Every Sunday, Huda Y. Zoghbi, MD, heads into her kitchen to prepare a new recipe for her family. She has come to learn a thing or two about ingredients and the planning and care that goes into making memories. There is the surprise of a new idea and doing something in a different way. The experience — both for the woman who loves to cook and those around her who love to eat — is transformative.
It is these qualities of the master cook that have allowed for similar transformations in her laboratory. As a pediatric neurologist, she takes on new questions about brain diseases with the same commitment it takes to head into the kitchen with a new list of ingredients every week, and never know what the result will be. Dr. Zoghbi sees unlimited possibilities to the number of diseases she can tackle because for any one of them “there are no real treatments.”
Her love of medicine has provided the same kinds of accolades that she receives at her Sunday night table. In June, Dr. Zoghbi was awarded the $500,000 coveted Gruber Neuroscience Prize for her body of work on the genetic and molecular underpinnings of neurological disorders.
Not surprisingly, the majority of the prize is going to support research on childhood neurological diseases. “The Patricia and Peter Gruber Foundation honors and encourages scientific achievements aimed at improving the human condition,” said Dr. Zoghbi, a professor of pediatrics, molecular and human genetics, neurology and neuroscience at Baylor College of Medicine, and Howard Hughes Medical Institute investigator. “We are working hard in hopes of making quality of life better for children with developmental disabilities.”
A LONG HISTORY OF DISCOVERY
Dr. Zoghbi began conducting research in her residency days at Baylor College of Medicine — and has never left the lab or Baylor. In 1993, she and her collaborator Harry T. Orr, PhD, discovered the genetic mutation in ATAXIN1 that causes spinocerebellar ataxia type 1 (SCA1).
Their collaboration and discoveries are helping to unravel the science behind protein aggregation and neurodegeneration. Her next major find was that mutations in the MECP2 gene cause Rett syndrome. Mutations in MECP2 proved to cause a variety of disorders besides Rett, including certain forms of childhood schizophrenia, bipolar disorder, intellectual disability, and autism. Dr. Zoghbi and her colleagues are now searching for ways to develop treatments for these diseases, “but there is a long way to go from a cause to a therapy,” she said.
In a study published in June in Science Translational Medicine, Dr. Zoghbi and her colleagues describe the network of proteins involved with autism and other conditions where patients share autistic features, and how the proteins interact together to cause symptoms that are shared across conditions. Working in collaboration with scientists at the Center for Cancer Systems Biology at the Dana-Farber Cancer Institute, they looked at 26 genes associated with the symptoms of autism and began asking the question: what do these genes have in common, if anything, and how do they independently trigger the same symptoms of autism. They asked: What is the protein interaction and are there features that are shared between the genes that could help explain this final common outcome? They identified 539 proteins that interact with 26 proteins associated with autism. They have identified new genes using this method and reported on three new copy number variations involving three genes in the network.
In 2000, Dr. Zoghbi became the youngest faculty member and the first woman at Baylor to be admitted to the Institute of Medicine. Four years later, she was elected into the National Academy of Sciences. And her commitment to push translational research to move from cause to therapy for her patients led to the discussion a few years ago to create the country's first neurological research institute dedicated to basic research into childhood neurological diseases.
Last year, the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital opened, and the first five floors of the 13-story building are brimming with brain power. Dr. Zoghbi is the institute's founding director.
Her interest in cerebellar development led to the identification of the mouse atonal homolog 1, or Math1. This gene is involved with many functions that take place during neuronal development and is involved with the abnormal growth of cancer cells in some subtypes of medulloblastoma.
Math1 is involved with the formation of hair cells in the inner ear and neurons that regulate balance and sense of the individual's position in space. When they pressed the gene further, they found that continuous activation caused granule cells in the hindbrain (of mice) to divide out of control. “We can begin to explore this system to develop treatments for age-related deafness and vestibular problems, as well as for medulloblastoma,” Dr. Zoghbi said.
Many of these discoveries involve new ways of looking at the loss or gain of proteins that can damage the brain. And the findings also point to the importance of epigenetics, the link between our genome and our environment, said Dr. Zoghbi. “This relationship has been giving us clues how we can change the net result of our biology without going in and replacing genes,” she said.
She and colleagues are searching for genes that could protect against the mutated form of the genes, as well. In the laboratory, they observe animals with mutations that have more subtle phenotypes and track these mutations to see what could be buffering the animals from more severe disease.
For Dr. Zoghbi and her team, the journey is always leading to surprises. For instance, they are always tweaking the expression of mutant and normal genes to discover how that leads to changes in behavior. A recent reduction in gene expression of MECP2 in the hypothalamus led the scientists to conclude that the gene plays a role in how an animal responds in a social situation, anxiety and feeding behavior. “It may have implications for conditions like autism,” said Dr. Zoghbi.
“There are numerous examples of basic science that has inspired translation into clinical treatment,” said Carol Barnes, PhD, Regents' Professor in the Departments of Psychology and Neurology, director of the Evelyn F. McKnight Brain Institute and Research Scientist in the Division of Neural Systems, Memory & Aging at the University of Arizona, and chair of the Selection Advisory Board to the Neuroscience Prize.
“What stands out about Dr. Zoghbi's discoveries is that the original inspiration for her science was her clinical observations — and her determination to ‘go to the bench’ to solve the mystery of the disorder. Her work has revealed probable underlying mechanisms of a number of postnatal neurologic disorders, for which the path to clinical treatment can now be realistically followed — this trajectory to discovery and potential treatment is simply inspirational.”