Small sensor sparks big interest

By LIDIA WASOWICZ, UPI Senior Science Writer  |  Aug. 14, 2003 at 10:00 AM
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SAN FRANCISCO, Aug. 14 (UPI) -- Small, sensitive, speedy, selective and simple, a new single-molecule sensor has all the makings of the ultimate detecting machine.

The first-of-its-kind nanoscale system -- more than 1,000 times smaller than the width of a human hair -- stands to play a big part in what some scientists see as a revolution in diagnostics.

Creation of the microtool, by physicists at the University of California, Los Angeles, could pave the way for early detection of cancer and other genetic diseases. It also could lead to timely identification of anthrax and other biowarfare agents and prompt determination of the potential power of a new drug, researchers told United Press International.

In the longer term, they envision the approach helping to commingle natural and artificial life in ways that blend and blur the line between the two.

"The single-molecule feature ... represents in principle the ultimate in sensitivity (you can't do better than detecting a single molecule)," said team leader Giovanni Zocchi, assistant professor of physics. "Unlike previous single-molecule experiments, which were impractically complicated for large-scale applications, the simplicity of this design lends itself to many applications," he told UPI.

Zocchi also is a member of the California NanoSystems Institute, a collaborative effort to catapult the state to the top ranks of the world's leading developers of technologies and systems operating at the molecular level.

The sensor could facilitate and accelerate the measurement of cellular response to various targets, be they toxins, treatments or tissue succumbing to disease, scientists said. The molecular method uses pieces of biological machinery to create artificial devices that can sense and diagnose extremely small amounts of DNA and RNA, the genetic material where the code of life is inscribed.

"Rapid DNA detection in a small, (simple) package equates to bedside detection of pathogens, genetic abnormalities, battlefield detection of biowarfare reagents, et cetera," said Kevin Plaxco, assistant professor of chemistry and biochemistry at the University of California, Santa Barbara, who is conducting competing studies in a related field.

"Hell, something this revolutionary would create its own applications -- things we can't possibly think of now," he told UPI.

Plaxco's own experiments, described in the Proceedings of the National Academy of Sciences, have produced a novel electronic DNA sensor he says could pave the way for such future marvels as devices for genetic sensitivity or an anthrax detector that a soldier could attach to his belt.

Plaxco praised the UCLA team's work for its novelty and practicality.

"While approaches already exist to detect single molecules, Zocchi's ... is far simpler, smaller and more robust than existing technologies and thus much more likely to be (used) in the real world," Plaxco said.

Already, Zocchi's team plans to test the sensor in experimental leukemia research to determine whether it can detect cancer recurrence at an earlier stage than existing diagnostic tools.

"This nanoscale, single-molecule method could lead to significant improvements in early diagnosis of genetic diseases, including the growing number of cancer forms for which genetic markers are known," said Zocchi, whose results also were published in PNAS. "The largest potential applications for this sensor may be in the drug discovery process, where the possibility of quickly gauging the gene expression response of cells to prospective drugs is crucial," he said.

In addition, a nanosensor based on the new technology could potentially detect minute traces of biological weapons by reading their characteristic genetic signature, he said.

"For biotech, we hope the higher sensitivity instrumentation based on this technology will allow us to monitor gene expression in small populations of cells, such as are met with in stem-cell research, for instance," Zocchi said. "For pharmaceutical research, we hope the simplification in the methodology ... will facilitate the test of the response of cells to new drugs."

The device still requires some perfecting, researchers cautioned.

"While the detector detects a single molecule, the concentration of (the target) in the sample must be relatively high for this single-molecule event to occur in less than an hour," Plaxco noted.

"If it can be improved so as to near its ultimate sensitivity limit, the approach could be a very helpful device for the detection of, say, anthrax on the battlefield."

Zocchi and company are so sure of the technology's marketability, they are seeking investors and partners to form a commercial venture. If they succeed in their enterprise, they expect to produce prototypes within three years.

"Our vision is that this technology will form the basis of superior instrumentation for diagnostics." Zocchi explained.

"We are talking about diagnostics of diseases which have a known genetic signature; this is an ever expanding set of diseases, as more and more genetics markers, e.g. for different forms of cancer (but many other diseases as well), are being discovered."

Zocchi expects his technology to hold the greatest and most immediate commercial appeal for medical diagnostics and clinical research.

"To give you an idea, the size of the U.S. market for gene-based medical diagnostics and clinical research is on the order of $3 billion annually," Zocchi said.

The sensor uses a single molecule to recognize the presence of a specific short segment in a mixture of DNA or RNA molecules, a feat Zocchi equates to finding a needle in a haystack.

The technology takes advantage of the characteristic of biomolecules, as scientists call proteins and DNA, to "move," or change shape, in response to external stimuli.

"The sensor exploits such 'conformational changes,'" Zocchi explained. "When the target molecule links with the sensor (which is a single DNA molecule), the sensor molecule changes shape and yanks on a small particle, which gets a little displaced (and) this displacement is detected optically."

The optical technique analyzes light leaking out behind a reflecting mirror to sense precisely the position of an object "beyond" the mirror.

"Instead of detecting the presence of the target, we detect the changing conformation of the probe when the target binds to it," Zocchi said.

Until now, only biological sensors in living cells were known to perform such a trick, scientists said.

Zocchi, research associate Mukta Singh-Zocchi, postdoctoral fellow Sanhita Dixit and graduate student Vassili Ivanov applied the method to create a chemical sensor with the same capability.

"I think this represents a promising new direction," Paul Hansma, professor of physic at the University of California, Santa Barbara, told UPI.

Zocchi, who began the research in 1996 while at the Niels Bohr Institute in Copenhagen, Denmark, said the work has been driven by his desire to explore the border between the living and the non-living.

"I have no doubt that eventually we will see artificial molecular devices which will possess some or all of the characteristics of life, such as self-assembly, self replication, self-repair and, possibly and most importantly, the capability to evolve," he said.

Creating artificial life would shake up humans' view of its biological counterpart, he noted.

"Will this be a new Copernican revolution (which, 500 years ago, put the position of the Earth in the universe into a different perspective)?" Zocchi marveled. "Will we be able to make artificial systems as marvelous as the living cell?"

Just as no one in 1960 could predict the invention of the transistor that year would spawn the Digital Age 30 years later so it remains to be seen what the nanotechnology world of tomorrow holds in store, Zocchi said.

"What we see now is that there are fantastic possibilities," he mused, "so this is no doubt a very worthy field of scientific endeavor."

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