{"487441":{"#nid":"487441","#data":{"type":"news","title":"Scientists Demonstrate Basics of Nucleic Acid Computing Inside Cells","body":[{"value":"\u003Cp\u003EUsing strands of nucleic acid, scientists have demonstrated basic computing operations inside a living mammalian cell. The research could lead to an artificial sensing system that could control a cell\u2019s behavior in response to such stimuli as the presence of toxins or the development of cancer.\u003C\/p\u003E\u003Cp\u003EThe research uses DNA strand displacement, a technology that has been widely used outside of cells for the design of molecular circuits, motors and sensors. Researchers modified the process to provide both \u201cAND\u201d and \u201cOR\u201d logic gates able to operate inside the living cells and interact with native messenger RNA (mRNA).\u003C\/p\u003E\u003Cp\u003EThe tools they developed could provide a foundation for bio-computers able to sense, analyze and modulate molecular information at the cellular level. Supported by the Defense Advanced Research Projects Agency (DARPA) and the National Science Foundation (NSF), the research was reported December 21 in the journal \u003Cem\u003ENature Nanotechnology\u003C\/em\u003E.\u003C\/p\u003E\u003Cp\u003E\u201cThe whole idea is to be able to take the logic that is used in computers and port that logic into cells themselves,\u201d said \u003Ca href=\u0022https:\/\/www.bme.gatech.edu\/bme\/faculty\/Philip-Santangelo\u0022\u003EPhilip Santangelo\u003C\/a\u003E, an associate professor in the \u003Ca href=\u0022https:\/\/www.bme.gatech.edu\/\u0022\u003EWallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University\u003C\/a\u003E. \u201cThese devices could sense an aberrant RNA, for instance, and then shut down cellular translation or induce cell death.\u201d\u003C\/p\u003E\u003Cp\u003EStrand displacement reactions are the biological equivalent of the switches or gates that form the foundation for silicon-based computing. They can be programmed to turn on or off in response to an external stimuli such as a molecule. An \u201cAND\u201d gate, for example, would switch when both conditions were met, while an \u201cOR\u201d gate would switch when either condition was met.\u003C\/p\u003E\u003Cp\u003EIn the switches the researchers used, a fluorophore reporter molecule and its complementary quenching molecule were placed side-by-side to create an \u201coff\u201d mode. Binding of RNA in one of the strands then displaced a portion of nucleic acid, separating the molecules and allowing generation of a signal that created an \u201con\u201d mode. Two \u201con\u201d modes on adjacent nucleic acid strands created an \u201cAND\u201d gate.\u003C\/p\u003E\u003Cp\u003E\u201cDemonstrating individual logic gates is only a first step,\u201d said Georg Seelig, assistant professor of computer science and engineering and electrical engineering at the University of Washington. \u201cIn the longer term, we want to expand this technology to create circuits with many inputs, such as those we have constructed in cell-free settings.\u201d\u003C\/p\u003E\u003Cp\u003EThe researchers used ligands designed to bind to specific portions of the nucleic acid strands, which can be created as desired and produced by commercial suppliers.\u003C\/p\u003E\u003Cp\u003E\u201cWe sensed molecules and showed that we could respond to them,\u201d said Santangelo. \u201cWe showed that we could utilize native molecules in the cell as part of the circuit, though we haven\u2019t been able to control a cell yet.\u201d\u003C\/p\u003E\u003Cp\u003EGetting basic computing operations to function inside cells was no easy task, and the research required a number of years to accomplish. Among the challenges were getting the devices into the cells without triggering the switches, providing operation rapid enough to be useful, and not killing the human cell lines that researchers used in the lab.\u003C\/p\u003E\u003Cp\u003E\u201cWe had to chemically change the probes to get them to work inside the cell and to make them stable enough inside the cells,\u201d said Santangelo. \u201cWe found that these strand displacement reactions can be slow within the cytosol, so to get them to work faster, we built scaffolding onto the messenger RNA that allowed us to amplify the effects.\u201d\u003C\/p\u003E\u003Cp\u003EThe nucleic acid computers ultimately operated as desired, and the next step is to use their switching to trigger the production of signaling chemicals that would prompt the desired reaction from the cells. Cellular activity is normally controlled by the production of proteins, so the nucleic acid switches will have to be given the ability to produce enough signaling molecules to induce a change.\u003C\/p\u003E\u003Cp\u003E\u201cWe need to generate enough of whatever final signal is needed to get the cell to react,\u201d Santangelo explained. \u201cThere are amplification methods used in strand displacement technology, but none of them have been used so far in living cells.\u201d\u003C\/p\u003E\u003Cp\u003EEven without that final step, the researchers feel they\u2019ve built a foundation that can be used to attain the goal.\u003C\/p\u003E\u003Cp\u003E\u201cWe were able to design some of the basic logical constructs that could be used as building blocks for future work,\u201d Santangelo said. \u201cWe know the concentrations of chemicals and the design requirements for individual components, so we can now start putting together a more complicated set of circuits and components.\u201d\u003C\/p\u003E\u003Cp\u003ECells, of course, already know how to sense toxic molecules and the development malignant tendencies, and to then take action. But those safeguards can be turned off by viruses or cancer cells that know how to circumvent natural cellular processes.\u003C\/p\u003E\u003Cp\u003E\u201cOur mechanism would just give cells a hand at doing this,\u201d Santangelo said. \u201cThe idea is to add to the existing machinery to give the cells enhanced capabilities.\u201d\u003C\/p\u003E\u003Cp\u003EApplying an engineering approach to the biological world sets this example apart from other efforts to control cellular machinery.\u003C\/p\u003E\u003Cp\u003E\u201cWhat makes DNA strand displacement circuits unique is that all components are fully rationally designed at the level of the DNA sequence,\u201d said Seelig. \u201cThis really makes this technology ideal for an engineering approach. In contrast, many other approaches to controlling the cellular machinery rely on components that are borrowed from biology and are not fully understood.\u201d\u003C\/p\u003E\u003Cp\u003EBeyond those already mentioned, the research team included Benjamin Groves, Yuan-Jyue Chen and Sergii Pochekailov from the University of Washington and Chiara Zurla and Jonathan Kirschman from Georgia Tech and Emory University.\u003C\/p\u003E\u003Cp\u003E\u003Cem\u003EThis material is based on work supported by the Defense Advanced Research Projects Agency (DARPA) under contract W911NF-11-2-0068 and by National Science Foundation CAREER award 1253691. The content is solely the responsibility of the authors and does not necessarily represent the official views of DARPA or the NSF.\u003C\/em\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003ECITATION\u003C\/strong\u003E: Benjamin Groves, et al., \u201cComputing in mammalian cells with nucleic acid strand exchange,\u201d (Nature Nanotechnology, 2015). \u003Ca href=\u0022http:\/\/dx.doi.org\/10.1038\/nnano.2015.278\u0022\u003Ehttp:\/\/dx.doi.org\/10.1038\/nnano.2015.278\u003C\/a\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EResearch News\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003EGeorgia Institute of Technology\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003E177 North Avenue\u003C\/strong\u003E\u003Cbr \/\u003E\u003Cstrong\u003EAtlanta, Georgia 30332-0181 USA\u003C\/strong\u003E\u003C\/p\u003E\u003Cp\u003E\u003Cstrong\u003EMedia Relations Contact\u003C\/strong\u003E: John Toon (404-894-6986) (\u003Ca href=\u0022mailto:joon@gatech.edu\u0022\u003Ejoon@gatech.edu\u003C\/a\u003E).\u003Cbr \/\u003E\u003Cstrong\u003EWriter\u003C\/strong\u003E: John Toon\u003C\/p\u003E","summary":null,"format":"limited_html"}],"field_subtitle":"","field_summary":[{"value":"\u003Cp\u003EUsing strands of nucleic acid, scientists have demonstrated basic computing operations inside a living mammalian cell. The research could lead to an artificial sensing system that could control a cell\u2019s behavior in response to such stimuli as the presence of toxins or the development of cancer.\u003C\/p\u003E","format":"limited_html"}],"field_summary_sentence":[{"value":"Using strands of nucleic acid, scientists have demonstrated basic computing operations inside a living mammalian cell."}],"uid":"27303","created_gmt":"2016-01-18 12:32:07","changed_gmt":"2016-10-08 03:20:24","author":"John Toon","boilerplate_text":"","field_publication":"","field_article_url":"","dateline":{"date":"2016-01-19T00:00:00-05:00","iso_date":"2016-01-19T00:00:00-05:00","tz":"America\/New_York"},"extras":[],"hg_media":{"487431":{"id":"487431","type":"image","title":"Studying gate in nucleic acid computing","body":null,"created":"1453233601","gmt_created":"2016-01-19 20:00:01","changed":"1475895242","gmt_changed":"2016-10-08 02:54:02","alt":"Studying gate in nucleic acid computing","file":{"fid":"204350","name":"and-gate.jpg","image_path":"\/sites\/default\/files\/images\/and-gate_0.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/and-gate_0.jpg","mime":"image\/jpeg","size":536890,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/and-gate_0.jpg?itok=8fEVDG18"}},"487411":{"id":"487411","type":"image","title":"Studying nucleic acid computing","body":null,"created":"1453233601","gmt_created":"2016-01-19 20:00:01","changed":"1475895242","gmt_changed":"2016-10-08 02:54:02","alt":"Studying nucleic acid computing","file":{"fid":"204348","name":"nucleic-acid-003.jpg","image_path":"\/sites\/default\/files\/images\/nucleic-acid-003_1.jpg","image_full_path":"http:\/\/www.tlwarc.hg.gatech.edu\/\/sites\/default\/files\/images\/nucleic-acid-003_1.jpg","mime":"image\/jpeg","size":1277759,"path_740":"http:\/\/www.tlwarc.hg.gatech.edu\/sites\/default\/files\/styles\/740xx_scale\/public\/images\/nucleic-acid-003_1.jpg?itok=NATPg55U"}}},"media_ids":["487431","487411"],"groups":[{"id":"1188","name":"Research Horizons"}],"categories":[{"id":"140","name":"Cancer Research"},{"id":"141","name":"Chemistry and Chemical Engineering"},{"id":"153","name":"Computer Science\/Information Technology and Security"},{"id":"146","name":"Life Sciences and Biology"},{"id":"135","name":"Research"}],"keywords":[{"id":"169826","name":"DNA strand displacement"},{"id":"171582","name":"molecular circuits"},{"id":"169827","name":"nucleic acid"},{"id":"169828","name":"nucleic acid computing"},{"id":"13850","name":"Philip Santangelo"}],"core_research_areas":[{"id":"39441","name":"Bioengineering and Bioscience"},{"id":"39451","name":"Electronics and Nanotechnology"}],"news_room_topics":[{"id":"71881","name":"Science and Technology"}],"event_categories":[],"invited_audience":[],"affiliations":[],"classification":[],"areas_of_expertise":[],"news_and_recent_appearances":[],"phone":[],"contact":[{"value":"\u003Cp\u003EJohn Toon\u003C\/p\u003E\u003Cp\u003EResearch News\u003C\/p\u003E\u003Cp\u003E\u003Ca href=\u0022mailto:jtoon@gatech.edu\u0022\u003Ejtoon@gatech.edu\u003C\/a\u003E\u003C\/p\u003E\u003Cp\u003E(404) 894-6986\u003C\/p\u003E","format":"limited_html"}],"email":["jtoon@gatech.edu"],"slides":[],"orientation":[],"userdata":""}}}