Difference between revisions of "Team:ETH Zurich/Applied Design"

 
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<h1 class="headline">CATE Treatment (Applied Design)</h1>
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<h1 class="headline">CATE in Action</h1>
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<section class="first">
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    <h1>Overview</h1>
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<p><em>This page will tell you all about the how we envision the treatment procedure with CATE to look like. To read about how we developed the idea of CATE, visit the <a href="https://2017.igem.org/Team:ETH_Zurich/Applied_Design">Story of CATE.</a> For details about the circuit behind the story, visit our <a href="https://2017.igem.org/Team:ETH_Zurich/Circuit"> Circuit page.</a> To read about the design principles that helped us structure, organize and execute our project, go to <a href="https://2017.igem.org/Team:ETH_Zurich/Design"> Design.</a></em></p>
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    <p>This is a prize for the team that has developed a synbio product to solve a real world problem in the most elegant way. The students will have considered how well the product addresses the problem versus other potential solutions, how the product integrates or disrupts other products and processes, and how its lifecycle can more broadly impact our lives and environments in positive and negative ways. To compete for the <a href="https://2017.igem.org/Judging/Awards">Best Applied Design prize</a>, please describe your work on this page and also fill out the description on the <a href="https://2017.igem.org/Judging/Judging_Form">judging form</a>. </p>
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<section>
 +
<h1>Introduction</h1>
 +
 
 +
<p>We decided to work with the probiotic <i>E. coli</i> Nissle 1917, due to its inherent tumor targeting capabilities and lack of pathogenicity, which make it the ideal chassis for development of precisely controllable features that we decided to integrate into the therapeutic. <a href="#bib1" class="forward-ref">[1]</a><a href="#bib2" class="forward-ref">[2]</a></p>
 +
 
 +
<p>We envision the treatment to follow the strategy described below. A short duration, enhanced safety and overall effectiveness are expected to be decisive factors for choosing CATE over conventional therapies. </p>
  
 
</section>
 
</section>
  
 
<section>
 
<section>
 +
<h1>Treatment Procedure</h1>
  
−
<p>
+
<figure class="process">
−
We envision the treatment with our novel bacterial cancer therapy - CATE, to follow the depicted strategy. A <i>short duration</i>, <i>enhanced safety</i> and <i>overall effectiveness</i> are expected to be decisive factors for choosing to treat with CATE instead of conventional therapies. </p>
+
  <img src="https://static.igem.org/mediawiki/2017/1/14/T--ETH_Zurich--process-02.png">
−
<p>The following steps will guide you through the treatment:</p>
+
</figure>
  
−
        <fieldset>
 
−
            <legend>1. Administration of the Bacterial Therapeutic</legend>
 
−
            <p>Following diagnostic procedures and the decision to use CATE, the patient will receive a soluble formulation of CATE in an intravenous injection. This is a quick and easy step for both the patient and the doctor.</p>
 
−
        </fieldset>
 
−
        <fieldset>
 
−
            <legend>2. Colonization of the Tumor Tissue</legend>
 
−
            <p>CATE distributes throughout the body and specifically populates the tumor tissue. Only in this special microenvironment, rich in nutrients and hidden from the immune system, CATE can grow to a high cell density. </p>
 
−
        </fieldset> 
 
  
−
        <hr> <p>CHECKPOINT 1</p>
+
<p>The procedure revolves around two safety Checkpoints, unique to our design. Checkpoint 1 is an internal checkpoint where the bacteria identify the tumor and decide if they can proceed with the treatment, while Checkpoint 2 represent and external checkpoint manipulated by the physician. With the combination of the two, we believe to have designed a system of superior security.</p>  
  
−
        <fieldset>
+
<p>The following steps will guide you through the treatment. To find out more about how each of the described steps works, click on the links below that will guide you to a detailed description of each function implemented in CATE.</p>
−
            <legend>3. Tumor Sensing</legend>
+
−
           
+
−
            <p>Only in the tumor tissue, two conditions necessary to pass the safety Checkpoint 1 are present. </p>
+
−
            <ul>
+
−
                <li>The first condition is the high cell density of the bacteria, that CATE can only reach in tumors because of their unique micro-environment.</li>
+
−
                <li>The second condition is the presence of a high concentration of lactate, a molecule typically overproduced by cancer cells. </li>
+
−
            </ul>
+
−
            <p>Only If these two conditions are satisfied, CATE will pass Checkpoint 1 and proceed to the next step. </p>
+
−
            <div class="legend2">CHECKPOINT 1</div>
+
−
        </fieldset>  
+
  
−
         <p>Read more about how CATE can identify tumors: <a href="https://2017.igem.org/Team:ETH_Zurich/Circuit/Fa_Tumor_Sensor">Function A: Tumor Sensor</a></p>
+
<fieldset>
 +
        <legend>1. Administration of the Bacterial Therapeutic</legend>
 +
         <p>Following diagnostic procedures and the decision to use CATE, the patient will receive a soluble formulation of CATE in an intravenous injection. This is a quick and easy step for both the patient and the doctor.</p>
 +
</fieldset>
  
−
         <hr>
+
<fieldset>
 +
         <legend>2. Colonization of the Tumor Tissue</legend>
 +
        <p>CATE distributes throughout the body and specifically populates the tumor tissue. Only in this special microenvironment, rich in nutrients and hidden from the immune system, CATE can grow to a high cell density. <a href="#bib5" class="forward-ref">[1]</a><a href="#bib6" class="forward-ref">[2]</a></p>
 +
</fieldset>  
  
−
        <fieldset>
+
<fieldset class="checkpoint">
−
            <legend>4. Anti-Cancer Toxin and MRI Contrast Agent Production</legend>
+
        <legend>3. Tumor Sensing</legend>
−
            <p>To pass Checkpoint 1, cell density of the bacteria in the tumor has to be high enough to kill it. Once this has been achieved, CATE will start to produce an Anti-Cancer Toxin. However, the toxin will not be released yet. It will reside in CATE until the second checkpoint has been passed. At the same time, CATE will also produce an MRI Contrast Agent. This will allow the doctor to confirm through an MRI scan that the Toxin is ready and the bacteria have indeed colonized the correct location. </p>
+
        <div class="legend_checkpoint">CHECKPOINT 1</div>
−
         </fieldset>
+
        <p>CATE is designed so that the two conditions necessary to pass the safety Checkpoint1 are only present in the tumor tissue and not in the healthy tissue. </p>
−
       
+
         <ul>
−
        <p>Find out more about <a href="https://2017.igem.org/Team:ETH_Zurich/Circuit/Fb_Contrast_Agent">Function B: MRI Contrast Agent</a></p>
+
            <li>The first condition is the high cell density of the bacteria, that CATE can only reach in tumors because of their unique microenvironment. <a href="#bib2" class="forward-ref">[2]</a></li>
−
        <p>Find out more about <a href="https://2017.igem.org/Team:ETH_Zurich/Circuit/Fc_Anti_Cancer_Toxin">Function C: Anti-Cancer Toxin</a></p>
+
            <li>The second condition is the presence of a high concentration of lactate, a molecule typically overproduced by cancer cells. <a href="#bib3" class="forward-ref">[3]</a></li>
 +
        </ul>
 +
        <p>Only if both of these conditions are fulfilled, CATE will pass Checkpoint 1 and proceed to the next step.</p>
 +
</fieldset>  
  
−
        <fieldset>
+
<p><a href="https://2017.igem.org/Team:ETH_Zurich/Circuit/Fa_Tumor_Sensor">Function A: Tumor Sensor</a></p>
−
            <legend>5. Magnetic Resonance Imaging</legend>
+
−
            <p>The patient is examined in an MRI machine and the doctor can inspect the location of CATE. Because the MRI Contrast Agent is produced together with the Anti-Cancer Toxin, the doctor can also be indirectly assured that enough of the Toxin is available to eradicate the tumor. This additional security step is unique to our bacterial cancer therapy with CATE. Neither conventional cancer treatments that include systemically administered toxic compounds, nor modern targeted therapies with engineered immune cells have the advantage of combining a molecular tumor-recognition with a location-approved toxicity-activation.</p>
+
−
        </fieldset>  
+
  
−
        <fieldset>
+
<fieldset>
−
            <legend>6. Focused Ultrasound</legend>
+
        <legend>4. Anti-Cancer Toxin Acummulation and MRI Contrast Agent Production</legend>
−
            <p>This step is directly coupled to Magnetic Resonance Imaging. Immediately after examining the MRI scan, the doctor can apply focused ultrasound specifically to the tumor site. Focused ultrasound is an emerging new medical technology that is already built in in modern MRI devices. It allows for high-energy sound waves outside of the audible spectrum (the same ones used by bats for navigation) to transmit their energy to a specific location in the inside of the body. This results in a temperature increase from 37&deg;C to 45&deg;C in a narrowly defined area of the tumor. It is applied to the tumor where CATE is present for 3 h.</p>
+
        <p>To pass Checkpoint 1, cell density of the bacteria in the tumor has to be high enough to kill it. Once this has been achieved, CATE will start to produce an Anti-Cancer Toxin. However, the toxin will not be released yet. It will reside in CATE until the second checkpoint has been passed. At the same time, CATE will also produce an MRI Contrast Agent. This will allow the doctor to confirm through an MRI scan that the Toxin is ready and the bacteria have indeed colonized the correct location. This additional security step is unique to our bacterial cancer therapy with CATE. Neither conventional cancer treatments that include systemically administered toxic compounds, nor modern targeted therapies with engineered immune cells have the advantage of combining an internal molecular tumor-recognition with the ability to externally verify and manipulate the treatment.</p>
−
        </fieldset>  
+
    </fieldset>
  
−
      <hr> <p>CHECKPOINT 2</p>
+
<p><a href="https://2017.igem.org/Team:ETH_Zurich/Circuit/Fb_Contrast_Agent">Function B: MRI Contrast Agent</a></p>
 +
<p><a href="https://2017.igem.org/Team:ETH_Zurich/Circuit/Fc_Anti_Cancer_Toxin">Function C: Anti-Cancer Toxin</a></p>
  
−
        <fieldset>
+
<fieldset>
−
            <legend>7. Heat Sensing</legend>
+
        <legend>5. Focused Ultrasound</legend>
−
            <p>The change in the temperature, from 37&deg;C to 45&deg;C, caused by the doctor via focused ultrasound, alerts CATE that Checkpoint 2 has been passed due to the release of a protein that has been blocking the activation of the Heat Sensing circuit. Then CATE continues with the next step of the treatment procedure.</p>
+
        <p> Immediately after examining the MRI scan, the doctor can apply focused ultrasound specifically to the tumor site. Focused ultrasound is an emerging medical technology that allows for high-energy sound waves outside of the audible spectrum (the same ones used by bats for navigation) to transmit their energy to a specific location on the inside of the body. <a href="#bib4" class="forward-ref">[4]</a> This results in a temperature increase in a narrowly defined area of the tumor.</p>
−
        </fieldset>  
+
    </fieldset>  
  
−
         <p>Find out more about
+
    <fieldset class="checkpoint">
−
<a href="https://2017.igem.org/Team:ETH_Zurich/Circuit/Fd_Heat_Sensor">Function D: Heat Sensor</a></p>
+
         <legend>6. Heat Sensing</legend>
 +
        <div class="legend_checkpoint">CHECKPOINT 2</div>
 +
        <p>The increase in the temperature, from 37&deg;C to 45&deg;C, caused by the  doctor via focused ultrasound, alerts CATE that Checkpoint 2 has been passed. A thermosensitive protein that has been blocking the activation of the Heat Sensing circuit until now is removed and CATE can continue with the next step of the treatment procedure.</p>
 +
    </fieldset>  
  
−
        <hr>
+
<p><a href="https://2017.igem.org/Team:ETH_Zurich/Circuit/Fd_Heat_Sensor">Function D: Heat Sensor</a></p>
  
−
        <fieldset>
+
<fieldset>
−
            <legend>8. Cell Lysis and Toxin Release</legend>
+
<legend>7. Cell Lysis and Toxin Release</legend>
−
            <p>After successfully going through Checkpoint 2, CATE is designed to produce a special protein that originates from bacteria-killing phages. This protein interferes with the bacterial cell wall synthesis which leads to pore formation and ultimately, the breakdown of CATE. This way, the previously accumulated Anti-Cancer Toxin is released to the tumor tissue.</p>
+
<p>After successfully going through Checkpoint 2, CATE is designed to produce a special protein that originates from bacteria-killing phages. This protein interferes with the bacterial cell wall synthesis which leads to pore formation and ultimately, the breakdown of CATE. This way, the previously accumulated Anti-Cancer Toxin is released to the tumor tissue.</p>
−
        </fieldset>  
+
  
−
        <p>Find out more about <a href="https://2017.igem.org/Team:ETH_Zurich/Circuit/Fe_Cell_Lysis">Function E: Cell Lysis</a></p>
+
</fieldset>
 +
<p><a href="https://2017.igem.org/Team:ETH_Zurich/Circuit/Fe_Cell_Lysis">Function E: Cell Lysis</a></p>
  
−
        <fieldset>
+
<fieldset>
−
            <legend>9. Cancer Killing</legend>
+
−
            <p>After the Anti-Cancer Toxin gets released, it enters the malignant cells. Once inside, it interferes with the cell cycle through stabilization of a  tumor-suppressor protein. This interference leads to the death of cancer cells through apoptosis. With this, CATE’s mission is accomplished.</p>
+
−
        </fieldset>  
+
  
−
         <!--<p>Read more about
+
<legend>8. Cancer Killing</legend>
−
<a href="https://2017.igem.org/Team:ETH_Zurich/Circuit/Fc_Cancer_Toxin">Function C: Anti-Cancer Toxin</a></p>-->
+
         <p>After the Anti-Cancer Toxin gets released, it enters the malignant cells. Once inside, it interferes with the cell cycle through multiple mechanisms, which include stabilization of a tumor suppresor protein and blocking of the transduction of growth signals. This interference inhibits the growth of cancer cells and ultimately results in their death. <a href="#bib9" class="forward-ref">[5]</a><a href="#bib6" class="forward-ref">[6]</a> With this, CATE’s mission is accomplished.</p>
 +
    </fieldset>  
  
 
</section>
 
</section>
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<section>
+
<section class="references">
−
     <h1>Inspiration</h1>
+
     <h1>References</h1>
−
     <p>Take a look at what some teams accomplished for this prize.</p>
+
     <ol>
−
    <ul>
+
        <li id="bib1">Forbes, Neil S. "Engineering the perfect (bacterial) cancer therapy." <cite>Nature reviews. Cancer</cite> 10.11 (2010): 785. <a href="https://doi.org/10.1038/nrc2934">doi: 10.1038/nrc2934</a></li>
−
        <li><a href="https://2016.igem.org/Team:NCTU_Formosa/Design">2016 NCTU Formosa</a></li>
+
<li id="bib2">Stritzker, Jochen, et al. "Tumor-specific colonization, tissue distribution, and gene induction by probiotic Escherichia coli Nissle 1917 in live mice." <cite>International journal of medical microbiology</cite> 297.3 (2007): 151-162. <a href="https://doi.org/10.1016/j.ijmm.2007.01.008">doi: 10.1016/j.ijmm.2007.01.008</a></li>
−
        <li><a href="https://2016.igem.org/Team:HSiTAIWAN/Product?locationId=Design">2016 HSiTAIWAN</a></li>
+
<li id="bib3">Hirschhaeuser, Franziska, Ulrike GA Sattler, and Wolfgang Mueller-Klieser. "Lactate: a metabolic key player in cancer." <cite>Cancer research</cite> 71.22 (2011): 6921-6925. <a href="https://doi.org/10.1158/0008-5472.CAN-11-1457">doi: 10.1158/0008-5472.CAN-11-1457</a></li>
−
        <li><a href="https://2016.igem.org/Team:Pasteur_Paris/Design">2016 Pasteur Paris</a></li>
+
<li id="bib4">Ebbini, Emad S., and Gail Ter Haar. "Ultrasound-guided therapeutic focused ultrasound: current status and future directions." <cite>International Journal of Hyperthermia</cite> 31.2 (2015): 77-89. <a href="https://doi.org/10.3109/02656736.2014.995238">doi: 10.3109/02656736.2014.995238</a></li>
−
    </ul>
+
    <li id="bib5">Yamada, Tohru, et al. "Bacterial redox protein azurin, tumor suppressor protein p53, and regression of cancer." <i>Proceedings of the National Academy of Sciences</i> 99.22 (2002): 14098-14103. <a href="https://doi.org/10.1073/pnas.222539699">doi: 10.1073/pnas.222539699</a></li>
−
</section>-->
+
    <li id="bib6">Bernardes, Nuno, et al. "Modulation of membrane properties of lung cancer cells by azurin enhances the sensitivity to EGFR-targeted therapy and decreased β1 integrin-mediated adhesion." <i>Cell Cycle</i> 15.11 (2016): 1415-1424. <a href="https://doi.org/10.1080/15384101.2016.1172147">doi: 10.1080/15384101.2016.1172147</a></li>
 +
</ol>
 +
</section>
 +
 
 +
 
 
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{{ETH_Zurich/Footer_N}}
 
{{ETH_Zurich/Footer_N}}

Latest revision as of 02:05, 2 November 2017

CATE in Action

This page will tell you all about the how we envision the treatment procedure with CATE to look like. To read about how we developed the idea of CATE, visit the Story of CATE. For details about the circuit behind the story, visit our Circuit page. To read about the design principles that helped us structure, organize and execute our project, go to Design.

Introduction

We decided to work with the probiotic E. coli Nissle 1917, due to its inherent tumor targeting capabilities and lack of pathogenicity, which make it the ideal chassis for development of precisely controllable features that we decided to integrate into the therapeutic. [1][2]

We envision the treatment to follow the strategy described below. A short duration, enhanced safety and overall effectiveness are expected to be decisive factors for choosing CATE over conventional therapies.

Treatment Procedure

The procedure revolves around two safety Checkpoints, unique to our design. Checkpoint 1 is an internal checkpoint where the bacteria identify the tumor and decide if they can proceed with the treatment, while Checkpoint 2 represent and external checkpoint manipulated by the physician. With the combination of the two, we believe to have designed a system of superior security.

The following steps will guide you through the treatment. To find out more about how each of the described steps works, click on the links below that will guide you to a detailed description of each function implemented in CATE.

1. Administration of the Bacterial Therapeutic

Following diagnostic procedures and the decision to use CATE, the patient will receive a soluble formulation of CATE in an intravenous injection. This is a quick and easy step for both the patient and the doctor.

2. Colonization of the Tumor Tissue

CATE distributes throughout the body and specifically populates the tumor tissue. Only in this special microenvironment, rich in nutrients and hidden from the immune system, CATE can grow to a high cell density. [1][2]

3. Tumor Sensing
CHECKPOINT 1

CATE is designed so that the two conditions necessary to pass the safety Checkpoint1 are only present in the tumor tissue and not in the healthy tissue.

  • The first condition is the high cell density of the bacteria, that CATE can only reach in tumors because of their unique microenvironment. [2]
  • The second condition is the presence of a high concentration of lactate, a molecule typically overproduced by cancer cells. [3]

Only if both of these conditions are fulfilled, CATE will pass Checkpoint 1 and proceed to the next step.

Function A: Tumor Sensor

4. Anti-Cancer Toxin Acummulation and MRI Contrast Agent Production

To pass Checkpoint 1, cell density of the bacteria in the tumor has to be high enough to kill it. Once this has been achieved, CATE will start to produce an Anti-Cancer Toxin. However, the toxin will not be released yet. It will reside in CATE until the second checkpoint has been passed. At the same time, CATE will also produce an MRI Contrast Agent. This will allow the doctor to confirm through an MRI scan that the Toxin is ready and the bacteria have indeed colonized the correct location. This additional security step is unique to our bacterial cancer therapy with CATE. Neither conventional cancer treatments that include systemically administered toxic compounds, nor modern targeted therapies with engineered immune cells have the advantage of combining an internal molecular tumor-recognition with the ability to externally verify and manipulate the treatment.

Function B: MRI Contrast Agent

Function C: Anti-Cancer Toxin

5. Focused Ultrasound

Immediately after examining the MRI scan, the doctor can apply focused ultrasound specifically to the tumor site. Focused ultrasound is an emerging medical technology that allows for high-energy sound waves outside of the audible spectrum (the same ones used by bats for navigation) to transmit their energy to a specific location on the inside of the body. [4] This results in a temperature increase in a narrowly defined area of the tumor.

6. Heat Sensing
CHECKPOINT 2

The increase in the temperature, from 37°C to 45°C, caused by the doctor via focused ultrasound, alerts CATE that Checkpoint 2 has been passed. A thermosensitive protein that has been blocking the activation of the Heat Sensing circuit until now is removed and CATE can continue with the next step of the treatment procedure.

Function D: Heat Sensor

7. Cell Lysis and Toxin Release

After successfully going through Checkpoint 2, CATE is designed to produce a special protein that originates from bacteria-killing phages. This protein interferes with the bacterial cell wall synthesis which leads to pore formation and ultimately, the breakdown of CATE. This way, the previously accumulated Anti-Cancer Toxin is released to the tumor tissue.

Function E: Cell Lysis

8. Cancer Killing

After the Anti-Cancer Toxin gets released, it enters the malignant cells. Once inside, it interferes with the cell cycle through multiple mechanisms, which include stabilization of a tumor suppresor protein and blocking of the transduction of growth signals. This interference inhibits the growth of cancer cells and ultimately results in their death. [5][6] With this, CATE’s mission is accomplished.

References

  1. Forbes, Neil S. "Engineering the perfect (bacterial) cancer therapy." Nature reviews. Cancer 10.11 (2010): 785. doi: 10.1038/nrc2934
  2. Stritzker, Jochen, et al. "Tumor-specific colonization, tissue distribution, and gene induction by probiotic Escherichia coli Nissle 1917 in live mice." International journal of medical microbiology 297.3 (2007): 151-162. doi: 10.1016/j.ijmm.2007.01.008
  3. Hirschhaeuser, Franziska, Ulrike GA Sattler, and Wolfgang Mueller-Klieser. "Lactate: a metabolic key player in cancer." Cancer research 71.22 (2011): 6921-6925. doi: 10.1158/0008-5472.CAN-11-1457
  4. Ebbini, Emad S., and Gail Ter Haar. "Ultrasound-guided therapeutic focused ultrasound: current status and future directions." International Journal of Hyperthermia 31.2 (2015): 77-89. doi: 10.3109/02656736.2014.995238
  5. Yamada, Tohru, et al. "Bacterial redox protein azurin, tumor suppressor protein p53, and regression of cancer." Proceedings of the National Academy of Sciences 99.22 (2002): 14098-14103. doi: 10.1073/pnas.222539699
  6. Bernardes, Nuno, et al. "Modulation of membrane properties of lung cancer cells by azurin enhances the sensitivity to EGFR-targeted therapy and decreased β1 integrin-mediated adhesion." Cell Cycle 15.11 (2016): 1415-1424. doi: 10.1080/15384101.2016.1172147