December 24, 2013 | 3
A professor at Baylor College of Medicine (B.C.M.) has received the Pearl Meister Greengard Prize for her pioneering work as a neuroscientist. The prestigious $100,000 prize is awarded annually to a distinguished woman in biomedical research. Huda Zoghbi discovered the genes for spinocerebellar ataxias (SCAs) type 1 in 1993, atonal homolog1 in 1996, and for Rett syndrome in 1999. In addition to teaching, she leads over 25 researchers in her neurogenetics lab at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, where she is also the director and a Howard Hughes Medical Institute investigator.
The Rockefeller University awards the prize annually to recognize women in the field of biomedical research. Nobel laureate Paul Greengard and his wife, sculptor Ursula von Rydingsvard, established the prize in 2004 in hopes it would influence the scientific community to recognize the significant contributions women have made to science. Greengard himself won the Nobel Prize in Physiology or Medicine for his discovery regarding events set off by neurotransmitters within the nervous system. He gave his portion of the prize, about $400,000, to fund the award.
Two previous winners of the Pearl Meister Greengard Prize have subsequently won the physiology or medicine Nobel (Elizabeth Blackburn and Carol Greider in 2009). In winning her award, Zoghbi says she “felt extremely humbled to be in the company of such great women [and to be] recognized by a man who has made so many contributions for science, yet he looks out for others.”
Zoghbi was born in Beirut, Lebanon. Neither of her parents went to college, but both understood the importance of education and science. Having fallen in love with Shakespeare, Zoghbi initially wanted to pursue literature in college. Her mother convinced her to study biology instead. While attending her first year of medical school at the American University of Beirut, the Lebanese Civil War broke out. Students had to live inside the medical school building for weeks at a time with their professors to continue their studies, because it was too dangerous to travel between home and school. She finished her freshman year of school in 1976 and headed to her sister’s residence in Texas with her two brothers. They planned to return to Lebanon for school. Due to the war, however, Zoghbi was not able to return and found herself searching for a medical school that would accept a transfer student in October (classes start in August).
Zoghbi only applied to two schools, as it was clear that no school was willing to accept a medical student two months late. She received acceptance at the Meharry Medical College in Nashville. After finishing the program, she again wanted to return to Lebanon. Her professors in Beirut advised her against it, however, because the war had intensified. She instead became a postdoctoral scholar at B.C.M. in Houston, where she has remained.
Inspired to research
Zoghbi started her pediatric residency at B.C.M. in 1979 and her neurology residency in 1982. In the fall 1983, Pediatrician Merlene McAlevy referred a Rett patient to Texas Children’s Hospital, affiliated with B.C.M., and sent the patient with a copy of the first account of Rett syndrome written in English. Zoghbi saw the patient and read the account. One week later, Zoghbi saw another patient who she immediately recognized as having Rett. The experience “shook” her, and she began to look for more patients by reviewing records and inviting them back to the clinic for evaluation. People with Rett experience language deficiencies, motor problems, seizures, balance issues, stereotyped behaviors typical of autism and breathing problems, among other ill effects. “”It is a disease that impacts the whole central nervous system,” Zoghbi says. Inspired to get to the bottom of the disorder, she decided to pursue research.
It was widely suspected that the genetic mutation for the syndrome was located on the X chromosome, because nearly all Rett’s patients are females, says Arthur Beaudet, B.C.M. geneticist and Zoghbi’s mentor.
Zoghbi set her sights on finding the gene on the chromosome, but Beaudet suggested she focus on a more solvable problem first. In 1985, it would not have been possible for Zoghbi to find a gene for a disorder that occurs for the first time in a family due to a genetic mutation. The mass amount of genetic data, and the technology necessary to read that amount of information, didn’t exist yet, Beaudet says. Zoghbi never stopped searching, collecting DNA samples and “slowly marching down the X chromosome to find the culprit.”
During this time, however, she mainly worked on spinocerebellar ataxias type 1 (SCA1), an inherited neurodegenerative disorder that affects balance and the motor system. Zoghbi collaborated with geneticist Harry Orr of the University of Minnesota on the project. On the same day in April 1993 they both found the SCA1 gene mutation in their respective labs and faxed their blots, which identified DNA mutations, to each other. Both of the blots made it to the paper describing the SCA1 gene discovery. “To have found the gene together, on the same day, was awesome,” Zoghbi says. “The moment we found the gene mutation stands out to me because it proves our collaboration was beautiful.”
While Zoghbi continued to work on SCA1, she conducted developmental neurobiology research on atonal homolog1 (Atoh1). In 1996, Zoghbi’s lab identified Atoh1 (also known as Math1). Over the next 15 years, she and other researchers found the gene proved critical for a diverse range of functions, including hearing, balance, breathing, and medulloblastoma, the highly malignant brain tumor that primarily affects children.
Her work in Rett syndrome made strides as she studied two families with two affected sisters in each and collaborated with geneticist Uta Francke, who herself was studying a separate family with three affected females and one severely affected male. Pooling their data narrowed the search to a region of approximately 10 million base pairs. From there, they sequenced genes one by one in a brute-force effort to identify causative gene, Zoghbi says. One day in August 1999 Zoghbi had just returned to the U.S. from an overseas trip to Beirut when her post-doctoral fellow, Ruthie Amir, called. Amir had been sequencing many genes and looking for one with mutations in multiple Rett patients. Amir asked me if she could come over and show me some data, because she had thought she found it, Zoghbi says. She brought her lab book and they went over images of the DNA sequence data, and she did indeed find it. “I was stunned, excited, and relieved [that we] finally found the cause of this perplexing disorder,” Zoghbi adds.
Found in every cell of the brain, the gene, MECP2, plays a critical role in the central nervous system. “The identification of the gene was the basis and the starting point of all the discoveries that followed,” says Christian Schaaf, assistant professor in the Department of Molecular Genetics at B.C.M. who considers Zoghbi his mentor and friend. The discoveries included figuring out the gene is critical for the function of practically every brain cell. It made mouse models of Rett syndrome possible, which recapitulate a lot of key features of the disorder, even the abnormal hand movement seen in patients. “They present a fantastic tool to study therapeutic interventions for Rett syndrome before moving into clinical trials with humans,” Schaaf says. Using the models, researchers found that Rett could be reversed in mice. Unfortunately, although symptoms of Rett syndrome can be alleviated, the disorder can’t be cured yet, nor can most sufferers live independently.
Winning the prize
Zoghbi hopes that winning the Pearl Meister Greengard Prize will “make the world aware that women are as important contributors in science as men are.” She also hopes her recognition encourages younger generations of women to seriously consider careers in science. “Students in middle school and high school may not be aware of how rewarding a scientific career might be for a woman,” Zoghbi says.
“I would do this over and over and over again. I would never trade this career with any other career,” Zoghbi says. “It’s really been so exciting to work with families, colleagues [and] students – to come to work not knowing what you will learn, but knowing you will learn something that will add to the greater pool of knowledge. I find that very rewarding.”
12 Digital Issues + 4 Years of Archive Access just $19.99X