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DNA computing is an emerging branch of
unconventional computing Unconventional computing is computing by any of a wide range of new or unusual methods. It is also known as alternative computing. The term ''unconventional computation'' was coined by Cristian S. Calude and John Casti and used at the First In ...
which uses DNA,
biochemistry Biochemistry or biological chemistry is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology and ...
, and
molecular biology Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and phys ...
hardware, instead of the traditional electronic computing. Research and development in this area concerns theory, experiments, and applications of DNA computing. Although the field originally started with the demonstration of a computing application by Len Adleman in 1994, it has now been expanded to several other avenues such as the development of storage technologies, nanoscale imaging modalities, synthetic controllers and reaction networks, etc.


A brief history of DNA computing and molecular programming

Leonard Adleman Leonard Adleman (born December 31, 1945) is an American computer scientist. He is one of the creators of the RSA encryption algorithm, for which he received the 2002 Turing Award, often called the Nobel prize of Computer science. He is also kno ...
of the
University of Southern California , mottoeng = "Let whoever earns the palm bear it" , religious_affiliation = Nonsectarian—historically Methodist , established = , accreditation = WSCUC , type = Private research university , academic_affiliations = , endowment = $8.1 ...
initially developed this field in 1994. — The first DNA computing paper. Describes a solution for the directed
Hamiltonian path problem In the mathematical field of graph theory the Hamiltonian path problem and the Hamiltonian cycle problem are problems of determining whether a Hamiltonian path (a path in an undirected or directed graph that visits each vertex exactly once) or ...
. Also available here:
Adleman demonstrated a proof-of-concept use of DNA as a form of computation which solved the seven-point
Hamiltonian path problem In the mathematical field of graph theory the Hamiltonian path problem and the Hamiltonian cycle problem are problems of determining whether a Hamiltonian path (a path in an undirected or directed graph that visits each vertex exactly once) or ...
. Since the initial Adleman experiments, advances have occurred and various
Turing machine A Turing machine is a mathematical model of computation describing an abstract machine that manipulates symbols on a strip of tape according to a table of rules. Despite the model's simplicity, it is capable of implementing any computer alg ...
s have been proven to be constructible. Since then the field has expanded into several avenues. In 1995, the idea for DNA-based memory was proposed by Eric Baum who conjectured that a vast amount of data can be stored in a tiny amount of DNA due to its ultra-high density. This expanded the horizon of DNA computing into the realm of memory technology although the ''in vitro'' demonstrations were made almost after a decade. The field of DNA computing can be categorized as a sub-field of the broader DNA nanoscience field started b
Ned Seeman
about a decade before Len Adleman's demonstration. Ned's original idea in the 1980s was to build arbitrary structures using bottom-up DNA self-assembly for applications in crystallography. However, it morphed into the field of structural DNA self-assembly which as of 2020 is extremely sophisticated. Self-assembled structure from a few nanometers tall all the way up to several tens of micrometers in size have been demonstrated in 2018. In 1994, Prof. Seeman's group demonstrated early DNA lattice structures using a small set of DNA components. While the demonstration by Adleman showed the possibility of DNA-based computers, the DNA design was trivial because as the number of nodes in a graph grows, the number of DNA components required in Adleman's implementation would grow exponentially. Therefore, computer scientist and biochemists started exploring tile-assembly where the goal was to use a small set of DNA strands as tiles to perform arbitrary computations upon growth. Other avenues that were theoretically explored in the late 90's include DNA-based security and cryptography, computational capacity of DNA systems, DNA memories and disks, and DNA-based robotics. In 2003
John Reif's group
first demonstrated the idea of a DNA-based walker that traversed along a track similar to a line follower robot. They used molecular biology as a source of energy for the walker. Since this first demonstration, a wide variety of DNA-based walkers have been demonstrated.


Applications, examples, and recent developments

In 1994
Leonard Adleman Leonard Adleman (born December 31, 1945) is an American computer scientist. He is one of the creators of the RSA encryption algorithm, for which he received the 2002 Turing Award, often called the Nobel prize of Computer science. He is also kno ...
presented the first prototype of a DNA computer. The TT-100 was a test tube filled with 100 microliters of a DNA solution. He managed to solve an instance of the directed
Hamiltonian path In the mathematical field of graph theory, a Hamiltonian path (or traceable path) is a path in an undirected or directed graph that visits each vertex exactly once. A Hamiltonian cycle (or Hamiltonian circuit) is a cycle that visits each vertex ...
problem. In Adleman's experiment, the Hamiltonian Path Problem was implemented notationally as “
travelling salesman problem The travelling salesman problem (also called the travelling salesperson problem or TSP) asks the following question: "Given a list of cities and the distances between each pair of cities, what is the shortest possible route that visits each cit ...
”. For this purpose, different DNA fragments were created, each one of them representing a city that had to be visited. Every one of these fragments is capable of a linkage with the other fragments created. These DNA fragments were produced and mixed in a
test tube A test tube, also known as a culture tube or sample tube, is a common piece of laboratory glassware consisting of a finger-like length of glass or clear plastic tubing, open at the top and closed at the bottom. Test tubes are usually placed in ...
. Within seconds, the small fragments form bigger ones, representing the different travel routes. Through a chemical reaction, the DNA fragments representing the longer routes were eliminated. The remains are the solution to the problem, but overall, the experiment lasted a week. However, current technical limitations prevent the evaluation of the results. Therefore, the experiment isn't suitable for the application, but it is nevertheless a
proof of concept Proof of concept (POC or PoC), also known as proof of principle, is a realization of a certain method or idea in order to demonstrate its feasibility, or a demonstration in principle with the aim of verifying that some concept or theory has prac ...
.


Combinatorial problems

First results to these problems were obtained by
Leonard Adleman Leonard Adleman (born December 31, 1945) is an American computer scientist. He is one of the creators of the RSA encryption algorithm, for which he received the 2002 Turing Award, often called the Nobel prize of Computer science. He is also kno ...
. * In 1994: Solving a
Hamiltonian path In the mathematical field of graph theory, a Hamiltonian path (or traceable path) is a path in an undirected or directed graph that visits each vertex exactly once. A Hamiltonian cycle (or Hamiltonian circuit) is a cycle that visits each vertex ...
in a graph with 7 summits. * In 2002: Solving a
NP-complete In computational complexity theory, a problem is NP-complete when: # it is a problem for which the correctness of each solution can be verified quickly (namely, in polynomial time) and a brute-force search algorithm can find a solution by trying ...
problem as well as a 3-SAT problem with 20 variables.


Tic-tac-toe game

In 2002, J. Macdonald, D. Stefanovic and M. Stojanovic created a DNA computer able to play
tic-tac-toe Tic-tac-toe (American English), noughts and crosses (Commonwealth English), or Xs and Os (Canadian or Irish English) is a paper-and-pencil game for two players who take turns marking the spaces in a three-by-three grid with ''X'' or ''O''. ...
against a human player. The calculator consists of nine bins corresponding to the nine squares of the game. Each bin contains a substrate and various combinations of DNA enzymes. The substrate itself is composed of a DNA strand onto which was grafted a fluorescent chemical group at one end, and the other end, a repressor group. Fluorescence is only active if the molecules of the substrate are cut in half. The DNA enzymes simulate logical functions. For example, such a DNA will unfold if two specific types of DNA strand are introduced to reproduce the logic function AND. By default, the computer is considered to have played first in the central square. The human player starts with eight different types of DNA strands corresponding to the eight remaining boxes that may be played. To play box number i, the human player pours into all bins the strands corresponding to input #i. These strands bind to certain DNA enzymes present in the bins, resulting, in one of these bins, in the deformation of the DNA enzymes which binds to the substrate and cuts it. The corresponding bin becomes fluorescent, indicating which box is being played by the DNA computer. The DNA enzymes are divided among the bins in such a way as to ensure that the best the human player can achieve is a draw, as in real tic-tac-toe.


Neural network based computing

Kevin Cherry and Lulu Qian at Caltech developed a DNA-based artificial neural network that can recognize 100-bit hand-written digits. They achieve this by programming on computer in advance with appropriate set of weights represented by varying concentrations weight molecules which will later be added to the test tube that holds the input DNA strands.


Improved speed with Localized (cache-like) Computing

One of the challenges of DNA computing is its speed. While DNA as a substrate is biologically compatible i.e. it can be used at places where silicon technology cannot, its computation speed is still very slow. For example, the square-root circuit used as a benchmark in field took over 100 hours to complete. While newer ways with external enzyme sources are reporting faster and more compact circuits, Chatterjee et al. demonstrated an interesting idea in the field to speedup computation through localized DNA circuits. This concept is being further explored by other groups. This idea, while originally proposed in the field computer architecture, has been adopted in this field as well. In computer architecture, it is very well-known that if the instructions are executed in sequence, having them loaded in the cache will inevitably lead to fast performance, also called as the principle of localization. This is because with instructions in fast cache memory, there is no need swap them in and out of main memory which can be slow. Similarly, i
localized DNA computing
the DNA strands responsible for computation are fixed on a breadboard like substrate ensuring physical proximity of the computing gates. Such localized DNA computing techniques have shown to potentially reduce the computation time b
orders of magnitude


Renewable (or reversible) DNA computing

Subsequent research on DNA computing has produce
reversible DNA computing
bringing the technology one step closer to the silicon-based computing used in (for example) PCs. In particular
John Reif
and his group at Duke University have proposed two different techniques to reuse the computing DNA complexes. The first design uses dsDNA gates, while the second design uses DNA hairpin complexes. While both the designs face some issues (such as reaction leaks), this appears to represent a significant breakthrough in the field of DNA computing. Some other groups have also attempted to address the gate reusability problem. Using strand displacement reactions (SRDs), reversible proposals are presented i
"Synthesis Strategy of Reversible Circuits on DNA Computers" paper
for implementing reversible gates and circuits on DNA computers by combining DNA computing and reversible computing techniques. This paper also proposes a universal reversible gate library (URGL) for synthesizing n-bit reversible circuits on DNA computers with an average length and cost of the constructed circuits better than the previous methods.


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 (
AND or AND may refer to: Logic, grammar, and computing * Conjunction (grammar), connecting two words, phrases, or clauses * Logical conjunction in mathematical logic, notated as "∧", "⋅", "&", or simple juxtaposition * Bitwise AND, a boolea ...
, OR, NOT) associated with
digital logic A logic gate is an idealized or physical device implementing a Boolean function, a logical operation performed on one or more binary inputs that produces a single binary output. Depending on the context, the term may refer to an ideal logic gate ...
from a DNA basis. Some of the different bases include DNAzymes, 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) * Polymerase-based strand displacement (PSD)


Toehold exchange

Beside simple strand displacement schemes, DNA computers have also been constructed using the concept of toehold exchange. In this system, an input DNA strand binds to a
sticky end DNA ends refer to the properties of the ends of linear DNA molecules, which in molecular biology are described as "sticky" or "blunt" based on the shape of the complementary strands at the terminus. In sticky ends, one strand is longer than the ...
, 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.


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 (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 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. Such controllers can potentially be used ''in vivo'' for applications such as preventing hormonal imbalance.


DNAzymes

Catalytic DNA (
deoxyribozyme Deoxyribozymes, also called DNA enzymes, DNAzymes, or catalytic DNA, are DNA oligonucleotides that are capable of performing a specific chemical reaction, often but not always catalytic. This is similar to the action of other biological enzyme ...
or DNAzyme) catalyze a reaction when interacting with the appropriate input, such as a matching
oligonucleotide Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, research, and forensics. Commonly made in the laboratory by solid-phase chemical synthesis, these small bits of nucleic acids ...
. These DNAzymes are used to build logic gates analogous to digital logic in silicon; however, DNAzymes are limited to 1-, 2-, and 3-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. . Also available here: http://www.lps.ens.fr/~vincent/smb/PDF/weiss-1.pdf 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. Stojanovic and MacDonald have used the E6 DNAzymes to build the
MAYA I Maya may refer to: Civilizations * Maya peoples, of southern Mexico and northern Central America ** Maya civilization, the historical civilization of the Maya peoples ** Maya language, the languages of the Maya peoples * Maya (Ethiopia), a populat ...
and
MAYA II MAYA-II ( Molecular Array of YES and ANDNOT logic gates) is a DNA computer, based on DNA Stem Loop Controllers, developed by scientists at Columbia University and the University of New Mexico and created in 2006. Replacing the normally silicon- ...
machines, respectively; Stojanovic has also demonstrated logic gates using the 8-17 DNAzyme. While these DNAzymes have been demonstrated to be useful for constructing logic gates, they are limited by the need for a metal cofactor to function, such as Zn2+ or Mn2+, and thus are not useful
in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...
. 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 A logic gate is an idealized or physical device implementing a Boolean function, a logical operation performed on one or more binary inputs that produces a single binary output. Depending on the context, the term may refer to an ideal logic ga ...
s. These logic gates have been used to create the computers MAYA I and
MAYA II MAYA-II ( Molecular Array of YES and ANDNOT logic gates) is a DNA computer, based on DNA Stem Loop Controllers, developed by scientists at Columbia University and the University of New Mexico and created in 2006. Replacing the normally silicon- ...
which can play
tic-tac-toe Tic-tac-toe (American English), noughts and crosses (Commonwealth English), or Xs and Os (Canadian or Irish English) is a paper-and-pencil game for two players who take turns marking the spaces in a three-by-three grid with ''X'' or ''O''. ...
to some extent.


Enzymes

Enzyme-based DNA computers are usually of the form of a simple
Turing machine A Turing machine is a mathematical model of computation describing an abstract machine that manipulates symbols on a strip of tape according to a table of rules. Despite the model's simplicity, it is capable of implementing any computer alg ...
; there is analogous hardware, in the form of an enzyme, and software, in the form of DNA. Benenson, Shapiro and colleagues have demonstrated a DNA computer using the FokI enzyme. Also available here

and expanded on their work by going on to show automata that diagnose and react to
prostate cancer Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that su ...
: under expression of the genes
PPAP2B Lipid phosphate phosphohydrolase 3 (LPP3), also known as phospholipid phosphatase 3 (PLPP3) and phosphatidic acid phosphatase type 2B (PAP-2b or PPAP2B), is an enzyme that in humans is encoded by the ''PPAP2B'' gene on chromosome 1. It is ubiquito ...
and GSTP1 and an over expression of
PIM1 Proto-oncogene serine/threonine-protein kinase Pim-1 is an enzyme that in humans is encoded by the ''PIM1'' gene. Pim-1 is a proto-oncogene which encodes for the serine/threonine kinase of the same name. The pim-1 oncogene was first described in ...
and HPN.. Also available here
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 protein 53, which itself is a tumor suppressor. 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". . Also available here

It should also be pointed out that the 'software' molecules can be reused in this case.


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 Wang tiles (or Wang dominoes), first proposed by mathematician, logician, and philosopher Hao Wang in 1961, are a class of formal systems. They are modelled visually by square tiles with a color on each side. A set of such tiles is selected, an ...
s. A DX array has been demonstrated whose assembly encodes an
XOR Exclusive or or exclusive disjunction is a logical operation that is true if and only if its arguments differ (one is true, the other is false). It is symbolized by the prefix operator J and by the infix operators XOR ( or ), EOR, EXOR, , ...
operation; this allows the DNA array to implement a
cellular automaton A cellular automaton (pl. cellular automata, abbrev. CA) is a discrete model of computation studied in automata theory. Cellular automata are also called cellular spaces, tessellation automata, homogeneous structures, cellular structures, tesse ...
which generates a
fractal In mathematics, a fractal is a geometric shape containing detailed structure at arbitrarily small scales, usually having a fractal dimension strictly exceeding the topological dimension. Many fractals appear similar at various scales, as ill ...
called the Sierpinski gasket. This shows that computation can be incorporated into the assembly of DNA arrays, increasing its scope beyond simple periodic arrays.


Capabilities

DNA computing is a form of
parallel computing Parallel computing is a type of computation in which many calculations or processes are carried out simultaneously. Large problems can often be divided into smaller ones, which can then be solved at the same time. There are several different f ...
in that it takes advantage of the many different molecules of DNA to try many different possibilities at once. For certain specialized problems, DNA computers are faster and smaller than any other computer built so far. Furthermore, particular mathematical computations have been demonstrated to work on a DNA computer. DNA computing does not provide any new capabilities from the standpoint of
computability theory Computability theory, also known as recursion theory, is a branch of mathematical logic, computer science, and the theory of computation that originated in the 1930s with the study of computable functions and Turing degrees. The field has sinc ...
, the study of which problems are computationally solvable using different models of computation. For example, if the space required for the solution of a problem grows exponentially with the size of the problem (
EXPSPACE In computational complexity theory, is the set of all decision problems solvable by a deterministic Turing machine in exponential space, i.e., in O(2^) space, where p(n) is a polynomial function of n. Some authors restrict p(n) to be a linear fu ...
problems) on von Neumann machines, it still grows exponentially with the size of the problem on DNA machines. For very large EXPSPACE problems, the amount of DNA required is too large to be practical.


Alternative technologies

A partnership between IBM and
Caltech The California Institute of Technology (branded as Caltech or CIT)The university itself only spells its short form as "Caltech"; the institution considers other spellings such a"Cal Tech" and "CalTech" incorrect. The institute is also occasional ...
was established in 2009 aiming at " DNA chips" production. A Caltech group is working on the manufacturing of these nucleic-acid-based integrated circuits. One of these chips can compute whole square roots. A compiler has been written
Online
in
Perl Perl is a family of two high-level, general-purpose, interpreted, dynamic programming languages. "Perl" refers to Perl 5, but from 2000 to 2019 it also referred to its redesigned "sister language", Perl 6, before the latter's name was offic ...
.


Pros and cons

The slow processing speed of a DNA computer (the response time is measured in minutes, hours or days, rather than milliseconds) is compensated by its potential to make a high amount of multiple parallel computations. This allows the system to take a similar amount of time for a complex calculation as for a simple one. This is achieved by the fact that millions or billions of molecules interact with each other simultaneously. However, it is much harder to analyze the answers given by a DNA computer than by a digital one.


See also

*
Biocomputer Biological computers use biologically derived molecules — such as DNA and/or proteins — to perform digital or real computations. The development of biocomputers has been made possible by the expanding new science of nanobiotechnology. The te ...
* Chemical computer * Computational gene * DNA code construction *
DNA digital data storage DNA digital data storage is the process of encoding and decoding binary data to and from synthesized strands of DNA. While DNA as a storage medium has enormous potential because of its high storage density, its practical use is currently severely ...
*
DNA sequencing DNA sequencing is the process of determining the nucleic acid sequence – the order of nucleotides in DNA. It includes any method or technology that is used to determine the order of the four bases: adenine, guanine, cytosine, and thymine. T ...
*
Membrane computing Membrane computing (or MC) is an area within computer science that seeks to discover new computational models from the study of biological cells, particularly of the cellular membranes. It is a sub-task of creating a cellular model. Membrane comput ...
*
Molecular electronics Molecular electronics is the study and application of molecular building blocks for the fabrication of electronic components. It is an interdisciplinary area that spans physics, chemistry, and materials science. The unifying feature is use of mo ...
* Peptide computing *
Parallel computing Parallel computing is a type of computation in which many calculations or processes are carried out simultaneously. Large problems can often be divided into smaller ones, which can then be solved at the same time. There are several different f ...
*
Quantum computing Quantum computing is a type of computation whose operations can harness the phenomena of quantum mechanics, such as superposition, interference, and entanglement. Devices that perform quantum computations are known as quantum computers. Though ...
*
Transcriptor A transcriptor is a transistor-like device composed of DNA and RNA rather than a semiconducting material such as silicon. Prior to its invention in 2013, the transcriptor was considered an important component to build biological computers. B ...
*
Wetware computer A wetware computer is an organic computer (which can also be known as an artificial organic brain or a neurocomputer) composed of organic material " wetware" such as "living" neurons. Wetware computers composed of neurons are different than conve ...


References


Further reading

* — The first general text to cover the whole field. * — The book starts with an introduction to DNA-related matters, the basics of biochemistry and language and computation theory, and progresses to the advanced mathematical theory of DNA computing. * — A new general text to cover the whole field.


External links


DNA modeled computing


* Dirk de Pol
''DNS – Ein neuer Supercomputer?''
In: Die Neue Gesellschaft / Frankfurter Hefte , Heft 2/96, Februar 1996, S. 170–172
‘DNA computer’ cracks code
Physics Web




Bringing DNA computers to life, in Scientific American



International Meeting on DNA Computing and Molecular Programming


{{DEFAULTSORT:Dna Computing Classes of computers Models of computation Molecular biology DNA DNA nanotechnology American inventions