Reporting in this week's issue of PLoS Medicine, the Duke team suggests that drawing a blood sample and then using gene-chip technology to scan thousands of genes in the DNA of lymphocytes (white blood cells found in the blood, gut and bone marrow) could rapidly determine whether someone requires treatment for radiation poisoning.
"The goal would be to develop a test that's practical and can be applied to thousands of people in a mass casualty situation," says senior study author John Chute, a professor of medicine at Duke. The team focused on lymphocytes because they are "cells that have a high rate of proliferation and are very sensitive to the effects of ionizing radiation" (waves or particles of energy capable of breaking the bonds of biological molecules such as DNA) and tend to damage very quickly. Physical symptoms of radiation poisoning may not show up for days to weeks.
Current methods for making such diagnoses involve culturing bone marrow cells drawn from the hip for up to a week to search for chromosomal damage, or repeatedly drawing blood over several days to measure accumulating damage to lymphocytes. Unfortunately, both these processes take longer than the critical 48-to-72-hour window during which treatment to reverse cell damage in the immune system would be most beneficial—when infection, bone marrow failure and heightened cancer risk can be avoided.
The researchers developed a mouse model for their radiation test, exposing mice to either low-level radiation that is normally harmless, levels that typically weaken the immune system or a lethal dose of radiation. Six hours after irradiating the animals, the scientists took blood samples. After analyzing thousands of genes in each group, the researchers zeroed in on signature patterns of roughly 100 gene changes that each radiation level created in the mice.
"There's a complex molecular biological response to radiation that seems very unique at different dose levels," Chute says. "The classes of genes that respond are unpredictable and not [generally] overlapping."
The team also did human trials in leukemia and lymphoma patients who were receiving large doses of radiation prior to undergoing bone marrow stem cell transplants. Patients tested just prior to irradiation and six hours later were compared with healthy subjects. The gene profiles discriminated between those who had and had not been exposed with 90 percent accuracy: 85 percent of the cancer patients were correctly identified, only 6 percent of the discriminations resulted in false positives (cancer patients, who had not yet received radiation treatment) and the healthy people were sorted out with 100 percent accuracy. Chute speculates the false positives and missed exposures were caused by exposure to radiation during previous cancer treatments. "There is [likely] some interference or noise created by people with cancer," or some other genotoxic stress, he says.
Chute believes that with current gene-chip technology the test will take three days to complete. But the group is in the process of refining its method by homing in on a set of 25 genes that could be reliably checked to determine within 12 to 24 hours not only whether exposure took place, but also the relative dosage received. By determining which genes are typically affected, new treatments for victims of exposure may also be attainable, says lead study author Holly Dressman, a molecular geneticist at Duke. "By identifying genes that are major players in the response to radiation," she says, "we hope to compile a list of future targets for protection against its harmful effects."
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