June 23, 2003 UCLA physicists have created a first-of-its-kind nanoscale sensor using a single molecule less than 20 nanometers long -- more than 1,000 times smaller than the thickness of a human hair -- the team reports in the June 24 issue of the Proceedings of the National Academy of Sciences.
The nano molecular sensor could help with early diagnosis of genetic diseases, and have numerous other applications for medicine, biotechnology and other fields, said Giovanni Zocchi, assistant professor of physics at UCLA, member of the California NanoSystems Institute and leader of the research team.
"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," Zocchi said. "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."
The research is federally funded by the National Science Foundation.
Zocchi's nanoscale sensor uses a single molecule to recognize the presence of a specific short sequence in a mixture of DNA or RNA molecules -- which he equates to finding a needle in a haystack.
"Traditional assays use an averaged procedure that detects a minimum amount of molecules, but our method can detect a single one," Zocchi said. "When a target molecule binds to the probe in the sensor, the probe molecule changes shape, and in its new conformation, pulls on the sensor. It is remarkable that a single molecule can actually move the sensor, because the relative sizes are comparable to one person trying to move a mountain, but mass is of no consequence at these miniscule scales."
The motion of the sensor is detected by an optical technique called "evanescent wave scattering," which analyzes light that leaks out behind a reflecting mirror. This evanescent wave can be used 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.
Zocchi's team is the first to report measurements of conformational changes in a single DNA molecule at the nanometer scale.
"This single molecule sensor could be an important component of 'a lab on a chip' technology for doing chemical analysis on a chip," Zocchi said.
Zocchi's team plans to use the nanoscale sensor for experimental leukemia research, to test whether the sensor's high sensitivity can detect a recurrence of cancer at an earlier stage than is now possible.
"If we can increase the sensitivity of the detector, then it may be possible to detect genetic diseases at an earlier stage," Zocchi said. "It may become possible to diagnose the presence of an abnormality in DNA at an early stage, or the expression of a certain gene that should not be expressed.
"A single molecule sensor has, in principle, extraordinary sensitivity. Unlike previous single molecule experiments, which were impractically complicated for large-scale applications, the simplicity of this design lends itself to many applications.
"An efficient high-sensitivity method would be an important tool for testing how cells react to a new drug. The nano sensor could also be a useful tool for stem cell research. A nano sensor based on this technology could potentially detect minute traces of biological weapons, based on a characteristic genetic signature. These are the first steps down a path toward devices that we expect will be really useful."
In addition to the applications, Zocchi is interested in the research for reasons of basic science.
"How do you regulate the functions in the cells?" he said. "In the cell, proteins are regulated by other molecules that can bind to it, changing the conformation of the protein. This process is called 'allosteric regulation,' when a molecule binds to a protein, changing the conformation and the activity of the protein. I'm interested in this conformational change, and in understanding the physical basis of this allosteric mechanism, which is central to the regulation in the cell. There is a biological understanding of this process, but not an understanding of the physics. We want to learn how the binding of this molecule changes the conformation."
Zocchi's co-authors of the paper are Mukta Singh-Zocchi, a UCLA research physicist; Sanhita Dixit, a postdoctoral scholar in his laboratory; and Vassili Ivanov, a UCLA graduate student.
Zocchi, who joined UCLA's faculty in 1999 after conducting research at the Niels Bohr Institute in Copenhagen, Denmark, is exuberant about the future of nanotechnology research at the California NanoSystems Institute -- a collaboration of UCLA and UC Santa Barbara -- and elsewhere.
"The future will undoubtedly see nano-bio composite devices applied to perform molecular tasks," Zocchi said. "Ultimately these efforts will lay the groundwork for creating artificial systems with more and more of the characteristics that have been unique to living things. Economy of scale allows nature to pack the most elaborate laboratory on Earth in the volume of a single bacterial cell; in the future, artificial systems may approach similar complexity."
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