Xenogen's Pamela Contag.

The ability to track the molecular action of disease or other biological processes within live subjects is a potentially invaluable tool for studying the broad array of drug targets identified by genomic and proteomic research.

Medical imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) can be deployed, but they demand expensive equipment beyond the reach of many labs and provide limited functional information. A simple but effective alternative is to use optical imaging techniques that exploit the properties of light-emitting enzymes.

This approach was pioneered at Stanford University in the mid-1990s by husband-and-wife team Christopher and Pamela Contag, together with David Benaron. The Stanford team infected mice with bacterial pathogens that had been engineered to carry the gene for luciferase, the enzyme that makes fireflies glow. As these pathogens spread through the mice, light emitted by the luciferase could be detected with a highly sensitive CCD camera.

In 1997, Pamela Contag left Stanford to form the company Xenogen to commercialize the technology. Based in Alameda, California, Xenogen now produces both the sensitive light recorders and software required for what it calls biophotonic imaging, and a family of transgenic mice and rats engineered to emit light when tagged genes are activated.

Because all imaging is in vivo, the technology allows longitudinal study design. “You start and end the experiment with the same animal and monitor the same animal over time — this allows you to use 60–80% fewer animals,” Contag notes. “That allows experiments to be run at more reasonable cost, and because we're looking at very early in the disease process, these disease models are less stressful for the animals.”

The company has now signed licensing deals with a string of pharmaceutical companies including AstraZeneca and Bristol-Myers Squibb. “More and more we're using our technology for drug discovery,” says Contag. “For instance, we have a whole series of animals that respond to toxicological stress. Or if drug metabolism is an issue, we have a series of animals that will tell you which enzyme is turned on.”

Xenogen is now developing its technology for use with human subjects, and is also working on improving image quality. Although current resolutions cannot match those of PET or MRI, the technique can provide much more functional information. “There are things you can learn using optical imaging you cannot using PET and MRI,” Contag says. “This is a desktop instrument, and that makes a huge difference as to where you apply it. It's very easy to use and the results are pretty spectacular.”

T.C.