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Treatments on the HorizonChapter and Verse on a Brain Killerby Ruth SoRelle, M.P.H.  More than 20 years ago, Huda Zoghbi, M.D., embarked on a journey to find the gene and, ultimately, a solution to a devastating disease called spinocerebellar ataxia type 1 (SCA 1). Today, she and her collaborators are close to understanding the disorder. A treatment for some symptoms is in the offing. There is still no cure. The task has taken longer than she expected. Along the way, she has made friends, acquired an entire scientific family of young scientists and come closer to making a difference in the lives of families who faced an uncertain and frightening future. She chose the disease pragmatically because she wanted to learn how to research an inherited neurological disorder. SCA seemed ideal. It is dominantly inherited, which means that one bad copy of a gene gives you the disease. The symptoms of SCA 1 do not show up for 20, 30 or 40 years. Zoghbi reasoned that if she found the gene and could puzzle out what it did, that time gap gave her a window in which she might be able to do something to help. What seemed an intellectual exercise, however, became highly personal as she witnessed the devastation the disease wreaked on families. She tracked down its victims on the dusty back roads of Montgomery County, Texas, knocking on screen doors and visiting in parlors littered with the walkers and wheelchairs to which SCA 1 consigned its sufferers. First, the disease took the ability to walk. Then it made it difficult for them to talk, to swallow and to breathe. Finally, it took their lives. A professional need became intensely personal as Zoghbi sought to answer the questions. Today, looking back on the scientific papers generated and the thousands of man hours logged in her laboratory and that of her closest collaborator, Harry Orr, Ph.D., Director of the Institute of Human Genetics at the University of Minnesota in Minneapolis, she said, "It's almost like reading a book." Chapter 1: Searching for the GeneArthur Beaudet, M.D., now Chair of BCM's Department of Molecular and Human Genetics, gave her the first clues—the family in Montgomery, Texas, whose DNA spelled disaster for at least half of its members. In 1985, then a fellow in Beaudet's laboratory, Zoghbi drove the country roads to meet them in their homes. "Once you get to know these families, visit them and understand their plight, that becomes your driver," she said. One family led to another, and eventually she began to collect blood and DNA from many. Some of the people she tracked down herself. Others found her and demanded to be part of the research. As one family member told The Houston Chronicle, "We were counseled in the family that we might get it. But no one realized the risk of passing it on to their children. This is the worst thing that could happen to a family." Two years passed before she had identified enough patients and obtained enough blood to allow her to go into the laboratory. "It was daunting, considering also that I knew nothing about research," she said. "This is what I cut my teeth on in science. When do you draw blood? How do you make cell lines and extract DNA? I was looking at a chromosome where the gene might be and I had only four informative markers on that particular arm of chromosome 6." Chromosomes look like strands of DNA beads divided in the middle by a band called the centromere. In the common representation, the part of the chromosome at the top is called the p (for petite) arm and the bottom or longer arm is the called q (because it's the next letter in the alphabet). In order to find a gene in the pre-human genome sequencing era, scientists had to use known places called markers on the chromosome as guideposts. As they manipulated the DNA, these guideposts gave them clues as to how close or far away a gene was. Walking the chromosome depended on markers, and Zoghbi spent her early years alone in the laboratory identifying them. "Lonely is a mild word for how it was," she said. In 1988, "we found the nice marker close to the gene," she said. By that time, she had her own laboratory, and more important she had identified a collaborator—thousands of miles away in Minnesota. Chapter 2: A Key CollaborationDr. Harry T. Orr had been following another family with the disorder and attempting to map the gene. Zoghbi was doing the same for her family, and at the time, it looked as though the genes were mapping to two different places on the genome. Zoghbi contacted him in 1988 with a proposition. "We are working on two different diseases," she said. "I will share these reagents (laboratory tools critical to gene identification). Let's work together." Orr agreed and they began the collaboration. Her gene mapped to an area on one side of a particular marker on the chromosome and his on the other. Then she had what she now calls her "eureka" moment. Her work involved several people in the family. One particular set of blood samples skewed her data to be on one side of the marker. What if that part of the family had actually gotten their gene from a spouse? It turned out that one spouse had died early in an accident and never showed symptoms. However, with that branch of the family reanalyzed keeping in mind the mutant gene came from a spouse, it became apparent she and Orr were working on the same gene. "I called Harry and said, 'I think we are working on the same disease,'" she said. Orr calls the exchange "the call," she said, and his first question was whether she wanted her reagents back. No. She wanted to continue working together, sharing the work in a collegial way. He agreed. They published back-to-back papers in 1990 and 1991, showing that they were closing in on the gene. In succeeding publications, she and Orr have been listed as senior authors, trading positions based on which of their labs did which work. Chapter 3: Finding the GeneFinding the gene cemented the 20-year-old collaboration. "It's a beautiful story," said Zoghbi. "When you have good will, good things will happen." She and Orr had split the areas of the genome that needed to be mapped. One spot overlapped. The gene was in the overlap. They identified the gene on the same day—April 8, 1993. They sent each other faxes announcing the discovery. The faxes virtually passed one another on the phone lines. The gene contained the code for a protein called ataxin 1. In the middle of the gene, the genetic code stutters, repeating the letters C (cytosine), A (adenine) and G (guanine), which code for an amino acid called glutamine. The number of repeats is crucial. Thirty-nine or fewer and you are OK. More than 40 and you have the disease. With each generation, the number of repeats goes up. As a result, the symptoms get worse and appear earlier. There are nine known so-called polyglutamine diseases—among them Huntington disease. They are all brain killers because they kill nerve cells. Chapter 4: Generating ModelsFinding the gene, however, gave them no clue about how to help patients. Their transparent collaboration enabled them to exchange information freely and strategize to get to that point. Orr and his lab made the first mouse model of SCA 1, and it was also the first model of a polyglutamine disease. They published that in the journal Cell. Later, Zoghbi and Orr collaborated with Juan Botas, Ph.D., an Associate Professor of Molecular and Human Genetics at BCM, to breed a fly with the mutant gene. That work also bore fruit in enabling them to understand the protein better. Chapter 5: Understanding the ProteinsThe next milestone came when they showed that losing the function of ataxin 1 does not cause disease. "If you lose ataxin 1, nothing happens. If you add the mutant form, you get the disease," she said. Then they demonstrated that the mutant form of ataxin 1 accumulates in large clumps called inclusions in the cell. The paper showed that by adding important folding components called chaperones one could actually change the size of these ataxin 1 aggregates. A paper from Orr's lab showed that the protein accumulates in the cell's nucleus. Turning the gene off in animals with SCA 1 who had developed coordination problems allowed them to recover, she said. That was another important milestone. Orr's lab identified what is called an amino acid residue—serine 776—that plays a key role in the toxicity of ataxin 1. Zoghbi's lab established which proteins interacted. More recently, they collaborated to identify the key proteins that interact in the brain to modify the disease. Another milestone, she said, was finding out that it was not the protein accumulated in inclusions that caused the disease. Ataxin 1 is most toxic when it is in solution and interacting with other proteins. "The rest of the world did not want to believe our data," she said. "The inclusion (or accumulation) of protein is the cell's attempt to protect it from the mutant protein." Chapter 6: Treating a SymptomAlong the way, they generated a new mouse model that reproduced all the features and devastation of the disease itself. The misfolding of ataxin 1 appeared to affect the expression of many genes in cerebellar neurons. "It was the earliest thing that happened in the disease," said Zoghbi. Because lithium—a really old drug often used to treat bipolar disorder—appears to affect gene expression positively and to protect neurons, they tried it in the mouse. Its coordination got better. Other tests showed that lithium affected learning and memory as well. Zoghbi is continuing to work with experts at the National Institutes of Health on a test of the drugs in humans. "Is this a cure?" she said. "No. While it improves many symptoms, we do not know how it will affect the disease in the long term." Chapter 7: Understanding what goes WrongIn their most recent paper in the journal Nature, Zoghbi and Orr nailed down what goes wrong. It is both a gain and a loss of function for the protein ataxin 1. Think of the cell's nucleus as a crowded neighborhood where function rests with the frequency with which proteins bump into each other. However, when proteins form cliques, associating only with one another, the interaction becomes toxic. When the mutant ataxin 1 bumps into a protein called RBM17, they bind together for a long time, excluding other partners. They gain too much function from their interaction and lose function because they do not bind to other important partners. None of this would occur, however, unless the amino acid residue serine 776 did not interact with RBM17 as well, further extending the length of their association. That makes the serine 776 residue a target in future research into treatments for SCA 1. These unbalanced associations between proteins may play a role in other neurodegenerative diseases as well—including Alzheimer's and Parkinson's. Chapter 8: The Future"There are many important small steps," said Zoghbi. The big ones build on the small steps. "Harry and I have had a lot of phone calls," she said. "We know what we want. We want to be practical. We want to do something for the patients. "We are thinking of strategies to inhibit the phosphorylation of the serine 776 or to inhibit its interaction with RBM17. We are working together toward this goal. We hope it will be the final chapter in the book." EpilogueDespite her goal in this disease, Zoghbi is quick to defend science for the sake of discovering how things work. That kind of science is important and the byproducts are immensely valuable in clinical medicine. "What drives everyone to do science is different. That is the beauty of it," she said. Other byproducts are important. She and Orr are quick to point out the importance of their unusual collaboration. His support in her endeavors have been invaluable, and their friendship has meant a lot to both. How close is it? "When her daughter was coming up here (to Minnesota) to camp one summer, I was the designated contact person," said Orr. Other collaborations are equally important. Zoghbi is loathe to name names because she fears leaving someone out. The contributions of everyone are important, she said. Among the most important interactions have been those with her students. Zoghbi said mentoring the young graduate students and post-doctoral students who work in her laboratory has been a learning experience. Not only does she have to discuss the science with them, but she must advise them on their careers. Janghoo Lim, Ph.D., the post-doctoral student who was first author on the most recent paper to come from Zoghbi's lab, appreciates the management skills that enable Zoghbi to advise a student on science, travel to a conference on the other side of the world and still take time to talk to him about where he goes next in his own scientific endeavors. "She is incredibly organized and she is caring," he said. Zoghbi hearkens back to her own laboratory days. "Between 1988 and 1993, I was still heavily at the bench," she said. That means she performed much of the laboratory work herself. Zoghbi knows that often the effects of her work extend beyond her—to patients and people. In addition to her work on SCA 1, she has found the gene for Rett Syndrome, a neurodevelopmental disease that affects the brains of mostly young girls. There too she has unraveled the track of an errant protein. Her studies of the gene Math 1 show that it affects cells critical for hearing and normal function of the intestine. She started with SCA 1, however, and while she never anticipated that the work would take this long, she is excited where the journey has taken her. "We now have a foothold to start thinking about therapeutics," she said. "It is exciting that we are moving in that direction." |
FeaturesTreatments on the Horizon: Chapter and Verse on a Brain Killer Two Brains are Better than One SpotlightCaring for Community at Home and Abroad Injecting a Little Scientist in Every Doctor Designing a Building in the Eyes of a Researcher Laser Treatments Best Left up to Doctors BriefsFalls in Elderly Indicate Illness Findings may Increase Survival after Injuries Some Like it Hot! Structure of Receptor for Chili Pepper and Pain Revealed Beware of Drinking Margaritas in the Sun Development/AlumniBCM Family Participates in Fundraising Campaign BCM Alums take D.C. Fellowships Seed Funding Leads to Breakthroughs Father, Daughter Team up for Health Care
Steps to Discovery and Innovation  Huda Y. Zoghbi, M.D., Professor of Molecular and Human Genetics, Pediatrics, Neurology and Neuroscience at Baylor College of Medicine and Howard Hughes Medical Institute Investigator
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Volume 4, Issue 2, Summer 2008 |
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