By Dean A. Haycock

Special To BioWorld Today

Richard Feynman was thinking small back in 1959.

"What I want to talk about is the problem of manipulating and controlling things on a small scale," the late physicist said in a talk delivered that year. "The problems of chemistry and biology can be greatly helped if our ability to see what we are doing, and to do things on an atomic level, is ultimately developed - a development which I think cannot be avoided."

The talk inspired others to think about nanotechnology, a young field that can be defined as the technology of the very small. Its goal is the development of machinery that can precisely control matter on the molecular and atomic levels. Proponents hope to devise molecular machines that will significantly advance progress in areas as diverse as computing and biotechnology.

One branch of the field, DNA nanotechnology, is turning the stuff of genes into machines. A paper in today's issue of Nature, "A nanomechanical device based on the B-Z transition of DNA," illustrates the progress taking place in this area. Nadrian Seeman, a professor in the department of chemistry at New York University, and his colleagues succeeded in creating a switchable molecular machine out of DNA.

It has been long known that DNA can be used as construction material on the nanometer scale. Seeman's lab used it to build cubes eight years ago, rings two years ago and self-assembling, two-dimensional crystals last year.

The researchers now report success in constructing a dynamic DNA assembly, a DNA device that moves in response to a signal. This molecular switch takes advantage of the ability of DNA to shift between two different forms.

The B form of DNA is what most people think of when they picture the molecule's natural, right-handed double helix. Connected by an imaginary line, the bases on the outside of a B DNA helix form smooth spirals. Short stretches of certain DNA polymers, however, can take on a different, left-handed configuration instead of the normal right-handed one. An imaginary line drawn through the bases of this form of DNA would appear as zigzag. The zigzag feature is reflected in the name given to this form, Z DNA.

Seeman and his colleagues constructed a device consisting of two rigid stretches of B DNA linked by a short region that, under defined conditions, can form left-handed Z DNA. The switch from B to Z occurs upon exposure to high ionic strength. Changing this factor causes the susceptible, short linking region in the middle of the device to switch from the B form to the Z form. This transition twists half of the device so that a portion of the molecule moves 2 to 6 nanometers. Previously described nanoscale devices move perhaps one-tenth of that distance, according to Seeman.

"This is the simplest sort of device possible, something rigid that changes its shape in response to an external stimulus," said Seeman, who considers the device a prototype.

Seeman and his co-authors were able to detect movement in their device because they attached two fluorescent dyes to portions of the device that are separated by the B to Z transition. When the two dye molecules are moved farther apart as a result of the device's action, less fluorescent energy is exchanged between them. A decrease in this fluorescent energy transfer, measured by fluorescence resonance energy transfer spectroscopy, indicates that switch has occurred.

"This is remarkable, in my opinion, at that scale and with that level of sophistication," said M. Reza Ghadiri, a professor at the Scripps Research Institute in La Jolla, Calif. "It certainly opens doors to many other wonderful things to do."

Ghadiri suggests, as an example, that the device might one day be adapted to sense specific oligonucleotide sequences. Combined with other nanodevices, the mechanical DNA device could help make possible molecular computing based on DNA. "It certainly has a clear path toward it," Ghadiri said.

Ten years ago Seeman predicted that the B to Z transition could be exploited to drive a DNA device. Back then, however, no DNA structure rigid enough to support a moving "arm" was available. The NYU researchers solved this problem when they discovered a DNA motif they named "double-crossover" (DX) DNA. DX consists of two double helixes joined to each other twice.

"We tend to think of DNA as a linear molecule [because] the helix axis is linear. But in certain processes, particularly in genetic recombination, there are branched intermediates," Seeman told BioWorld Today. He compared these nonlinear examples of DNA to an intersection in a road. "If you think of the four curbstones being the strands of DNA, you can design sequences such that they will come together to form a four-branched molecule."

The switching device described in the Nature paper consists of two rigid DX molecules connected by 4.5 double-helical turns. One domain of each of these molecules is attached to the 4.5-turn connecting helix. The two other domains of each DX molecule lie on the same side of the device when in the B form. It is these domains that move apart when the B to Z transition is initiated.

The authors suggest that "it should be possible to incorporate this mechanical control in any figure or array produced by DNA nanotechnology so long as a free swivel containing proto-Z DNA can be included in the design." And by substituting proteins or other macromolecules for the dye molecules, biologists and chemists might be able to use similar nanodevices to study proximity effects in different systems. It is not clear whether this type of dynamic assembly could ever be used as a miniature motor. Combining the DNA B-Z transition device with other nanoscale devices, however, could lead to further significant advances in the quest to manipulate and control things on a small scale.

The work was funded by the National Institute of General Medical Sciences, Office of Naval Research, National Science Foundation/DARPA and the Information Directorate of the Air Force Research Laboratory in Rome, N.Y. n