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Scheduled to soon have a hip replacement, he offered Lifton some bone samples, which were accepted with great appreciation. “Being able to study gene expression on living bone is a real rarity,” says Lifton. Those bone chips harvested during the surgery are already showing promise for developing therapies that would mimic the LRP5 mutation's mechanism of action.
Ironically, Packard's wife has osteoporosis. “It's just a miserable condition,” he says. If Lifton, other scientists, and drug developers at pharmaceutical companies can develop a medication that affects osteoporosis patients much like the LRP5 mutation does Packard, the damage experienced by millions, including Packard's wife, could potentially be repaired. Today's therapies, by contrast, can only slow the disease's progression.
Like many genetic scientists, Lifton also does large studies that may involve hundreds of members of the same family. He has recruited thousands of patients for his research and often gets invited to family reunions to collect DNA and clinical histories from a large segment of a family at one time. “The response is overwhelmingly enthusiastic,” he says. “People say, `This is a problem for my family. Of course I want to participate.' It is all very inspiring to me.”
Similarly, Edwin M. Stone—an HHMI investigator at the University of Iowa who studies eye disorders and other related genetic syndromes—keeps pictures posted in his laboratory of patients with whom he has worked. “The message is: These colorless tubes of DNA we're handling represent human beings, their families, and a lot of things really important to them,” says Stone. “Science is exciting, challenging, and interesting, but all that pales compared with the impact it has on the lives of real human beings. And when you see an obstacle and say, `Gee, it isn't going to work,' the thing that makes you want to start over and push your shoulder into it is the interaction with patients.”
Val C. Sheffield, Stone's University of Iowa collaborator for more than a decade and a fellow HHMI investigator, agrees. “I like to go to the clinic,” he says. “It keeps you focused on what's important.”
Stone and Sheffield have discovered many of the genes responsible for blindness-inducing eye diseases, including common and rare forms of glaucoma and macular degeneration. But the beginnings of their disease gene-hunting collaboration came about by chance, “an encounter,” says Stone, “that had nothing to do with the disease.” In Stone's first weeks as an ophthalmology resident interested in visual genetics, he was taking the history and performing a physical on a child who was scheduled to undergo a routine surgical procedure. While sitting in the examination room waiting for the surgeon, he chatted with the child's mother about genetics. She mentioned that numerous people in her family had developed an unusual form of blindness—a condition that sometimes struck in childhood and progressively resulted in loss of central vision.
A few days later, Stone drove 100 miles across Iowa to a pizzeria the family owned. They had closed the restaurant for the evening and invited 60 relatives for dinner. By the time he headed home, Stone had built a family tree, taken clinical histories, and collected blood samples from everyone in the place. It turned out that those with the visual disorder had a rare inherited form of macular degeneration called Best disease, also known as vitelliform macular dystrophy. Best disease starts when cysts grow in the macula, the central part of the retina responsible for fine visual detail and color perception. When the cysts burst, they cause the macula to deteriorate, leading to loss of vision.