Pediatric Research Impacts and Benefits from All of Biomedical Science Susan B. Shurin, MD1, and Valerie P. Castle, MD2
U
S and international investment in biomedical research impacting child health, the establishment and growth of the National Institutes of Health (NIH) funding including investments in child health research made by many institutes and centers to Pediatric Departments, and Children’s Hospitals have all contributed to dramatic improvements in the survival of children born prematurely. These improvements have come from understandings in basic biology, the natural history of diseases, and improved technologies for disease management. Although disparities in survival persist in this country and around the world, basic1 research supported by the NIH has provided critical insight that has advanced neonatal care and childhood survival. As examples: (1) childhood cancer mortality rates declined by more than 50% between 1975 and 20062; (2) life expectancy of persons born with cystic fibrosis has increased from 7 years in 1970 to 37 years in 20103; (3) infant mortality in the US declined from 55.7 per 1000 live births in 1935 to 6.9 in 20004; and (4) maternal mortality in the US declined from 900 maternal deaths per 100 000 live births in 1900 to 12.7 in 2007. As life expectancy has increased, there has been increasing emphasis on research and care delivery on the quality of life and burden of disease. Advances in child health extend into adulthood and old age.
NIH Investment in Pediatric Research Includes Broad Areas of Biomedical Science Developmental Origins of Health and Disease Biomedical research reflects a life course continuum. Disorders of development may manifest at any age, and prevention and preemption of disease are most effective early in life. Many diseases that present in childhood may also manifest in adulthood, and many diseases presenting in adulthood have their origins in early life. Advances in fundamental biology have enhanced appreciation of the impact of early life influences on lifelong health and substantial data increasingly supports relationships between prenatal health and later adult health and disease. Ischemic heart disease, renal disease, hypertension, and type 2 diabetes are linked to birth weight and early development.5 NIH investment in several key areas highlights the importance of broad-based biomedical research investment in developmental origins of health and disease. As an example, research on the biology of obesity seeks to understand the complex interactions between genetic, epigenetic, immunologic, psychological, sociobehavioral, and societal factors in this major public health problem. Understanding the recent rapid increases in rates of obesity is essential to determine how and NIH
National Institutes of Health
when to intervene to achieve a lasting effect. High rates of overweight and other major risk factors for type 2 diabetes in middle school age children is the basis for current trials of schoolbased diet and exercise interventions, and basic research into the development of obesity using complex animal model systems is now identifying critical changes to the immune and inflammatory response as obesity develops. Emerging programs and priorities at the NIH will continue to build new knowledge critical to child health. As examples, the structure and function of the human brain is the focus of the Brain Research through Advancing Innovative Technologies6 effort, which builds upon an ongoing initiative in pediatric imaging,7 and the Grand Challenges in Mental Health recognizes that mental, neurologic, and substance abuse disorders impose massive burden on many populations. This effort will address pediatric interventions, recognizing that interventions in adulthood have limited success. Genomics and Regenerative Medicine Genomic approaches have been more rapidly integrated into diagnosis of inherited diseases in children than in adults. In 1962, the Eunice Kennedy Shriver National Institute of Child Health and Human Development took the lead in newborn screening for phenylketonuria at its inception.8 The Eunice Kennedy Shriver National Institute of Child Health and Human Development has worked closely with other institutes and centers, Health Resources and Services Administration, and the Centers for Disease Control and Prevention since 2003, and the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children, which was formed to advise the Secretary of Health and Human Services on newborn screening. As genomic technologies have become more broadly applicable, increasingly sophisticated approaches such as whole genome sequencing are being employed in diagnosis and screening, with pediatric patients being the primary focus of diagnosis.9 Improved understanding of the human genome and the complex interactions of noncoding with coding regions, cisand trans-acting factors, the impact of pre- and postnatal nutrition, and the microbiome are providing glimpses of how these processes can go right and wrong. The development of induced pluripotent stem cells and animal and laboratory models of organ development have yet to produce improvements in health
From the 1National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; and 2Department of Pediatrics, Mott Children’s Hospital, University of Michigan Health System, Ann Arbor, MI Funded by the NIH. The views expressed are those of the authors, and do not represent the views of the US Department of Health and Human Services or the NIH. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpeds.2014.03.027
4
Vol. 165, No. 1 July 2014 but are providing clues that should impact not just medical treatments, but also public health interventions that can have population-wide impacts. Multiple NIH institutes are ensuring that these rapidly evolving diagnostic and screening approaches are appropriately introduced and implemented.
Pediatric Research Is Valued What are the take-home messages from the NIH funding experiences of pediatric research and researchers over the past decade? First, pediatric research and pediatric institutions have fared well in both public investment and productivity. In 2011, the NIH invested more than $3.2 billion in funding dedicated to pediatric research across its institutes and centers, out of a total NIH budget of $30.9 billion.10 Second, continuing improvements in maternal and child health have increased life expectancy in many countries around the world. These advances increase, rather than decrease, the importance of research on early life influences and exposures because the consequences of adverse outcomes are cumulative, and have long-term impacts on families, communities, and nations. Third, pediatric investigators—who have maintained highly competitive science in the extremely challenging environment of the past several decades—have several crucial roles to play in ensuring that the expanding opportunities of the early 21st century are exploited to benefit the health of children and succeeding generations of adults. Communication of the crucial roles of early developmental events on childhood and adult disease, including those which are prenatal and gestational, is increasingly appreciated by the public at large and by policy makers. Research that provides opportunity to impact early life exposures to improve life-long health will be supported by the public, legislators, and policy makers. It remains our responsibility to advance this understanding. Communication with the public and policy makers about the importance of public funding of research is vital. The impacts of basic research findings are rarely evident until many years after discovery and publication. The impact of findings of early life events on health later in life has similarly taken many decades to appreciate. Pediatric researchers must broadly advocate for investment in basic and translational biomedical research to ensure that investigators engaged in work, which may later bring powerful new tools to bear on the health of children, continue their pioneering work, whether or not such applications are evident early on. Discoveries such as restriction endonucleases11 are not specific to pediatrics, but their applications have transformed scientific exploration and benefited children and adults alike.12 Support of the next generation of pediatric investigators is essential. Pediatric researchers have held their own despite the decline in the success of applications to the NIH with the decrease in its buying power. If investigators with specific interest in the health and diseases of children are to bring emerging technologies and discoveries to addressing pediatric questions, they must be inspired, nurtured, supported, and encouraged. This is a challenge for all of biomedicine. Pediatric departments
must continue to attract diversified support from philanthropy, industry, and foundations—a task that falls to academic pediatric leadership. Institutional leaders must enhance the resources and incentives, enabling investigators to collaborate across disciplines and organizational boundaries, exploit expertise, which may advance discovery wherever such expertise may be, and ensure that funding resources are used wisely and effectively. Pediatric research and researchers share the fate of the broader world of biomedical research. Embracing common opportunities and challenges, exploiting the unique role of pediatrics in medicine and science, and taking a strong stand in support of ongoing research investment will enable us to achieve the promise of improved future child health. In summary, the rich history of accomplishment and contributions of US biomedical research discovery has from its earliest time included enactment of public policy and public investment focused on improving the health and lives of women and children. This legacy has contributed to positioning our nation as a leader in biomedical research and discovery. n The authors are grateful to Carol Bleakley and Deepshikha Roychowdhury (NIH Office of Extramural Research) and Sarah Glavin (Eunice Kennedy Shriver National Institute of Child Health and Human Development) for providing data on trends in funding of pediatric departments and children’s hospitals.
References 1. Callaghan WM. Overview of maternal mortality in the United States. Semin Perinatol 2012;36:2-6. 2. Smith MS, Seibel NS, Alteckuse SF. Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 2010;28:2625-34. 3. Slieker MG, Uiterwaal CS, Sinaasappel M. Birth prevalence and survival in cystic fibrosis: a national cohort study in The Netherlands. Chest 2005; 128:2309-15. 4. Singh GK, van Dyck PC. Infant mortality in the United States, 19352007: Over seven decades of progress and disparities. A 75th Anniversary Publication. Health Resources and Services Administration, Maternal and Child Health Bureau. Rockville, Maryland: U.S. Department of Health and Human Services; 2010. 5. Power C, Kuh D, Morton S. From developmental origins of adult disease to life course research on adult disease and aging: insights from birth cohort studies. Annu Rev Public Health 2013;34:7-28. 6. National Institutes of Health. The brain initiative. Available at: http:// www.nih.gov/science/brain/. Accessed March 12, 2014. 7. National Institutes of Health. The NIH MRI of Normal Brain Development. Available at: http://pediatricmri.nih.gov/nihpd/info/abstracts. html. Accessed March 12, 2014. 8. National Institutes of Health. Brief history of newborn screening. Available at: http://www.nichd.nih.gov/health/topics/newborn/conditioninfo/ pages/history.aspx. Accessed March 12, 2014. 9. Yang Y, Muzny DM, Reid JH, Bainbridge MN, Willis A, Ward PA, et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med 2013;369:1502-11. 10. National Institutes of Health. Research portfolio online research tools. Available at: http://report.nih.gov/categorical_spending.aspx. Accessed March 12, 2014. 11. Nobelprize.org. Nobel lecture: Restriction Endonucleases, Simian Virus 40, and the New Genetics. Available at: http://www.nobelprize.org/nobel_prizes/ medicine/laureates/1978/nathans-lecture.html. Accessed March 12, 2014. 12. Vorstman JA, Ophoff RA. Genetic causes of developmental disorders. Curr Opin Neurol 2013;26:128-36. 5
U
S and international investment in biomedical research impacting child health, the establishment and growth of the National Institutes of Health (NIH) funding including investments in child health research made by many institutes and centers to Pediatric Departments, and Children’s Hospitals have all contributed to dramatic improvements in the survival of children born prematurely. These improvements have come from understandings in basic biology, the natural history of diseases, and improved technologies for disease management. Although disparities in survival persist in this country and around the world, basic1 research supported by the NIH has provided critical insight that has advanced neonatal care and childhood survival. As examples: (1) childhood cancer mortality rates declined by more than 50% between 1975 and 20062; (2) life expectancy of persons born with cystic fibrosis has increased from 7 years in 1970 to 37 years in 20103; (3) infant mortality in the US declined from 55.7 per 1000 live births in 1935 to 6.9 in 20004; and (4) maternal mortality in the US declined from 900 maternal deaths per 100 000 live births in 1900 to 12.7 in 2007. As life expectancy has increased, there has been increasing emphasis on research and care delivery on the quality of life and burden of disease. Advances in child health extend into adulthood and old age.
NIH Investment in Pediatric Research Includes Broad Areas of Biomedical Science Developmental Origins of Health and Disease Biomedical research reflects a life course continuum. Disorders of development may manifest at any age, and prevention and preemption of disease are most effective early in life. Many diseases that present in childhood may also manifest in adulthood, and many diseases presenting in adulthood have their origins in early life. Advances in fundamental biology have enhanced appreciation of the impact of early life influences on lifelong health and substantial data increasingly supports relationships between prenatal health and later adult health and disease. Ischemic heart disease, renal disease, hypertension, and type 2 diabetes are linked to birth weight and early development.5 NIH investment in several key areas highlights the importance of broad-based biomedical research investment in developmental origins of health and disease. As an example, research on the biology of obesity seeks to understand the complex interactions between genetic, epigenetic, immunologic, psychological, sociobehavioral, and societal factors in this major public health problem. Understanding the recent rapid increases in rates of obesity is essential to determine how and NIH
National Institutes of Health
when to intervene to achieve a lasting effect. High rates of overweight and other major risk factors for type 2 diabetes in middle school age children is the basis for current trials of schoolbased diet and exercise interventions, and basic research into the development of obesity using complex animal model systems is now identifying critical changes to the immune and inflammatory response as obesity develops. Emerging programs and priorities at the NIH will continue to build new knowledge critical to child health. As examples, the structure and function of the human brain is the focus of the Brain Research through Advancing Innovative Technologies6 effort, which builds upon an ongoing initiative in pediatric imaging,7 and the Grand Challenges in Mental Health recognizes that mental, neurologic, and substance abuse disorders impose massive burden on many populations. This effort will address pediatric interventions, recognizing that interventions in adulthood have limited success. Genomics and Regenerative Medicine Genomic approaches have been more rapidly integrated into diagnosis of inherited diseases in children than in adults. In 1962, the Eunice Kennedy Shriver National Institute of Child Health and Human Development took the lead in newborn screening for phenylketonuria at its inception.8 The Eunice Kennedy Shriver National Institute of Child Health and Human Development has worked closely with other institutes and centers, Health Resources and Services Administration, and the Centers for Disease Control and Prevention since 2003, and the Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children, which was formed to advise the Secretary of Health and Human Services on newborn screening. As genomic technologies have become more broadly applicable, increasingly sophisticated approaches such as whole genome sequencing are being employed in diagnosis and screening, with pediatric patients being the primary focus of diagnosis.9 Improved understanding of the human genome and the complex interactions of noncoding with coding regions, cisand trans-acting factors, the impact of pre- and postnatal nutrition, and the microbiome are providing glimpses of how these processes can go right and wrong. The development of induced pluripotent stem cells and animal and laboratory models of organ development have yet to produce improvements in health
From the 1National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; and 2Department of Pediatrics, Mott Children’s Hospital, University of Michigan Health System, Ann Arbor, MI Funded by the NIH. The views expressed are those of the authors, and do not represent the views of the US Department of Health and Human Services or the NIH. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpeds.2014.03.027
4
Vol. 165, No. 1 July 2014 but are providing clues that should impact not just medical treatments, but also public health interventions that can have population-wide impacts. Multiple NIH institutes are ensuring that these rapidly evolving diagnostic and screening approaches are appropriately introduced and implemented.
Pediatric Research Is Valued What are the take-home messages from the NIH funding experiences of pediatric research and researchers over the past decade? First, pediatric research and pediatric institutions have fared well in both public investment and productivity. In 2011, the NIH invested more than $3.2 billion in funding dedicated to pediatric research across its institutes and centers, out of a total NIH budget of $30.9 billion.10 Second, continuing improvements in maternal and child health have increased life expectancy in many countries around the world. These advances increase, rather than decrease, the importance of research on early life influences and exposures because the consequences of adverse outcomes are cumulative, and have long-term impacts on families, communities, and nations. Third, pediatric investigators—who have maintained highly competitive science in the extremely challenging environment of the past several decades—have several crucial roles to play in ensuring that the expanding opportunities of the early 21st century are exploited to benefit the health of children and succeeding generations of adults. Communication of the crucial roles of early developmental events on childhood and adult disease, including those which are prenatal and gestational, is increasingly appreciated by the public at large and by policy makers. Research that provides opportunity to impact early life exposures to improve life-long health will be supported by the public, legislators, and policy makers. It remains our responsibility to advance this understanding. Communication with the public and policy makers about the importance of public funding of research is vital. The impacts of basic research findings are rarely evident until many years after discovery and publication. The impact of findings of early life events on health later in life has similarly taken many decades to appreciate. Pediatric researchers must broadly advocate for investment in basic and translational biomedical research to ensure that investigators engaged in work, which may later bring powerful new tools to bear on the health of children, continue their pioneering work, whether or not such applications are evident early on. Discoveries such as restriction endonucleases11 are not specific to pediatrics, but their applications have transformed scientific exploration and benefited children and adults alike.12 Support of the next generation of pediatric investigators is essential. Pediatric researchers have held their own despite the decline in the success of applications to the NIH with the decrease in its buying power. If investigators with specific interest in the health and diseases of children are to bring emerging technologies and discoveries to addressing pediatric questions, they must be inspired, nurtured, supported, and encouraged. This is a challenge for all of biomedicine. Pediatric departments
must continue to attract diversified support from philanthropy, industry, and foundations—a task that falls to academic pediatric leadership. Institutional leaders must enhance the resources and incentives, enabling investigators to collaborate across disciplines and organizational boundaries, exploit expertise, which may advance discovery wherever such expertise may be, and ensure that funding resources are used wisely and effectively. Pediatric research and researchers share the fate of the broader world of biomedical research. Embracing common opportunities and challenges, exploiting the unique role of pediatrics in medicine and science, and taking a strong stand in support of ongoing research investment will enable us to achieve the promise of improved future child health. In summary, the rich history of accomplishment and contributions of US biomedical research discovery has from its earliest time included enactment of public policy and public investment focused on improving the health and lives of women and children. This legacy has contributed to positioning our nation as a leader in biomedical research and discovery. n The authors are grateful to Carol Bleakley and Deepshikha Roychowdhury (NIH Office of Extramural Research) and Sarah Glavin (Eunice Kennedy Shriver National Institute of Child Health and Human Development) for providing data on trends in funding of pediatric departments and children’s hospitals.
References 1. Callaghan WM. Overview of maternal mortality in the United States. Semin Perinatol 2012;36:2-6. 2. Smith MS, Seibel NS, Alteckuse SF. Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 2010;28:2625-34. 3. Slieker MG, Uiterwaal CS, Sinaasappel M. Birth prevalence and survival in cystic fibrosis: a national cohort study in The Netherlands. Chest 2005; 128:2309-15. 4. Singh GK, van Dyck PC. Infant mortality in the United States, 19352007: Over seven decades of progress and disparities. A 75th Anniversary Publication. Health Resources and Services Administration, Maternal and Child Health Bureau. Rockville, Maryland: U.S. Department of Health and Human Services; 2010. 5. Power C, Kuh D, Morton S. From developmental origins of adult disease to life course research on adult disease and aging: insights from birth cohort studies. Annu Rev Public Health 2013;34:7-28. 6. National Institutes of Health. The brain initiative. Available at: http:// www.nih.gov/science/brain/. Accessed March 12, 2014. 7. National Institutes of Health. The NIH MRI of Normal Brain Development. Available at: http://pediatricmri.nih.gov/nihpd/info/abstracts. html. Accessed March 12, 2014. 8. National Institutes of Health. Brief history of newborn screening. Available at: http://www.nichd.nih.gov/health/topics/newborn/conditioninfo/ pages/history.aspx. Accessed March 12, 2014. 9. Yang Y, Muzny DM, Reid JH, Bainbridge MN, Willis A, Ward PA, et al. Clinical whole-exome sequencing for the diagnosis of Mendelian disorders. N Engl J Med 2013;369:1502-11. 10. National Institutes of Health. Research portfolio online research tools. Available at: http://report.nih.gov/categorical_spending.aspx. Accessed March 12, 2014. 11. Nobelprize.org. Nobel lecture: Restriction Endonucleases, Simian Virus 40, and the New Genetics. Available at: http://www.nobelprize.org/nobel_prizes/ medicine/laureates/1978/nathans-lecture.html. Accessed March 12, 2014. 12. Vorstman JA, Ophoff RA. Genetic causes of developmental disorders. Curr Opin Neurol 2013;26:128-36. 5
