Huda Zoghbi
For a few months during medical school, Huda Zoghbi slept in a windowless closet inside a women’s bathroom at the American University of Beirut. Outdoors, the Lebanese civil war raged, making daily trips between home and lectures too dangerous. She and her classmates ate in the hospital cafeteria, which they accessed through an underground tunnel. At night, she fell asleep atop her sleeping bag, listening to the irregular blasts of exploding bombs.
Zoghbi had not always been so committed to studying medicine. In high school, she developed a passion for Shakespeare and English literature. Left to her own devices, she would have pursued writing as a career, but this possibility dismayed her mother, a full-time homemaker, who pressed Zoghbi to become a physician. Zoghbi was good at biology and liked the subject, her mother contended—and medicine would provide independence. Zoghbi pushed back repeatedly. Eventually, realizing that her mother had a point, she relented.
After Zoghbi’s first year of medical school, her parents sent her and her siblings to safety in the United States. Zoghbi intended to visit a sister for a few months and then return home, but the continuing war thwarted her plans. She wound up finishing medical school in the States, graduating in 1979. Zoghbi gravitated toward pediatrics. Of the possible specialties, neurology enticed her because she relished the detective work. Before touching her patients or running a medical test, she could engage her mind in the puzzle that confronted her. Interviews alone allowed her to map the problem to a particular part of the brain and develop a provisional diagnosis.
Although intellectually satisfying, this specialty soon became emotionally fraught. She grew frustrated at how often she had to tell her patients’ families that their child had a devastating disorder—but that no cure or treatment existed.
As this reality weighed on her, she saw a patient with a provocative disease. This girl had walked, begun to talk, and otherwise progressed typically until she was almost two years of age. She had enjoyed playing with toys, turning book pages, and singing E-I-E-I-O from “Old MacDonald Had a Farm.” Then she started losing words, wringing her hands, avoiding eye contact, and holding her breath or hyperventilating. Having just read a paper from Europe about an unusual condition called Rett syndrome—the first report of this illness in an American medical journal—Zoghbi recognized the hallmark symptoms. A week later, a different child walked into the exam room wringing her hands. Zoghbi quickly realized that this girl, too, had Rett syndrome. This strange ailment with its odd progression intrigued Zoghbi. How could a child develop normally and then lose skills—particularly as neurons did not disappear? What kind of havoc in the brain could propel people into this state?
Although the infirmity seemed to crop up sporadically rather than run in families, Zoghbi had a hunch that it arose because of a genetic mistake: The symptoms were extremely consistent from one person to the next and all of the reported patients were girls. If she could find the gene, she’d have a tool that would help her figure out why the disease takes so long to set in and how it triggers its characteristic neurological problems. With this eventual goal, she began collecting DNA samples. Before she could hunt down the hypothetical gene that underlies Rett syndrome, however, she needed to learn how to do research. Tracking down the genetic cause of a rare disease that does not cluster in families would pose massive challenges even to an experienced genetics investigator, which she was not. To learn the required skills, she signed on as a postdoc with Arthur Beaudet at Baylor College of Medicine, in Houston, and decided to study a different illness—an inherited progressive balance disorder called spinocerebellar ataxia type 1 (SCA1) that can eventually interfere with eating and breathing. She continued this work after she established her own lab at the same institution in 1988.
Zoghbi teamed up with Harry Orr at the University of Minnesota to isolate the gene responsible for SCA1. From patient histories, a curious feature of the disease jumped out at her. In some families, each subsequent generation produces younger affected individuals. As Zoghbi listened to a seminar about a different illness that shares this attribute, a particular point struck her. The other disorder results from expansion of a repeated triplet sequence in the genetic code—and it can lengthen as the gene is passed down. The expanding genetic stutter exacerbates symptom severity and decreases the age of onset. Zoghbi decided to look for a similar repeat inspinocerebellar ataxia patients. In 1993, she and Orr discovered exactly that kind of genetic mark, a finding that pinpointed the gene they sought. Furthermore, they found that the size of the repeat inversely correlates with the age at which symptoms appear.
Subsequent work on mice and flies by Zoghbi and her colleagues has probed the normal function of the gene and suggested that protein misfolding promotes SCA1’s destructive effects. These findings are opening new avenues toward potential therapeutics and have enhanced scientists’ understanding of other neurodegenerative problems, including Alzheimer’s and Parkinson’s diseases. In the meantime, Zoghbi had been banking DNA from Rett patients and their parents since her postdoc, and she had begun to stalk the hypothetical gene. In most cases, only one girl in a family had Rett syndrome—but in two families, sisters with different fathers came down with the disease. Although Zoghbi knew of only these two families with more than one affected individual each (four patients total), the apparent inheritance pattern suggested that the syndrome arose from a marred gene that resides on the X chromosome.
As a first step, Zoghbi excluded regions of the X chromosome that were not shared between half siblings. Although this process whittled down the suspect area, it left a vast stretch of DNA and a daunting experimental task. Funding agencies, reviewers at scientific journals, and colleagues were skeptical that she would succeed. Rett syndrome was rare, most families had only one affected member, and the malady did not likely result from a genetic glitch anyway. They told her she was wasting her time.
Weary of this response, Zoghbi stopped telling people that she was pursuing the project. Now in stealth mode and stuck with a sizable piece of the chromosome, she convinced members of her lab to undertake the tedious job of analyzing genes—one by one—in the DNA span of interest, looking for sequence changes carried by people with the disease but not by unaffected individuals. Along the way, two additional affected families emerged, which helped focus the search. Through a painstaking process over a period of seven years, the team ruled out 19 genes.
At summer’s end in 1999—16 years after Zoghbi had seen her first Rett patient—she returned from a visit to her parents in Lebanon. Jetlagged, she put her key in the door as the phone rang. Her postdoc had been calling every few minutes to tell her the big news. The 20th gene contained DNA-sequence glitches in patients and not their unaffected relatives. Zoghbi finally had captured her prey. Work from other labs had pointed toward the Rett protein’s function. It likely quashes the activity of other genes by binding to a methyl chemical group on the DNA. Zoghbi subsequently found that the mature mouse brain depends on the continuous operation of this protein. She is now elucidating how it evokes the neurological symptoms of the disease and figuring out why brain cells take time to register its absence. Perturbations in the Rett gene can also cause symptoms of autism spectrum disorders. Clinical manifestations depend on the exact genetic flaw and the percentage of cells in which the normal copy of the gene is active.
Zoghbi has made seminal contributions not only to our understanding of the genetics and pathology of spinocerebellar ataxia type 1 and Rett syndrome, but also to the study of balance. She has demonstrated that even complex brain physiology—and the illnesses that surface when it goes awry—can be rendered approachable by a combination of basic genetics, molecular neuroscience, inspiration, and sheer determination.
Author: Evelyn Strauss, Ph.D.