Team:Slovenia/IdeaChallenge

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<li><a href='https://2012.igem.org/Team:Slovenia/TheSwitchDesignedTALregulators'><span>Designed TAL regulators</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/TheSwitchDesignedTALregulators'><span>Designed TAL regulators</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/TheSwitchMutualRepressorSwitch'><span>Mutual repressor switch</span></a></li>  
<li><a href='https://2012.igem.org/Team:Slovenia/TheSwitchMutualRepressorSwitch'><span>Mutual repressor switch</span></a></li>  
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<li><a href='https://2012.igem.org/Team:Slovenia/TheSwitchPositiveFeedbackLoopSwitch'><table class="newtable"><tr class="newtable"><td class="newtable"><span>Positive feedback loop switch</span></td><td class="newtable"><img style="margin-right:-15px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>
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<li><a href='https://2012.igem.org/Team:Slovenia/TheSwitchPositiveFeedbackLoopSwitch'><table onclick="window.location = 'https://2012.igem.org/Team:Slovenia/TheSwitchPositiveFeedbackLoopSwitch';" class="newtable"><tr class="newtable"><td class="newtable"><span>Positive feedback loop switch</span></td><td class="newtable"><img style="margin-right:-15px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>
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     <li><a href='https://2012.igem.org/Team:Slovenia/TheSwitchControls'><table class="newtable"><tr class="newtable"><td class="newtable"><span>Controls</span></td><td class="newtable"><img style="margin-right:-81px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
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     <li><a href='https://2012.igem.org/Team:Slovenia/TheSwitchControls'><table onclick="window.location = 'https://2012.igem.org/Team:Slovenia/TheSwitchControls';" class="newtable"><tr class="newtable"><td class="newtable"><span>Controls</span></td><td class="newtable"><img style="margin-right:-81px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
  </ul>
  </ul>
</li>
</li>
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<li><a href='https://2012.igem.org/Team:Slovenia/SafetyMechanismsEscapeTag'><span>Escape tag</span></a></li>  
<li><a href='https://2012.igem.org/Team:Slovenia/SafetyMechanismsEscapeTag'><span>Escape tag</span></a></li>  
<li><a href='https://2012.igem.org/Team:Slovenia/SafetyMechanismsTermination'><span>Termination</span></a></li>  
<li><a href='https://2012.igem.org/Team:Slovenia/SafetyMechanismsTermination'><span>Termination</span></a></li>  
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     <li><a href='https://2012.igem.org/Team:Slovenia/SafetyMechanismsMicrocapsuleDegradation'><table class="newtable"><tr class="newtable"><td class="newtable"><span>Microcapsule degradation</span></td><td class="newtable"><img style="margin-right:-15px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
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     <li><a href="https://2012.igem.org/Team:Slovenia/SafetyMechanismsMicrocapsuleDegradation"><table onclick="window.location = 'https://2012.igem.org/Team:Slovenia/SafetyMechanismsMicrocapsuleDegradation';" class="newtable"><tr class="newtable"><td class="newtable"><span>Microcapsule degradation</span></td><td class="newtable"><img style="margin-right:-15px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
  </ul>
  </ul>
</li>
</li>
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<li><a href='https://2012.igem.org/Team:Slovenia/ImplementationHepatitisC'><span>Hepatitis C</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/ImplementationHepatitisC'><span>Hepatitis C</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/ImplementationIschaemicHeartDisease'><span>Ischaemic heart disease</span></a></li>  
<li><a href='https://2012.igem.org/Team:Slovenia/ImplementationIschaemicHeartDisease'><span>Ischaemic heart disease</span></a></li>  
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     <li><a href='https://2012.igem.org/Team:Slovenia/ImplementationImpact'><table class="newtable"><tr class="newtable"><td class="newtable"><span>Impact</span></td><td class="newtable"><img style="margin-right:-86px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
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     <li><a href='https://2012.igem.org/Team:Slovenia/ImplementationImpact'><table onclick="window.location = 'https://2012.igem.org/Team:Slovenia/ImplementationImpact';" class="newtable"><tr class="newtable"><td class="newtable"><span>Impact</span></td><td class="newtable"><img style="margin-right:-86px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
 
 
  </ul>
  </ul>
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  <ul>
  <ul>
<li><a href='https://2012.igem.org/Team:Slovenia/Modeling'><span>Overview</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/Modeling'><span>Overview</span></a></li>
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     <li><a href='https://2012.igem.org/Team:Slovenia/ModelingPK'><table class="newtable"><tr class="newtable"><td class="newtable"><span>Pharmacokinetics</span></td><td class="newtable"><img style="margin-right:-15px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
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     <li><a href='https://2012.igem.org/Team:Slovenia/ModelingPK'><table onclick="window.location = 'https://2012.igem.org/Team:Slovenia/ModelingPK';" class="newtable"><tr class="newtable"><td class="newtable"><span>Pharmacokinetics</span></td><td class="newtable"><img style="margin-right:-15px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
<li><a href='https://2012.igem.org/Team:Slovenia/ModelingMethods'><span>Modeling methods</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/ModelingMethods'><span>Modeling methods</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/ModelingMutualRepressorSwitch'><span>Mutual repressor switch</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/ModelingMutualRepressorSwitch'><span>Mutual repressor switch</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/ModelingPositiveFeedbackLoopSwitch'><span>Positive feedback loop switch</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/ModelingPositiveFeedbackLoopSwitch'><span>Positive feedback loop switch</span></a></li>
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<li><a href='https://2012.igem.org/Team:Slovenia/ModelingQuantitativeModel'><table class="newtable"><tr class="newtable"><td class="newtable"><span>Experimental model</span></td><td class="newtable"><img style="margin-right:-15px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
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<li><a href='https://2012.igem.org/Team:Slovenia/ModelingQuantitativeModel'><table onclick="window.location = 'https://2012.igem.org/Team:Slovenia/ModelingQuantitativeModel';" class="newtable"><tr class="newtable"><td class="newtable"><span>Experimental model</span></td><td class="newtable"><img style="margin-right:-15px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
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     <li><a href='https://2012.igem.org/Team:Slovenia/ModelingInteractiveSimulations'><table class="newtable"><tr class="newtable"><td class="newtable"><span>Interactive simulations</span></td><td class="newtable"><img style="margin-right:-15px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
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     <li><a href='https://2012.igem.org/Team:Slovenia/ModelingInteractiveSimulations'><table onclick="window.location = 'https://2012.igem.org/Team:Slovenia/ModelingInteractiveSimulations';" class="newtable"><tr class="newtable"><td class="newtable"><span>Interactive simulations</span></td><td class="newtable"><img style="margin-right:-15px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
  </ul>
  </ul>
</li>
</li>
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  <ul>
<li><a href='https://2012.igem.org/Team:Slovenia/Notebook'><span>Experimental methods</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/Notebook'><span>Experimental methods</span></a></li>
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     <li><a href='https://2012.igem.org/Team:Slovenia/NotebookLablog'><table class="newtable"><tr class="newtable"><td class="newtable"><span>Lablog</span></td><td class="newtable"><img style="margin-right:-90px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
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     <li><a href='https://2012.igem.org/Team:Slovenia/NotebookLablog'><table onclick="window.location = 'https://2012.igem.org/Team:Slovenia/NotebookLablog';" class="newtable"><tr class="newtable"><td class="newtable"><span>Lablog</span></td><td class="newtable"><img style="margin-right:-90px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>  
<li><a href='https://2012.igem.org/Team:Slovenia/NotebookLabSafety'><span>Lab safety</span></a></li>  
<li><a href='https://2012.igem.org/Team:Slovenia/NotebookLabSafety'><span>Lab safety</span></a></li>  
  </ul>
  </ul>
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<li><a href='https://2012.igem.org/Team:Slovenia/Team'><span>Team members</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/Team'><span>Team members</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/TeamAttributions'><span>Attributions</span></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/TeamAttributions'><span>Attributions</span></a></li>
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<li><a href='https://2012.igem.org/Team:Slovenia/TeamCollaborations'><table class="newtable"><tr class="newtable"><td class="newtable"><span>Collaborations</span></td><td class="newtable"><img style="margin-right:-20px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>
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<li><a href='https://2012.igem.org/Team:Slovenia/TeamCollaborations'><table onclick="window.location = 'https://2012.igem.org/Team:Slovenia/TeamCollaborations';" class="newtable"><tr class="newtable"><td class="newtable"><span>Collaborations</span></td><td class="newtable"><img style="margin-right:-20px;" width="25px" src="https://static.igem.org/mediawiki/2012/e/ee/Svn12_hp_new.png"></img></td></tr></table></a></li>
<li><a href='https://2012.igem.org/Team:Slovenia/TeamGallery'><span>Gallery</span></a></li>  
<li><a href='https://2012.igem.org/Team:Slovenia/TeamGallery'><span>Gallery</span></a></li>  
<li><a href='https://2012.igem.org/Team:Slovenia/TeamSponsors'><span>Sponsors</span></a></li>  
<li><a href='https://2012.igem.org/Team:Slovenia/TeamSponsors'><span>Sponsors</span></a></li>  
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<h1>Challenge</h1>
<h1>Challenge</h1>
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<p>
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<p>Pharmacological therapy usually includes only a single or few therapeutics to treat the selected pathology, such as an infection, cancer or inflammation (Walsh, 2010). After application of pharmacological therapy medicine relies on the body’s own ability to heal and regenerate. With advances in medical research, we have unraveled biochemical pathways governing different stages of diseases. We now understand the role of growth factors and other endogenous mediators in the regeneration and healing processes. Often a defined temporal sequence of different factors is required for the best therapeutic effect however they are very seldom used in current medicine.</p>
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Pharmacological therapy usually includes only a single or few therapeutics to treat the selected pathology, such as infection, cancer or inflammation (Walsh, 2010). After the application of these therapeutics medicine relies on our body’s ability to heal and regenerate. With daily advances in basic research, we are able to unravel mysteries concerning the biochemical pathways governing different stages of diseases. We now know many growth factors and other endogenous mediators are involved in the regeneration and healing processes. Often a defined temporal sequence of different factors is required for the best therapeutic effect, however they are very seldom used in current medicine.
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<p>Some biopharmaceuticals used in therapy have <b>side effects</b> that range from mild to serious, sometimes requiring discontinuation or modification of therapy. For example the systemic inhibition of tumor necrosis factor-alpha used to treat arthritis may increase the risk of infection, the application of interferon alpha for treatment of hepatitis C infection causes nausea, and some biological drugs may promote hepatic dysfunction or have other serious side effects. </p>
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<p>An additional important aspect connected to the application of biological drugs is the <b>high cost</b> of therapy. The annual cost of biological therapy for rheumatoid arthritis ranges from 15,000 – 25,000 dollars for a single patient in comparison to nonbiologic therapy cost of 100 – 300 dollars per patient per year. Treatment of hepatitis C with biologics costs from 6,000 15,000 dollars per year and for some other diseases the cost may exceed 100,000 dollars, which is out of reach of most patients, even in wealthy countries. </p>
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Some biopharmaceuticals used in therapy have <b>side effects</b> that range from mild to serious, requiring discontinuation or modification of therapy. For example the systemic inhibition of tumor necrosis factor-alpha used to treat arthritis may increase the risk of infection, application of interferon-alpha for treatment of hepatitis C infection causes nausea in patients, while some biological drugs may promote hepatic dysfunction or have other serious side effects.
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Probably the most important aspect connected to the application of biological drugs is the <b>high cost</b> of therapy. The annual cost of biological therapy for rheumatoid arthritis ranges from 15,000 – 25,000 dollars in comparison to nonbiologic therapy cost of 100 – 300 dollars per annum, 6,000- 15,000 dollars for hepatitis C and for some others it may exceed 100,000 dollars, which is out of reach of most patients, even in wealthy countries.
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<b>Table 1.</b> Biopharmaceutical Spending And Availability In Ten Countries, 2005 (Danzol et al., 2006)
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<b>Table 1. </b> Biopharmaceutical Spending And Availability In Ten Countries, 2005 (Danzol et al., 2006).
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<p>Many biopharmaceutical proteins are expressed in bacterial systems, which can be excellent producers; however bacterial endotoxins must be thoroughly removed before the administration to patients as even picomolar concentrations of an endotoxin may activate immune cells. In the production of biologics, downstream processing and formulation of the drug is very demanding. For example, the (komentar: točno katera? The first?) interferon alpha formulation was found to oxidize at room temperature, which affected its tertiary structure, decreasing its effectiveness and raising the immune response to the modified protein. The formulation and storage procedures had to be optimized to reduce antibody formation. Similar post-manufacturing structural changes have been implicated in other immune-mediated responses to recombinant proteins (Purcell et al., 2008). </p>
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Many biopharmaceutical proteins are expressed in bacterial systems, which can be excellent producers, however bacterial endotoxins must be thoroughly removed before the administration to patients as even picomolar concentrations of an endotoxin may activate immune cells. In the production of biologics, downstream processing and formulation of the drug is very demanding. For example, an interferon alpha formulation was found to oxidize at room temperature, changing the tertiary structure of the protein, decreasing its effectiveness and raising the immune response to the modified protein. The formulation and storage procedures had to be optimized to reduce antibody formulation. Similar post-manufacturing structural changes have been implicated in other immune-mediated responses to recombinant proteins (Purcell et al., 2008).  
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<p>Therapies based on biopharmaceuticals in most cases require periodic invasive applications. Due to the systemic administration adverse effects are often observed. Furthermore, large quantities of therapeutic substances must often be applied because of their nonspecific distribution throughout the body. Coupled with expensive production and purification this imposes a great burden on health systems. </p>
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Therapies based on biopharmaceuticals in most cases require periodic invasive application. Due to the systemic administration adverse effects are often observed. Furthermore, large quantities of therapeutic substances must often be applied because of their nonspecific distribution throughout the body. Coupled with expensive production and purification this imposes a great burden on health systems.
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Therefore advanced methods of targeted delivery of biopharmaceuticals represents an <b>opportunity for synthetic biology</b>. We reasoned that it should be possible to design a biological system that will deliver therapeutics <b>where</b> they are needed, <b>when</b> they are needed <b>in the amount and type</b> in which they are needed. This should decrease the amount of therapeutics in the systemic circulation thus reducing the harmful side effects as the biopharmaceuticals will be targeted to the specific tissue. This will not only potentially increase the effectivness of the therapy but should also make it more affordable. On the other hand different therapeutic regimens are also possible through the application of tools of synthetic biology.  
+
Therefore advanced methods of targeted delivery of biopharmaceuticals represent an <b>opportunity for synthetic biology</b>. We reasoned that it should be possible to design a biological system that will deliver therapeutics or their combinations <b>where</b> they are needed, <b>when</b> they are needed and <b>in the amount</b> in which they are needed. The <b>main advantage</b> could be the development of <b>advanced therapies, consisting of combinations of different effectors in a selected temporal order</b>, made available by the tools of synthetic biology. In situ production of biological drugs in the affected tissue should decrease the unwanted amount of therapeutics in the systemic circulation, thus reducing the harmful side effects. This will not only increase the effectiveness of the therapy but could also make it more affordable.
</div>
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Latest revision as of 20:42, 26 October 2012


Challenge

Pharmacological therapy usually includes only a single or few therapeutics to treat the selected pathology, such as an infection, cancer or inflammation (Walsh, 2010). After application of pharmacological therapy medicine relies on the body’s own ability to heal and regenerate. With advances in medical research, we have unraveled biochemical pathways governing different stages of diseases. We now understand the role of growth factors and other endogenous mediators in the regeneration and healing processes. Often a defined temporal sequence of different factors is required for the best therapeutic effect however they are very seldom used in current medicine.

Some biopharmaceuticals used in therapy have side effects that range from mild to serious, sometimes requiring discontinuation or modification of therapy. For example the systemic inhibition of tumor necrosis factor-alpha used to treat arthritis may increase the risk of infection, the application of interferon alpha for treatment of hepatitis C infection causes nausea, and some biological drugs may promote hepatic dysfunction or have other serious side effects.

An additional important aspect connected to the application of biological drugs is the high cost of therapy. The annual cost of biological therapy for rheumatoid arthritis ranges from 15,000 – 25,000 dollars for a single patient in comparison to nonbiologic therapy cost of 100 – 300 dollars per patient per year. Treatment of hepatitis C with biologics costs from 6,000 – 15,000 dollars per year and for some other diseases the cost may exceed 100,000 dollars, which is out of reach of most patients, even in wealthy countries.

USCANFRGERITSPUKJPAUSMEX
Biologic sales, exmanufacturer ($US millions) $34,957 $1,142 $3,828 $3,736 $2,106 $2,009 $1,864 $5,051 $553 $65

Many biopharmaceutical proteins are expressed in bacterial systems, which can be excellent producers; however bacterial endotoxins must be thoroughly removed before the administration to patients as even picomolar concentrations of an endotoxin may activate immune cells. In the production of biologics, downstream processing and formulation of the drug is very demanding. For example, the (komentar: točno katera? The first?) interferon alpha formulation was found to oxidize at room temperature, which affected its tertiary structure, decreasing its effectiveness and raising the immune response to the modified protein. The formulation and storage procedures had to be optimized to reduce antibody formation. Similar post-manufacturing structural changes have been implicated in other immune-mediated responses to recombinant proteins (Purcell et al., 2008).


Opportunities for synthetic biology in medical therapy

Figure 1. Engineered therapeutic mammalian cells can respond to specific signals by the production of desired therapeutics.

Therapies based on biopharmaceuticals in most cases require periodic invasive applications. Due to the systemic administration adverse effects are often observed. Furthermore, large quantities of therapeutic substances must often be applied because of their nonspecific distribution throughout the body. Coupled with expensive production and purification this imposes a great burden on health systems.

Therefore advanced methods of targeted delivery of biopharmaceuticals represent an opportunity for synthetic biology. We reasoned that it should be possible to design a biological system that will deliver therapeutics or their combinations where they are needed, when they are needed and in the amount in which they are needed. The main advantage could be the development of advanced therapies, consisting of combinations of different effectors in a selected temporal order, made available by the tools of synthetic biology. In situ production of biological drugs in the affected tissue should decrease the unwanted amount of therapeutics in the systemic circulation, thus reducing the harmful side effects. This will not only increase the effectiveness of the therapy but could also make it more affordable.

References

Danzon, P.M. and Furukawa, M.F. (2006) Prices and availability of biopharmaceuticals: an international comparison. Health Aff. 25, 1353-62.

Purcell, R.T. and Lockey, R.F. (2008) Immunologic Responses to Therapeutic Biologic Agents. J. Investig. Allergol. Clin. Immunol. 18, 335–342.

Walsh., G (2010) Biopharmaceutical benchmarks 2010. Nat. Biotechnol. 28, 917- 924.


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