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DNA computing
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==Methods== There are multiple methods for building a computing device based on DNA, each with its own advantages and disadvantages. Most of these build the basic logic gates ([[Logical AND|AND]], [[Logical OR|OR]], [[Logical NOT|NOT]]) associated with [[digital logic]] from a DNA basis. Some of the different bases include DNAzymes, [[oligonucleotide|deoxyoligonucleotides]], enzymes, and toehold exchange. === Strand displacement mechanisms === The most fundamental operation in DNA computing and molecular programming is the strand displacement mechanism. Currently, there are two ways to perform strand displacement: * [[Toehold mediated strand displacement]] (TMSD)<ref name=":5" /> * Polymerase-based strand displacement (PSD)<ref name=":0" /> === Toehold exchange === Besides simple strand displacement schemes, DNA computers have also been constructed using the concept of toehold exchange.<ref name=":4" /> In this system, an input DNA strand binds to a [[sticky end]], or toehold, on another DNA molecule, which allows it to displace another strand segment from the molecule. This allows the creation of modular logic components such as AND, OR, and NOT gates and signal amplifiers, which can be linked into arbitrarily large computers. This class of DNA computers does not require enzymes or any chemical capability of the DNA.<ref>{{Cite journal|last1=Seelig|first1=G.|last2=Soloveichik|first2=D.|last3=Zhang|first3=D. Y.|last4=Winfree|first4=E.|s2cid=10966324|date=8 December 2006|title=Enzyme-free nucleic acid logic circuits|journal=Science|volume=314|issue=5805|pages=1585β1588|bibcode=2006Sci...314.1585S|doi=10.1126/science.1132493|pmid=17158324|url=https://authors.library.caltech.edu/22753/2/DNA_logic_circuits2006_supp.pdf}}</ref> === Chemical reaction networks (CRNs) === The full stack for DNA computing looks very similar to a traditional computer architecture. At the highest level, a C-like general purpose programming language is expressed using a set of [[Chemical reaction networks|chemical reaction networks (CRNs)]]. This intermediate representation gets translated to domain-level DNA design and then implemented using a set of DNA strands. In 2010, Erik Winfree's group showed that DNA can be used as a substrate to implement arbitrary chemical reactions. This opened the way to design and synthesis of biochemical controllers since the expressive power of CRNs is equivalent to a Turing machine.<ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /> Such controllers can potentially be used ''in vivo'' for applications such as preventing hormonal imbalance. ===DNAzymes=== Catalytic DNA ([[deoxyribozyme]] or DNAzyme) catalyze a reaction when interacting with the appropriate input, such as a matching [[oligonucleotide]]. These DNAzymes are used to build logic gates analogous to digital logic in silicon; however, DNAzymes are limited to one-, two-, and three-input gates with no current implementation for evaluating statements in series. The DNAzyme logic gate changes its structure when it binds to a matching oligonucleotide and the fluorogenic substrate it is bonded to is cleaved free. While other materials can be used, most models use a fluorescence-based substrate because it is very easy to detect, even at the single molecule limit.<ref name="weiss"> {{Cite journal | last1 = Weiss | first1 = S. | s2cid = 9697423 | title = Fluorescence Spectroscopy of Single Biomolecules | doi = 10.1126/science.283.5408.1676 | journal = Science | volume = 283 | issue = 5408 | pages = 1676β1683 | year = 1999 | pmid = 10073925|bibcode = 1999Sci...283.1676W }}. Also available here: http://www.lps.ens.fr/~vincent/smb/PDF/weiss-1.pdf </ref> The amount of fluorescence can then be measured to tell whether or not a reaction took place. The DNAzyme that changes is then "used", and cannot initiate any more reactions. Because of this, these reactions take place in a device such as a continuous stirred-tank reactor, where old product is removed and new molecules added. Two commonly used DNAzymes are named E6 and 8-17. These are popular because they allow cleaving of a substrate in any arbitrary location.<ref> {{Cite journal |last1=Santoro |first1=S. W. |last2=Joyce |first2=G. F. |year=1997 |title=A general purpose RNA-cleaving DNA enzyme |journal=Proceedings of the National Academy of Sciences |volume=94 |issue=9 |pages=4262β4266 |bibcode=1997PNAS...94.4262S |doi=10.1073/pnas.94.9.4262 |pmc=20710 |pmid=9113977 |doi-access=free}}. Also available here: [http://www.pnas.org/content/94/9/4262.full.pdf] </ref> Stojanovic and MacDonald have used the E6 DNAzymes to build the [[MAYA I]]<ref> {{Cite journal |last1=Stojanovic |first1=M. N. |last2=Stefanovic |first2=D. |year=2003 |title=A deoxyribozyme-based molecular automaton |journal=Nature Biotechnology |volume=21 |issue=9 |pages=1069β1074 |doi=10.1038/nbt862 |pmid=12923549 |s2cid=184520}}. Also available here: [https://web.archive.org/web/20120401132040/http://www.cs.duke.edu/courses/cps296.6/current/papers/SS03.pdf] </ref> and [[MAYA II]]<ref> {{Cite journal |last1=MacDonald |first1=J. |last2=Li |first2=Y. |last3=Sutovic |first3=M. |last4=Lederman |first4=H. |last5=Pendri |first5=K. |last6=Lu |first6=W. |last7=Andrews |first7=B. L. |last8=Stefanovic |first8=D. |last9=Stojanovic |first9=M. N. |year=2006 |title=Medium Scale Integration of Molecular Logic Gates in an Automaton |journal=Nano Letters |volume=6 |issue=11 |pages=2598β2603 |bibcode=2006NanoL...6.2598M |doi=10.1021/nl0620684 |pmid=17090098}}. Also available here: [http://www.ece.gatech.edu/research/labs/bwn/nanos/papers/Medium_Scale_Integration_of_Molecular.pdf] </ref> machines, respectively; Stojanovic has also demonstrated logic gates using the 8-17 DNAzyme.<ref> {{Cite journal |last1=Stojanovic |first1=M. N. |last2=Mitchell |first2=T. E. |last3=Stefanovic |first3=D. |year=2002 |title=Deoxyribozyme-Based Logic Gates |url=https://figshare.com/articles/Deoxyribozyme-Based_Logic_Gates/3638808 |journal=Journal of the American Chemical Society |volume=124 |issue=14 |pages=3555β3561 |doi=10.1021/ja016756v |pmid=11929243|bibcode=2002JAChS.124.3555S }}. Also available at [http://www.dna.caltech.edu/courses/cs191/paperscs191/stojanovic_mitchell_stefanovic2002.pdf] </ref> While these DNAzymes have been demonstrated to be useful for constructing logic gates, they are limited by the need of a metal cofactor to function, such as Zn<sup>2+</sup> or Mn<sup>2+</sup>, and thus are not useful [[in vivo]].<ref name="weiss" /><ref> {{Cite journal | last1 = Cruz | first1 = R. P. G. | last2 = Withers | first2 = J. B. | last3 = Li | first3 = Y. | title = Dinucleotide Junction Cleavage Versatility of 8-17 Deoxyribozyme | doi = 10.1016/j.chembiol.2003.12.012 | journal = Chemistry & Biology | volume = 11 | issue = 1 | pages = 57β67 | year = 2004 | pmid = 15112995| doi-access = free | hdl = 11375/23673 | hdl-access = free }} </ref> A design called a ''stem loop'', consisting of a single strand of DNA which has a loop at an end, are a dynamic structure that opens and closes when a piece of DNA bonds to the loop part. This effect has been exploited to create several [[logic gate]]s. These logic gates have been used to create the computers MAYA I and [[MAYA II]] which can play [[tic-tac-toe]] to some extent.<!-- --><ref>Darko Stefanovic's Group, [https://digamma.cs.unm.edu/wiki/bin/view/McogPublicWeb/MolecularLogicGates Molecular Logic Gates] {{Webarchive|url=https://web.archive.org/web/20100618033006/https://digamma.cs.unm.edu/wiki/bin/view/McogPublicWeb/MolecularLogicGates |date=2010-06-18 }} and [https://digamma.cs.unm.edu/wiki/bin/view/McogPublicWeb/MolecularAutomataMAYAII MAYA II, a second-generation tic-tac-toe playing automaton] {{Webarchive|url=https://web.archive.org/web/20100618001044/https://digamma.cs.unm.edu/wiki/bin/view/McogPublicWeb/MolecularAutomataMAYAII |date=2010-06-18 }}.</ref> ===Enzymes=== Enzyme-based DNA computers are usually of the form of a simple [[Turing machine]]; there is analogous hardware, in the form of an enzyme, and software, in the form of DNA.<ref>{{cite journal | last = Shapiro | first = Ehud | author-link = Ehud Shapiro | title = A Mechanical Turing Machine: Blueprint for a Biomolecular Computer | journal = Interface Focus | publisher = [[Weizmann Institute of Science]] | date = 1999-12-07 | volume = 2 | issue = 4 | pages = 497β503 | url = http://www.wisdom.weizmann.ac.il/~udi/DNA5/scripps_short/index.htm | doi = 10.1098/rsfs.2011.0118| pmid = 22649583 | pmc = 3363030 | archive-url=https://web.archive.org/web/20090103224150/http://www.wisdom.weizmann.ac.il/~udi/DNA5/scripps_short/index.htm |archive-date=2009-01-03 | access-date = 2009-08-13 }}</ref> Benenson, Shapiro and colleagues have demonstrated a DNA computer using the [[FokI]] enzyme<ref name="shapiro">{{Cite journal |last1=Benenson |first1=Y. |last2=Paz-Elizur |first2=T. |last3=Adar |first3=R. |last4=Keinan |first4=E. |last5=Livneh |first5=Z. |last6=Shapiro |first6=E. |year=2001 |title=Programmable and autonomous computing machine made of biomolecules |journal=Nature |volume=414 |issue=6862 |pages=430β434 |bibcode=2001Natur.414..430B |doi=10.1038/35106533 |pmc=3838952 |pmid=11719800}}. Also available here: [http://www.technion.ac.il/~keinanj/pub/110.pdf] {{Webarchive|url=https://web.archive.org/web/20120510194658/http://www.technion.ac.il/~keinanj/pub/110.pdf|date=2012-05-10}}</ref> and expanded on their work by going on to show automata that diagnose and react to [[prostate cancer]]: under expression of the genes [[PPAP2B]] and [[GSTP1]] and an over expression of [[PIM1]] and [[HPN (gene)|HPN]].<ref name="shapiro_cancer">{{Cite journal|last1=Benenson|first1=Y.|last2=Gil|first2=B.|last3=Ben-Dor|first3=U.|last4=Adar|first4=R.|last5=Shapiro|first5=E.|year=2004|title=An autonomous molecular computer for logical control of gene expression|journal=Nature|volume=429|issue=6990|pages=423β429|bibcode=2004Natur.429..423B|doi=10.1038/nature02551|pmc=3838955|pmid=15116117}}. Also available here: [https://web.archive.org/web/20131023055858/http://www.wisdom.weizmann.ac.il/~udi/papers/automoleculcomp_nat04.pdf An autonomous molecular computer for logical control of gene expression]</ref> Their automata evaluated the expression of each gene, one gene at a time, and on positive diagnosis then released a single strand DNA molecule (ssDNA) that is an antisense for [[MDM2]]. MDM2 is a repressor of [[p53|protein 53]], which itself is a tumor suppressor.<ref> {{Cite journal | last1 = Bond | first1 = G. L. | last2 = Hu | first2 = W. | last3 = Levine | first3 = A. J. | doi = 10.2174/1568009053332627 | title = MDM2 is a Central Node in the p53 Pathway: 12 Years and Counting | journal = [[Current Cancer Drug Targets]] | volume = 5 | issue = 1 | pages = 3β8 | year = 2005 | pmid = 15720184}} </ref> On negative diagnosis it was decided to release a suppressor of the positive diagnosis drug instead of doing nothing. A limitation of this implementation is that two separate automata are required, one to administer each drug. The entire process of evaluation until drug release took around an hour to complete. This method also requires transition molecules as well as the FokI enzyme to be present. The requirement for the FokI enzyme limits application ''in vivo'', at least for use in "cells of higher organisms".<ref name="kahan08"> {{Cite journal |last1=Kahan |first1=M. |last2=Gil |first2=B. |last3=Adar |first3=R. |last4=Shapiro |first4=E. |year=2008 |title=Towards molecular computers that operate in a biological environment |journal=Physica D: Nonlinear Phenomena |volume=237 |issue=9 |pages=1165β1172 |bibcode=2008PhyD..237.1165K |doi=10.1016/j.physd.2008.01.027}}. Also available here: [http://www.ece.gatech.edu/research/labs/bwn/nanos/papers/Towards_molecular_computers_that_operate_in_a_biological_environment.pdf] </ref> It should also be pointed out that the 'software' molecules can be reused in this case. === Algorithmic self-assembly === [[Image:Rothemund-DNA-SierpinskiGasket.jpg|thumb|DNA arrays that display a representation of the [[Sierpinski gasket]] on their surfaces. Click the image for further details. Image from Rothemund ''et al.'', 2004.<ref name="rothemund04winfree" />]] {{Main|DNA nanotechnology#Algorithmic self-assembly|l1 = DNA nanotechnology: Algorithmic self-assembly}} DNA nanotechnology has been applied to the related field of DNA computing. DNA tiles can be designed to contain multiple sticky ends with sequences chosen so that they act as [[Wang tile]]s. A DX array has been demonstrated whose assembly encodes an [[Exclusive or|XOR]] operation; this allows the DNA array to implement a [[cellular automaton]] which generates a [[fractal]] called the [[Sierpinski gasket]]. This shows that computation can be incorporated into the assembly of DNA arrays, increasing its scope beyond simple periodic arrays.<!-- --><ref name="rothemund04winfree">{{Cite journal | last1 = Rothemund | first1 = P. W. K. | last2 = Papadakis | first2 = N. | last3 = Winfree | first3 = E. | doi = 10.1371/journal.pbio.0020424 | title = Algorithmic Self-Assembly of DNA Sierpinski Triangles | journal = PLOS Biology | volume = 2 | issue = 12 | pages = e424 | year = 2004 | pmid = 15583715| pmc =534809 | doi-access = free }}</ref>
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