Iowa State University

Inside Iowa State
June 6, 1997

Hot on the trail of single molecules

by Saren Johnston, Ames Laboratory

Suppose you lost a contact lens in a bubble bath. After a tirade of expletives and taking care not to disturb your sudsy surroundings, you'd start scanning the patches of floating foam. But chances are you'd never spot your lens among all the glistening bubbles. And even if you did, it probably would slip away with the slightest ripple of the water and disappear right before your blurry eyes.

More elusive than a contact lens

If you can imagine the bubble bath scenario, you have some idea of the challenge Ed Yeung faced in trying to pinpoint and follow the fate of a single molecule in solution. But Yeung, program director for physical and biological chemistry and a distinguished professor of chemistry, has found a way to do just that and gain insight on each step of a chemical reaction. And that knowledge ultimately could lead to improved diagnoses for AIDS and cancer.

"The ability to observe one molecule reacting with another molecule may have great implications in the fields of medicine, catalysis and biotechnology," said Yeung. "Looking ahead, maybe we'll be able to detect a single HIV virus or one copy of a specific gene in DNA."

Yeung and postdoctoral fellow Xiao-Hong Xu have been successful in tracking the motion and the decomposition of single molecules of rhodamine, a highly fluorescent compound, in water solution. In addition, they are able to track DNA that has been tagged with rhodamine, also in water solution. Their research was published in the Feb. 21 issue of Science.

Blazing a new frontier

Detection of single molecules in solution has been accomplished before, but Yeung and Xu's technique is distinct because it is the first to offer continuous monitoring. Now "zeroing in on" single molecules no longer will require that they be immobilized. Researchers will be able to track their meanderings in their natural environment -- liquid solution.

The ability to follow single molecules as they move through liquids will make it possible to gather more detailed information about their individual behaviors and physical and chemical properties. This represents a significant advancement over traditional methods, which only can determine the characteristics of molecules based on population averages from bulk studies.

The need for speed -- tracking molecules in motion

Yeung describes the new technique for single molecule detection as a relatively simple combination of an optical microscope and an intensified charge-coupled device (ICCD) camera, both stock commercial instruments. Using carefully adjusted laser power, he induces a molecule in solution to emit light. By opening the shutter of the camera for a long period of time, Yeung can image either a thin layer of solution or a liquid-surface interface and document molecular activity. This can be done in a single photograph in which the motion of each molecule appears as an individual blur.

"An ICCD camera is just a sophisticated camcorder," Yeung said, "but there's a special way of operating it that gives you time resolution that's maybe a hundred or more times faster than prior techniques. And speed in data collection is essential, since molecules in solution cannot be kept in a confined space."

The entire process of molecule-tracking and data-gathering is accomplished with sub-millisecond time resolution. The information collected shows that each single molecule has unique traits and reaction rate, which deviate from measurements previously acquired by looking at millions of molecules and averaging their properties.

"People have been able to monitor single molecules in the gas phase for a long time," Yeung said, "because in gases you have better control and fewer interfering species. Now we're bringing that kind of study to the solution phase, where most biochemical reactions occur."

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