Team:Slovenia/TheSwitch

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<h1>Biological therapy</h1>
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<h1>Universal switch </h1>
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Biological drugs represent medical drugs produced by biotechnology that include biological macromolecules such as nucleic acids, proteins or microorganisms. Since the biosynthetic human insulin made via recombinant DNA technology in 1982 as the first substance approved for therapeutic use, there are currently more than 160 registered biological drugs approved for therapy. Due to their high specificity and efficiency, biological drugs are rapidly becoming a standard therapy for a vast array of diseases. Protein based products are expected to be 4 out of 5 top-selling drugs on the global market by the end of 2013. The estimated global market value for biologicals is 90 billion dollars, which represents 13,8 % of all pharmaceutics. Biological drugs can be used in almost any field of medicine but are mainly restricted to several diseases, such as cancer, autoimmune diseases, infectious diseases, AIDS/HIV, diabetes and cardiovascular diseases.
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<p>Our project is based on production of biopharmaceuticals by engineered cells and with tight but versatile regulation and safety in mind, we set out to contribute some fundamental advances to synthetic biology.</p>
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<p>We considered two options of regulating production of therapeutic proteins in mammalian cells:</p>
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<li>The first would be a prosthetic network where the cells are engineered to sense endogenous signals such as for example blood glucose levels. This signal would control the production of a therapeutic protein (such as insulin), which in turn affects the level of the endogenous signal (i.e. glucose) and is thus regulated by a kind of a feedback loop. This type of system can replace the function of a defective tissue or organ, hence the name prosthetic. Although a very attractive option, such a system would need to be tailor-made for a specific disease.</li>
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For the second option we regarded a cellular genetic network that produces the therapeutic protein of choice, but can be controlled by an external signal such as small molecular drugs or metabolites which can be administered orally or topically. Instead of requiring a continuous presence of an activating or repressing signal, the system should function as a bistable or multistable switch, requiring only a short signal pulse to change into any selected state. This type of a toggle switch has already been implemented in mammalian cells based on prokaryotic transcription factors fused to the eukaryotic transactivator (eg. VP16, VP64) or transrepressor (eg. KRAB) domains (Carlsson et al., 2012).
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<tr class="inliner"><td class="inliner"><b>Figure 1.</b> Top 10 classes of pharmaceuticals in clinical use (source of data: IMS Health).</td></tr>
 
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Once prescribed to treat only rare genetic diseases, biologics have rapidly become a more common therapeutic option for different disease conditions. There are numerous advantages of biologics over non-biologics, especially for chronic diseases such as arthritis, where biologics can provide much better long-term outcomes. Some examples of biologics on the market are antibodies such as TNFR in arthritis therapy or HER2/neu in breast cancer, interferon alpha used for the induction of antiviral response and insulin which is indispensable in diabetes therapy. The use of biopharmaceuticals often leads to faster recovery and can reduce the amount of additional therapy needed. With the use of biologics we are able to replace a protein or a hormone that is missing or is down-regulated in a patient in a safe and efficient manner that has not been possible before (e.g. hemophilia, growth hormone…). In general biologic therapy is more efficient in treating many chronic diseases than its traditional counterparts as it is not palliative and focused simply on symptom control but acts on the pathways that represent the core of the disease.
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Next: <a href='https://2012.igem.org/Team:Slovenia/IdeaChallenge'>Challenge >></a>
Next: <a href='https://2012.igem.org/Team:Slovenia/IdeaChallenge'>Challenge >></a>
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Revision as of 12:33, 25 September 2012


Universal switch

Our project is based on production of biopharmaceuticals by engineered cells and with tight but versatile regulation and safety in mind, we set out to contribute some fundamental advances to synthetic biology.

We considered two options of regulating production of therapeutic proteins in mammalian cells:

  • The first would be a prosthetic network where the cells are engineered to sense endogenous signals such as for example blood glucose levels. This signal would control the production of a therapeutic protein (such as insulin), which in turn affects the level of the endogenous signal (i.e. glucose) and is thus regulated by a kind of a feedback loop. This type of system can replace the function of a defective tissue or organ, hence the name prosthetic. Although a very attractive option, such a system would need to be tailor-made for a specific disease.
  • For the second option we regarded a cellular genetic network that produces the therapeutic protein of choice, but can be controlled by an external signal such as small molecular drugs or metabolites which can be administered orally or topically. Instead of requiring a continuous presence of an activating or repressing signal, the system should function as a bistable or multistable switch, requiring only a short signal pulse to change into any selected state. This type of a toggle switch has already been implemented in mammalian cells based on prokaryotic transcription factors fused to the eukaryotic transactivator (eg. VP16, VP64) or transrepressor (eg. KRAB) domains (Carlsson et al., 2012).
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