Mitsandbox

From 2012.igem.org

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<h3>In Vivo Molecular Computation Using RNA Strand Displacement in Mammalian Cells</h3>
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<h3>Tissues by Design</h3>
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<p>Our project focuses on tissue self-construction to achieve specific patterns of cell differentiation (initially with fluorescence, ultimately with cell fate regulators) with genetic circuits. To accomplish this, we focused on three components: cell-cell communication pathways, intracellular information processing circuits, and cell-cell adhesion. Through engineered control of these mechanisms, we are investigating how programmed local rules of interactions between cells can lead to the emergence of desired global patternings.</p>
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Imagine being able to diagnose and destroy diseased cells using RNA. This can be accomplished by using RNA strand displacement cascades that recognize certain mammalian cell-specific biomarkers, such as characteristic mRNA strands or metabolites, use these as abstract inputs to digital logic gates, and then yield a wide array of desired outputs.
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<p><img src="https://static.igem.org/mediawiki/2011/5/51/Simulation.jpg" style="max-width:800px; margin-right:10px;"/></p></br>
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<p>Above is the result of a simulation run, starting with undifferentiated cells and ending with a pattern.</p>
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We propose a new method of implementing the paradigms of sensing, processing, and actuation inside mammalian cells by applying the mechanism of DNA strand displacement from the field of nucleic acid computation to RNA. Traditional synthetic biology approaches seem to have hit a barrier in terms of the number of regulatory components that can be used predictably and reliably, limiting the complexity of cellular circuits.
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<p>Specifically, for cell-cell signaling, we developed a modular juxtacrine platform, using Notch and Delta proteins. For intracellular information processing circuits, as a proof of concept, we build a 2-input AND gate. For cell-cell adhesion, the final output of our system, we used cadherin.
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Below is an animation depicting our project components. The cell-cell signaling of Notch-Delta interaction leads to the cleavage of the Notch intracellular domain, which enters the nucleus and after logic processing, expresses cadherins, which cause cells to adhere to similarly expressing cells.
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On the other hand, the strand displacement method of molecular computing within mammalian cells is highly modular, scalable, and orthogonal. We have demonstrated that RNA can be used as a processing medium, and have proposed novel in vivo NOT gates, which along with AND and OR gates can directly be produced inside mammalian cells. Currently, we are developing modeling platforms to explore kinetics of strand displacement reactions in vivo, as well as designing actuation systems that allow the RNA logic to interface with a variety of protein outputs.
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<div align="center"><iframe width="400" height="300" src="http://www.youtube.com/embed/rGOB0gMxf_8" frameborder="0" allowfullscreen></iframe></div>
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We developed software tools to model the behavior of our system. Below is a sample of a simulation of cells with genetic circuits and how they differentiate.
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Our integrated approach can fundamentally impact the fields of biological engineering, biomedical engineering, and medical diagnostics.  
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<div align="center"><iframe width="400" height="300" src="http://www.youtube.com/embed/dbz4VegsJOw?rel=0&amp;hd=1" frameborder="0" allowfullscreen></iframe>
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Latest revision as of 15:17, 9 August 2012

In Vivo Molecular Computation Using RNA Strand Displacement in Mammalian Cells

Imagine being able to diagnose and destroy diseased cells using RNA. This can be accomplished by using RNA strand displacement cascades that recognize certain mammalian cell-specific biomarkers, such as characteristic mRNA strands or metabolites, use these as abstract inputs to digital logic gates, and then yield a wide array of desired outputs.



We propose a new method of implementing the paradigms of sensing, processing, and actuation inside mammalian cells by applying the mechanism of DNA strand displacement from the field of nucleic acid computation to RNA. Traditional synthetic biology approaches seem to have hit a barrier in terms of the number of regulatory components that can be used predictably and reliably, limiting the complexity of cellular circuits.



On the other hand, the strand displacement method of molecular computing within mammalian cells is highly modular, scalable, and orthogonal. We have demonstrated that RNA can be used as a processing medium, and have proposed novel in vivo NOT gates, which along with AND and OR gates can directly be produced inside mammalian cells. Currently, we are developing modeling platforms to explore kinetics of strand displacement reactions in vivo, as well as designing actuation systems that allow the RNA logic to interface with a variety of protein outputs.



Our integrated approach can fundamentally impact the fields of biological engineering, biomedical engineering, and medical diagnostics.


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