January 10, 2000

Brookhaven Scientists Create New Ways
to Tag and Track Molecules

UPTON, NY-Scientists at the U.S. Department of Energy's Brookhaven National Laboratory are developing a wide array of metallic "tags" to label proteins and other molecules. These tags will expand the toolbox scientists use to decode molecular structures, diagnose and treat diseases, and trace the movement of antibodies and drugs within cells.

"These labels help us tag and see microscopic cell components, and solve the structure of molecules to see how the molecules work," says James Hainfeld, a Brookhaven biophysicist. Hainfeld is guest-editor of the September 1999 issue of the Journal of Structural Biology, which features the most current work in this field, known as heavy metal cluster labeling.

The range of applications is limited only by the scientists' ability to custom-design the appropriate tag for the task.

For example, metal particles are used in home pregnancy test kits, producing the readable pink color when proteins associated with pregnancy are present. Similarly, scientists use the metal particles to track the movement of drugs within cells. A California company has used gold-labeled molecules to follow the delivery of an antifungal drug into its target cells. "By using gold labels, they were able to demonstrate the efficacy of the treatment. Otherwise you can't really see what's going on."

In another study, a metallic tag helped identify one of the key infection-initiating proteins on the surface of the Hepatitis B virus. "If you can understand where these proteins are and how they work, you can understand the virus better," Hainfeld says. That knowledge might eventually lead to ways to defeat the virus.

Tags can also be used to label the products of bioengineering and to detect the presense of antibodies, potentially increasing the sensitivity of some diagnostic techniques. Some tags might even serve as "magic bullets" to deliver cell-killing radiation doses directly to cancer cells without causing harm to the surrounding healthy tissue.

To date, the Brookhaven scientists have developed and/or are using tags made from a variety of metals, including gold, platinum, irridium and paladium. "Each element has its own chemistry, so some of them form larger clusters, some of them smaller ones," Hainfeld says. The Brookhaven group has made tags that range in size from four atoms to more than 100,000 atoms.

Once the scientists have produced a core with the number of metal atoms they need, they use organic chemistry methods to attach a variety of organic molecules around the outside. "By varying the organic molecules surrounding the metal cluster, you can tailor-make the label to bind to the molecules you want to study," Hainfeld says.

So scientists can design labels that bind to specific areas on a protein, for example. When scientists then analyze these proteins using X-ray crystallography, a technique used regularly at Brookhaven's National Synchrotron Light Source, the locations of these labels help reveal the structure of the protein at the molecular level. Alternatively, scientists can trace the location of the labeled moleucles within viruses or cells using an electron microscope, such as Brookhaven's Scanning Transmission Electron Microscope.

In addition to editing the special issue of the Journal, Hainfeld is coauthor on five of the included papers. Papers by Brookhaven biologists Joseph Wall and Paul Freimuth are also included, as are works by scientists from a variety of other research organizations in the U.S., Europe and Israel.

The U.S. Department of Energy's Brookhaven National Laboratory creates and operates major facilities available to university, industrial and government personnel for basic and applied research in the physical, biomedical and environmental sciences, and in selected energy technologies. The Laboratory is operated by Brookhaven Science Associates, a not-for-profit research management company, under contract with the U.S. Department of Energy.

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