parts.mit.edu/igem07/index.php/Missouri_Miners Biological Timer - Missouri Miners 2007]
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* [http://parts.mit.edu/igem07/index.php/Ljubljana Virotrap - Ljubljana 2007]
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* [http://parts.mit.edu/igem07/index.php/Taipei/Taipei GlucOperon - Taipei 2007]
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* [http://parts.mit.edu/igem07/index.php/Berkeley_LBL Solar Bacter - Berkeley_LBL 2007]
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* [http://parts.mit.edu/igem07/index.php/Berkeley_UC Bactoblood - Berkeley_UC 2007]
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== iGEM judging tracks ==
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* Foundational Research - basic science and engineering research
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* Information Processing - genetically encoded control, logic, and memory
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* Energy - biological fuels, feedstocks, and other energy projects
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* Environment- sensing bioremediation of environmental state
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* Health & Medicine - applied projects with the goal of directly improving the human condition
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== Other ==
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[http://openwetware.org/wiki/IGEM:Idea_exchange Idea exchange - iGEM ideas posted by other teams]
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=Our project=
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Our abstract
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==A first idea: cancer treatment with genetically modified blood cells==
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As cancer cells need a lot of energy to replicate themselves, they should be well provided with blood. Therefore, blood cells could be the right choice for in situ treatment of cancer. First, we should immobilize these blood cells on the cancer cells. Subsequently, these blood cells should secrete specific agents that reduce the activity of the cancer cells. (These 2 steps may come in handy if we want to split up in 2 subgroups)
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===Notes===
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* Sounds like a great idea! [http://en.wikipedia.org/wiki/Avastin Anti-angiogenic therapy] is one of the big hopes for anti-tumor treatments. But let's keep in mind that angiogenesis (the formation of blood vessels) is only a late hallmark of tumors [http://www.google.be/url?sa=t&ct=res&cd=1&url=http%3A%2F%2Fwww.weizmann.ac.il%2Fhome%2Ffedomany%2FBioinfo05%2Flecture6_Hanahan.pdf&ei=-7E2SLbLGJCE1wblseHQDQ&usg=AFQjCNHirXaVMmdQNGl-72bk5jRva4106Q&sig2=L18rRG56VaP9wIB_mAENpA (more about these hallmarks of cancer -PDF)]. It is however a '''significant barrier''' to break through if the tumor has to grow past a certain (very limited) size. So this would be more like a therapy for later-stage malignancies, which would also be great because it's often the metastasis (the spreading of) of the tumor that is causing the more visible effects of the cancer. (pain, deterioration, ... and eventually, if untreated death). - [[user:Zeunas|Jonas]] 12:09, 23 May 2008 (UTC)
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* Anyhow, if we proceed with this idea, it will be a challenge to get everything ready and produced in the erythrocyte (red blood cell) before it loses it's nucleus and thus also the ability to initiate ''de novo'' transcription. And to keep all this machinery silent in non-docked erythrocytes. I'm liking this challenge though. Besides this has an upside as well as I feel that consequences would be less severe in this non-cell if things go awry in the system. :) - [[user:Zeunas|Jonas]] 17:30, 23 May 2008 (UTC)
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* I just thought of something that might be quite critical. If I recall correctly, there are 3 main ways in which tumors acquire blood supply.
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:# The first one is through a recapitulation of embryonic development. This is the recruitment of vascular endothelial precursors or the activation of local endothelium via factors like VEGF (angiogenic sprouting or intussusceptive growth). In this case, the 'vessels' of the tumor blood supply are lined mostly with endothelial cells which are actually NOT malignant, but are kind of working together with the tumor cells.
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:# A successful cancer metastasis (a secondary tumor, derived from the original) will co-opt blood vessels and these will thus also be lined mostly with endothelium cells.
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:# The third way to achieve blood supply is through vasculogenic mimicry, where the tumor cells actually DO line the bloodstream and mimic the normal vascular endothelium. Here tumor biomarkers should be directly displayed to the passing erythrocytes and would thus be potential targets for use in this approach.
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: OK, now for my point. In all these cases the vessels are highly abnormal, both structurally and functionally. They've got many holes, inhomogeneous bloodflow, are leaky, ... so it's very likely there will be exposed markers we can focus on but this will probably not always be the case. So I'm really liking this idea! - [[user:zeunas|Jonas]] 14:17, 23 May 2008 (UTC)
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==A second idea: bacteria clean virusses in animals==
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This is an improvement of the idea of Ljubljana: we cannot reprogram the immune system, but we can reprogram bacteria. So, what we could do is make bacteria produce viral receptors (challenge 1) which are modified so that when a virus attaches to them, a restriction enzyme is transcribed (challenge 2). This RE degrades the viral DNA and the bacterial DNA, thus killing the bacterium. This way, the bacteria clean all virusses from the body. When this is established, we can induce a suicide signal for the bacteria (challenge 3).
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Big problems:
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* Is it possible to make a eukaryotic virus attack a prokaryote (also a fundamental question)?
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* Immunogenicity bacterium (cf. Bactoblood)! [[User:Bmoeyaert|Bmoeyaert]]
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= Our project details=
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== Part 2 ==
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== The Experiments ==
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== Part 3 ==
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= Results =
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Latest revision as of 21:33, 3 October 2008

  dock/undock dropdown  

Dr. Coli, the bacterial drug delivery system

Our team’s project is Dr. Coli, an E. coli bacterium that produces a drug when and where it is needed in the human body. It does this in an intelligent way, such that the drug production meets the individual patient’s needs. And when the patient is cured, Dr. Coli eliminates itself from the body. To achieve this, a molecular timer registers the time since the last disease signal sensed. Then after a certain time, Dr. Coli self-destructs. However, when the disease flares up again – above a certain noise level - the timer is reset and new drug is produced. Finally, the timer will not start counting during the production of Dr. Coli, thanks to its disease-memory.

Dr. Coli thus has several advantages over classical drugs, and, if proven successful, could have many medical applications. One example could be the delivery of a vasoactive intestinal peptide as a potential treatment for Crohn's disease.

Within the time frame of the iGEM competition, we aim at delivering a proof of concept of Dr. Coli. For the input and output of the system, i.e. sensing the disease signal and producing the appropriate amount of drug, we use a dummy system. The most important assets of our proof of concept are the different control mechanisms. Since these are very much dependent on kinetic and other constants, Dr. Coli heavily relies on proper modeling.

Essential aspects of Dr. Coli

Dr. Coli delivers drugs in situ

Pictogram input.png Pictogram output.png

Dr. Coli produces a drug when it senses a certain disease signal in the human body. In our project, we replaced the input disease marker by a dummy input of anhydrotetracyclin. The proportional output drug production is mimicked with a fluorescent protein.

Dr. Coli self-destructs

Pictogram filter.png Pictogram inverter.png
Logo reset.jpg Pictogram celldeath.png

When the patient is cured, Dr. Coli is no longer needed and will eliminate itself from its host. Therefore, we placed an inverter, a molecular timer and a cell death mechanism in cascade. When no input signal is present, the inverter initiates the molecular timer, eventually leading to cell death. Upon renewed presence of the disease signal, the molecular timer is reset. A filter, finally, ensures that the timer is not reset when only “noisy” disease signals are sensed.

Dr. Coli in production

Pictogram memory.png

To enable the production of Dr. Coli without it self-destructing, we included a memory device. This is a stable switch that is activated by the first input signal. Only from then on, the clock can start ticking towards cell death.

Retrieved from "http://2008.igem.org/Team:KULeuven/Project"