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Closing in on cancer

New biosensor technology may ease cancer risk-assessment

The sooner you find it, the better. But the indications that an individual may have an increased risk of getting cancer are often difficult to spot. Tucked away, these clues lurk in the twists and turns of the body's DNA.

Uncovering the clues has traditionally been a complex and time-consuming practice, but now Ames Laboratory researchers have come up with a highly sensitive and selective method to speed that process.

Gerald Small, an Ames Lab senior chemist and an Iowa State University distinguished professor, and Ryszard Jankowiak, an Ames Lab senior scientist, have de-veloped a unique biosensor technology that provides immediate information about DNA damage from cancer-causing pollutants called carcinogens. Damage to DNA, which carries the genetic code of life, is a critical first step in the development of cancer.

Tracking adducts

When carcinogens enter the body and are activated, they can react with the DNA to form DNA adducts, chemical compounds in which the carcinogen is attached to the DNA. If the body's natural defense systems do not properly repair the damage caused by these adducts, the result can be the birth of a renegade cell. Uncontrolled proliferation of such a cell results in cancer.

A reliable way scientists can assess cancer risk is to keep track of DNA adducts formed in human cells. Small and Jankowiak are developing a novel means for detection of certain DNA adducts that can be found in urine. The newly developed biosensor chip technique is simpler and potentially more practical than previous methods.

"This scientific advance holds the promise of making it easier and less expensive to identify cancer-causing chemicals in the body, giving physicians a warning sign before the cancer grows and spreads," says Secretary of Energy Spencer Abraham.

Jankowiak leads the biosensor chip research project, which also includes Marc Porter, an ISU chemistry professor and director of ISU's Microanalytical Research Center. Jeremy Kenseth, who recently received his Ph.D. under Porter's supervision, and Scott Duhachek, a former postdoctoral fellow who worked with Small and Jankowiak, also made significant contributions to the project.

The biosensor technology is based on a unique gold chip that was constructed by Kenseth. The chip can be used to detect fluorescent DNA adducts adducts that emit light when excited by a laser. Bound to the chip's surface are special antibodies, proteins that serve as the body's natural defense system against infectious agents. Scientists can develop antibodies in the laboratory to be so selective that they will preferentially bind a specific DNA adduct.

The chip in action

The biosensor chip includes a single-layer linker molecule that adsorbs to the bare gold. The chip with the linker molecule can be exposed to a drop of solution containing an antibody specific to the DNA adduct of interest. The linker serves as a coupling agent, binding the antibody to the chip. This process creates an active surface area that can, in turn, bind molecules of those adducts specific to the antibody when the chip is exposed to a liquid sample. With the new biosensor chip technology, scientists could test for the presence of a certain adduct in a sample of urine by simply dipping a chip containing the corresponding antibody into processed urine. The adducts of interest would bind to the antibody and fluoresce when scanned with a laser beam at low temperature minus 4 Kelvin (minus 452 degrees Fahrenheit). The data gathered from the laser scanning would then be used to produce a detailed fingerprint for adduct identification, providing vital information for cancer risk-assessment.

"The biosensor chip technology has the potential to play a significant role in the advancement of cancer research," says Ames Laboratory Director Tom Barton. "It demonstrates, once again, the diversity of Ames Laboratory's scientific efforts and the commitment of our scientists to perform cutting-edge research that may improve the lives of people throughout the world."

The glycerol effect

Jankowiak explains that initially they were unable to detect fluorescence at room temperature. However, he notes that the addition of a thin layer of glycerol to the surface of the chip led to a dramatic increase in fluorescence intensity at room temperature. "Cooling the chip further increased the intensity by a factor of 10," he says.

Although Jankowiak is still investigating the glycerol-induced fluorescence enhancement, some insight already has been achieved. For example, he says, "We know that the distance from DNA adduct to the gold surface has increased by a factor of two, since the antibody adopts a more upright orientation on the surface in the presence of glycerol. This accounts for the significant increase in the observed fluorescence intensity due to the decrease in surface quenching by the underlying gold." However, he notes that a great deal more research is needed to determine whether it would be possible to take advantage of the glycerol effect in the manufacture of biosensor chips.

The biosensor research team is investigating other enhancements to the chip technology, including making chips with upright orientation of the antibody and increased distance between the bound DNA adduct and the supporting surface. The team is also looking at developing chips with several addresses for different antibodies that bind different adducts, and using surfaces other than gold.

"The more adducts that can be identified, the more complete the picture of DNA damage resulting from exposure to mixtures of carcinogens," says Small.

Jankowiak adds, "We are currently looking at adducts implicated in breast and prostate cancer. One day this technology could lead to significant advances in pre-cancer diagnosis."


For more information:
Ryszard Jankowiak, (515) 294-4394

Research funded by:
DOE Office of Biological and Environmental Research
National Cancer Institute


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