Biomod/2013/Todai/Project

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      Cancer is one of the most malignant diseases. In cancer, cells get abnormal, divide and grow uncontrollably, forming malignant tumors, and invade human body. It accounts for about 13 percent of deaths in the world.
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      Cancer is one of the most common diseases in the world. Cancer cells divide abnormally and grow uncontrollably, resulting in the formation of malignant tumors, and invading human body. Cancer causes about 13 percent of the all human deaths worldwide (WHO 2007).
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      One of the most effective medical treatments for cancer is chemotherapy, but it often has severe side effects. This is because anti-cancer drugs attack not only cancer cells but also normal cells, damaging normal tissue and organs. According to <a target="_blank" href="http://www.cancer.org/" style="color:#e00000;">the American cancer society</a>, these side effects include pain, vomiting, limphedemia, sexual decline and various symptoms, which seriously decrease quality of life.
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Chemotherapy is a popular medical treatments for the cancer, however, it often attacks normal cells in addition to the cancer cells, damaging normal tissue and organs, which cause severe side effects. According to <a target="_blank" href="http://www.cancer.org/" style="color:#e00000;">the American cancer society</a>, these side effects include pain, vomiting, limphedemia, sexual decline and various symptoms, which seriously decrease quality of life.
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       To improve cancer-specificity, drug delivery system has also developed recently, but it is difficult to customize a delivery system one by one corresponding to each drug.
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       To improve cancer-specificity, drug delivery system (DDS) has developed, but it is difficult to optimize a delivery system for each drug.
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       Team Todai nanORFEVRE are trying to make <span style="font-weight:bolder;color:#e00000;">cancer-specific drug which doesn’t need delivery system</span>.
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       Team Todai nanORFEVRE are trying to make <span style="font-weight:bolder;color:#e00000;">cancer-specific drug which doesn’t need delivery system(DDS)</span>.
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      To realize a cancer-cell-killing system with high specificity, we first focused on a mechanism in the human immune system called membrane attack complex (MAC), which functions when bacteria infect our body. In the system of MAC, subunits penetrate the membrane, oligomerize, and form a pore through the bacteria membrane. Then the subunits disrupt the lipid bilayer and lead the targeted cells to lysis and die. Subunits show citotoxity only after forming a pore. They don’t kill the cell simply by penetrating it. Molecules on the surface of harmless cells prevent MAC from sticking in (and forming pores), so MAC will only show citotoxity to foreign cells such as bacteria.
+
To achieve a cancer-cell-killing system with high specificity, we first took attention to a mechanism in the human immune system called membrane attack complex (MAC), which operates when bacteria infect our body. In the system of MAC, subunits penetrate the membrane, oligomerize, and form a pore into the bacteria membrane. Then the subunits disrupt the lipid bilayer, inducing targeted cells lysis and deathThe point of this system is that the subunits show citotoxity only after forming a pore. MAC do not kill the cell simply by penetration, as molecules on the surface of harmless cells prevent MAC from sticking in (and forming pores). Therefore, MAC will only show citotoxity to foreign cells such as bacteria.
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      We decided to kill the (cancer) cells. But the natural cancer-recognition is far more complicated than referred above, in which a lot of molecules are related. So we had to device artificial approach for the cancer-recognition system. Actually, there is a research that tries to develop pore-forming proteins like MAC <span class="ref-sup"><a href="#proref-1">[1]</a></span>,but in that research they could not reach the point of discrimination.
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In fact, the natural cancer-recognition is far more complicated than referred above, in which a lot of molecules are related. So it is much difficult to mimic the whole system, leading us to take a simple synthetic biological approach.
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      Then, we thought about using DNA for recognition system. In situ computation by DNA was reported in <i>Nature Nanotechnology</i>(Maria Rudchenko et al.(2013)).
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In the previous study, Rausch et al. used peptides to develop pore-forming proteins like MAC <span class="ref-sup"><a href="#proref-1">[1]</a></span>,but in that research they could not recognize the specific cells. To achieve the recognition system, we thought about to use DNA. Recently, in situ computation by DNA was reported (Maria Rudchenko et al. (2013)).<span class="ref-sup"><a href="#proref-2">[2]</a></span> In that study, DNA was used as logic circuits: using surface antigens as inputs and generating DNA strands as outputs. Rudchenko et al. said that it may be possible to use their logic circuit for other self assembling systems and DNA machinery. We, therefore, thought that it might be possible to make cancer-recognition system using DNA.
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      <span class="ref-sup"><a href="#proref-2">[2]</a></span>
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      DNA was used as logic circuits which uses surface antigens as inputs and generates DNA strands as outputs. They said it may be possible to use this logic circuit for other self assembling systems and DNA machinery. By using DNA, we thought we can make cancer-recognition system.
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      Therefore, our general idea is explained as follows. Subunits stick in normal and cancer cells nonspecifically. Then only when cancer-specific antigens are expressed, DNA computing circuit puts out certain DNA strand. And this strand triggers oligomerization of the subunits and citotoxity is induced. To control oligomerization by DNA strand, we think several mechanisms. For example, using output strand in the toehold system
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Our general idea is explained as follows. 1) Subunits stick in normal and cancer cells nonspecifically. 2) In case of cancer-specific antigens are existed, DNA computing circuit puts out certain DNA strand. 3) And this strand triggers oligomerization of the subunits (e.g. connecting subunits by hybridization), and cytotoxicity is induced to the cancer cell. Overall, our subunits may oligomerize only on the cancer cells and kill only cancer cells.
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      <span class="ref-sup"><a href="#proref-3">[3]</a></span>
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      that triggers hyblidization of subunits. Overall, subunits oligomerize only on the cancer cells and kill only cancer cells. We believe that our Oligomeric Cell Killer has the potential to treat cancer and other diseases like infection, and as the basis of DNA origami robotic system in which multiple molecules coordinate according to logic computation performed by DNA itself.
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DNA itself has information embedded in the sequence. Using DNA computation and DNA-protein hybrid system, in which multiple molecules coordinate, we believe that our “Oligomeric Cell Killer" has the potential to treat cancer and other diseases like infection.
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      Our general idea can be divided into two steps, <span style="color:#e00000">cancer-recognition</span> and <span style="color:#e00000;">killing</span>. DNA computing circuit for recognition was developed in the past research<span class="ref-sup"><a href="#proref-2">[2]</a></span>, so we set the goal of the biomod 2013 <span style="font-weight:bolder;color:#e00000;">the development of pore-forming DNA origami for the killing system</span>. To achieve this goal, we thought about biomolecular robotic system named as Oligomeric Cell Killer explained in  
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Our general idea can be divided into two steps, <span style="color:#e00000">cancer-recognition</span> and <span style="color:#e00000;">killing</span>. Since DNA computing circuit for recognition has already reported, we set our summer goal of the biomod 2013 <span style="color:#e00000">to develop pore-forming DNA origami for the killing system</span>. To achieve this goal, we thought about biomolecular robotic system named as “Oligomeric Cell Killer" explained in <a target="_blank" href="http://openwetware.org/wiki/Biomod/2013/Todai/Design" style="color:#e00000">
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      <a target="_blank" href="http://openwetware.org/wiki/Biomod/2013/Todai/Design"  
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       the Design page
       the Design page
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       We can divide the project goal <b>"the development of pore-forming DNA origami for the killing system"</b> into following five steps.
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       We can divide the project goal into following five steps.
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       <li>DNA strands assemble to form designed structures.</li>
       <li>DNA strands assemble to form designed structures.</li>
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       <li>The formed subunits oligomerize in the solution.</li>
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       <li>The formed subunits oligomerize in solution.</li>
       <li>Subunits stick in the membrane.</li>
       <li>Subunits stick in the membrane.</li>
       <li>Subunits oligomerize on the membrane.</li>
       <li>Subunits oligomerize on the membrane.</li>
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       <span style="color:#e00000">However</span>,
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       As a first step toward our goal, we started with simple DNA origami structure: <a target="_blank"
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      our project remains still very complicated and before actually using Oligomeric Cell Killer in the experiments, we should know what conditions should be set. So we also designed
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      <a target="_blank"
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       href="http://openwetware.org/wiki/Biomod/2013/Todai/Design#2.Cylinder in barrel by DNA origami">
       href="http://openwetware.org/wiki/Biomod/2013/Todai/Design#2.Cylinder in barrel by DNA origami">
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       <span style="color:#e00000">Cylinder in barrel by DNA origami as the simple model of Oligomeric Cell Killer</span></a>,
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       <span style="color:#e00000">Cylinder in Barrel.</span></a>,
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      and perform experiments referred above with it <span style="color:#e00000">first</span>.
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        <a name="proref-3">
 
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        [3] Transcription Regulation System Mediated by Mechanical Operation of a DNA Nanostructure
 
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          Masayuki Endo, Ryoji Miyazaki, Tomoko Emura, Kumi Hidaka, and Hiroshi Sugiyama
 
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              Journal of the American Chemical Society 2012 134 (6), 2852-2855
 
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Revision as of 05:35, 31 August 2013


Project-Todai nanORFEVRE-

 Project


 Background and problem




Cancer is one of the most common diseases in the world. Cancer cells divide abnormally and grow uncontrollably, resulting in the formation of malignant tumors, and invading human body. Cancer causes about 13 percent of the all human deaths worldwide (WHO 2007).






Chemotherapy is a popular medical treatments for the cancer, however, it often attacks normal cells in addition to the cancer cells, damaging normal tissue and organs, which cause severe side effects. According to the American cancer society, these side effects include pain, vomiting, limphedemia, sexual decline and various symptoms, which seriously decrease quality of life.








To improve cancer-specificity, drug delivery system (DDS) has developed, but it is difficult to optimize a delivery system for each drug.











Team Todai nanORFEVRE are trying to make cancer-specific drug which doesn’t need delivery system(DDS).





 Solution


To achieve a cancer-cell-killing system with high specificity, we first took attention to a mechanism in the human immune system called membrane attack complex (MAC), which operates when bacteria infect our body. In the system of MAC, subunits penetrate the membrane, oligomerize, and form a pore into the bacteria membrane. Then the subunits disrupt the lipid bilayer, inducing targeted cells lysis and deathThe point of this system is that the subunits show citotoxity only after forming a pore. MAC do not kill the cell simply by penetration, as molecules on the surface of harmless cells prevent MAC from sticking in (and forming pores). Therefore, MAC will only show citotoxity to foreign cells such as bacteria.     


In fact, the natural cancer-recognition is far more complicated than referred above, in which a lot of molecules are related. So it is much difficult to mimic the whole system, leading us to take a simple synthetic biological approach.


In the previous study, Rausch et al. used peptides to develop pore-forming proteins like MAC [1],but in that research they could not recognize the specific cells. To achieve the recognition system, we thought about to use DNA. Recently, in situ computation by DNA was reported (Maria Rudchenko et al. (2013)).[2] In that study, DNA was used as logic circuits: using surface antigens as inputs and generating DNA strands as outputs. Rudchenko et al. said that it may be possible to use their logic circuit for other self assembling systems and DNA machinery. We, therefore, thought that it might be possible to make cancer-recognition system using DNA.



Our general idea is explained as follows. 1) Subunits stick in normal and cancer cells nonspecifically. 2) In case of cancer-specific antigens are existed, DNA computing circuit puts out certain DNA strand. 3) And this strand triggers oligomerization of the subunits (e.g. connecting subunits by hybridization), and cytotoxicity is induced to the cancer cell. Overall, our subunits may oligomerize only on the cancer cells and kill only cancer cells.

DNA itself has information embedded in the sequence. Using DNA computation and DNA-protein hybrid system, in which multiple molecules coordinate, we believe that our “Oligomeric Cell Killer" has the potential to treat cancer and other diseases like infection.





 Project Goals

Our general idea can be divided into two steps, cancer-recognition and killing. Since DNA computing circuit for recognition has already reported, we set our summer goal of the biomod 2013 to develop pore-forming DNA origami for the killing system. To achieve this goal, we thought about biomolecular robotic system named as “Oligomeric Cell Killer" explained in the Design page .


We can divide the project goal into following five steps.


  • DNA strands assemble to form designed structures.
  • The formed subunits oligomerize in solution.
  • Subunits stick in the membrane.
  • Subunits oligomerize on the membrane.
  • Subunits form the pore and kill the cell.

As a first step toward our goal, we started with simple DNA origami structure: Cylinder in Barrel.,




 References


Joshua M. Rausch, Jessica R. Marks, and William C. Wimley
PNAS 2005 102 (30) 10511-10515; published ahead of print July 14, 2005, doi:10.1073/pnas.0502013102

Maria Rudchenko, Steven Taylor, Payal Pallavi, Alesia Dechkovskaia, Safana Khan, Vincent P. Butler Jr, Sergei Rudchenko & Milan N. Stojanovic
Nature Nanotechnology 8, 580–586 (2013) doi:10.1038/nnano.2013.142








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