Photo: Pam Francis

Life During Wartime It was 1975 and Huda Zoghbi had just started medical school at American University in western Beirut when war erupted in Lebanon. “Things were fine for the first six months, but it soon became dangerous to leave the campus,” she says. “Bombs were falling everywhere. I lived a mile and a half from campus, but I couldn’t go home.” Instead, she and her classmates hunkered down for the semester. Zoghbi bunked in the ladies’ room, which was not without its benefits. “I could wash up in the morning and go straight to class,” she says. Others slept in the hallways to avoid being near windows at night. Even so, the students were never totally safe. Zoghbi remembers sitting with a friend one evening. “We saw this big red thing come flying right between us,” she says. It was a bomb fragment tearing through the spot where moments before they had been holding hands. Read more... Related Stories: The Puzzle of Rett Syndrome Polyglutamine Diseases: A Devastating Genetic Stutter Learning in the Lab Huda Zoghbi, Career Highlights

Huda Y. Zoghbi, M.D.
By Karen Hopkin

On a shelf in Huda Zoghbi’s office at the Baylor College of Medicine sits a photo of Zoghbi and a group of people in her lab. The students, scientists, and technicians in the picture stand around a big cake celebrating the successful completion of Seung-Yun Yoo’s Ph.D. thesis. The silver frame that surrounds the photo, a gift from Yoo, bears the inscription, “I love you, mom.”

The affectionate engraving reflects the commitment that Zoghbi feels toward her students, her colleagues and collaborators, her friends, her family, and her patients. “It’s all about relationships,” Zoghbi says of her career. The people around Zoghbi provide her with the support, guidance, and inspiration to carry out her research—exploring diseases that lay waste to the human nervous system.

Zoghbi wasn’t always dedicated to a life of science. “In high school I liked biology,” she says. “But I loved literature. I fell in love with Shakespeare, with poetry.” She hoped to major in literature and write poetry—but her mother put a stop to that. “She said that literature could be my hobby,” says Zoghbi. “But she wanted me to go to medical school, graduate, and open a clinic—to keep my life simple,” she laughs.

The budding poet listened to her mother, and she did well in medical school. “I enjoy anything as long as it’s intellectually stimulating,” Zoghbi says. After graduating, she went to Baylor, where she intended to go into pediatric cardiology. Until she did a rotation in neurology. “I just loved it,” she says. “Neurology grabbed me because of how logical it is. You observe the patient, analyze her symptoms, and work backward to figure out exactly which part of the brain is responsible for the problem. You solve anatomical riddles by paying attention to details, listening to the patient, and then putting all the information together. It’s like a puzzle.” At the same time, Zoghbi found herself fascinated by disorders that affect the brain. “The brain is so vulnerable—so many things can go wrong,” she says.

In the second year of her residency, Zoghbi encountered a very puzzling patient. The girl had been a perfectly healthy child, playing and singing and otherwise acting like a typical toddler. At the age of two, she stopped making eye contact, shied away from social interactions, ceased to communicate, and started obsessively wringing her hands. “She made a huge impression on me,” says Zoghbi. What caused this sudden neurological deterioration? she wondered. And why was the child normal for so long?

The girl, it turns out, was a victim of Rett syndrome, a disorder that occurs primarily in females. Girls with this rare neurodevelopmental disorder develop normally for about 6 to 18 months and then start to regress, losing the ability to speak, walk, and use their hands to hold, lift, or even point at things.

With the help of the volunteers at the clinic, Zoghbi identified a half dozen girls who had Rett syndrome. All had been given the wrong diagnosis. She wanted to help these children, but in the end Zoghbi decided that she could do more for her patients at the lab bench than in the clinic. “Seeing these girls was so frustrating,” she says. “I couldn’t handle having to walk in, give the parents the bad news, and walk out.”

So Zoghbi set aside her clinical work to devote herself to research. The switch was a bit frightening at first because, Zoghbi says, she “knew less molecular biology than the technicians” in the lab. But after three years of training, Zoghbi acquired the skills she needed to track down the genes that underlie neurological disorders.

Zoghbi wanted to start by studying Rett syndrome, but her scientific colleagues advised against it. “A lot of people told me I was ridiculous, that I would be wasting my time,” she says. Many physicians doubted that Rett was a unique syndrome. “One very famous neurologist from a top institution said we were just putting a new name on an old diagnosis: cerebral palsy,” says Zoghbi. And even if Rett were a “new” disease, it was a sporadic disease so rare—striking 1 child in 10,000 to 15,000—that finding the gene responsible would be almost impossible. “After a while,” says Zoghbi, “I stopped telling people I was working on Rett.”

And for a time she did stop working on Rett—or at least put it on a back burner while she studied another disease, spinocerebellar ataxia type 1 (SCA1). This neurological disorder strikes later in life, when people reach their 30s or 40s. Patients with SCA1 experience a deterioration of balance and coordination that renders them unable to walk or talk clearly, or eventually to even swallow or breathe. To help her track down the gene that causes SCA1, Zoghbi first identified a large family that seemed particularly prone to the disorder. She went from house to house in rural Montgomery, Texas—50 miles north of Houston—to meet and examine members of the family. Of the 200 people she visited, 60 had the disease. “I felt so sad for the family,” says Zoghbi. “They were very poor. They had no plumbing, no bathrooms. And they had no idea what was wrong with them. They thought they had rickets because they couldn’t walk so well.

“When I cloned the gene,” she says, “I called them first.”

After her success with SCA1, Zoghbi turned her attention back to Rett because, she says, “nobody could tell me not to.” And 16 years after she saw her first patient with Rett syndrome, Zoghbi and her collaborators identified the gene responsible for the disorder.

“It wasn’t all success,” Zoghbi says of the journeys that led her to these genes. “I had more negative data than you can imagine.” But she stuck with it because of the patients. “I worked with these families, I got to know them, and I wanted to help in some way,” says Zoghbi. “When you see the plight of these patients and their families, how can you quit? They hadn’t given up on me. How could I give up on them?”

Along the way, Zoghbi relied on the support of her collaborators, her husband, and even her children. “I’ve always involved my kids in what I’m doing,” she says—and that includes her science. “I once submitted a manuscript to Science or Nature and was anxiously awaiting the verdict,” says Zoghbi. “And my daughter said, ‘If I were you I would have sent it to Nature Genetics. They’re always so good and efficient with their reviews.’ She was 13 at the time.”

And Zoghbi still keeps in touch with the families who let her into their lives. “When they call, I’m happy that I have something to tell them,” she says. “Maybe we don’t yet have a treatment. Maybe we don’t yet have a cure. But every six months, I can say we’re another step closer.”

“In 10 years,” says Zoghbi, “I hope we’ll have drugs to slow the progression of neurodegenerative diseases.” In a way, she’d just be returning a favor. “For me,” says Zoghbi, “I wouldn’t be where I am without my patients.”
 

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