Team:Wageningen UR

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     <a href="https://2013.igem.org/Team:Wageningen_UR/Why_Aspergillus_nigem" class="tour"><span class="startt">Start</span><span class="tourr">Tour</span></a>
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        <div class="intro">
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The discovery of secondary metabolites has had a profound influence on the development of human medicines. It was Alexander Fleming who in 1928 discovered the first antibiotic, penicillin, that would conquer some of mankind's most ancient scourges, including syphilis, gangrene and tuberculosis. The production of these secondary metabolites in most cases involves a large backbone enzyme that contains multiple catalytic domains and whose genetics is rether complex. One of our goals is to establish a modular system of domain shuffling to generate a plethora of novel enzymes with new and improved functionalities. The possibilities are endless as there are various different domains from fungi that can be added, removed, reordered, exchanged or even customized in this synthetic biology approach. The production of lovastatin, a drug used in lowering LDL cholesterol for patients suffering from cardiovascular disease, has been chosen as a proof of principle. Currently, it is produced in the fungi Aspergillus terreus, which also produces less desirable toxins. Thus try to transfer the entire lovastatin metabolic pathway from A. terreus into another microorganism like Aspergillus niger is one aspect of our goals. The goals also includs host engineering and biosensor in Aspergillus niger.
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==Introduction==
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==Project navigation==
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<p class="intro">The discovery of secondary metabolites has had a profound impact on the development of human medicines such as penicillins, cephalosporins. However, the widespread deployment of pharmaceuticals derived from secondary metabolites is severely limited by our ability to implement economically viable large-scale production systems. While advances in metabolic engineering and process technology have allowed the biobased production of fuels and chemicals to occur at an unprecedented scale, the production of many useful secondary metabolites has lagged behind. This is in part due to the slow growth and low productivity of the organisms that naturally produce these compounds, but also due to the complexity of the biochemical pathways involved in their biosynthesis. Therefore, using synthetic biology tools to identify, optimize and transplant these biosynthetic pathways into more productive host organisms is a major opportunity to overcome current technological limitations and ultimately to disseminate crucial medical treatments to people without the means to afford pharmaceuticals produced via traditional organic synthesis. <br/><br/>
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In order to pave the way for next-generation metabolic engineering, it was necessary to go beyond established standards. <i>Escherichia coli</i> is undoubtedly the most well-characterized organism in existence and has been the primary workhorse of fundamental synthetic biology research. However, despite the spectacular achievements in understanding and manipulating all levels of its physiology, when it comes to industrial-scale production, <i>E. coli</i> is far from an ideal cell factory. In contrast, yeasts and fungi are naturally more robust, more productive, and are easier to separate in downstream processing. The filamentous fungus <i>Aspergillus niger</i> is widely used in the production of organic acids due to its unmatched ability to secrete metabolites. Due to its inherent biosynthetic capabilities, the recent development of effective genome engineering tools makes it an ideal platform for advanced metabolic engineering applications. <br/><br/>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Secondary_metabolites"><img src="https://static.igem.org/mediawiki/2013/4/41/Secmet.png" alt="Secondary metabolites"/></a></span>
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In order to establish <i>A. niger</i> as a viable platform organism, we took a threefold approach:<br/>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Lovastatin"><img src="https://static.igem.org/mediawiki/2013/4/42/Lov.png" alt="Lovastatin"/></a></span>
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a) The modularization and refactoring of a heterologous biosynthetic enzyme complex. <br/>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Flux_balance_analysis"><img src="https://static.igem.org/mediawiki/2013/b/b2/Mtlab.png" alt="Modeling"/></a></span>
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b) The development of a versatile molecular toolkit to facilitate the analysis of its physiology including in-situ ATP and pH biosensors, chromoproteins to screen transformants, and fluorescent cytoskeleton proteins to visualize <i>A. niger</i>’s cellular structure.<br/>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Chromoproteins"><img src="https://static.igem.org/mediawiki/2013/b/bc/Chro.png" alt="Chromoproteins"/></a></span>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Cytoskeleton_and_septa"><img src="https://static.igem.org/mediawiki/2013/d/d9/Cyt.png" alt="Infrastructure"/></a></span>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/ATP_biosensor"><img src="https://static.igem.org/mediawiki/2013/3/3a/Biosens.png" alt="Biosensors"/></a></span>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Engineering_morphology"><img src="https://static.igem.org/mediawiki/2013/b/b5/Hostcell.png" alt="Host engineering"/></a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Secondary_metabolites">Secondary metabolites</a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Lovastatin">Lovastatin</a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Flux_balance_analysis">Modeling</a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Chromoproteins">Chromoproteins</a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Cytoskeleton_and_septa">Infrastructure</a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/ATP_biosensor">Biosensors</a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Engineering_morphology">Host engineering</a></span>
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            <a href="#" id="one" class="on">Secondary metabolites</a>
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            <a href="#" id="two">Toolbox</a>
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            <a href="#" id="three">Host engineering</a>
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            <a href="" target="_blank" id="videolink">Project video</a>
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c) A r-evolutionary engineering method to develop a host strain with reduced mycelial cohesiveness for improved productivity.</p>
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<div class="achievements">
<div class="achievements">
     <div class="achieve bronze">
     <div class="achieve bronze">
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         <a href="https://2013.igem.org/Team:Wageningen_UR/Medals"><img src="https://static.igem.org/mediawiki/2013/f/f2/Bronze.png" alt="Bronze medal">Bronze medal</a>
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         <a href="https://2013.igem.org/Team:Wageningen_UR/Achievements"><img src="https://static.igem.org/mediawiki/2013/f/f2/Bronze.png" alt="Bronze medal">Bronze medal</a>
         <div class="moreinfo">
         <div class="moreinfo">
             <p class="check">Team registration</p>
             <p class="check">Team registration</p>
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     <div class="achieve silver">
     <div class="achieve silver">
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         <a href="https://2013.igem.org/Team:Wageningen_UR/Medals"><img src="https://static.igem.org/mediawiki/2013/0/0b/Silver.png" alt="Silver medal">Silver medal</a>
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         <a href="https://2013.igem.org/Team:Wageningen_UR/Achievements"><img src="https://static.igem.org/mediawiki/2013/0/0b/Silver.png" alt="Silver medal">Silver medal</a>
         <div class="moreinfo">
         <div class="moreinfo">
             <p class="check">Experimentally validate that at least one new BioBrick Part or Device of your own design and construction works as expected</p>
             <p class="check">Experimentally validate that at least one new BioBrick Part or Device of your own design and construction works as expected</p>
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     <div class="achieve gold">
     <div class="achieve gold">
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         <a href="https://2013.igem.org/Team:Wageningen_UR/Medals"><img src="https://static.igem.org/mediawiki/2013/3/32/Goldmed.png" alt="Silver medal">Gold medal</a>
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         <a href="https://2013.igem.org/Team:Wageningen_UR/Achievements"><img src="https://static.igem.org/mediawiki/2013/3/32/Goldmed.png" alt="Silver medal">Gold medal</a>
         <div class="moreinfo">
         <div class="moreinfo">
             <p class="check">Help any registered iGEM team from another school or institution by, for example, characterizing a part, debugging a construct, or modeling or simulating their system</p>
             <p class="check">Help any registered iGEM team from another school or institution by, for example, characterizing a part, debugging a construct, or modeling or simulating their system</p>
             <p class="check">Your project may have implications for the environment, security, safety and ethics and/or ownership and sharing. Describe a novel approach that your team has used to help you and others consider these aspects of the design and outcomes of synthetic biology efforts. Please justify its novelty and how this approach might be adapted and scaled for others to use</p>
             <p class="check">Your project may have implications for the environment, security, safety and ethics and/or ownership and sharing. Describe a novel approach that your team has used to help you and others consider these aspects of the design and outcomes of synthetic biology efforts. Please justify its novelty and how this approach might be adapted and scaled for others to use</p>
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            <p class="check">Improve the function of an existing BioBrick Part or Device (created by another team or your own institution in a previous year), enter this information in the 'Experience' section of that Parts's Registry entry), create a new registry page for the improved part, and submit this part to the iGEM Registry (submissions must adhere to the iGEM Registry guidelines).</p>
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==Human practices==
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==Project navigation==
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<html><div class="outline">
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        <div class="cell one">
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Secondary_metabolites"><img src="https://static.igem.org/mediawiki/2013/4/41/Secmet.png" alt="Secondary metabolites"/></a></span>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Lovastatin"><img src="https://static.igem.org/mediawiki/2013/4/42/Lov.png" alt="Lovastatin"/></a></span>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Modeling"><img src="https://static.igem.org/mediawiki/2013/b/b2/Mtlab.png" alt="Modeling"/></a></span>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Chromoproteins"><img src="https://static.igem.org/mediawiki/2013/b/bc/Chro.png" alt="Chromoproteins"/></a></span>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Infrastructure"><img src="https://static.igem.org/mediawiki/2013/d/d9/Cyt.png" alt="Infrastructure"/></a></span>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Biosensors"><img src="https://static.igem.org/mediawiki/2013/3/3a/Biosens.png" alt="Biosensors"/></a></span>
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            <span><a href="https://2013.igem.org/Team:Wageningen_UR/Host_engineering"><img src="https://static.igem.org/mediawiki/2013/b/b5/Hostcell.png" alt="Host engineering"/></a></span>
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        <div class="text one">
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Secondary_metabolites">Secondary metabolites</a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Lovastatin">Lovastatin</a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Modeling">Modeling</a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Chromoproteins">Chromoproteins</a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Infrastructure">Infrastructure</a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Biosensors">Biosensors</a></span>
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            <span class="line"><a href="https://2013.igem.org/Team:Wageningen_UR/Host_engineering">Host engineering</a></span>
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        </div>
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    </div>
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    <div class="scale">
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            <a href="#" id="one" class="on">Secondary metabolites</a>
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            <a href="#" id="two">Toolbox</a>
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            <a href="#" id="three">Host engineering</a>
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            <a href="" target="_blank" id="videolink">Project video</a>
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==Scientific Interactions==
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         <a href="https://2013.igem.org/Team:Wageningen_UR/IgemNL"><img src="https://static.igem.org/mediawiki/2013/4/40/Igemnl.png" alt="iGEM Netherlands">iGEM Netherlands</a>
         <a href="https://2013.igem.org/Team:Wageningen_UR/IgemNL"><img src="https://static.igem.org/mediawiki/2013/4/40/Igemnl.png" alt="iGEM Netherlands">iGEM Netherlands</a>
         <a href="https://2013.igem.org/Team:Wageningen_UR/Conference"><img src="https://static.igem.org/mediawiki/2013/8/87/Posterpres.png" alt="Poster presentation">Poster presentation</a>
         <a href="https://2013.igem.org/Team:Wageningen_UR/Conference"><img src="https://static.igem.org/mediawiki/2013/8/87/Posterpres.png" alt="Poster presentation">Poster presentation</a>
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         <a href="https://2013.igem.org/Team:Wageningen_UR/Masterclass"><img src="https://static.igem.org/mediawiki/2013/7/7b/Discpsyc.png" alt="Discursive psychology">Discursive psychology</a>
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         <a href="https://2013.igem.org/Team:Wageningen_UR/Masterclass"><img src="https://static.igem.org/mediawiki/2013/7/7b/Discpsyc.png" alt="Masterclass">Masterclass</a>
         <a href="https://2013.igem.org/Team:Wageningen_UR/Collaborations"><img src="https://static.igem.org/mediawiki/2013/1/12/Collabs.png" alt="Collaborations">Collaborations</a>
         <a href="https://2013.igem.org/Team:Wageningen_UR/Collaborations"><img src="https://static.igem.org/mediawiki/2013/1/12/Collabs.png" alt="Collaborations">Collaborations</a>
         <a href="https://2013.igem.org/Team:Wageningen_UR/Science_cafe"><img src="https://static.igem.org/mediawiki/2013/f/f9/Sciencecafe.png" alt="Science café">Science café</a>
         <a href="https://2013.igem.org/Team:Wageningen_UR/Science_cafe"><img src="https://static.igem.org/mediawiki/2013/f/f9/Sciencecafe.png" alt="Science café">Science café</a>
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         <h2>Sponsors</h2>
         <h2>Sponsors</h2>
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         <a href="https://www.facebook.com/beauvillemedia" target="_blank" class="sponsor" title="Beauville Media"><img src="https://static.igem.org/mediawiki/2013/5/5e/Beauville-media.png" alt="Beauville Media" style="display:block; vertical-align:bottom;"/></a>
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Latest revision as of 03:50, 5 October 2013

StartTour

Introduction

The discovery of secondary metabolites has had a profound impact on the development of human medicines such as penicillins, cephalosporins. However, the widespread deployment of pharmaceuticals derived from secondary metabolites is severely limited by our ability to implement economically viable large-scale production systems. While advances in metabolic engineering and process technology have allowed the biobased production of fuels and chemicals to occur at an unprecedented scale, the production of many useful secondary metabolites has lagged behind. This is in part due to the slow growth and low productivity of the organisms that naturally produce these compounds, but also due to the complexity of the biochemical pathways involved in their biosynthesis. Therefore, using synthetic biology tools to identify, optimize and transplant these biosynthetic pathways into more productive host organisms is a major opportunity to overcome current technological limitations and ultimately to disseminate crucial medical treatments to people without the means to afford pharmaceuticals produced via traditional organic synthesis.

In order to pave the way for next-generation metabolic engineering, it was necessary to go beyond established standards. Escherichia coli is undoubtedly the most well-characterized organism in existence and has been the primary workhorse of fundamental synthetic biology research. However, despite the spectacular achievements in understanding and manipulating all levels of its physiology, when it comes to industrial-scale production, E. coli is far from an ideal cell factory. In contrast, yeasts and fungi are naturally more robust, more productive, and are easier to separate in downstream processing. The filamentous fungus Aspergillus niger is widely used in the production of organic acids due to its unmatched ability to secrete metabolites. Due to its inherent biosynthetic capabilities, the recent development of effective genome engineering tools makes it an ideal platform for advanced metabolic engineering applications.

In order to establish A. niger as a viable platform organism, we took a threefold approach:
a) The modularization and refactoring of a heterologous biosynthetic enzyme complex.
b) The development of a versatile molecular toolkit to facilitate the analysis of its physiology including in-situ ATP and pH biosensors, chromoproteins to screen transformants, and fluorescent cytoskeleton proteins to visualize A. niger’s cellular structure.
c) A r-evolutionary engineering method to develop a host strain with reduced mycelial cohesiveness for improved productivity.


Achievements

Bronze medalBronze medal

Team registration

Complete Judging form

Team Wiki

Present a poster and a talk at the iGEM Jamboree

Document at least one new standard BioBrick Part or Device used in your project/central to your project and submit this part to the iGEM Registry

Silver medalSilver medal

Experimentally validate that at least one new BioBrick Part or Device of your own design and construction works as expected

Submit this new part to the iGEM Parts Registry

Your project may have implications for the environment, security, safety and ethics and/or ownership and sharing. Describe one or more ways in which these or other broader implications have been taken into consideration in the design and execution of your project

Silver medalGold medal

Help any registered iGEM team from another school or institution by, for example, characterizing a part, debugging a construct, or modeling or simulating their system

Your project may have implications for the environment, security, safety and ethics and/or ownership and sharing. Describe a novel approach that your team has used to help you and others consider these aspects of the design and outcomes of synthetic biology efforts. Please justify its novelty and how this approach might be adapted and scaled for others to use

Improve the function of an existing BioBrick Part or Device (created by another team or your own institution in a previous year), enter this information in the 'Experience' section of that Parts's Registry entry), create a new registry page for the improved part, and submit this part to the iGEM Registry (submissions must adhere to the iGEM Registry guidelines).

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