The Jackson Laboratory
Dr. John is also a professor at the Jackson Laboratory, Bar Harbor, Maine, and a research assistant professor of ophthalmology at Tufts University School of Medicine, Boston.
The Molecular Basis of Glaucoma
Simon John attributes his early interest in science to a library book about rainbows, an uncle who taught him to use a microscope, and the snakes he caught near his Welsh hometown. His passion for genetics was sparked by his father, who bred finches as a hobby. John watched with amazement as his father mated the drabbest birds to produce offspring with stunning cinnamon plumage. “That got me interested in natural variation from a very early age,” he says.
John now studies the genetics of glaucoma, a potentially blinding eye disease that affects up to 70 million people worldwide. It results from damage to the optic nerve and is often preceded by high intraocular pressure. Partly because of his own poor eyesight, John empathizes with people who have more serious problems. “I want to understand the mechanism of glaucoma, with the goal of suggesting new ways to improve vision care,” he explains.
He became interested in this complex disease while studying the causes of high blood pressure, because he wondered if certain peptides might also control pressure inside the eye. Scouring the scientific literature, he was shocked to discover how little was known about glaucoma at the molecular level.
When he moved to the Jackson Laboratory in Maine in 1995, John decided to study glaucoma in an animal model. “I thought it would be easy to take the genes we had implicated in high blood pressure and work with them in the mouse eye,” he says.
But many scientists who studied glaucoma at that time had a low opinion of the mouse. “Some people told me I was wasting my time using mice for glaucoma research, because mice were anatomically inappropriate,” John says.
Through painstaking anatomical studies, John showed that the pertinent structures in the eyes of mice and men have a lot in common. Over their early years at the Jackson Laboratory, he and his group developed the first mouse models of glaucoma, developed the necessary tools for studying them, and adapted human eye exams to mice. “Now all of the powerful tools of classical and modern mouse genetics can be used to study glaucoma,” he says. “I’m very proud of the way that has taken off.”
Using one of these mouse models, John’s group discovered that errors in a gene that codes for a type of collagen cause a glaucoma-like condition. Realizing that this collagen also strengthens blood vessels, they showed that the gene predisposes mice and humans to bleeding in the brain. “This work suggests possible behavioral and medical interventions that could massively reduce the risk of hemorrhagic complications and sudden death in families with this gene,” John says. “For example, individuals in those families could avoid playing contact sports or exercising too vigorously.”
Other mouse models have generated some surprising suggestions for preventing glaucoma. John studied a mouse with defects in a gene called Cyp1b1, which human geneticists had associated with a devastating glaucoma of infants and toddlers. By crossing those mice and strains with other genetic constitutions, John discovered a gene that modulates the effects of Cyp1b1 defects on the eye. That gene codes for an enzyme that makes L-DOPA, a naturally occurring amino acid used to treat Parkinson’s disease. When John’s group spiked the drinking water of female mice with L-DOPA before and during pregnancy, the effects of the Cyp1b1 defects were largely prevented. “That’s very exciting, because there are many ways to adjust L-DOPA levels,” he says. If L-DOPA has the same effect in humans and passes the appropriate safety trials, it could be given to pregnant women who have a defective Cyp1b1 gene and whose children are at risk for glaucoma. Or such women might get enough L-DOPA simply by eating beans.
Another insight into glaucoma prevention was totally unexpected. John was studying mice that are prone to a type of glaucoma in which the iris falls apart and the eye’s drainage channels become damaged by pigment and debris. By the time the animals are middle aged, their optic nerve is usually ruined because of the high pressure inside the eye.
To explore mechanisms contributing to this condition, John’s group gave the mice one high dose of radiation before transplanting them with bone marrow. As the animals aged, most of them had healthy optic nerves, even though they still had iris disease and high intraocular pressure. “We could hardly believe it. That was the biggest surprise of my career,” says John, who then contacted scientists who are following the lives of more than 10,000 survivors of the Hiroshima and Nagasaki atomic bombs. It turned out that the survivors who received the highest dose of radiation from the atomic bombs were the least likely to have glaucoma.
In collaboration with physicists and engineers, John is devising ways to target specific amounts of radiation to parts of the tiny mouse eye so he can determine the molecular mechanism of protection. If this project pans out in mice and humans, it might one day be possible for ophthalmologists to give patients a dose of radiation that would be as safe as a dental x-ray and that would protect against glaucoma for life. “That’s a pipe dream right now,” John says. “But it will be fantastic if it works.”