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2011 Neuroscience Prize

Huda Zoghbi

Huda Y. Zoghbi was born and raised in Beirut, Lebanon. Neither of her parents went to college, but her father, who worked from the age of 17 as an extractor of olive oil, was a self-taught scholar. “He loved learning, and he always pushed my sister and brothers and me to read,” Zoghbi recalls.

Zoghbi wanted to study Shakespeare and other English literature in college, but her mother insisted that she study science so she could go into medicine. “She said that as a woman I would have a much more secure career in medicine,” Zoghbi recalls. So she majored in biology at the American University of Beirut, and then, in 1975, enrolled in the university’s medical school. That was the year, however, that civil war erupted in Lebanon. “There were bombs and bullets falling all around the campus,” says Zoghbi. “We finished the year living in the basements of buildings.”

After her youngest brother was injured by shrapnel, Zoghbi was sent with both her brothers to the United States to spend the summer with their sister, who was living in Texas. “My parents thought things would calm down during the summer,” she says. “But things went from bad to worse, and we couldn’t re-enter Lebanon anymore.” Zoghbi quickly searched for a U.S. medical school that would accept her late application—and found herself welcomed at Meharry Medical College in Nashville, Tennessee, where she completed her medical training in 1979.

Although she thought she would become a pediatric cardiologist, Zoghbi found herself drawn to neurology during her residency at Baylor College of Medicine in Houston, Texas. “I really became fascinated with neurological disorders. They’re like puzzles. You take a history from a patient and observe the patient’s symptoms and then work backwards to figure out what part of the brain is involved,” she says.

Zoghbi intended to be a clinical pediatric neurologist, but soon turned to research. “I was encountering a lot of patients who had devastating neurological problems, and many of them were genetic,” she recalls. “All we could do was make a diagnosis, but we didn’t know the cause. I found that really quite devastating, particularly after I got pregnant with my first child. That’s really when I started feeling the pain of the parents amplified.”

While still a resident at Baylor, Zoghbi met a five-year-old girl named Ashley with the neurodevelopmental brain disorder known as Rett syndrome. She had been a typical, healthy child until about the age of 18 months, when she became withdrawn, avoided eye contact, and eventually stopped talking. She also suffered from seizures and obsessively wrung her hands—other common symptoms of Rett syndrome. “She made a very big impression on me,” says Zoghbi. Looking through Baylor’s medical records, Zoghbi discovered more girls with similar devastating symptoms. “I knew then that I wanted to find out what was causing them,” she said.

“Most people go into science because they’re curious about something,” she adds. “I have to say that I went to into it to discover something that might help the patient.”

After completing her residency in 1985, Zoghbi took a postdoctoral research fellowship at Baylor’s Institute of Molecular Genetics. Three years later, in 1988, she started her own lab there, where she has remained ever since.

Although Zoghbi was eager to research Rett syndrome, her mentor at Baylor, molecular biologist and geneticist Arthur L. Beaudet, MD, suggested she begin with a more “tractable” problem: spinocerebellar ataxias (SCAs), a family of brain disorders that are caused by a degeneration of the spinal cord and the cerebellum, an area of the brain essential to motor control and coordination. In 1993, in collaboration with Dr. Harry Orr at the University of Minnesota, Zoghbi announced the discovery of the genetic mutation responsible for SCA type 1. They also found that the product of that mutant gene is a protein called ataxin-1, which becomes large and sticky, eventually disabling cerebellar cells involved in controlling movement. That discovery launched a search for drugs that might clear the sticky and damaging tangles caused by ataxin-1, and thus slow down the progression of SCA1 or prevent it altogether. It also provided scientists with a deeper understanding of the role of protein aggregation in other neurodegenerative diseases.

After her success with SCAs, Zoghbi returned to the puzzle of Rett syndrome. At the time, it was not known if Rett syndrome was genetic, for the disorder has no clear familial transmission. Most families have only one person affected by the disorder. Undeterred, Zoghbi decided to go on a full-blown gene hunt, and in 1999, she and her collaborators announced that they had identified MECP2 as the gene responsible for Rett syndrome. This discovery explained many of Rett’s puzzling symptoms, for MECP2 encodes a protein (methyl-CpG-binding protein 2) whose activity performs a crucial role in the function of mature brain cells. The discovery of MECP2 also explained why the disease occurs mainly in girls. The gene lies on the X chromosome, and thus girls, with two X chromosomes, have one healthy copy of the gene. But when males inherit a mutated MECP2, they have no chance of a healthy copy, and are likely to die soon after birth. Those males who survive tend to have milder MECP2 mutations, which can cause autism, intellectual disability, and even psychosis.

Another major finding from Zoghbi’s lab has been the identification of Math1, a kind of “master gene” that plays a critical role in the formation of hair cells in the inner ear and in the formation of specialized neurons in the cerebellum and spinal cord involved in balance and proprioception (the unconscious sense of one’s position in space). Further investigations revealed that abnormal activation of Math1 can lead to the continuous proliferation of granule cells in the hindbrain in mice. The nonstop growth of these cells is a factor in the development of a common childhood brain tumor called medulloblastoma. Zoghbi and her team have found that if they remove or knock out Math1 in mice, the animals do not develop the tumor.

“Math1 turned out to be a medically relevant gene,” says Zoghbi. “It’s a beautiful example of how doing science for science’s sake opens up new pathways that benefit mankind.”

Zoghbi is married to cardiologist William A. Zoghbi, MD, who holds the William L. Winters Endowed Chair of Cardiovascular Imaging at the Methodist DeBakey Heart Center, is director of the Cardiovascular Imaging Institute at The Methodist Hospital in Houston, and is the president-elect for the American College of Cardiology. They met during medical school in Beirut. They have a 26-year-old daughter, Roula, who works in public health, and a 24-year-old son, Anthony, who is a second-year medical student.