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A Healthy NIH Intramural Program: Structural Change or Administrative Remedies? Appendix C SUMMARY OF ACHIEVEMENTS OF NIH INTRAMURAL PROGRAMS The development of new treatments and cures for human diseases most often begins with discoveries that elucidate basic, fundamental processes in cell function. However, which of the so-called “basic science” discoveries will lead to clinical amelioration of disease is not easy to predict and, thus, such discoveries serve as irreplaceable foundations for the complex of knowledge required for advances in health care and disease prevention. Important contributions to both basic science and clinical practice have been made by the NIH intramural program. The partial list that follows is divided into four categories and has been assembled from the responses of individual institutes to a request by the study directors. The first category encompasses a group of advances with direct clinical applications. The second category contains some discoveries that lie between the distinctions of clinical versus basic science advances. Thus, this second category gives examples of discoveries whose direct clinical applications are clearly foreseeable but not yet fully realized. The third category, basic science, outlines numerous contributions of the NIH intramural program to an extended understanding of normal and abnormal physiological and cell biological processes. Finally, the fourth category lists some special programs or studies that do not easily fit into the other categories. Information supplied by the National Institutes of Health.
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A Healthy NIH Intramural Program: Structural Change or Administrative Remedies? ADVANCES IN CLINICAL PRACTICE AND APPLICATIONS Development of new vaccines against important bacterial infections of infants and children, including Hemophilus influenzae type B, pertussis, and typhoid. Development of a curative therapy for cystinosis, an inborn error of metabolism. Discovery of AZT as an effective agent against human immunodeficiency virus (HIV or AIDS virus). Development of chemotherapy to preserve kidney function in patients with systemic lupus erythematosus. Development of effective treatments for alpha 1-antitrypsin deficiency state which have additional application to biochemical abnormalities in emphysema. Advances in surgical treatment of hypertrophic cardiomyopathy. Development of new strategies for use of coronary bypass surgery in treatment of chronic stable angina. Significant contributions to technical and theoretical development of nuclear magnetic resonance and optical spectroscopy. Demonstration that the drug, 5-azacytidine, increased fetal hemoglobin synthesis thus exerting beneficial effects in patients with severe beta thalassemia or sickle cell anemia. Development of treatments which lessen the symptoms of malignant pheochromocytoma and identification of a marker, neuropeptide Y, which distinguishes this tumor from other pathological conditions. Development of methods to assess the tone of the sympathetic nervous system; these have been useful in diagnosis and treatment of hypertension. Demonstration that the drug, cyclophosphamide, induces long-term remission of symptoms in systemic vasculitis.
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A Healthy NIH Intramural Program: Structural Change or Administrative Remedies? ACHIEVEMENTS IN BASIC SCIENCE THAT ARE CLOSE TO CLINICAL APPLICATION Discovery of the human immunodeficiency virus (HIV) to be the cause of AIDS. Discovery of the causative agent of Lyme Disease. Establishment of ways to separate the various abnormalities in immune system function resulting from AIDS infection. Development of a vaccine, effective in animals, for hepatitus B virus. Discovery of the first cancer-causing retrovirus in humans. Determination of the complete structure of the human receptor for IgE, an immunoglobulin which plays a role in allergic attacks. Demonstration that some patients with angina have normal external coronary arteries, but have abnormal arteries within the wall of the heart. Assignment of the human globin genes to chromosomes 11 and 16. Determination of the molecular defects in various types of abnormal lipoprotein metabolism. Discovery of “slow” viruses which cause degenerative brain disease. Definition of the molecular events which underlie Gaucher’s Disease. Demonstration that persons recovering from liver damage caused by exposure to halothane, an anesthetic, produce antibodies to a liver enzyme. Discovery that persons with hypertension vary in their responses to salt intake. Some are salt-sensitive and other’s are salt-resistant as a result of differing levels of dopamine, which affects kidney function. Description of the processes that cause interstitial lung disorders and identification of the important role played by T-helper lymphocytes in sarcoidosis. Discovery of polyomavirus, Rauscher virus, and Moloney leukemia and sarcoma viruses.
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A Healthy NIH Intramural Program: Structural Change or Administrative Remedies? Demonstration of the role of iron in the regulation of gene expression. Identification of genes that code for cellular proteins involved in the breakdown and processing of cancer-causing substances, toxins, and drugs. Discovery of an oncogene that led to the identification of the gene for cystic fibrosis and of another oncogene that codes for a growth factor. The measurement of brain glucose metabolism with positron emission tomography, which allows for assessment of brain activity in relatively discrete brain regions. Such studies have shown reliable patterns of brain damage in patients with Alzheimer’s disease. Discovery of the toxic effects of the enzyme, aldose reductase, in diabetes. Such effects probably underlie the complications of diabetes, such as blindness and nerve damage. Inhibitors of the toxic enzyme have been developed and are now in clinical trials.
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A Healthy NIH Intramural Program: Structural Change or Administrative Remedies? ACHIEVEMENTS IN BASIC SCIENCE Identification of different patterns of gene expression during the various stages of blood cell maturation and differentiation. Demonstration of central role of the enzyme, protein kinase C, in tumor promotion. Discovery that, in muscle fibers, myosin forms two types of crossbridges with actin, thus refining existing knowledge of the biomechanical basis of muscle contraction. Demonstration of the processes by which proteins in a cell are structurally modified within the cell to allow for specific physiological actions. Definition of mechanisms involved in acetylcholine receptor changes in development of the junction between nerve and muscle. Demonstration of the role of cyclic AMP in the expression of proteins required for development of synapses between neurons. Characterization of different types of the protein phospholipase C, important in signal transduction mechanisms in cells, and demonstration that the sub-types of this protein are differentially present in specific cells and tissues. Development of tissue culture methods for mammalian brain cells which allow extremely precise electrical, biochemical, and physiological measurements to be made. Development of recombinant DNA techniques, the first cloning of a mammalian gene. First demonstration of the molecular basis of antibody diversity. Discovery of plasma cell tumor induction in mice, which led to the development of hybridomas (cells formed by the fusion of an antibody-producing cell with a tumor cell). Discovery of interleukin-2, which is produced by a certain immune system cells called T lymphocytes; interleukin-2 also promotes the proliferation of T lymphocytes. Determination of the structure and function of the receptor for interleukin-2. Maintenance in culture conditions of individual nephrons, the working unit of the kidney, allowing measurement of a variety of kidney functions that include transport mechanisms and the role of osmolytes in normal and abnormal conditions.
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A Healthy NIH Intramural Program: Structural Change or Administrative Remedies? Experiments leading to a new hypothesis that suggests that NADH (a critical molecule involved in energy metabolism), contained in small, intracellular compartments called mitochondria, may be central to the regulation of energy metabolism in tissues such as the heart and kidney. Definition of mechanisms involved in muscle contraction, including the biochemistry of actin polymerization, a necessary chemical reaction during muscle contraction. Discovery of a new class of molecules, similar to myosin of muscle cells, which probably function in movements of non-muscle cells. Identification and cloning of the earliest genes to be expressed during embryo growth in vertebrates and determination of the products of those genes. Discovery of transforming growth factors (alpha and beta), which are substances secreted from cells that have been changed in culture from normal to malignant (transformed). These factors stimulate growth of normal cells and may play a role in normal developmental mechanisms. Cloning of basic myelin protein, a part of the substance, myelin, which forms an insulating sheath around certain parts of neurons called axons. Disturbances in myelin formation underlie certain neurological disorders. Demonstration that biological molecules such as cyclic AMP, glucocorticoids, nerve growth factor, and activators of protein kinase C can act together to regulate the genes that code for enkephalin and neuropeptide Y, substances found to function in the brain and many other tissues. Discovery of the mechanism for pertussis toxin effects on signal transduction across cell membranes in which a toxin enzyme structurally modifies a membrane protein required for transmembrane signalling. The type of structural modification of proteins effected by toxin enzymes is also effected by normal cellular enzymes resulting in a variety of cell regulatory mechanisms.
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A Healthy NIH Intramural Program: Structural Change or Administrative Remedies? Determination of the amino acid sequence of a human plasma apolipoprotein and of the gene structure of several plasma apolipoproteins. Gene transfer and expression in intact animals using retroviral vectors. Achievement of successful “gene therapy” of a defective cell in tissue culture by microinjection of a cloned normal gene. Demonstration that adoptive cellular transfer can cause regressions of human cancer (LAK/IL-2). The enzyme, RNA polymerase, is essential for the normal synthesis of RNA. The enzyme has been studied in terms of the mechanism by which it joins certain molecules to form a perfect copy of the genetic message necessary for protein synthesis. Contributions to the knowledge of structure, organization, expression, and evolution of the proteins that form the lens of the eye. Changes in these proteins occur during the development of cataracts. Analysis of the effects of eye movements on visual processing by single neurons that transmit visual messages. The combination of behavioral and physiological techniques with computer modeling has allowed for precise studies of the neural organization of the visual system.
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A Healthy NIH Intramural Program: Structural Change or Administrative Remedies? SPECIAL PROGRAMS AND ACHIEVEMENTS Development of nationwide cancer maps and cancer atlases. The Diet, Nutrition, and Cancer Program: An intramural initiative involving diet and nutrition intervention studies and the newer chemoprevention studies and trials. The Surveillance, Epidemiology, and End Results Program (SEER) is an intramural program which provides a statistical survey capability for tracking cancer incidence, morbidity, and mortality in the nation. Demonstration of the utility of gas chromotography to drug, steroid, and vitamin analysis. Introduction of the applications of mass spectrometry. Quantitation of amounts of luminal narrowing caused by atherosclerotic plaques in patients with acute myocardial infarction, healed myocardial infarction, angina pectoris, and sudden coronary death. Extensive program of evaluation of prosthetic heart valves and the mechanisms of their failure. Development of useful equipment and technology including: closed circuit blood centrifuge, disposable membrane artificial lung, countercurrent chromatography, global analysis for time-resolved fluorescence spectroscopy, the porous bottomed culture dish, a purification method to standardize hemoglobin in the development of a blood substitute, and a new stopped-flow calorimeter for studies of drug binding to DNA. The Baltimore Longitudinal Study on Aging has continued now for thirty years with a subject pool of more than 1,000. Recently, data from this study has shown that decreased cardiac output is not an automatic sequela of age. This study has also provided evidence that an individual’s personality tends to be remarkably stable over long periods of life experience.