Issue link: https://tmcpulse.uberflip.com/i/532968
t m c ยป p u l s e | j u ly 2 0 1 5 12 Beyond SCA1, the work on this dis- order has helped us better understand Alzheimer's and Parkinson's disease and has provided us insight and new strategies to tackle those more com- mon diseases. Another discovery, the identifi- cation of the gene that causes Rett syndrome, was one of the most import- ant pieces of evidence proving that sporadic (not inherited) autism could be genetically determined. At the time of the Rett gene discovery, in 1999, we had no idea that most autism spec- trum disorders were caused by genetic defects. The Rett gene was one of the first genes discovered that can cause autism and other neuropsychiatric problems. Identifying the gene for Rett syndrome also allows us to accurately diagnose children early and thereby intervene sooner and more successfully with physical therapy. We've also learned that the Rett syndrome gene is important for all aspects of brain function. At the time of the discovery, we had no idea how important it was, but now, after a decade of research, we know it impacts all neurological functions. It tells you when to stop eating by controlling the neurons in your brain that signal when you've had enough food. It's essential to remembering a conversation or reacting to stress. It is important when it comes to learning something new or coordinating movement. It controls the activity of so many brains cells and is a critical gene for many of the brain's functions. We also discovered that mutations in the same gene not only may cause Rett syndrome, but can also cause other disorders such as juvenile schizophre- nia, bipolar disorder (a specific form), as well as classic autism and various intellectual disabilities. The impact of the work is well beyond what we first anticipated when we embarked on the Rett syndrome project. People thought of Rett syndrome as an iso- lated disorder, but we have learned so much more about other disorders and diseases, including how critical certain molecules are for our brain function, by studying Rett. And then there's one more very sig- nificant point. We study these disorders top down, meaning that we start with a patient, drill down to the cause, and drill still further to find the mechanism of disease. But we also have a very interesting project that started bottom up. It started not with a patient, but with an extremely obscure, small organism: a fruit fly. People don't think about how important fruit flies are. In fact, humans and fruit flies share most of the import- ant genes that control development, behavior and physiology. In 1993, I was discussing interest- ing genes with my Baylor colleague Dr. Hugo Bellen. I asked, 'What is an interesting gene in the fruit fly?' And he replied, 'Well, there's this gene called Atonal that's really important for balance and coordination in the fruit fly, and perhaps it's important in mam- mals as well.' Because of my interest in balance disorders, I decided to find the equivalent gene for Atonal in the mouse and see if it's relevant. In 1993, no one had really taken genes from fruit flies, mice, and humans to compare them. It was unusual at the time. My colleague, Dr. Bellen, and I wrote a grant together to further pursue this idea. Reviewers told us the idea would never amount to anything. Despite the naysayers, I went ahead and identified the mouse gene and started studying it. As it turned out, this gene is very important. It is the gene that makes the little hair cells inside the cochlea and vestibular system inside the inner ear (hair cells are the mecha- noreceptors for hearing and not actual hairs in the ear). The hair cells inside the cochlea sense sound and transmit that information to the brain. If you move your head, the hair cells sense the movement and transmit that informa- tion to the brain to help retain balance. The gene, in fact, is extremely import- ant for many components of balance. It turns out the gene also appears to be important for certain brain cancers. In one of the most common child brain tumors, this gene becomes hyper- functional. It's also critical for special neurons in the brain responsible for breathing. These are the neurons that are vulnerable in sudden infant death syndrome. The gene is also important for making the cells in the intestine that secrete mucus, neuropeptides and antimicrobial peptides. And the gene is important for you to be able to feel things through touch receptors. If you are playing the piano, you can feel the difference between the white keys and the black keys because of the mecha- no-sensitive cells that depend on this gene. All of this depends on this one particular gene. We started with a gene from a lowly organism, and by studying it in mammals, we discovered the gene is critically important for numerous functions. Now labs around the world are studying this gene and testing it in cancer, hearing and deafness. Those lit- tle hair cells are what become damaged when you hear a loud sound or as you age, causing a loss of hearing and even deafness. If we can find a way to help recreate the hair cells, it may serve as a potential therapy down the line. We also hope to gain a better understanding of neonatal breathing to prevent sudden infant death syndrome through study- ing this gene. Q | What inspired you to start the Jan and Dan Duncan Neurological Research Institute? A | I've loved being in the lab working on my research. As you can tell, it took a long time to answer the questions that drew me to research in the first place, but in the end we did succeed. Our hard work paid off in areas we never expected, like the fly gene that turned out to be so important for mankind. When you have this kind of experience, you become very committed to the lab and hooked on the excitement of being a scientific investigator. Any time someone approached me about becoming a department chair, a dean, or other such similar role, I was com- pletely uninterested. I loved being in the lab and didn't want to leave. This remained the case until Cynthia and Tony Petrello, along with Dr. Feigin, challenged me to think hard about what more we could do for childhood neurological diseases. Why are so few childhood neurological diseases being studied in depth? Why is progress so slow? What can we do to change this? The Petrellos' lovely daughter, Carena, has a neurological disability. I initially reviewed her records because her parents thought she might have Rett syndrome. But she does not. We continued to talk and get to know one another. The Petrellos visited academic medical centers around the country, but they could not find any place where there was an integrated approach to neurological disorders. They wanted to better understand how I had made my discoveries. I explained that I attributed my success to the brilliant people working alongside me, as well as to my ongoing collaborations. I had created my own interdisciplinary, inte- grated program to make things happen My dream for the NRI is that the work happening here will allow us to better understand how the brain works and result in discoveries that will truly help patients with devastating neurological disorders.