childrens hospital LOS ANGELES Bench to Bedside of Childrens Hospital Los Angeles Richard B. Simerly, PhD The brain in motion: Axons (in red) travel from one part of the hypothalamus to another, establishing connections important in regulation of feeding during development. UNLOCKING THE BRAIN S MYSTERIES spearheads a new program to understand the brain how it develops and what we can do when things go wrong in the critical science for the 21st century. Neuroscience Program Tackles Basic Questions About the Brain H ow do the neurocircuits in the human brain get wired before birth and after? What role do hormones play in establishing that wiring to impact such fundamental processes as reproduction, feeding and metabolism? Richard B. Simerly, PhD, has dedicated his career to finding out. The vast unknown territory of the brain has fascinated Dr. Simerly since he was a young boy. Though raised in a family of liberal arts people, he preferred dissecting frogs over dissecting historical essays. Once he started reading about brain research, he says, being a neuroscientist was all I ever wanted to do. Today, the developmental neurobiologist is the director of the new Neuroscience Program in The Saban Research Institute of Childrens Hospital Los Angeles, and a major point person for the hospital s extensive collaborations with neuroscience researchers at the University of Southern California (USC). The rate of discovery is speeding up. Most of what we know about the brain has been learned in the past 20 years, says Dr. Simerly, formerly a senior scientist at the Oregon National Primate Research Center and Oregon Health & Science University. Neuroscience is a criti... continued on page 2 B2B Winter2006.r11.indd 1 2/1/06 10:47:21 AM
UNLOCKING THE BRAIN S MYSTERIES... continued from page one cally important science for the 21 st century, says Yves A. DeClerck, MD*, director of. Furthering our understanding of the brain its influences and its development is a major priority as we sit on the edge of major discoveries. Brain Basics Dr. Simerly s fundamental research into how the brain grows and functions is making waves in the field of neuroendocrine development and obesity. He currently has three grants from the National Institutes of Health (NIH) for research centered on the development of neurocircuits in the forebrain. His newest focus leptin, an appetite-suppressing hormone has inspired headlines. Experiments in his lab have found that leptin serves as a developmental signal which impacts the growth of the same neural circuits that mediate leptin s actions later in life. (See page 3.) Dr. Simerly is a professor of pediatrics at the Keck School of Medicine, and professor of biology in the neurobiology section at USC. He was recruited in a nationwide search by a committee that included representatives of USC s University Park Campus, the Keck School of Medicine and the California Institute of Technology. Heading the effort was neuroscientist Zach W. Hall, PhD, now president of the California Institute for Regenerative Medicine, the voter-approved agency charged with funding stem cell research. The search was a truly collaborative process, notes Floyd H. Gilles, MD*, director of the Childrens Brain Center and head of the Division of Neurology at Childrens Hospital Los Angeles. Our goal was to find someone who combines an understanding of human disease processes with a deep knowledge of underlying neurobiology. Dr. Simerly s team will provide a nucleus of basic science in developmental neurobiology, which will feed a wide range of research Richard B. Simerly, PhD, left, with Floyd H. Gilles, MD projects within the Childrens Brain Center, directed by Dr. Gilles. (See page 7.) Most of what we know about the brain has been learned in the last 20 years. Dr. Richard Simerly The Neuroscience Program received key funding from three sources: $3 million from the Associates Endowment for Neuroscience and Imaging Research, $3 million from the Saban Family Foundation and $1.5 million from the Provost s Office at USC. Such funding is absolutely critical, says Dr. Simerly. With government resources spread thin and a lengthy grant-making process, it can be difficult for a laboratory to move rapidly to make technological improvements and compete for scientific talent. Childrens Hospital Los Angeles has made the decision to be a top-flight research institute, which is only possible with privately endowed funding such as this, says Dr. Simerly. He plans to rely on this and other funding to attract top-notch scientists to the Neuroscience Program. His objective: establish six neuroscience laboratories in within five years, each working individually and together to reveal more of the brain s secrets an aggressive but achievable goal. Dr. Simerly was drawn to by the opportunity to more directly affect the lives of children and adults. He s excited about the cutting-edge imaging work in the Small Animal Imaging Facility at The Saban Research Institute, headed by Rex Moats, PhD*, and Marvin D. Nelson, Jr., MD*, and in the Congressman Julian Dixon Cell Imaging Facility, headed by Thomas D. Coates, MD*. Revolutionary technologies are emerging, says Dr. Simerly. Some of the brain pathways we re studying are very small and difficult to see, even with MRI. What will help is further development of contrast agents and ways of visualizing these small pathways. Collaborative Power Another appeal of his new post, he adds, is the chance to work with other scientists within The Saban Research Institute, as well as with those at the Neuroscience Research Institute on USC s University Park Campus and the Zilka Neurogenetics Institute at the Keck School of Medicine. These alliances and... continued on page 3 2 Bench to Bedside Winter 2006 B2B Winter2006.r11.indd 2 2/1/06 10:47:36 AM
UNLOCKING THE BRAIN S MYSTERIES... continued from page two the investment in the training of new neuro-researchers are expected to yield fertile opportunities for increasing insights into the brain. Physician-scientists from joined forces with the neuroscience advisory committee of the USC Provost s Office to craft a new graduate program in developmental neurobiology. Students will be able to pursue advanced research studies at The Saban Research Institute, the Keck School of Medicine and the University Park campus. Among other collaborative projects, Dr. Simerly is involved in multi-level studies in obesity with Alan G. Watts, PhD, head of the Neuroscience Research Institute and of the neurobiology section in the Department of Biological Sciences at USC. Dr. Watts laboratory is interested in the neural mechanisms regulating feeding and how development affects them, while Dr. Simerly s lab is focusing on how hormonal signals during development specify the architecture of the feeding circuits. In fall 2005, the team received funding from the NIH s National Institute of Diabetes and Digestive and Kidney Diseases to form a consortium that also involves scientists at the University of Michigan and at Johns Hopkins University. The goal: to understand signaling events during development that influence how the brain regulates energy balance. This project fits perfectly with the NIH s directive to take scientists with complementary expertise and put them together to work on important problems, says Dr. Simerly. That s what I want to do here at The Saban Research Institute create groups of people in developmental neurobiology that link with clinical research at Childrens Hospital and with other research efforts at USC and beyond. Working together, we will be well-positioned to make significant progress. Every bit of progress is essential in a field still considered in its early stages. Brain research lags behind other disciplines because, until recently, many questions have not been approachable. Scientists had to wait to find new ways to reveal the brain s inner workings. First, special microscopes and other imaging technologies had to be developed. Then, decades later, the computational power of computers had to catch up. The effective combination of digital technology with microscopic technology in neuroscience is a relatively recent event. Combined with new genetic model systems, says Dr. Simerly, these new imaging tools are fundamentally expanding the range of questions we can ask all of which make this an exciting time to be a neuroscientist. Furthering our understanding of the brain is a major priority as we sit on the edge of major discoveries. Dr. Yves DeClerck LEPTIN: OBESITY BREAKTHROUGH? Leptin, a hormone secreted by fat cells, acts on the neurocircuits that regulate whether or not we want to eat. Until recently, its role in the body s metabolic engine has been little understood. Studies in the laboratory of Richard B. Simerly, PhD, are helping to change that. Much of Dr. Simerly s career has been spent studying neurocircuits that influence reproduction and develop under the influence of such hormones as estrogen. A few years ago, his team became interested in a set of neurocircuits that affect feeding and metabolism. Our investigations demonstrate that leptin which really functions as a starvation signal influences assembly of key neural circuits in the brain, says Dr. Simerly, director of the Neuroscience Program at. (See page 1.) Dr. Simerly and his colleagues found that in leptindeficient mice, neurons that normally respond to the hormone don t make connections with other parts of the brain involved in food intake and the mice become fat. When the mice receive leptin immediately after birth, the neural circuits controlling food intake form normally and the mice maintain normal weight. However, the same isn t true of adult mice. Despite infusions of new leptin, their neurocircuitry doesn t right itself and the mice stay overweight. Leptin doesn t necessarily dictate a set weight for an individual, but it may be among the factors that influence the range of weights each person has during his or her life. If we can someday identify a way to extend the brain s plasticity period, adds Dr. Simerly, it may be possible to rescue damaged circuits at any Axons are busy making new wiring in the hypothalamus, time of life. an important supervisory center in the brain. 3 Bench to Bedside B2B Winter2006.r11.indd 3 Winter 2006 2/1/06 10:47:39 AM
RESEARCH IMAGING INITIATIVE Scientists are Seeing Inside the Brain in Revolutionary New Ways Archeologists report that prehistoric man bored holes in human skulls to study the brain and perform surgery. Since then, scientists have invented increasingly sophisticated tools to discover the brain s secrets. In 1929, the human electroencephalograph (EEG) debuted to measure electrical activity. The first pictures from magnetic resonance imaging (MRI) appeared in 1980. Today, scientists at Childrens Hospital Los Angeles are refining and maximizing the newest techniques in imaging. This is a pivotal time in imaging research, when we can begin to answer some difficult questions, notes Marvin D. Nelson, Jr., MD*, director of the Imaging Research Initiative in The Saban Research Institute and head of the Department of Radiology at Childrens Hospital. This side view of the adult human brain shows the left sensory-motor area (red) which normally controls right-hand motor activities. The opposite half of the brain controls lefthand activities. In wide-ranging neurological studies, investigators are working to: track the role of hormones in signaling brain function devise new contrast agents and techniques to sharpen images of brain tissues and identify specific biological targets 4 Bench to Bedside Winter 2006 determine the chemical makeup of brain tumors to formulate new treatments invent ways to get revealing images of newborn brains better understand the development of neuroblastoma, a nerve-cell cancer, and diseases of the brain s white matter map out metabolic problems, such as the genetic disorder, Phenylketonuria (PKU), and study the brain in action and as it grows with functional MRI (fmri). Stefan Blüml, PhD*, helped lead the way in designs for an MR-compatible incubator to safely obtain high-quality images of infant brains, in collaboration with the hospital s Center for Newborn and Infant Critical Care. Within the incubator s temperature-controlled environment, even fragile newborns can be analyzed with two to three times the image quality than previously possible. In his current studies, Dr. Blüml is collaborating with Floyd H. Gilles, MD*, director of the Childrens Brain Center, on brain tumor research employing magnetic resonance spectroscopy. It uses signals from the protons of chemicals to generate a biochemical fingerprint of areas of the brain. Imaging may speed up the process of identifying agents that fight tumors by non-invasively measuring their progress. We want to identify variations between tumors and what significance those variations carry, says Dr. Blüml. Functional MRI the latest in neuro-imaging technology displays the As seen in these fmri scans of newborn brains, babies show a bilateral response in both halves of the brain when doing a single-hand task. This unique ability of the unmatured brain to recruit both brain parts may someday help scientists to identify developmental delays caused by injury. brain s structure and how it functions by measuring blood flow. In the scans, specific areas of the brain light up as various processes occur. We want to see what s going on in the brain and how it s connected from the first day of life. Dr. Stephan Erberich Stephan G. Erberich, PhD*, developed neonatal fmri to create pictures of the newborn brain s response to visual, auditory and touch stimuli. We want to see what s going on in the brain and how it is connected from the first day of life. Dr. Erberich s team has conducted more than 200 clinical studies on newborns, starting with pre-term babies with periventricular leukomalacia, an injury of the white matter, which is associated with developmental problems. The scientists found that, even with a single-handed task, babies have bilateral activity, a pathway not available later in life. With this information, notes Dr. Erberich, we could possibly identify a clinical marker for developmental delay caused by injury of the infant s brain if an area shows only unilateral activity. This may lead to new diagnostic tools for autism and attention deficit disorder, as well as visual or hearing impairment. Within The Saban Research Building, Rex Moats, PhD*, directs the 1,200- square-foot Small Animal Imaging Facility where highly advanced imaging studies at the cellular level are carried out, laying the groundwork for clinical trials. This facility is an incredibly powerful tool to monitor development in a non-invasive way, says Richard B. Simerly, PhD*, director of the Neuroscience Program in The Saban Research Institute. Thanks to work being done there, we will be able to get a window on development we haven t had before. B2B Winter2006.r11.indd 4 2/1/06 10:47:43 AM
Many children suffer from neurological conditions for which there are presently few answers. A Note from the Director Yves A. DeClerck, MD* Director, Vice President of Research, Childrens Hospital Los Angeles Please join us in this important research endeavor. Sooner or later, every growing and successful institution faces a choice: either continue to improve at what it has always done well and has earned a reputation doing, or go in a new, unfamiliar direction. This is referred to as the dilemma between growing in depth or in breadth. Several years ago, as began a rapid expansion, we confronted this question. Our leadership and faculty made the bold decision to accomplish both kinds of growth. We would continue to invest in our existing strengths and priority programs by developing new research space, obtaining new research equipment and recruiting additional investigators. At the same time, we would develop an ambitious new program in neuroscience. We were inspired by the importance of this discipline in the 21 st century and its relevance to finding better cures for children. Many children suffer from failure of brain development, congenital brain damage, epilepsy, brain tumors and other neurological conditions for which there are presently few answers. Our decision has required careful planning, a strong partnership with the University of Southern California and other scientific institutions, plus support from the community and our generous donors. Our diligent efforts have been rewarded with the recruitment of Richard Simerly, PhD, to lead the Neuroscience Program. On behalf of The Saban Research Institute and the children we serve, I invite your continued support as lifesaving scientific frontiers are explored on both new and established fronts. 5 Bench to Bedside Winter 2006 B2B Winter2006.r11.indd 5 2/1/06 10:47:52 AM
OPTIC NERVE HYPOPLASIA Studies Seek to Uncover Leading Cause of Blindness in Children O ptic nerve hypoplasia (ONH) the single leading cause of blindness in young children has a formidable opponent in neuro-ophthalmologist Mark S. Borchert*, MD, head of the Division of Ophthalmology at Childrens Hospital Los Angeles. ONH, the congenital underdevelopment or absence of the optic nerve, is occurring at epidemic levels worldwide. For several years, Dr. Borchert has directed a nationwide study to identify patterns in occurrence of ONH and to develop earlier diagnosis and treatment techniques through improved identification of prenatal risk factors. His research is supported by the One Small Voice Foundation. ONH may occur by itself or along with neurological or hormonal abnormalities which affect motor skills, intelligence and speech. These problems can include a poorly functioning pituitary gland the point where Dr. Borchert s research intersects with fundamental studies into the anatomy and physiology of the hypothalamus (the area of the brain where the pituitary gland is located) conducted by Richard B. Simerly, PhD, director of the Neuroscience Program in. (See page 1.) The investigators plan to pursue collaborative research that capitalizes on Dr. Simerly s discoveries about the brain and Dr. Borchert s clinical expertise. This is true bench-to-bedside work, says Dr. Borchert, referring to how ideas move from brainstorm to laboratory bench to new treatments. Another area of research is the development of noninvasive technologies for analyzing the concentration of specific molecules in the anterior chamber of the eye, which provides an accurate reflection of their concentrations in the blood. In his Childrens Hospital laboratory, Dr. Borchert and his team have developed a device that measures glucose in the aqueous humor watery fluid in the anterior chamber of the eye. The new technology is based on Raman spectroscopy, which says that when a monochromatic light shines on something, photons scatter back at different wavelengths. That shift in wavelengths is characteristic of specific molecules and acts as a molecular fingerprint of the object s chemical composition. Such a technique could possibly allow the non-invasive monitoring of how children metabolize drugs or respond to insulin treatment. Laboratory studies with the Childrens Center for En- docrinology, Metabolism and Diabetes have proven successful. Dr. Borchert has initiated clinical studies to demonstrate the experimental device is safe and successful in humans. So far, tests have been done with a table-sized model. He envisions the ultimate product about the size of a handheld electronic device, allowing diabetics to easily carry it in their pockets. The device may prove beneficial for neurological conditions. The aqueous humor has a nearly identical chemical makeup to cerebral spinal fluid, making it a possible surrogate for studying diseases that affect spinal fluid or for testing new drugs. We could then use the window of the cornea to bypass a spinal tap or other invasive tests, says Dr. Borchert. Dr. Borchert s clinical investigations at Childrens Hospital intersect with basic brain research at The Saban Research Institute. This is true bench-to-bedside work, he says. The top image shows a normal optic nerve as seen through an ophthalmoscope. The bottom photo reveals a small optic nerve, a distinguishing characteristic of optic nerve hypoplasia, the single leading cause of blindness in young children. 6 Bench to Bedside B2B Winter2006.r11.indd 6 Winter 2006 2/1/06 10:47:55 AM
UNDERSTANDING THE BRAIN Childrens Hospital Los Angeles Makes Neuroscience a Priority T he best, most enduring ideas can take time to hatch. The Childrens Brain Center at Childrens Hospital Los Angeles and the new Neuroscience Program of basic research in The Saban Research Institute are the result of a carefully designed scientific and business plan initiated in 1998 by The Saban Research Institute s leadership and approved by the Childrens Hospital Los Angeles Board of Directors. At that time, The Saban Research Institute identified neuroscience as a major research priority. Out of that determination came the Childrens Brain Center, which pools the intellectual assets of nearly 30 faculty members in 12 medical disciplines. It combines them with the basic developmental neurobiology work in The Saban Research Institute s Neuroscience Program, which began to take shape in 2005, and is part of the new University of Southern California graduate program in Developmental Neurobiology. Having these disciplines work in close collaboration is a rarity that happens at only a few places across the country, notes Floyd H. Gilles, MD*, head of the Childrens Brain Center and the Division of Neurology at Childrens Hospital. Each week, physicians and scientists gather at Childrens Brain Center meetings to review cases, treatment ideas and research findings. Around the table is a rich collection of specialists, including neurologists, neurosurgeons, developmental neurobiologists, physicists, a neuro-ophthalmologist, neuro-oncologists, psychiatrists and others. Together, they re trying to deepen knowledge about such brain-related conditions as epilepsy, autism, attention deficit disorder (ADD), depression, blindness, rehabilitation of brain injuries and more. We re all dedicated to untangling these complex questions about the brain, says Dr. Gilles. What excites scientists in laboratories and those who work at patients bedsides is the opportunity to solve some previously unanswerable questions. Among them is how hormones control or affect the plasticity (impressionability) of a child s brain, as well as how long that plasticity period lasts and whether science can influence it. Among other projects, Childrens Brain Center researchers are working to: develop an implantable computer chip to detect seizures in people with epilepsy, which affects some 300,000 children under age 14 in the U.S. (Lan S. Chen, MD*) examine depression in children with medical problems (Susan B. Turkel, MD*) determine through imaging how children with autism or ADD process auditory information. (Andrew J. Kim, MD*; Virdette Brumm, PhD*; Stephan G. Erberich, PhD*) use the anterior chamber of the eye as a window, allowing measurement with Raman spectroscopy of molecules of glucose, alcohol and drugs (Mark S. Borchert, MD*, and J.L. Lambert, PhD*) Inspiring this work are its potential benefits. What we learn here will help young children with serious brain disorders, says Dr. Gilles, and may one day translate to new treatments for adults. Pediatric brain tumors with the same diagnosis can exhibit markedly different features on magnetic resonance images, illustrated by two cases of medulloblastoma, a common brain tumor in children. Researchers hope to use this information and other biochemical fingerprints to individualize treatments. THE DEVELOPING BRAIN What does plasticity mean in reference to the brain? It s the ability of the central nervous system to change over time. Neuroscientists use the term to refer to the brain s impressionable quality its ability to absorb new information most especially, during early development. When is the brain at its most plastic state? The human brain is far more plastic in early life than in adulthood. Young children s brains are more open to learning and enrichment. At the same time, greater plasticity also means their brains are more vulnerable to developmental problems or environmental factors. How long does the period of plasticity last? The human brain begins to form at three weeks postconception and is most actively developing in the first three years after birth. Scientists are discovering, however, that neural development continues to take place at every age. Events that influence the brain early on may play a role later in storing information as we gain new skills. The brain isn t a static organ, explains Floyd H. Gilles, MD, director of the Childrens Brain Center. We generate new neural connections all our lives. 7 Bench to Bedside Winter 2006 B2B Winter2006.r11.indd 7 2/1/06 10:47:59 AM
HOW YOU CAN HELP Join Us In Finding Answers to The Brain s Many Riddles The human brain is both a marvel and a mystery. For centuries, it has been inaccessible to scientists eager to understand it and to find solutions to so far unanswerable neurological conditions. At of Childrens Hospital Los Angeles, we are asking fundamental questions about how the brain develops and grows, and are devising new ways to peer inside its deepest recesses. Richard Simerly, PhD, tracks hormones that influence brain development. This image shows neurons, stained red, from the amygdala, a part of the forebrain that regulates emotions. Seen in green are synapses (nerve terminals). We invite you to support the Neuroscience Program at, with its groundbreaking science and medical education programs. Much of this work is experimental. It relies on ah-hah moments of sudden inspiration. It relies on teamwork, the meeting of many minds. It relies on painstaking steps that take years, even decades, to connect. Government funding isn t enough. It won t finance the idea that needs fuel to grow. It often can t act fast enough to keep pace with the demands of technology. You are an important partner in this mission. With your philanthropic support of, you can make it possible for this important research to continue and to flourish. To explore the many ways you can further our cause, please contact Melany Duval, associate vice president of major and planned gifts, at 323-671-1705 or mduval@chla.usc.edu. Bench to Bedside Editor: Candace Pearson Designer: Emjay Creative Nonprofit Organization U.S. POSTAGE PAID Los Angeles, CA Permit No. 22460 of Childrens Hospital Los Angeles PO Box 27980 Los Angeles, CA 90027-0980 Return Service Requested w w w. C h i l d r e n s H o s p i t a l L A. o r g B2B Winter2006.r11.indd 8 2/1/06 10:48:04 AM