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While large numbers of patients are often needed for biomedical studies, sometimes an encounter with a single patient can also contribute to, even radically alter, a scientist's thinking. In 1999, HHMI investigator Huda Y. Zoghbi announced to a group of reporters gathered at Baylor College of Medicine that she had found the gene mutation responsible for Rett syndrome, an inherited disease that strikes young girls and leaves them severely disabled for life. Sitting in the first row at the news conference was Ashley Fry, by then a bright-eyed, dark-haired young woman. Zoghbi made sure to invite Ashley, even though she could not understand the proceedings. “The person who put me on the road to that discovery needed to be there,” says Zoghbi.
Years before that day, as a pediatric neurology resident in Houston, in 1983, Zoghbi fully intended to go into clinical practice. “I was not planning on becoming a scientist,” she recalls. But then she encountered three-year-old Ashley and her parents, and Zoghbi's life changed.
Ashley had been developing normally until, at age 18 months, she suddenly lost control of her hands and had trouble standing and walking. Then she regressed in other ways, including losing most of her communication skills, and she began having seizures. Eventually, she developed severe scoliosis—curvature of the spine—which required several surgeries. Her deterioration stabilized, but her developmental progress came to a halt. “How,” Zoghbi asked, “could something going so well suddenly change so terribly?”
Other neurologists had told Ashley's parents that they must have been wrong about their daughter's seemingly abrupt deterioration. She likely had cerebral palsy, they insisted, a disorder that begins at birth, never permits normal development, and causes continuing deterioration. Convinced that her symptoms did not fit this diagnosis, her parents had become increasingly frustrated and disenchanted by the time they encountered Zoghbi.
“To me, at the first meeting,” recalls Ashley's father, Clifford Fry, an economics consultant based in College Station, Texas, “Huda Zoghbi was just another doctor in the room.”
But she listened to the parents' report on their daughter's development and sudden change. “I knew from talking with them that it wasn't there at birth, and I was intrigued.” The same month Zoghbi met the Fry family, a group of European investigators published a clinical paper describing other young girls with a condition exactly like Ashley's. It was called Rett syndrome. “I realized that what Ashley was experiencing must be Rett syndrome and that the syndrome must be caused by a genetic defect, given its occurrence in girls only.” After that visit, Zoghbi and Ashley's parents knew they were dealing with a disease with identifiable symptoms. With that meeting, Zoghbi's plans for her future changed. She redirected her training to obtain research skills in molecular genetics. Today, Zoghbi runs a large neurogenetics research laboratory at Baylor and is one of the world's leaders in the study of childhood neurological disorders.
Zoghbi's goal was to identify the gene mutation responsible for Rett syndrome; it took her another 16 years. In 1999, she finally announced that she had found the culprit, a gene encoding a protein called “methyl-CpG-binding protein 2,” or MECP2. The protein normally silences several genes during certain periods of central nervous system maturation. But in Rett syndrome, a child has a mutated form of the MECP2 gene that prevents the protein from silencing genes at the appropriate times in the maturing nervous system. This results in normal development for a period followed by sudden nervous-system deterioration at a specific moment in infancy.