Method could yield futuristic devices smaller than cells for "smart delivery" of drugs
William Shih, PhD, is senior author on the study
By combining the art of origami with nanotechnology, Dana-Farber
Cancer Institute researchers have folded sheets of DNA into multilayered
objects with dimensions thousands of times smaller than the thickness
of a human hair.
These tiny structures could be forerunners of custom-made biomedical
nanodevices such as "smart" delivery vehicles that would sneak drugs
into patients' cells, where they would dump their cargo on a specific
While creation of structures from single layers of DNA has been
reported previously, William Shih, PhD, senior author of the study
appearing in the May 21 issue of Nature, said the multi-layer
process he and his colleagues developed should enable scientists to make
customized DNA objects approximating almost any three-dimensional
Multilayered objects are more rigid and stable, thus better able to
withstand the intracellular environment, which "is chaotic and violent,
like being in a hurricane," Shih said. "We think this is a big advance."
Shih is a researcher in Dana-Farber's Cancer Biology program and an
assistant professor in the Department of Biological Chemistry and
Molecular Pharmacology at Harvard Medical School.
Models of 3-D DNA "origami" nanostructures, self-assembled as parallel arrays of double helices. (Shawn Douglas illustration)
Masters of the ancient Japanese art of origami make a series of folds
in a single piece of paper to form stunningly intricate models of
animals and other shapes. "We focus on doing this with DNA," explained
While DNA is best known as the stuff of which genes are made, here
the scientists use long DNA molecules strictly as a building component,
not a blueprint for making proteins. Shih and his colleagues reported in
the Nature paper that they were able to construct a number of
DNA objects, including a genie bottle, two kinds of crosses, a square
nut, and a railed bridge.
DNA origami is an outgrowth of research in nanotechnology — using
atoms and molecules as building blocks for new devices that can be
deployed in medicine, electronics, and other fields.
Scientists envision using the minuscule structures — which are about
the size of small viruses — to mimic some of the "machines" within cells
that carry out essential functions, like forming containers for
molecular cargos and transporting them from one place to another.
"This is something that nature is very good at — making many complex
machines with great control. Nature optimizes cellular technology
through millions of years of evolution; we don't have that much time, so
we need to come up with other design approaches," Shih said.
DNA origami are built as a sheet of parallel double-helices, each
consisting of two intertwined strands made up of units called
nucleotides. Long strands of DNA serving as a "scaffold" are folded back
and forth by short strands of DNA serving as "staples" that knit
together segments of the scaffold.
The DNA sheet, which Shih likens to the thin bamboo mat that sushi
chefs use to prepare maki rolls with filling, is then programmed to curl
on itself into a series of layers that are locked in place by staples
that traverse multiple layers.
With the design in hand, the scientists then order the DNA staple
strands from a company, which take about three days to be synthesized
and shipped. Fabricating the desired structure involves mixing the DNA
scaffold and staple strands, quickly heating the mixture, and then
slowly cooling the sample.
This process coaxes the DNA to "self-assemble" and make billions of
copies of the desired object. The process takes about a week, though the
researchers intend to improve this rate. Finally, the researchers can
check the finished product using an electron microscope.
The tiny machines the researchers are aiming for could, for example,
act as navigation aids to guide bubble-like sacs filled with medicines.
"These machines could be placed on the outside of the drug-delivery
vehicles to help them cross biological barriers, or help them outwit
mechanisms that are trying to remove things from the bloodstream, so
they can reach their target," suggested Shih.
The technology could also be useful in diagnostics of the future.
While current lab tests can measure the concentration of different
substances in the body, it may be possible with DNA "to measure the
concentration of something within a single cell," said Shih.
In addition to Shih and Douglas, authors of the Nature paper
include Hendrik Dietz, PhD, Tim Liedl, PhD, Björn Högberg, PhD, and
Franziska Graf, of Dana-Farber and Harvard Medical School.
The research was supported by grants from the National Institutes of
Health, the Claudia Adams Barr Program, the Wyss Institute for
Biologically Inspired Engineering at Harvard, and several fellowships.
Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National