Our discovery of the role of the tyrosinase gene is another area ripe for a clinical look. We discovered that mice with a mutation in the tyrosinase gene, coupled with a second culprit gene, Cyp1b1, had severe eye-drainage structure malformations similar to those that cause glaucoma in people. When we put L-DOPA, a product of tyrosinase, in the drinking water of pregnant mice deficient in CYP1B1 and tyrosinase, their pups did not have severe structural abnormalities. We want clinicians to take this result and run with it, though it may be safer to modulate the tyrosinase gene than to directly manipulate L-DOPA.

David K. Dueker is a clinician in Saudi Arabia, where early-onset glaucoma involving CYP1B1 is common, often resulting in childhood blindness. Dave would like to study the impact of fava beans, a dietary staple in the region that is rich in L-DOPA. He wants to ask: "If a woman with the CYP1B1 mutation has a baby with a milder form of glaucoma, was she eating a lot of fava beans? That is, was she medicating herself with L-DOPA without knowing it?" We'd like to complement this epidemiology with mouse studies, which I hope can do his patients some good. These L-DOPA studies may also help patients with glaucoma caused by several other genes that affect tyrosine hydroxylase, another enzyme that makes L-DOPA. Disturbances in L-DOPA may be a unifying theme in these glaucoma cases.

The last area I want to mention is furthest from clinical application, but still very exciting. Through serendipity, we discovered that radiation plus bone-marrow transfer in mice provides complete protection from glaucoma! While studying a form of the disease called pigmentary glaucoma, we observed that none of the glaucoma-prone mice we irradiated had any glaucoma damage. This was a hugely surprising outcome that we just couldn't fathom. So we did it a second and third time, and got the same results. In about 96 percent of the animals, protection was complete. We seemed to stop the disease dead in its tracks—long-term.

This effect doesn't seem to be unique to the mouse strain. A group studying atom-bomb survivors of Hiroshima and Nagasaki found that the people with the highest radiation exposures seemed to be protected from glaucoma. Now our challenge is to understand the mechanisms involved. Maybe there's a way those mechanisms can be "bottled" and turned into medications or preventive measures down the road.

Interview by Cori Vanchieri

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