Team:KULeuven/Project

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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

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

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

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.

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+== Dr. Coli,  the bacterial drug delivery system ==
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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.
+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 [https://2008.igem.org/Team:KULeuven/Model/Overview modeling].
+==Essential aspects of Dr. Coli==
+===Dr. Coli delivers drugs ''in situ''===
+<div class="floatleft">[[Image:pictogram_input.png|40px]]
+[[Image:pictogram_output.png|40px]]</div>
+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.
+===Dr. Coli self-destructs===
+<div class="floatleft">[[Image:pictogram_filter.png|40px]]
+[[Image:pictogram_inverter.png|40px]]</div>
+<div class="floatleft">[[Image:logo_reset.jpg|40px]]
+[[Image:pictogram_celldeath.png|40px]]</div>
+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.
-== A bacterial drug delivery system ==
+===Dr. Coli in production===
-Our team works on '''a bacterial drug delivery system''', for instance for the production of a peptide such as vasoactive intestinal peptide as a potential treatment for Crohn's disease. The bacterial drug delivery systems will have several advantages over classical drugs. These are (a) the bacterium will produce the exact amount of drug necessary for each individual by means of an indirect feedback control mechanism, (b) the bacterium will die upon a long symptomless period and (c) a possible development towards drugs being taken up in the bloodstream. The elaboration of such a system in a couple of months is, however, not viable. Therefore, we have decided in favour of constructing something more like a scaffolding, a proof of concept, that uses dummy in- and output and leaves room for case-dependent interpretation. Crohn's disease is, for us, only an example, rather than a limitation.
+[[Image:pictogram_memory.png|40px|left]]
-A dummy '''input''' has been found in a light-sensing device. This is an easy-to-use system, that allows fast switching between input signals 0, noise or 1. The dummy '''output''' signal is, for more or less the same reasons, expression of a fluorescent protein. Its signal is easy to follow in time and intensity, in a non-invasive way. This input-output line is the main backbone of the project. However, without decent control, this system is worthless. First, the project includes a way of '''filtering''' noise out of the input signal. Secondly, we want the system to shut down once the infection has been overcome. Therefore, an '''inverter''', a '''clock''' and a '''cell death''' mechanism have been placed in cascade. That way, when no input signal is present, the inverter makes sure a clock starts and keeps ticking, eventually leading to cell death after some time. And thirdly, it is interesting to be able to shut down and '''reset''' the clock upon renewed presence of input signal to overcome a phase of latently present input signal. The quick-witted scientist will of course notice that this system is doomed to fail, as all cells will die on their own. That is why the fourth and last control mechanism is a '''memory''' device. This stable switch is activated by the first input signal, and remains in a set ''ON'' state for the rest of its life. Only in this ''ON'' state, the clock can start ticking. These control mechanisms are very much dependent on kinetic and other constants. Therefore, proper '''modeling''' of this system is indispensable. In a later stadium, '''data analysis''' will prove its function in fine-tuning the model. We hope that these interactions between experiments in vitro and in silico will lead us to decent results.
+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.