Research in Diseases, Disorders, and Health Conditions
Life Stages, Human Development, and Rehabilitation
Interactions among biological processes and physical and psychosocial factors in the environment shape an individual’s health and functional capacities from the earliest formation of cells, tissues, organs, and organ systems through childhood, adulthood, and old age. NIH research in this area focuses on healthy developmental processes and the ways in which these processes diverge, causing or contributing to much of the nation’s heavy burden of disease and disability. Some disorders of altered developmental processes, such as neural tube defects, are apparent at birth. Others, including intellectual and developmental disabilities, obesity, cardiovascular and metabolic diseases, cancers, mental illnesses, and dementias, may not emerge until months, years, or decades later.
Human development progresses most rapidly during gestation and early childhood but continues throughout the course of life. Each developmental stage lays the foundation for health or illness in subsequent stages. This means that the developmental aspects of NIH research have critical implications for public health. Understanding precisely what happens during developmental “windows” of heightened sensitivity to infections, toxic exposures, personal behaviors, and a host of other environmental factors is essential to learning how and when to intervene most effectively to prevent or lessen chronic and disabling conditions. This concept, which has been termed the Developmental Origins of Health and Disease (DOHaD), is based on extensive human epidemiologic data and experimental animal models. DOHaD data and models from NIH-supported research demonstrate that the risk of poor adult health is associated with environmental influences during fetal development and infancy, as well as influences affecting transgenerational inheritance. Initial research on DOHaD focused primarily on nutritional factors contributing to disease; however, other environmental factors during development are now also being linked to the risk of non-communicable diseases such as diabetes, cardiovascular disease, metabolic syndrome, and chronic lung diseases. The potential implications of DOHaD research are great, as more than 35 million deaths per year—60 percent of all global deaths—are attributed to non-communicable diseases.97
This area of NIH research also encompasses medical rehabilitation, including tissue regeneration, to optimize the functioning of individuals with disabling conditions. Medical rehabilitation research is the study of physiologic mechanisms, methods of treatment, and devices that serve to improve, restore, or replace underdeveloped, lost, damaged, or deteriorated function. A key aspect of medical rehabilitation research is its focus on the effects of functional problems on the whole person, rather than a single organ system. Thus, it views the individual in the context of a dynamic system of interacting variables, including biological, psychosocial, and environmental factors.
The role of developmental processes in the risks for common and rare disorders and in rehabilitation science means that the scope of NIH research in life stages, human development, and rehabilitation is quite broad. This research area includes basic research on molecular and cellular processes to gain insights into the trajectories of human development and disease and even to harness developmental processes such as cell differentiation for therapeutic and rehabilitative uses. This research area also includes the collection and analysis of data over the lifespan or over a specific period of interest, such as childhood or older age. Such studies can suggest the relative contributions to health or to specific disorders of environmental exposures and ongoing developmental and disease processes. Also included are studies of specific disorders with an emphasis on an individual’s life stage or developmental status.
As the institute with statutory responsibility for child health and human development research, NICHD conducts and supports research programs in reproductive health and in the developmental processes that begin before conception and continue through adolescence. As the Institute with statutory responsibility for research on aging, NIA conducts and supports research on both the maintenance and loss of functions during the aging process, diseases associated with aging, and the problems and needs of older individuals and their caregivers. NINR supports research across all life stages to build the scientific foundation for clinical practice and managing and eliminating symptoms caused by illness, and it also is the designated lead institute for end-of-life research. NIEHS focuses on the influences of environmental agents on the development and progression of specific diseases.
Numerous other ICs support life stages, human development, and rehabilitation research in cancer, diabetes, addiction, mental health, musculoskeletal and neurological disorders, and other areas relevant to their missions. ORWH, among its many roles, works across all ICs to develop and support opportunities for research and training in the study of disorders relevant to women’s health across the lifespan and sex and gender differences in disease. Mission-specific rehabilitation research is supported by multiple Institutes, including NEI, NIA, NIBIB, NICHD, NIDCD, NIDCR, and NINDS. A focal point for this research is NICHD’s National Center on Medical Rehabilitation Research, which emphasizes the rehabilitation and lifelong care of people with physical disabilities resulting from stroke, injury, and other disorders.
Many sections of this report include data on the burden of illness of specific conditions in which developmental-environmental interactions are or may be implicated. Comprehensive data on the total burden of these conditions do not appear to be available. The magnitude of this burden, however, is exemplified by just a single condition, the complex problem of obesity and its associated conditions, including type 2 diabetes, cardiovascular disease, pregnancy complications, certain cancers, osteoarthritis, liver and gall bladder disease, and depression. CDC estimates the prevalence of obesity among individuals ages 20 years and older in the U.S. as 35.7 percent, and the prevalence of obesity plus overweight as 68.8 percent.98 Overweight and obesity also exert a substantial economic toll on the U.S., with the combination of direct health care costs plus indirect costs, such as lost wages caused by illness, estimated to be $117 billion for the year 2002.
Estimating the burden of functional limitations for which rehabilitation may be indicated is complicated by lack of consensus on the definition of “disability,” appropriate survey measures, and other issues. The Institute of Medicine (IOM) defines disability as impairments in body structure or function, limitations on activities such as dressing and other daily personal care, and limitations on participation in such activities as school and work. IOM reported that between 40 million and 50 million individuals99 or about one in seven Americans, have some type of disability.
97Alwan A. WHO Action Plan for the Global Strategy for the Prevention and Control of Noncommunicable Diseases. Geneva, Switzerland: World Health Organization, 2008. Available at: http://www.who.int/nmh/Actionplan-PC-NCD-2008.pdf.
98Flegal KM, et al. JAMA. 2012;307(5):491–7. PMID: 22253363.
99 For more information, see http://www.nap.edu/openbook.php?record_id=11898&page=1
NIH funding for rehabilitation research was $458 million in FY 2010 and $459 in FY 2011 for non-ARRA (regular appropriations) and $93 million in FY 2010 for ARRA appropriations.100Currently, NIH does not collect the trans-NIH funding data necessary to provide an aggregate figure for expenditures on life stages and human development research.
The goal of NIH life stages, human development, and rehabilitation research is to enable individuals to achieve a full life with the best health and function at every life stage. Understanding complex developmental pathways to health or illness throughout the life course is critical to creating new ways to prevent disease and disability before they become symptomatic, or even preempting the disease process before it starts. Basic, clinical, and translational research all rest on the fundamental concept of developmental science, that the formation and function of cells, tissues, organs, organ systems, and the fully formed individual are sensitive to protective or harmful environmental factors, and especially so at specific stages. These factors include physical agents, such as industrial and agricultural chemicals; tobacco, alcohol, and other drugs of abuse; microbial infections; nutritional deficits; and even medical treatments, such as pharmaceuticals and radiation. Powerful environmental influences also include behaviors of individuals and of those with whom a person lives or works, and norms and values of households, families, schools, workplaces, and communities. Sex and gender differences affect developmental trajectories and disease risks. All such factors can have immediate, intermediate, and/or long-term effects on human health and function.
100For funding of various Research, Condition, and Disease Categories (RCDC), see http://report.nih.gov/categorical_spending.aspx.
In studies of the most fundamental molecular and cellular processes, NIH scientists continually expand understanding of how development typically progresses, what goes awry and why, and how health is affected. For example, epigenetic influences on the expression of genes may be critical mechanisms for gene/environment interactions that influence health and development. Understanding these subtle interactions is an essential step toward discovering treatments and preventive strategies. NIH has established the Common Fund Epigenomics Program to stimulate the creation of important new scientific resources for epigenetics researchers and thus speed progress toward applications that affect human health and common, complex human diseases. A major effort in the program is characterizing the epigenome; that is, creating a catalog of stable epigenetic modifications that occur in the genome (all genes encoded in the DNA). Among other things, Common Fund epigenomics resources may become the basis for studies of diabetes, including the effects of the intrauterine environment on later risk of disease development.
Basic research in developmental biology also may enable scientists to harness powerful normal cellular processes for therapeutic purposes. Research on cell senescence, a significant factor in normal aging, one day may yield understanding of cellular mechanisms that act to block the development of cancer as well as specific characteristics of aging. Goals of human embryonic stem cell research include explaining critical events in early human development that could lead to developing customized regenerative medical interventions. Sex and gender differences affect developmental trajectories and disease risks. Basic research is only one essential component of the NIH portfolio of multiple methodological approaches to understanding human development. For example, with NIH support, investigators are assembling a unique database of anatomical neuroimages of children’s brains over time. This database also will include clinical, behavioral, demographic, and cognitive data on the children, thus enabling scientists to understand the multiple dimensions of normal human brain development. This knowledge is also critical to understanding the effect of environmental “insults” to the brain, such as drug use during pregnancy. Such understanding is essential in elucidating intellectual and developmental disabilities, pediatric neurological diseases, and many other disorders that emerge in childhood. The multi-decade Baltimore Longitudinal Study of Aging (BLSA) has created a wealth of information that has helped scientists—and the public—understand distinctions between physical changes attributable to the aging process and those caused by disease. These data have yielded important insights on, among other things, relationships between age-related changes in the arteries and cardiovascular disease and differences between normal declines in cognitive ability related to age and those associated with Alzheimer’s disease (AD) and related conditions.
“Life stages” or “life course” research is a concept that informed landmark epidemiological and longitudinal studies. These studies linked risks of major adult-onset disorders, including type 2 diabetes, hypertension, stroke, and heart disease, to environmental influences in uteroand in early childhood. The life-course research model has expanded to include a greater number of developmental stages and a wide array of environmental factors and conditions of interest, with a goal of determining how—and when—to intervene to prevent or treat disease. The NIH-supported Breast Cancer and the Environment Research Centers (BCERC) is a transdisciplinary initiative cosponsored by NCI and NIEHS, in which basic scientists, epidemiologists, clinicians, and community partners work together to examine the effects of environmental exposures that may predispose a woman to breast cancer throughout her life. Specific attention is given to puberty, menopause, pregnancy, and other windows of susceptibility when the developing breast may be at particular risk from environmental exposures.
NIH-supported research on maternal and childhood obesity seeks to understand complex interactions among genetic, psychological, physiological, familial, community, environmental, and other factors in this major public health problem. The goals of such research include understanding the rapid, recent increases in rates of obesity and determining how and when to intervene to achieve lasting effect. NIH findings of high rates of overweight and other major risk factors for type 2 diabetes in middle school students are the basis for current trials of school-based diet and exercise interventions. The goal of the interventions is to decrease the children’s short- and longer-term risks for obesity and type 2 diabetes.
Research that led to universal newborn screening for phenylketonuria and for hypothyroidism and immediate initiation of treatment for affected infants to protect their developing brains has virtually eliminated intellectual and developmental disabilities (IDDs) associated with these conditions. NIH is funding a major initiative to speed the development of highly efficient technology for screening newborns for very large numbers of additional rare genetic conditions and to accelerate the discovery of treatments for such conditions. This initiative also includes support for networked facilities that can translate scientific discoveries quickly into clinical practice.
NIH investments in understanding and developing interventions for Fragile X and Down syndromes and other IDDs include support for 14 IDD centers. These centers provide core research resources in genetics and proteomics as well as clinical infrastructure for a wide range of studies. Multiple NIH-supported programs focus on autism spectrum disorder. For example, the Autism Centers for Excellence include (a) six centers focusing research on possible causes of autism spectrum disorder, including genetic, immunological, and environmental factors, and (b) five networks focusing on causes, preventive interventions, and improved treatment. High priority will be placed on identifying autism spectrum disorder risk factors, biological signatures of autism spectrum disorder, and evaluating interventions in understudied populations. NIH established an intramural research program to accelerate development and testing of innovative treatments for autism spectrum disorder. This program has already evaluated hundreds of children and tested three novel compounds.
Retinopathy of prematurity (ROP) is abnormal blood vessel development in the eyes of some infants born severely premature, which can lead to blindness if not treated in time. NEI is funding a clinical trial that uses telemedicine as a tool for doctors to remotely diagnose ROP in premature infants born in rural and underserved areas. Other pediatric vision research is addressing the increasing incidence of myopia (nearsightedness). Recent NEI research has found that the amount of time children spend outdoors may reduce the risk of developing myopia, whereas near work, such as reading a book or a computer screen, is not necessarily related to myopia and other refractive errors, as long hypothesized.
The tendencies toward risky behaviors attributed to immaturity of the brain in adolescence makes this developmental stage of interest in studies of substance abuse and addiction. In seeking to understand how developmental stage may influence vulnerability to, or protection from drug abuse, scientists are beginning to understand how a range of environmental variables, including quality of parenting, drug exposure, socioeconomic status, and neighborhood characteristics, influence brain development and behavior. Recent studies have uncovered specific genetic variants linked to heightened risk of future drug problems in those who started using during adolescence. Researchers also are testing preventive strategies such as universal approaches that engage broad youth audiences to address a panoply of risk behaviors; selective interventions that target groups of individuals at increased risk (relative to the general population); indicated prevention interventions that focus on individuals who have begun using drugs but are not yet diagnosed with a disorder; or tiered interventions that include a combination of universal, selective, and indicated approaches. Better understanding of relationships between developmental stages and disease processes may be critical to the efficacy of therapeutic interventions. In another example, NIH-supported research on brain development in children with attention-deficit/hyperactivity disorder (ADHD) showed a normal pattern of brain development but with a significant delay in maturation of the prefrontal cortex between the ages of five and 15 years. Scientists now are investigating the effects of treatment on rates of cortical maturation.
On the other end of the age spectrum, NIH conducts and supports a large and diverse research portfolio on aging and age-related diseases, including biochemical, genetic, and physiological mechanisms of aging in humans and animal models; structure and function of the aging nervous system; social and behavioral aspects of aging processes; and pathophysiology, diagnosis, treatment, and prevention of age-related diseases and disabilities. One of the longest ongoing longitudinal studies of aging ever conducted, the Baltimore Longitudinal Study of Aging (BLSA)has been active for over half a century. The main focus has been to describe physiological parameters and longitudinal trajectories of change in these parameters in participants of different ages, initially free of major diseases at the time of enrollment. The underlying goal is to discriminate changes due to “normal aging” from those generated by age-associated conditions. Findings from the BLSA in this regard have contributed substantially to current knowledge of the physiology of aging. Incorporating major technological advancements in assessment of physiologic and biomarkers of aging and theoretical refinements, the BLSA continues to pursue the following objectives: (1) describe longitudinal trajectories of the major aging phenotypes, (2) identify genetic, physiological, behavioral and environmental factors that affect the rate of change in these phenotypes and (3) understand the interrelationship between aging phenotypes and highly prevalent chronic conditions and their independent and joint impact on age-related decline in physical and cognitive function.
In order to develop a comprehensive picture of the health and disability of older Americans, NIH supports the Health and Retirement Study (HRS) and the National Health and Aging Trends Study (NHATS). The HRS has surveyed more than 22,000 Americans aged 50 and older every two years since 1992, collecting data on income, work, assets, pension plans, health insurance, disability, physical health and functioning, cognitive functioning, psychosocial stress, and health expenditures. Self-report and biomarker measures of health are combined with Medicare data on utilization of health services. ARRA funds have facilitated the expansion of the study to include participant genotyping and doubling the minority sample.The National Health and Aging Trends Study (NHATS) replaced the National Long-Term Care Survey as the source of research data on national disability trends and dynamics among the senior population of the U.S. This study has just completed the collection of baseline data, which will become available to the research community in spring 2012.
Clinical trialsare being supported by NIH in order to understand the potential genetic factors that contribute to exceptional survival (the Long Life Family Study). These trials will test treatments for health conditions common to old age, including testosterone supplementation to delay or prevent frailty in older men; effects of exercise on mood, health, and cognition; and, an array of interventions for menopausal symptoms.
Research on normal maturational processes may lead to new ways to treat or prevent disorders associated with aging. NIH conducts and supports a large and diverse portfolio of research on aging and age-related diseases and conditions, including the biochemical, genetic, and physiological mechanisms of aging in humans and animal models; structural and functional changes in the aging nervous system; social and behavioral aspects of aging processes and the place of older people in society; and the pathophysiology, diagnosis, treatment, and prevention of age-related diseases, degenerative conditions, and disabilities. For example, NIDCD-funded investigators hope to identify gene mutations that contribute to age-related hearing loss, understand structural consequences of such mutations, and investigate protein function of these genes to inform better prevention and treatment strategies.
NIA’s Interventions Testing Program (ITP), which began in 2003, supports the testing of interventions including foods, diets, drugs, and hormones with the potential to extend the lifespan and delay disease and dysfunction in a mouse model of aging. ITP investigators found that the drug rapamycin can increase lifespan in both male and female mice. Further research is ongoing.
Age-related macular degeneration (AMD), the leading cause of blindness in older Americans, will impose an increasing burden in future years as the baby boomer generation ages. The Age-Related Eye Disease Study (AREDS) demonstrated that antioxidant vitamin and mineral supplements reduced the progression to advanced AMD by about 25 percent. Building on these landmark findings, the follow up study is assessing additional supplements (lutein, zeaxanthin, and long-chain omega-3 fatty acids) as a treatment for AMD and cataracts. It is also evaluating effects of eliminating beta-carotene and/or reducing zinc in the original AREDS formulation on AMD progression.
NIH makes major investments in research to understand the onset and progress of Alzheimer’s disease, the most common form of dementia in aging, and to discover how to slow its progress and, ultimately, to prevent it. In April 2010, NIH held a State of the Science Conference on Preventing AD and Cognitive Decline in which the conference panel determined that there is insufficient scientific evidence to support use of any interventions to prevent cognitive decline or Alzheimer’s disease. In 2009, expert panels convened by the NIA and Alzheimer’s Association began meeting to update the clinical diagnostic criteria for the disease. Completed in April 2011, the NIA/Alzheimer’s Association Diagnostic Guidelines for Alzheimer’s disease established a paradigm for diagnosing and researching the disorder. The updated guidelines cover the full spectrum of Alzheimer’s disease as it gradually develops over many years and addresses the use, primarily in the research setting, of brain imaging and biomarkers that may help diagnose Alzheimer’s disease at earlier stages.
At all stages of life, individuals with chronic or critical illnesses and their families and clinical caretakers need evidence-based guidance and support in managing chronic illness and transitioning to the end of life. End-of-life science seeks to understand dying with respect to the needs of dying persons and formal and informal caregivers. It includes research on such issues as: alleviation of symptoms, psychological care, near-death preferences, advance directives, and family decision-making. Likewise, end-of-life research addresses the cultural, spiritual, age-, and disease-specific factors that make each person’s experience at the end of life unique. NIH end-of-life research applies biological, behavioral, and social science strategies to advance the understanding of the dynamic interactions of these various factors and to develop interventions that optimize patient and caregiver quality of life across care settings and cultural contexts. NIH recently sponsored an initiative to develop and test interventions to enhance end-of-life and palliative care, which providers can implement across multiple settings, illnesses, and cultural contexts. NIH-supported Centers in Self Management or End-of-Life research are important loci for interdisciplinary research in this area. In August 2011, NINR, in partnership with NIA, NCCAM, ORDR, ORWH, and the NIH CC Office of Bioethics, convened a three-day national summit on “The Science of Compassion: Future Directions in End-of-Life and Palliative Care.” The summit examined the state of research and clinical practice in end-of-life and palliative care and provided an opportunity for scientists, health care professionals, and public advocates to come together to catalyze and shape the future research agenda for this critical scientific area.
The goal of rehabilitation science is to enable individuals with functional impairments associated with congenital disorders, chronic diseases, or events such as stroke or traumatic injury to live full and productive lives, as independently as possible. Developmental stages are a central consideration in this research, because differences among age groups, including physiology and physical size, psychosocial trajectories, and expected lifespan, must all be taken into account in rehabilitation interventions.
An important focus of rehabilitation research is the interface between medicine and engineering. Scientists explore innovative biomedical technologies and test their capacity to resolve stubborn medical problems and enhance mobility, sensory, and other functions of individuals with disabling conditions. NIH projects in rehabilitation neuroscience also pursue the development of prosthetics and other devices to restore or enhance the capacity to function in those who lose limbs because of injury, combat, or complications from diseases such as diabetes. Researchers are capitalizing on new advances in technology that resulted in a successful prototype “bionic arm” to create a next-generation “bionic hand.” Rerouting nerve endings and attaching more electrodes could restore a rudimentary sense of touch and allow users to control robotic fingers with their brain.
Basic processes of cellular and molecular development and function offer great potential for rehabilitation research and clinical applications. Scientists are seeking to understand both the mechanisms that underlie functional impairments and the therapeutic potential of such basic developmental processes as cell differentiation. A major collaboration between the NIH intramural program and the Department of Defense is the new Center for Neuroscience and Regenerative Medicine (CNRM) whose mission is to enhance the health, productivity, independence, and quality-of-life of people with disabilities by supporting a broad range of research, including efforts to understand the underlying biology of injury and disability, and the body’s normal mechanisms of recovery and adaptation. These activities include a special emphasis on research related to spinal cord injury (SCI), traumatic brain injury (TBI), and stroke. The Center’s mission also includes catalyzing advances in treatment, rehabilitation, and long-term recovery for individuals experiencing TBI. Even seemingly mild forms of TBI can seriously disrupt short- and long-term brain function. Because past studies of single agents were largely unsuccessful in improving TBI outcomes, new efforts involve multiple drug combinations and molecules to inhibit swelling, inflammation, and other biochemical reactions that can harm brain tissue after TBI. One such combination under study is progesterone and vitamin D. Progesterone is known to protect the brain from injury; however, it is much less effective in individuals who have low levels of vitamin D. Other efforts address the difficulties with concentration and attention often reported by individuals with TBI. One relevant project compares the effectiveness of behavioral therapy, centered on improving concentration and emotional control, to drug treatment with methylphenidate, often prescribed for attention deficit disorder.
The Clinical Center is working with many ICs in leading the investigator-coordinated NIH intramural Bone Marrow Stromal Cells (BMSC) Transplantation Center, where clinical grade BMSCs, shown to have a therapeutic effect on several injuries and diseases, are being produced and used for the treatment of patients with acute graft-versus-host disease. Ultimately, the BMSCs produced by this Center could be used for the treatment of a variety of human diseases and disorders.
NIDCR supports interdisciplinary basic and translational research for engineering and regeneration of functional oral and craniofacial tissues, including research aimed at improving the capacity of oral and craniofacial tissues to heal and regenerate themselves with the help of a variety of novel therapeutic agents. In one example, NIDCR is supporting a study that demonstrates how mechanical forces originating outside a cell become transmitted into cell's nucleus to direct early tooth development. This advance will help to derive new approaches that employ mechanical and other biophysical forces to mimic early developmental events for regeneration of an adult tooth, and has important implications for skeletal bone development as well.101
NIH participates with DoD and other agencies for the Armed Forces Institute of Regenerative Medicine in a multi-agency effort to develop and advance treatment options for severely wounded service men and women (http://www.nibib.nih.gov/About/Overview/DDSTFactSheet and http://www.afirm.mil/) . Research projects aim to develop new products and therapies to address the growing prevalence of complex and life-threatening injuries and help those who have been wounded to reach their highest potential. Research projects are advancing wound healing therapies that prevent and manage scar formation; developing novel treatments to reduce the high morbidity and mortality from burn wounds; developing therapies that promote regeneration of bone material for craniofacial reconstruction; and developing finger and limb reconstruction, regeneration or transplantation.
101Mammoto T, et al. Developmental Cell. 2011;21 (4): 758–769). PMID: 21924961.