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WRITTEN STATEMENT OF DR. WILLIAM MOBLEY
DIRECTOR OF THE CENTER FOR RESEARCH AND TREATMENT OF DOWN SYNDROME AT STANFORD UNIVERSITY ON BEHALF OF THE DOWN SYNDROME RESEARCH AND TREATMENT FOUNDATION

On Funding Down Syndrome Research At the National Institutes of Health and Centers for Disease Control and Prevention
Subcommittee on Labor, Health and Human Services, Education and Related Agencies
House Committee on Appropriations

March 30, 2004

Mr. Chairman and members of the Subcommittee, I thank you for the opportunity to testify on the importance of federal funding for Down syndrome research at both the National Institutes of Health (NIH) and the Centers for Disease Control and Prevention (CDC). I am Director of the Center for Research and Treatment of Down Syndrome at Stanford and also serve as Chairman of the Department of Neurology and Neurological Sciences and Director of the Neuroscience Institute.

I am testifying on behalf of the Down Syndrome Research and Treatment Foundation, a non-profit organization that supports bio-medical research relating to cognitive dysfunction in Down syndrome and to the discovery and development of new treatments to improve cognition and enhance the lives of those living with the disorder.

Down syndrome is one of the most common birth defects, affecting approximately 350,000 people in this country and about one in every 800 live births. Down syndrome is caused by an extra copy of the 21st chromosome. The disorder is not inherited, but rather results from an error in the normal segregation of chromosomes that occurs during the development of either the egg or the sperm. The extra chromosome results in a number of health problems, but neurological abnormalities are the most disabling. Most people with Down syndrome have mental retardation falling in the mild to moderate range, and many have significant speech and language difficulties. Persons with Down syndrome are also at a significantly higher risk of developing Alzheimer's Disease - which results in a further loss of cognitive functioning -- by the time they are 35 years old.

Private and public services, including early intervention, special education and job training, have greatly improved the lives of those who have Down syndrome. Nevertheless, cognitive challenges make it difficult for most to live independently during adulthood. It is estimated that the costs associated with health care, education, housing and community support to persons with Down syndrome total $6 billion annually. This amount could be reduced substantially if medical treatments could be developed to ameliorate or reverse the learning difficulties associated with Down syndrome. Moreover, such treatments would greatly enhance the lives of those living with the disorder and their families.

Finding ways to treat Down syndrome is what motivates researchers like myself. We want to find ways to translate basic research advances in genetics, cell biology and neurobiology into treatments that help those with Down syndrome to learn more easily and effectively, function in their communities more independently and live richer lives. Until recently, the thought of developing bio-medical treatments to improve neurological functioning for persons with Down syndrome was thought to be unrealistic. It was believed that this genetic disorder, which involves an entire chromosome, was too complex to understand and too difficult to study. Moreover, many believed that by the time a child was born with Down syndrome it was too late to reverse or modify deleterious affects on brain function.

However, scientific advances are revolutionizing our ability to understand and treat disorders of the nervous system. The harvest of new concepts and tools now available to neuroscientists, the majority of which resulted from NIH funding, have made it possible as never before to view with optimism the ability to provide relief for those with disorders of the nervous system. With respect to Down syndrome, we expect to find that extra copies of specific genes are linked to specific abnormalities in the structure and function of the brain. Using advanced methods, we believe that we can isolate the effects of specific genes and determine how their expression in the brain can cause problems with cognition. We also now appreciate as never before that brain function can be modified, in both children and adults, and we are learning how such changes occur. Therefore, today we can boldly predict that Down syndrome is not too complex to understand, it is not too difficult to treat, and it is not too late to treat.

Last year, George Will appeared before this Subcommittee and spoke candidly of the need to focus future Down syndrome bio-medical research on enhancing cognition through studies to elucidate the genetics and neurobiology of Down syndrome. He spoke of the need, using the insights developed in basic research, to discover medical treatments to enhance the ability of the brain to learn. In the year since his testimony, those of us who have been focusing our research on cognition have made much progress. We are close to identifying a gene on chromosome 21 that may be responsible for certain abnormalities in nerve cell structure that occur during aging in persons with Down syndrome. We also have a much better understanding of structural and functional abnormalities that characterize synapses. These are the points of information transfer between neurons, and their function is vital to the ability of the brain to learn and remember. Together with the results of earlier work, our studies have shown that synapses are abnormal in Down syndrome. Increasingly, we understand how these changes are linked to abnormal cognition. This progress, occurring as a result of the work of many different laboratories, is due largely to the ability, using mouse models of Down syndrome, to explore in great detail abnormalities in the structure and function of the nervous system. The Down syndrome research community has carried out painstaking studies to define these abnormalities, document the time of their occurrence and develop careful methods to quantitate them. We now have begun to explore their genetic and cell biological basis. We feel that the future holds great promise not just for defining the mechanisms responsible for abnormal brain structure and function, but also for beginning the process of discovering treatments that enhance brain function, including cognition.

It is noteworthy that these studies are expected also to contribute new insights for persons with Alzheimer's disease. As indicated, all persons with Down syndrome show the neuropathological hallmarks of Alzheimer's disease by age 35. Many go on to show cognitive decline in later life, an event that further compromises their ability to function independently. The research on Down syndrome is expected to illuminate the search for the cellular events that trigger Alzheimer's disease in people without Down syndrome. Indeed, since everyone with Down syndrome is currently destined to show the neuropathological changes of Alzheimer's disease, the goal of understanding the earliest changes in Alzheimer's disease and of discovering early diagnostic markers may well benefit from studies in people with Down syndrome. Conversely, studies of Alzheimer's disease should provide important clues to the cause of declining cognition in elderly people with Down syndrome. In the end, our goal is to effectively treat cognitive failure in Down syndrome and in Alzheimer's disease. We believe that this goal can be achieved more rapidly by investing in research on the neurobiology of Down syndrome.

Although we have made substantial progress, one of the greatest obstacles we face in moving our studies forward is a shortage of mice for basic research. The mouse we use for much of the research on Down syndrome, the Ts65Dn mouse, has an extra copy of a segment of mouse chromosome 16 that harbors many of the genes on human chromosome 21. Thus, these mice are trisomic for many of the same genes found in three copies in people with Down syndrome. As George Will testified last year, these mice are difficult and expensive to breed, and there just aren't enough of them. Researchers must wait six months to a year to receive a small fraction of the mice they need for on-going research. This predicament is seriously impeding research. In order to solve the problem, we need funding to produce more mice. Over the last year we have been working closely with the National Institutes of Health (NIH), most particularly the National Institute of Child Health and Human Development (NICHD), to find a solution. We are encouraged that NICHD is working on a plan to increase the supply of the Ts65Dn mice. We wish to work with them on a longer-term solution to develop additional and better mouse models that could be made available in large numbers to the entire research community. We look forward to continuing to work with NICHD and other NIH institutes to secure the funding and the necessary contractual commitments to overcome this serious obstacle to advancing Down syndrome research. We hope that over the next few months we can report to you some progress on this issue.

In addition to working with NIH on providing mice for research, we have been encouraging NIH to focus resources on elucidating the neurobiology of Down syndrome. An important focus for this work is synaptic structure and function in neuronal circuits important for cognition. The Down syndrome research community has just begun to scratch the surface of this important area, but we are encouraged that much will be learned that ultimately will be important for both understanding and treating cognitive problems. We are pleased to report that the new Director of the National Institute of Neurological Disorders (NINDS), Dr Story Landis, has agreed to sponsor a Down syndrome workshop this year to identify research priorities. NINDS will be coordinating this workshop with several other Institutes, including NICHD, NIA and NHGRI. One of the aims of this workshop is to invite researchers from other fields to participate and contribute to research on the neurobiology of Down syndrome.

I feel strongly that in order to advance Down syndrome research, we must expand the field. It is only through the infusion and cross-fertilization of new ideas coming from scientists who are experts in other areas of research that we will be able to understand the complex genetic, molecular and cellular disturbances that characterize the neurobiology of Down syndrome. Without these advances, and without the ability to create the interdisciplinary links needed to exploit them, it will be difficult if not impossible to develop needed treatments. Importantly, we need to encourage bright, young scientists to contribute to this field of research. I know that Dr. Elias Zerhouni, Director of NIH, and Dr. Story Landis share this view and believe strongly that bio-medical science and neuroscience will prosper only in so far as we are able to attract the very best and brightest to the work. The needed infusion of new investigators with new ideas is as important for Down syndrome as for any other area of research.

In fact, the NIH Road Map envisions just this sort of infusion of new ideas and collaboration among scientists of various disciplines. I commend Dr. Zerhouni for his vision and leadership in setting forth the NIH Road Map. This bold initiative underscores the importance of translational science - i.e. basic science discoveries that are efficiently translated into effective treatments for those who are suffering. Moreover, the Road Map also correctly concludes that the "scale and complexity of today's biomedical research problems increasingly demands that scientists move beyond the confines of their own disciplines and explore new organizational models for team science." This requires changing the culture of research in this country. I believe that the NIH Road Map is an important step in creating this new culture.

At the Center for Research and Treatment of Down Syndrome, we take Dr. Zerhouni's challenge seriously. In fact, we have structured and organized our Center around an approach that is interdisciplinary, integrative and translational. For example, we believe that understanding cognition requires the participation of investigators in a number of disciplines - genetics, molecular and cellular biology, the biology of neural circuits and behavior. Therefore, our research includes all these disciplines, and we collaborate frequently, sharing ideas and research findings. Through this interdisciplinary collaboration, we believe that we are well on our way to elucidating some of the mechanisms that compromise brain function and cognition in Down syndrome.

At the Center we also strive to effectively integrate basic and clinical studies by engaging the participation of both basic scientists and clinicians. Studies in people must both motivate and be informed by studies in animal models of Down syndrome. Effective integration also demands that we share our ideas with other scientists in other institutions. Because we want to attract the most talented investigators in the world to work on Down syndrome, we are working with the Down Syndrome Research and Treatment Foundation to create a national consortium to integrate the work we do at Stanford with that being carried on at other academic institutions and by investigators in government and industry.

Our ultimate objective at the Center is to translate our research findings into effective treatments. As I said at the beginning of this testimony, what motivates me as a researcher is to discover the keys to abnormal brain function in Down syndrome that can be used to create new treatments that change lives. At the Center we believe that the best way to do that is by building an intellectual environment that encourages and supports the translation of basic science into practical clinical application. We hope that our model, which we believe carries out the intent and thrust of the NIH Road Map, will be replicated in academic institutions throughout the country.

Indeed, if the Road Map model is widely adopted, the research that results will accelerate progress in finding treatments for many disorders and diseases. Considering only disorders of the nervous system, one can envision more rapid progress in Parkinson's disease, stroke, amyotrophic lateral sclerosis, multiple sclerosis, brain tumors, affective disorders, and pain. I am intrigued by the possibility that the culture that could develop would encourage more effective sharing of data and research reagents, would identify more effectively the expertise needed to solve difficult problems, and would discover ways to more quickly and flexibly provide funds to complete projects critically linked to advances in understanding and treating disease. Indeed, cross talk between investigators would be expected to hasten the introduction of new concepts and tools useful for solving research problems. I am struck, for example, that studies on Down syndrome could point to novel approaches for investigating the biology of cancer. It is remarkable that in people with Down syndrome there is a substantially decreased incidence of certain solid tumors (Yang et al., Lancet 359: 1019, 2002; Hasle et al., Lancet: 355; 165-169, 2000). In one series, as compared to people without Down syndrome, only half the number of expected cases was found and no case of breast cancer was detected, a result that was highly statistically significant. It seems clear that we have much to learn from studying the influence of trisomy 21 on the biology of solid tumors. A culture that respects and supports integration of effort and interdisciplinary collaboration would facilitate such studies and enhance our ability to both understand and treat disease.

An extremely interesting feature of Down syndrome is the wide variation between people in the extent of abnormal cognition. Thus, while some people can speak and function at a very good level and live independently, many do not. And yet they all have the same genetic defect, an extra copy of chromosome 21. How is this possible? A likely cause is that genes on other chromosomes act to modify the effect of the extra 21st chromosome. A patient with a higher level of function benefits from these genes to a greater extent than someone with a lower level of function. Presumably, any number of differences in gene structure or expression could be responsible. Understanding what actually happens and learning how to exploit this mechanism might be used to help all people with Down syndrome. It may soon be possible to carry out a genome-wide association study to look for modifiers of severity in Down syndrome. NINDS has joined with 18 other NIH Institutes to sponsor the International HapMap Consortium (www.hapmap.org), which is defining the nature of human genome variation across all of the human chromosomes. NHGRI has taken on responsibility for management of this international project, which is halfway through a three year timetable and doing extremely well. The outcome will be a resource that can be used to identify variants associated with common diseases, including Down syndrome. What is learned in studying Down syndrome might well be used to understand better the biological basis of variation in people with Alzheimer's disease, Parkinson's disease, stroke, etc. Finally, it worth pointing out that the technical advances that may be necessary for treatments to regulate the expression of individual genes in people with Down syndrome may prove useful for other disorders, such as Rett syndrome and others.

There is one other area of research that I would like to address - an area that I feel is essential to effectively translating science into treatments and one that is sometimes overlooked by basic researchers. We must inform basic research by producing data through epidemiological studies. Through such studies we learn about how diseases affect populations. Importantly, data often come to light that change our views of underlying disease mechanisms. These insights lead to development of better hypotheses and better experiments. For example, we know through certain epidemiological studies that Down syndrome males may outlive females. This finding is at variance with the general population, where the data demonstrate that females outlive males. We do not know why the Down syndrome population may be different, although a number of possibilities have been considered. For one, it is suspected that females with Down syndrome are more prone to congenital cardiac anomalies and are more likely to require treatment for atrioventricular canal defects during childhood. Further research is needed to allow the Down syndrome research community to formulate better hypotheses, do better experiments and eventually to discover treatments that allow females with Down syndrome to live longer, more productive lives. Importantly, the answers to this question in Down syndrome may contribute to our understanding of the effects of heart disease or, more generally, to understand better the reasons for the discrepancy between the longevity of females and males in the general population.

Thus, epidemiological studies on Down syndrome are critical to advancing Down syndrome research. This is why we have asked this Subcommittee to appropriate funding for two epidemiological studies of Down syndrome at the Centers for Disease Control and Prevention, National Center on Birth Defects and Development Disabilities. We thank the Subcommittee and the conferees for including in the FY 2004 conference agreement sufficient funds, above the request for CDC, to initiate two studies to (1) obtain an accurate estimate of the number of people in the United States living with Down syndrome and to identify them by age and ethnic group, and (2) document the onset and course of secondary and related developmental and mental disorders in individuals with Down syndrome. The CDC has begun to plan those studies and further funding is needed to actually get them underway in FY 2005. Therefore, we are asking the Subcommittee to include in its FY 2005 appropriations bill $2.5 million for these studies at the CDC.

The studies are valuable from two perspectives. First, researchers still do not know how many people in the United States are living with Down syndrome by age or ethnic group. Recent studies have shown that persons with Down syndrome are living longer - from just 9 years in 1929, and 16 years in 1961, to 75 years today. We need better data to help us understand why in certain ethnic groups those with Down syndrome have a higher mortality rate early in childhood and how premature aging affects mortality rates. This data would also be a valuable tool for helping state and federal agencies and private non-profit groups to plan for housing, education and other services that will be needed by persons with Down syndrome in the years ahead.

Second, a large amount of anecdotal evidence suggests that the number of persons with Down syndrome who have autism or other mental disorders is increasing. Reliable data on this observation would be useful in indicating certain risk factors that may require assessment. Data would also be useful in helping to understand and make possible correlations between the incidence of Down syndrome and other disorders.

In conclusion, I report to you today that much has been accomplished in Down syndrome research, but much more has to be done. We cannot and will not be successful in continuing this vital research and to translating our findings into effective treatments unless the work on Down syndrome becomes a higher priority that results in increased funding. If NIH signals that Down syndrome is an important area for basic and clinical research, the research community will listen. This in turn will stimulate the submission of better and more creative grant applications that compete more effectively for limited funding. In the end, declaring Down syndrome an important research topic will do much to increase funding and to accelerate progress. We realize in this time of increasing budget deficits that it is important to bring both private and public funding resources together to meet the funding demands for this research. The Down Syndrome Research and Treatment Foundation is committed to raising private money to contribute significantly to the research. Nonetheless, because the research is multi-institutional, multidisciplinary and costly, requiring substantial infrastructure and core facilities, a large public federal investment is needed. The importance of NIH funding for Down syndrome research cannot be overstated.

During times of tight budgets, it may be tempting to de-emphasize research. And yet, research - particularly medical research - is the best investment we can make in health care for our country. If we are concerned about cutting future health care costs, we must look for ways to prevent those costs from occurring. As I have stated throughout this testimony, research advances that lead to the ability to more effectively treat cognitive and other problems experienced by people with Down syndrome is not just a hope - it is a goal within our reach. My colleagues and I need are committed to achieving this goal.

I thank the subcommittee for giving me the opportunity to testify.