DNA robots the future of medical treatment and molecular factories
24 May 2010
Autonomous molecular 'robots' made from DNA that could be used
as nanoscale therapeutic devices or as a production line to build
complex molecules have been built by a multidisciplinary team of US
The team from Columbia University, Arizona State University, the
University of Michigan, and the California Institute of Technology
(Caltech) have programmed a DNA robot to start, move, turn, and stop
while following a DNA track. The work has been published in the
The development could ultimately lead to molecular systems that
might one day be used for medical therapeutic devices and
molecular-scale reconfigurable robots made of many simple units that
can reposition or even rebuild themselves to accomplish different
Milan N Stojanovic, a faculty member in the Division of
Experimental Therapeutics at Columbia University, led the project
and teamed up with Erik Winfree, associate professor of computer
science, computation and neural systems, and bioengineering at
Caltech, Hao Yan, professor of chemistry and biochemistry at Arizona
State University and an expert in DNA nanotechnology, and with Nils
G. Walter, professor of chemistry and director of the Single
Molecule Analysis in Real-Time (SMART) Center at the University of
Michigan in Ann Arbor.
The traditional view of a robot is that it is "a machine that
senses its environment, makes a decision, and then does something —
it acts", said Erik Winfree, associate professor of computer
science, computation and neural systems, and bioengineering at
Shrinking robots down to the molecular scale would provide, for
molecular processes, the same kinds of benefits that classical
robotics and automation provide at the macroscopic scale. Molecular
robots, in theory, could be programmed to sense their environment
(say, the presence of disease markers on a cell), make a decision
(that the cell is cancerous and needs to be neutralized), and act on
that decision (deliver a cargo of cancer-killing drugs).
Or, like the robots in a modern-day factory, they could be
programmed to assemble complex molecular products. The power of
robotics lies in the fact that once programmed, the robots can carry
out their tasks autonomously, without further human intervention.
With that promise, however, comes a practical problem: how do you
program a molecule to perform complex behaviours?
"In normal robotics, the robot itself contains the knowledge
about the commands, but with individual molecules, you can't store
that amount of information, so the idea instead is to store
information on the commands on the outside," says Walter. And you do
that, says Stojanovic, "by imbuing the molecule's environment with
"We were able to create such a programmed or 'prescribed'
environment using DNA origami," said Yan. DNA origami, an invention
by Caltech Senior Research Associate Paul WK Rothemund, is a type of
self-assembled structure made from DNA that can be programmed to
form nearly limitless shapes and patterns (such as smiley faces or
maps of the Western Hemisphere or even electrical diagrams).
Exploiting the sequence-recognition properties of DNA base
pairing, DNA origami are created from a long single strand of DNA
and a mixture of different short synthetic DNA strands that bind to
and "staple" the long DNA into the desired shape. The origami used
in the Nature study was a rectangle that was 2 nanometers
(nm) thick and roughly 100 nm on each side.
The researchers constructed a trail of molecular "bread crumbs"
on the DNA origami track by stringing additional single-stranded DNA
molecules, or oligonucleotides, off the ends of the staples. These
represent the cues that tell the molecular robots what to do —
start, walk, turn left, turn right, or stop, for example — akin to
the commands given to traditional robots.
The molecular robot the researchers chose to use — dubbed a
"spider" — was invented by Stojanovic several years ago, at which
time it was shown to be capable of extended, but undirected, random
walks on two-dimensional surfaces, eating through a field of bread
To build the 4-nm-diameter molecular robot, the researchers
started with a common protein called streptavidin, which has four
symmetrically placed binding pockets for a chemical moiety called
biotin. Each robot leg is a short biotin-labeled strand of DNA.
"This this way we can bind up to four legs to the body of our
robot," Walter said. "It's a four-legged spider," quips Stojanovic.
Three of the legs are made of enzymatic DNA, which is DNA that binds
to and cuts a particular sequence of DNA. The spider also is
outfitted with a "start strand" — the fourth leg — that tethers the
spider to the start site (one particular oligonucleotide on the DNA
"After the robot is released from its start site by a trigger
strand, it follows the track by binding to and then cutting the DNA
strands extending off of the staple strands on the molecular track,"
"Once it cleaves," Yan said, "the product will dissociate, and
the leg will start searching for the next substrate." In this way,
the spider is guided down the path laid out by the researchers.
Finally, explains Yan, "the robot stops when it encounters a patch
of DNA that it can bind to but that it cannot cut," which acts as a
sort of flypaper.
Although other DNA walkers have been developed before, they've
never ventured farther than about three steps. "This one," said Yan,
"can walk up to about 100 nanometers. That's roughly 50 steps."
"This in itself wasn't a surprise," said Winfree, "since Milan's
original work suggested that spiders can take hundreds if not
thousands of processive steps. What's exciting here is that not only
can we directly confirm the spiders' multistep movement, but we can
direct the spiders to follow a specific path, and they do it all by
In fact, using atomic force microscopy and single-molecule
fluorescence microscopy, the researchers were able to watch directly
spiders crawling over the origami, showing that they were able to
guide their molecular robots to follow four different paths.
"Monitoring this at a single molecule level is very challenging,"
Walter said. "This is why we have an interdisciplinary,
multi-institute operation. We have people constructing the spider,
characterizing the basic spider. We have the capability to assemble
the track, and analyze the system with single-molecule imaging.
That's the technical challenge."
The scientific challenges for the future, Yan says, "are how to
make the spider walk faster and how to make it more programmable, so
it can follow many commands on the track and make more decisions,
implementing logical behaviour."
"In the current system," said Stojanovic, "interactions are
restricted to the walker and the environment. Our next step is to
add a second walker, so the walkers can communicate with each other
directly and via the environment. The spiders will work together to
accomplish a goal." Adds Winfree, "The key is how to learn to
program higher-level behaviors through lower-level interactions."
Such collaboration ultimately could be the basis for developing
molecular-scale reconfigurable robots — complicated machines that
are made of many simple units that can reorganize themselves into
any shape — to accomplish different tasks, or fix themselves if they
For example, it may be possible to use the robots for medical
applications. "The idea is to have molecular robots build a
structure or repair damaged tissues," says Stojanovic.
"You could imagine the spider carrying a drug and bonding to a
two-dimensional surface like a cell membrane, finding the receptors
and, depending on the local environment," Yan said, "triggering the
activation of this drug."
Such applications, while intriguing, are decades or more away.
"This may be 100 years in the future," Stojanovic said. "We're so
far from that right now."
"But," Walter said, "just as researchers self-assemble today to
solve a tough problem, molecular nanorobots may do so in the