hen James Raleigh developed a tool for detecting stubborn tumors, he had no idea how far it would go. It has found its way into studies of liver damage and organ transplants, and even into outer space.

Researchers use the tool, known as a hypoxia marker, to detect cells lacking oxygen. Raleigh originally intended the marker as a way to identify hypoxic cells in tumors because hypoxic cells are three times more likely to resist radiation treatment. He figured if oncologists knew beforehand which tumors were hypoxic, then they could modify radiation treatments to be more beneficial. But Raleigh and other researchers are finding out that hypoxia plays a role in many diseases and processes in the body other than cancer.

Raleigh, professor of radiation oncology and toxicology, invented his first hypoxia marker when he was a senior scientist at the Cross Cancer Institute and an adjunct professor at the University of Alberta in Canada. When he came to Carolina, one of the draws was the prospect of a collaboration with the N.C. State University (NCSU) School of Veterinary Medicine. Donald Thrall, professor of veterinary medicine at NCSU, was working with dogs that had spontaneous cancers, and he wanted to use Raleigh's hypoxia marker to see if hypoxic cells really do resist treatment.

"The dog model is interesting because dogs grow up with people and experience the same kind of environment as humans, so when you look at dog tumors, even though dogs are a very different species, the tumors look very much like human tumors," Raleigh says.

"It was this collaboration with NCSU that led to the development of an improved hypoxia marker that was more convenient in a clinical setting than the earlier version."

ere's how the marker works: a drug, pimonidazole, is injected into the patient and diffuses through the whole body. Once pimonidazole gets into regions that are short of oxygen, electrons attach to it and activate the drug. The activated pimonidazole then binds to proteins in cells and is detected in biopsied tissue by special antibodies that Raleigh developed and patented and that Shu-Chuan Chou, a research analyst in Raleigh's lab, has helped perfect. In tumors that have hypoxic cells, the antibodies appear as brown stains.

Raleigh explains that even normal tissues have gradients of oxygen. Every time you take a breath, blood vessels deliver oxygen to all tissues of the body. Cells next to blood vessels consume the oxygen, so cells that are farther away get less oxygen, causing them to become hypoxic. But hypoxic cells in themselves are not bad.

"In fact," Raleigh says, "normal organs make use of oxygen gradients, and so as long as you don't upset those gradients, the tissue is quite happy."

The problem with tumor tissue is that hypoxic cells tend to resist radiation treatment, and they also tend to make tumors more aggressive by causing them to spread more quickly and invade locally—which may explain why some tumors grow back after they've been treated. Raleigh isn't sure why hypoxic cells tend to be more aggressive but suspects it may have something to do with gene expression—with certain proteins found in hypoxic cells.