The Potential of Interdisciplinary Research to Solve Problems in the Brain, Behavioral, and Clinical Sciences
All knowledge begins with a question.
— Neil Postman
To address the health needs of the new millennium, both single disciplinary research and interdisciplinary—including translational—approaches will be needed. This chapter focuses specifically on the contributions, past and expected, of some fields of interdisciplinary science. The research questions described in this chapter will call for integrated efforts to develop methods for prevention, diagnosis, and treatment of disease and to understand the basic mechanisms of brain and behavior. Approaches to interdisciplinary research are diverse. The examples in this chapter illustrate translational research that applied clinical findings to basic science and vice versa, collaborations across disciplines, integration of past disciplinary efforts to create a new perspective, and the synergy created by central facilities that bring people together. The committee emphasizes that interdisciplinary research is an approach, not an end. It should arise out of a challenge; that is, it should develop in response to a problem that cannot be embraced by a single discipline.
Many problems require single disciplinary scientific approaches. Historically, single disciplines grew out of bodies of knowledge in efforts to promote a coherent and ordered focus of investigation and study. Single disciplines enable in-depth and technically adroit approaches to complex problems. As described in chapter 3, the constraints of training and getting started in a career make single disciplinary research the preferred route for many young investigators. The disciplinary approach to research is intellectually rewarding and leads to important findings. Investigators in single disciplinary work have contributed enormously to our understanding of basic biology and human health—B. F. Skinner
in operant conditioning, von Bekesey in audition, and Hodgkin and Huxley in nerve conduction are examples. Furthermore, single disciplinary efforts often feed into interdisciplinary and translational efforts.
NEUROSCIENCE: EVOLUTION OF A DISCIPLINE
The brain has been studied for millennia. As early as the fourth century BC Hippocrates recognized the involvement of the brain with sensation and with epilepsy. In the mid-1600s, Thomas Willis, an English anatomist, provided a detailed description of the structures of the brain. Two hundred years later scientists began to correlate structures with functions. For example, Paul Broca related a clinical pathology to a structural defect noted on autopsy and Eduard Hitzig and Gustav Fritsch found that electrical stimulation of specific cortical areas produced movement. By the mid-1800s many histologists were describing the cellular components of the nervous system. (For example, see the section on Ramon y Cajal that follows.) Early in the nineteenth century, neurophysiology was gaining momentum with the efforts of scientists such as Charles Sherrington and Edgar Adrian, and neurochemistry was developing, with Henry Dale's isolation of acetylcholine.25, 53
Up until a few decades ago scientists engaged in these endeavors identified themselves as anatomists, physiologists, psychologists, biochemists, and so on. In 1960 the International Brain Research Organization was founded to promote cooperation among the world' s scientific resources for research on the brain.41 In 1969, the Society for Neuroscience was founded to bring together those studying brain and behavior into a single organization; its membership has grown from 1000 in 1970 to over 25,000 in 2000.86 Within the new discipline, neuroscientists are integrating a variety of perspectives to gain insights into fundamental questions about the nervous system in health and disease. Neuroscience is a clear example of a discipline of today arising from interdisciplinary approaches of the past. The discipline of neuroscience arose by combining the efforts of scientists in different fields to solve common scientific problems. It is a dynamic discipline in which new fields continue to be integrated (for example, informatics and molecular biology). The growth of this discipline has been so prodigious, the territories it covers so broad, and the methods it employs so varied that neuroscience itself is beginning to fragment into subdisciplines. One such subdiscipline is cognitive neuroscience, which is itself evolving as a new discipline.
DISCIPLINARY WORK PROVIDES A FOUNDATION
Disciplinary research has an important place in the scientific enterprise. As the examples here illustrate, the efforts of scientists in their own fields can create the tools or provide the basis for many future efforts. Interdisciplinary approaches often build on single disciplinary discoveries.
Human Genome Project
The Human Genome Project was established in 1988.85 Before it could become a reality, however, decades of disciplinary efforts were necessary to lay the foundations. In 1944, Avery et al.5 discovered that DNA carried the genetic message. The structure of DNA was first unraveled by Watson and Crick99 in 1953, and the genetic code was worked out in the middle 1960s. 22 In the early 1970s, the methodology of recombinant DNA was published. 103 Years of basic research on enzymes such as restriction endonucleases, polymerases, ligases, and reverse transcriptases, provided the tools that are the basics of the methodology for the Human Genome Project. For example, when Temin and Mizutani93 and Baltimore7 first described reverse transcriptase in 1970, they were focused on how some viruses copy their genetic messages from RNA to DNA in host cells. The enzyme became the focus of biochemists and virologists trying to understand its characteristics. On the basis of their findings, the enzyme was recognized as important for the analysis of the genome.
Having evolved from independent, single disciplinary efforts, the Human Genome Project has expanded into a prime example of interdisciplinary research, involving scientists in a variety of disciplines, such as biology, chemistry, genetics, physics, mathematics, and computer science. The enormous data management problems arising from the wealth of information generated in genomic analyses require new and more powerful computational methods. In addition, important contributions to the analysis of the ethical and legal implications come from philosophy, jurisprudence, and ethics. The developing knowledge base is expected to serve as the foundation for new interdisciplinary efforts to understand the function of genes and the contribution of genetic diversity to both health and disease. The implications go beyond medicine and human health to applications in energy, environmental protection, agriculture, and industrial processes.63, 64, 70, 95
Neuroanatomy of Ramon y Cajal
Santiago Ramon y Cajal won the Nobel Prize in 1906 for his work on the histology of the nervous system. Because Ramon y Cajal used the newest stains, optical microscopy, and anatomical approaches, one could argue that this innovator's research reflects the coalescence of multiple disciplines into a single discipline. His methods became the standard tools of the neuroanatomist. He shared the Nobel Prize with Camillo Golgi, whose principal contribution was a stain with a unique property: it revealed an entire cell and its processes. Despite the discrete entities stained, Golgi continued to support the prevailing belief that the nervous system was a continuous network of fibers. Ramon y Cajal, however, reinterpreted the observations to support the “neuron doctrine,” which today is basic to our understanding of central nervous system organization. His
histological studies provided detailed representations of cells from many parts of the nervous system and created a starting point for understanding their connections, their physiology, and their pathophysiology. Ramon y Cajal's work is still cited in reports on subjects as varied as gene expression in rat brain,51 electrophysiology of synaptic currents,8 and axonal regeneration in spinal cord.23
TRANSLATIONAL RESEARCH: TO THE CLINIC AND BACK AGAIN
The following examples illustrate how clinical and basic researchers can join together to advance a field. In one case, a chance conversation about a clinical observation led to a basic science breakthrough in understanding pathology. In the other case, a patient's unfortunate circumstances created the stimulus for a field that continues to integrate basic and clinical investigation.
Breakthrough in Sickle Cell Anemia
While they served together on an advisory committee, William Castle, a clinician, described to Linus Pauling, a physical chemist, his observation that in sickle cell disease the red blood cells were abnormally shaped only when deoxygenated. Pauling hypothesized that the abnormal shape of the red blood cells in the patients was a result of an altered shape of the oxygen-carrying hemoglobin molecule. On his return to his laboratory, Pauling and a young colleague, Harvey Itano, attempted to distinguish normal hemoglobin from sickle cell hemoglobin by using a variety of physical and chemical methods. With a new electrophoresis technique, they found a difference in mobility suggesting that the two forms of hemoglobin had different electrical charges.89 The results were published in a Science paper titled, “Sickle Cell Anemia, a Molecular Disease.”72 The paper reasoned that genetic control of the amino acid composition of hemoglobin was responsible for the hereditary nature of the disease. The field of genetic medicine was born of the interaction between a bedside clinical investigator and a basic laboratory scientist. From this first recognition of the molecular basis of the pathology has followed the development of treatments: drugs that address the pathophysiology of the disease16 and nitric oxide,35 bonemarrow transplantation,98and the promise of gene therapy.49, 55, 92 The development of animal models71, 76 promises to continue to bridge the gap between laboratory and clinic.
THE STORY OF PATIENT HM
In an effort to control a severe case of epilepsy, a patient known as HM had most of the temporal lobes of his brain removed bilaterally in the early 1950s. The consequences were unexpected. HM was unable to form new memories. He
could remember his childhood and he could recognize his mother. But, although he could learn a name or memorize a number for a very short time, the information was lost to him after a few minutes.81 HM's condition provided a clinical model that stimulated extensive laboratory efforts to understand the neurobiology of memory. Mishkin59 reproduced the lesions of HM in primates to develop an animal model to study the process of memory. With the evidence of hippocampal and medial temporal lobe involvement in memory formation, many basic laboratory investigations focused on neurophysiological mechanisms, neuroanatomic substrates, and behavioral deficits in animal models. As the understanding of memory grew, the impairment in HM and other unfortunate patients was reevaluated.20, 21, 58, 75, 88 For example, the testing of HM's capabilities supported the laboratory-generated hypothesis that there are different kinds of memory processes. Although HM does not recall having met a visitor or recall the process of learning a task like mirror writing, he can improve his skill at mirror writing at a normal rate and even retain the skill for weeks.29 Clinical observations of memory loss continue to stimulate the basic animal research efforts with clinically relevant questions. 87 The advent of new imaging technologies, such as functional magnetic resonance imaging, and new noninvasive recording methods, such as magnetoencephalography, continue to enhance the interactions between clinical and basic research.21, 28, 87
INTERDISCIPLINARY RESEARCH: MAKING PROGRESS
Several interdisciplinary programs have been running long enough to demonstrate the added value of interactive efforts. Whether developed through the encouragement of a funding agency or through the leadership of an individual, these programs illustrate the breadth of what can be achieved when disciplines come together to solve a problem. The role of the leader of an interdisciplinary team is analogous to that of an orchestra conductor who coordinates highly specialized experts to produce harmonious outcomes. The leader would be expected to converse freely with persons in disparate fields and to facilitate the interactions among team members. The expectation for the team members is to be responsible for issues involving their expertise and to develop a working knowledge of each others' fields. The composition of the “orchestra” would not be fixed, but, rather, would change depending on the particular problem at hand. With time, participants would expand their understanding of other fields while continuing to contribute their own expertise.
Cardiovascular Health and Behavior
In recent years, fields that have not traditionally embraced interdisciplinary research have begun to recognize that it is essential. For example, the National
Heart, Lung, and Blood Institute Task Force on Behavioral Research in Cardiovascular, Lung, and Blood Health and Disease concluded in 1998 that collaborations between behavioral and medical researchers would provide a better understanding of disease. Many Americans are living with heart disease, including more than 13 million who have angina pectoris or who have suffered a myocardial infarction.65 Management of their disease and prevention of recurrent disease are foci of attention for behavioral and clinical scientists.
Recent studies have demonstrated that such behaviors as smoking, lack of exercise, and inappropriate diet can increase the risk of heart disease. Epidemiological studies, clinical investigation, and experiments in animal models have provided new understanding of the physiological links between behavior and pathology. In addition, personality traits, exposure to stress, socioeconomic status, and social support have been found to influence the risk of cardiovascular disease. Extensive research collaborations among experts in many fields—including psychologists, neurobiologists, cardiologists, and comparative pathologists—provided evidence that stress, anger, and lifestyle influence the pathophysiology of coronary heart disease. 43, 46 Large interdisciplinary clinical trials are in progress to determine whether psychosocial interventions can reduce morbidity and mortality in heart diseases.10, 84 Continued interdisciplinary research is likely to produce new advances in the prevention and management of cardiovascular disease.
Schizophrenia is a chronic and disabling mental disorder. Diverse symptoms encompass abnormalities in perception, thinking, speech, affect (expression of emotion), and behavior. Hallucinations, delusions, and social withdrawal are commonly associated with the disease. Schizophrenia usually first manifests itself in young adults. Patients suffer from public stigma because of their unusual behavior. Although treatments are available, adherence to treatment regimens is a problem, in part because of the side effects of the pharmaceutical agents. Although we are using schizophrenia as though it were a single disease, it would be more accurate to use the schizophrenias because of the likelihood of underlying disease heterogeneity.
There is now general agreement among experts in schizophrenia that abnormal brain development from many causes underlies the disease. 9 Advances in neuroimaging have shown that some people with schizophrenia have abnormally large ventricles (fluid-filled cavities) within the brain.52, 100 Schizophrenia has been associated with impaired migration of neurons in the brain during fetal development.2 Both genetics and environmental factors influence development of the disease. Twin studies and other genetic epidemiological assessments indicate clearly that a genetic predisposition to the disease exists. 44, 45, 73 Some data suggest a link between schizophrenia and maternal viral infection during gestation.101
Recent studies have brought together multiple disciplines in attempts to understand the disease in its entirety. For example, the combined use of such neuroimaging techniques as positron emission tomography (PET) to look at blood flow and magnetic resonance imaging to look at structures, genetic analyses, cognitive testing, and clinical trials of pharmaceutical agents to evaluate patients with schizophrenia is allowing progress toward the development of interventions for the disease.4 Continued interdisciplinary efforts in schizophrenia research —including epidemiology, genetics, structural brain abnormalities, development, behavior, and virology—should advance the understanding and treatment of the disease.
INTERDISCIPLINARY RESEARCH: FUTURE DIRECTIONS
Major advances in human health are increasingly contingent on interdisciplinary research that requires close collaboration between biomedical and behavioral scientists. Although research in single disciplines has made and will continue to make important contributions to understanding chronic diseases, current efforts are needed to solve problems that stem from multiple domains. The committee heard from the directors of several of the National Institutes of Health (NIH) about fields ripe for interdisciplinary research (see Appendix B), including:
The management of symptoms at the end of life: the complex interaction of clinical symptoms (including biochemical, neurological, endocrine, immune, and psychological status), therapeutics, and ethics.
Alcoholism: integration of neuroscience, genetics, molecular biology, neurochemistry, electrophysiology, imaging, and more.
The “oldest old:” complex health and social concerns in those over 85 years old.
Vulnerability to addiction: merging genetics, environmental risk, protective factors, behavior, and neuroscience.
Treatment research, including adherence issues: bringing to bear behavioral, psychosocial, pharmacological therapeutic, and clinical concerns.
Clearly, many problems that face today's society require coordinated efforts in multiple disciplines. The following examples can give a flavor of the benefits that an interdisciplinary approach could provide.
on immune function and mental attitude can influence patient outcomes and prolong hospital stays.47 Gender, genetics, and cultural background affect how a person responds to painful stimuli; stress also modulates pain. There are many types of pain, and they have different neural pathways and different underlying mechanisms. Some painkillers are addictive, and the risk of chemical dependence needs to be considered in studying pain and its control (for reviews see: Melzack, 199956 and Good, 199934 ).
The study of pain requires coordinated efforts in a number of disciplines to develop therapeutic approaches (for example, see Dubner and Gold, 199924 ). Imaging technology can provide a better understanding how the of brain functions during painful experiences. Cellular electrophysiology can elucidate the neuronal mechanisms involved and define potential sites for pharmacological intervention. Neurochemistry can identify and characterize trophic factors and neurotransmitters that influence the modulation and perception of pain. Genetic analyses can elucidate inherited susceptibility to pain. Social, psychological, and cultural approaches can provide a better understanding of the interaction of sociocultural environments and the neurophysiological substrates of pain. Such understandings will provide new insights into pharmacological and behavioral means of coping with pain.67
Injuries, both intentional and unintentional, are the leading cause of death of people 1–44 years old. They continue to be the cause of many deaths and serious disabilities throughout life, although other causes (e.g., heart disease, cancer, stroke) become more common in later life.13, 14 Many injuries that do not cause death result in lifelong serious disabilities, such as spinal cord paraplegia and quadriplegia. Injury in the elderly is often the precipitating event in terminal illness, especially pneumonia.62, 94 The term unintentional injury is now used, rather than accidents, to indicate that they are subject to the same epidemiological analysis of the interaction of host, agent, and environment as any other cause of death or disability.39, 40 Unintentional injuries result from characteristics of the injured (e.g., temperament and neurological status) and from agents in the physical and social environment. Prevention programs can control the environment (for example, with safety caps on medicines and poisons, seatbelts and airbags in automobiles, safer and more engineered roads) or change individual behavior (for example, with helmet use by bicycle riders, and reduction in drinking and driving).40 Future research will be greatly enhanced by interdisciplinary efforts of psychologists, neuroscientists, engineers, regulatory agencies, and device manufacturers working together on epidemiological studies and interventions.
In late 1999, Jeffrey Koplan, director of the Centers for Disease Control and Prevention, issued a report on the growing obesity epidemic in the United States.60 The report documents the alarming increase in obesity during the 1990s. According to the report, the prevalence of obesity (defined as 30% over ideal body weight) increased from 12% in 1991 to 17.9% in 1998. Obesity increased in all states and all demographic groups, including race, education level, and age. Over the same interval, physical inactivity, a major contributor to obesity, was essentially unchanged. Since obesity is associated with many chronic illnesses, including heart disease and diabetes, those trends pose a major public health concern. According to Koplan, “overweight and physical inactivity account for more than 300,000 premature deaths each year in the United States, second only to tobacco-related deaths.”12 Even in children as young as 5 to 10 years old, over half those considered overweight already show at least one risk factor for heart disease.
Obesity prevention and control provide fertile ground for interdisciplinary research. Both genetic and environmental factors influence body weight. Understanding of the behavioral components that contribute to obesity, including inactivity and overeating, is necessary for effective interventions. 36 Sociocultural differences in the prevalence of obesity among ethnic and socioeconomic groups require clarification. In addition, the physiological mechanisms that regulate appetite and metabolism need to be elucidated. In the middle 1990s, a concerted effort was made to find genes that contribute to obesity.18 The hormones mediating appetite (including leptin, neuropeptide Y, and melanocyte-stimulating factor) are under active investigation. Additional physiological factors that control dietary intake, energy expenditure, and energy regulation must be better understood.11 New information on hypothalamic pathways that influence food intake26, 78 has increased theoretical understanding of body weight regulation but is still far from clinical application. Understanding and clinically addressing dietary behavior require an integration of the genetic, endocrine, metabolic, and neurophysiological components with environmental factors and cultural factors.
EFFECTIVE FUNDING INITIATIVES IN INTERDISCIPLINARY RESEARCH
Many interdisciplinary efforts arise out of serendipity, but many arise out of need and the ripeness of research problems. Targeted programs in interdisciplinary research have yielded valuable knowledge and clinical results. Two such programs supported by NIH are described below as examples of initiatives that the committee found to be model programs.
Alzheimer's Disease Centers
Research in Alzheimer's disease has made rapid progress as a direct result of opportunities for interdisciplinary investigation fostered by NIH. Almost 2 decades ago, despite the great need for research on the medical and social problems resulting from Alzheimer's disease and related dementias associated with aging, there was little activity. The lack of interest was coupled with the widespread misunderstanding that dementia is a natural consequence of aging.
The National Institute on Aging (NIA) recognized that advances in understanding Alzheimer's disease required the coordinated efforts of neurologists, psychiatrists, neuropathologists, psychologists, neurochemists, molecular biologists, geneticists, and epidemiologists in an interdisciplinary approach to address the neurological, behavioral, familial, and social implications. To address that need, NIA developed a Request for Applications (RFA) for Alzheimer's Disease Research Centers (ADRCs). These clinical centers were required to have both cores and scientific projects. The mandated cores were clinical to recruit patients with dementing illnesses, neuropathological to archive neuropathology specimens, educational to provide scientists and the general public with information about the dementias, and administrative. The scientific projects were investigator-initiated clinical or basic neuroscience studies of dementing diseases and included at least two pilot projects.69 A small number of ADRCs were created at first. As the ADRCs proved effective, additional funds were allocated and the number of centers grew. Later, NIA created Alzheimer's Disease Core Centers (ADCCs), which supported only core facilities with the expectation that other investigator-initiated studies would be stimulated by the availability of the funded cores.68 NIA now funds 29 Alzheimer's Disease Centers around the country.6
The development of the Alzheimer's Disease Center programs was scientifically beneficial. Advances in understanding of the basic pathophysiology of Alzheimer's disease have been striking, with promises of effective preventive strategies in the near future. Among the advances arising from the centers is delineation of the neuropathological changes, including the deposition of senile plaques, the development of neurofibrillary tangles, and the loss of neurons from critical brain regions.17, 33, 61, 82, 102 Discovery of the alleles of apolipoprotein E revealed an important risk factor for Alzheimer's disease.19, 38, 48, 74, 77, 80, 90, 91 With the development of transgenic mice that express some of the neuropathological changes of Alzheimer's disease, an animal model is available to further the understanding of the basic biology of the disease and to test promising therapies.30 Those advances are leading to medications to improve cognition and others that might even prevent symptoms.79
The targeted allocation of federal funds by NIH led to the development of PET as a means of studying the metabolism and biochemistry of the brain. In the late 1970s and early 1980s, PET technology had matured enough to be highly promising, but requiring further development to make a scientific impact. In 1985, NINCDS put out an RFA to create “Brain Imaging Research Centers” to advance the use of the technology in studying dynamic changes in the brain under normal and pathological conditions.66 The terms of the RFA required the interdisciplinary collaboration of clinicians and scientists, including areas such as nuclear medicine, neurology, psychiatry, and neuroradiology. Members of the team needed to comprehend each specialist's field at some level to understand the possibilities of the new technology. The RFA asked for proposals that included development of cores facilities and hypothesis-driven scientific research projects. Following peer review, five centers were funded.
The effort led to substantial advances in understanding of biochemical processes in the human brain in health and disease. The studies included examination of regional cerebral blood flow, glucose metabolism, oxygen metabolism, and localization and concentration of biochemical substances, such as dopamine receptors, gamma-aminobutyric acid receptors, and opiate receptors.97 The PET centers also advanced understanding of numerous neurological disorders, including stroke, epilepsy, Alzheimer's disease, Parkinson 's disease, multiple system atrophy, and alcoholism, to name just a few.1, 3, 27, 31, 32, 37, 42, 54, 57, 96 Cognitive psychology was advanced by combining psychological activation of the resting brain with PET studies of cerebral blood flow as a marker of changes in metabolic rate of the relevant brain regions (for a review, see Sergent 199483 ). The recent development of functional magnetic resonance imaging has superseded PET for activation studies because of the lower costs involved. The development of single photon emission computed tomography, which can be performed with radioactive pharmaceuticals that have a long half-life, led to widespread imaging of the brain's metabolic and biochemical processes.
FINDINGS AND RECOMMENDATIONS
A great many interdisciplinary programs currently exist. Whether developed through the encouragement of a funding agency or the leadership of an individual, these programs illustrate the breadth of what can be achieved when disciplines come together to solve a problem. To ensure the future of interdisciplinary research for solutions to complex problems, training is essential to prepare the next generation of investigators to tackle these interdisciplinary tasks.
Funding agencies can be influential in moving fields forward by organizing funding mechanisms around specified opportunities, technologies, or problems. To allow optimal use of funding dollars, it is important to target the problems
that would most benefit from interdisciplinary approaches. Only after these problems are recognized should resources be allocated toward them. To identify such problems, lines of communication between sponsors and researchers should be established.
Recommendation 1: Federal and private research sponsors should seek to identify areas that can be most effectively investigated with interdisciplinary approaches. This should be done by engaging the research community through symposia, working groups, or ad hoc committees. Funding mechanisms, such as Requests for Applications or Proposals, should be developed to address the identified areas.
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