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Fundamental and clinical research and patient care: A triad for progress in reproductive medicine
Fundamental and clinical research and patient care: A triad for progress in reproductive medicine Lawrence D. Longo, MD Loma Linda, California This essay reviews select instances in the modern history of reproductive medicine, with particular emphasis on the past 25 years since the establishment of the National Institute of Child Health and Human Development. It considers five examples of how fundamental and clinical research have contributed to patient care and, in turn, received stimulus from them; that is, fertility regulation and reproductive endocrinology, prematurity and the initiation of parturition, antenatal testing of fetal maturity, antenatal diagnosis, and neonatal intensive care. Finally, some lessons regarding the interrelationships between research and clinical obstetrics and gynecology are considered. (AM J OBSTET GvNECOL 1988;159:6-12.)
Key words: Investigation, basic science, clinical care, mother, child, National Institute of Child Health and Human Development I am honored to participate in Child Health Day, this twenty-fifth anniversary of the National Institute of Child Health and Human Development, and this centennial observance of the founding of the National Institutes of Health. Chiseled on the portals of this clinical center are the words of Jack Masur (1908-1969), designer and first director of the Clinical Center from 1948 to 1951: "Hospitals with long traditions of excellence have demonstrated abundantly that Research enhances the vitality of teaching. Teaching lifts the standards of service, and Service opens new avenues of investigation." This credo, which encapsulates the essence of this institution, serves as the theme of my remarks; that is, that in reproductive science, as in most everything else in medicine, fundamental research complements clinical research to improve patient care. In turn, observations at the bedside stimulate the search for key scientific discoveries. I have been given the astonishing task of herein summarizing a century of progress in reproductive medicine, and the role of obstetrics and gynecology in child health, particularly as it relates to the National Institute of Child Health and Human DeFrom the Division of Perinatal Biology, Departments of Physiology and Obstetrics and Gynecology, School of Medicine, Loma Linda University. Supported by United States Public Health Service Grant No. HD-03807. Presented at the celebration of Child Health Day, Clinical Research Center, National Institutes of Health, Bethesda, Md., October 2, 1987, on the occasion of the twenty-fifth anniversary of the National Institute of Child Health and Human Development and the one hundredth anniversary of the National Institutes of Health. Reprint requests: Lawrence D. Longo, MD, Division of Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA 92350.
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velopment. Because of time constraints, I shall consider only a few highlights in this rich heritage.
1887 and the Laboratory of Hygiene The forerunner of the National Institutes of Health, the Laboratory of Hygiene, opened in 1887 as a oneroom attic laboratory at the Marine Health Service Hospital, Staten Island, N.Y. It came into existence largely through the influence of Surgeon General John Brown Hamilton (1847-1898) and under the direction of Joseph James Kinyoun (1860-1919). By that year medicine had advanced considerably in the century since the founding of the Republic. Rudolph Ludwig Karl Virchow's (1821-1902) cellular pathology' gave a rational basis for understanding many disease states, while Louis Pasteur's (1822-1895) 2 and Robert Koch's (18431910)' microbiology gave hope to the elimination of infectious disease. It was just a few years before this that one of America's first major contributions to medicine, the discovery of ether anesthesia, had lessened the terror of surgery and childbirth. With the development of women's hospitals gynecology developed as a specialty, and with the rise of lying-in hospitals obstetrics moved out of the home. The year this great institution was founded ( 1887) saw gynecologists considering topics such as the proper treatment of uterine ftexions and displacements, advancements in pelvic surgery for tumors of the ovaries and uterus, the proper treatment of salpingitis and pelvic abscess, and the role of uterine disease as a cause of severe neurosis, so-called hysteroneuroses. They also were considering the proper treatment of typhoid fever in pregnancy and eclampsia, the course of labor in the woman with a deformed pelvis, the best method for reducing an inverted puerperal uterus, the
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treatment of puerperal endometritis, and the use of electrotherapy in the treatment of numerous disorders, gynecologic as well as obstetric.1·1 The first journal exclusively devoted to the field of women's diseases, The American Journal of Obstetrics and Diseases of Women and Children, appeared in 1868 and by 1876 the American
Gynecological Society was well established. The diseases of children were still a branch of obstetrics and gynecology. This, then, was the background of the specialty just a century ago. 1912 and the child welfare movement
By 1912 when the Hygienic Laboratory had reached the maturity of a quarter of a century, it had moved to new facilities at 25th and E Streets in this nation's capitol. Its name had been changed to the Public Health Service Laboratory and its research programs had expanded to include diseases other than those that were communicable. Reproductive medicine at this time was in its embryonic stage. Ernest Henry Starling ( 1866-1927) had coined the term hormone just a few years earlier8 and with William Maddock Bayliss (1860-1924) had developed the theory of endocrine control of internal secretions.9 Experiments had demonstrated the ovarian dependence of the menstrual cycle, 10 that experimental hypophysectomy profoundly affected the reproductive system, 11 and the oxytocic action of posterior pituitary injection. 12 Additional contributions to reproductive endocrinology at this time included the first definite description of the cyclic changes in the endometrium" and the attribution of pregnancy-induced changes in the mammary glands to the developing fetus and placenta.11 However, most of these contributions were English or German in origin, rather than American. Reproductive medicine also began to advance in the field of maternal and child health, initially as a social movement and only later in original research. During the first decade of this century a veritable crusade developed for the improved care of pregnant women and their newborn infants. Initially this movement had its roots in concern for the astonishingly high death rates of young children. Pediatricians, obstetricians, nurses, public health workers, and women's groups strove to establish well-baby clinics, assure clean milk supplies, and eliminate the waves of epidemic infections that accounted for a huge loss of life. Soon it was realized, however, that without properly managed pregnancy, the benefits of pure milk were limited. Concurrently the works of John William Ballantyne (1861-1923) 15 and John Whitridge Williams (1866-1931)' 6 • 17 helped focus attention on several facts: (1) the enormous numbers of mothers who died of pregnancy-related disorders and other conditions, (2) that to a great extent diseases of young children had their origin during fetal
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life, and (3) that the fetus could be treated by correcting the underlying pathologic condition in the pregnant mother. These ideas contributed greatly to an increased interest in the care of children and their mothers. In addition, they led to the organization of the Association for the Study and Prevention of Infant Mortality, which promoted numerous studies in maternal and child care. As a consequence of recommendations of a White House Conference on Child Welfare Standards, the Children's Bureau of the Department of Labor was established in 1912 for the purpose of" ... investigating and reporting on all matters pertaining to the welfare of children and child life among all classes of people." Under the leadership of Julia Clifford Lathrop ( 1858-1932), the Bureau conducted numerous early studies relating to maternal and child health.'" 1937 and the National Institutes of Health
By 1937 the Public Health Service Research Program was 50 years old and had been reorganized into the National Institutes of Health, largely as a result of Louisiana Senator Joseph Ransdell ( 1858-1954), whose bill to create the Institutes to focus on the fundamental problems of the diseases of man was passed by Congress in 1930 and signed by President Herbert Hoover (18741964). The following year the National Institutes of Health moved to the Bethesda campus on land donated by Mr. and Mrs. Luke I. Wilson. At the urging of then Surgeon General Thomas Parran (1892-1968), President Franklin D. Roosevelt ( 1882-1945) allocated funds to construct the three original buildings on this campus. In reproductive research the 1930s were a time of ferment. Selmar Aschheim ( 1878-1965) and Bernhard Zondek ( 1891-1966) had announced their test for diagnosing pregnancy'• and had also isolated pituitary gonadotrophic hormone!" Steroid hormones were also under active investigation. Edgar Allen ( 1892-1943) and Edward Adelbert Doisy ( 1893-1986) had isolated estrogen 21 and George Washington Corner ( 1889-1981) and Willard Myron Allen (1904-) had discovered progesterone. 22 Guy Frederick Marrian (1904-1981) had isolated both pregnanediol 23 and estriol, 21 and Adolf Friedrich Johann Butenandt ( 1903-) had crystalized both progesterone 25 and androsterone. 26 Also, by the mid- l 930s obstetrics and gynecology had matured as a specialty, with the joining together of most departments of gynecology and obstetrics. The American Board of Obstetrics and Gynecology was established (1930) and a few departments conducted original research. 1962 and the National Institute of Child Health and Human Development In 1945 at the end of World War II, Vannevar Bush (1890-1974), the President's Science Advisor, outlined
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his visionary policies for the federal support of peacetime health research in his "Science-The Endless Frontier." 27 Bush foresaw both the vital need for fundamental biomedical research and the key role that the nation's universities and colleges could play in advancing knowledge in the health sciences by letting minds explore. By 1961 a Center for Research in Child Health had been established in the Division of General Medical Sciences. In addition, a task force had reported that year to President John F. Kennedy (1917-1963) that research into the physical, intellectual, and emotional growth of children was severely handicapped by not having a centralized organizational structure. The group called for a new institute to launch a concentrated attack against disorders of development. Because at that time, by law, each institute had as its mission to increase understanding and to develop treatments for specific diseases, new laws had to be written and enacted. Thus on October 17, 1962, near the seventy-fifth birthday of the (by then designated) National Institutes of Health, Public Law 87-838 was passed, which authorized creation of the National Institute of Child Health and Human Development (and the National Institute of General Medical Sciences). A few months later the National Institute of Child Health and Human Development was physically established, with authorization to conduct research and training relating to maternal health, child health, and human development. By the year this Institute was founded, the American College of Obstetricians and Gynecologists ( 1951) had been organized and reproductive investigators had banded into the Society for Gynecologic Investigation ( 1953).28 At this time reproductive problems of interest included metabolic alterations in diabetes in pregnancy and pregnancy-induced hypertension, urinary estriol excretion in the pregnant woman with diabetes, the pathogenesis of disseminated intravascular coagulation, the use of veratrim and hydralazine in the treatment of pregnancy-induced hypertension, electronic monitoring of fetal heart rate patterns and the meaning of bradycardia, diagnosis of the inadequate luteal phase, Stein-Leventhal syndrome, the hormonal activity of ovarian tumors, testicular feminization, urethral suspension procedures for stress incontinence, and the optimal surgical treatment of pelvic lymph node metastasis from carcinoma of the cervix.2 9 • ' 0 Many of these problems are still with us today. Fundamental versus clinical research
To many individuals, physicians as well as laymen, the word "research" connotes an activity conducted by a rather aloof, or at least dispassionate, scientist in an "ivory tower" with little or no relevance to problems of the real world. Others would make a rather arbitrary
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and sometimes specious distinction between those studies designated as "basic" and those that are "applied." A unique endowment of the National Institutes of Health has been the support of both fundamental and clinical research for the amelioration of disease and improvement in patient care. For reproductive medicine the National Institute of Child Health and Human Development has singularly advanced this ideal in many areas; allow me to recite just five examples. (Because so many outstanding workers have played a role in these advances, with few exceptions I shall not cite individual names.) First, the two sides of the coin of fertility are contraception and infertility. At the time of the National Institute of Child Health and Human Development's founding, the "population explosion" was emerging as a major issue, while at the same time the infertility rate in our society was 10% to 15% (where it remains). Clinical trials were first demonstrating the efficacy of "the Pill," spurring new developments in basic reproductive endocrinology. For instance, determination of the chemical composition of luteinizing hormonereleasing hormone (gonadotropin-releasing hormone) gave impetus to an enormous amount of work that has helped to unravel the mysteries of the normal hypothalamic-pituitary-ovarian relationships, and to gain a deeper understanding of the mechanisms by which polypeptide and steroid hormones act. In turn, this fundamental work has led to the development of a number of analogs and blocking compounds for clinical use. Just one example is the use of gonadotropinreleasing hormone analogs that show great promise in the treatment of endometriosis and precocious puberty, as well as in fertility regulation and the management of other conditions. In addition, the deeper understanding of fundamental reproductive endocrinology and technologic advances has literally sparked a new "industry" of in vitro fertilization and the transfer of embryos and gametes in patients with infertility. Recent discoveries in cell and molecular biology promise to save our intellectual souls, giving hope of even more powerful tools to manage the yin of infertility and the yang of contraception. Another example of the interactions between fundamental and clinical research and patient care is in the area of prematurity and the initiation of parturition. Roughly 7% of infants are born too soon, and prematurity is the major factor accounting for newborn morbidity and mortality. Indeed, if one were to judge from the patient population in most of this nation's tertiary care centers, premature labor and its sequelae have reached epidemic proportions. To a great extent this clinical problem has stimulated important research into the elegantly orchestrated regulation of hormones in the fetus and mother that eventuates in parturition.
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To date much of this effort has focused on the myometrium, decidua, chorioamnion, and the fetal adrenal gland. To arrive at a more complete understanding, present and future studies must elucidate the roles of the fetal pituitary gland, hypothalamus, and, perhaps, higher centers. In concert with this fundamental work is a two-pronged attack both to prevent prematurity by the identification of mothers at high risk and to improve the treatment of such women with (3-mimetic and other uterolytic drugs. A related area in which enormous advances have occurred is that of antenatal testing of lung maturity and the prevention and treatment of hyaline membrane disease-respiratory distress syndrome. The challenge of understanding the role of pulmonary surfactant, as well as more accurate diagnosis of fetal development, sparked fundamental research into surfactant biochemistry and metabolism. This, in turn, led to more precise evaluation of maturational state by the "profiles" of lung phospholipids and, almost incidentally, establishment of the relative safety of amniocentesis. An exciting topic of research in this field is the use of surfactant (human, animal, and synthetic) in the prevention and treatment of respiratory distress in the newborn. Another example of the interdependence of clinical obstetrics and pediatrics and both fundamental and "applied" research is in the field of antenatal diagnosis. More than a quarter of a million infants in this nation are affected by fetal abnormalities. Fundamental research in birth defects has progressed on several fronts. For example, advances in genetics have led to more accurate diagnosis of trisomy and other chromosomal abnormalities. In turn, this has led to rather startling advances in molecular genetics that allow in utero screening for numerous conditions. An example of this is the diagnosis of phenylketonuria, an enzyme deficiency that if left untreated results in severe mental retardation but that can be controlled by a special diet during childhood. The in utero diagnosis of neural tube defects and congenital hypothyroidism is also a reality. Complementing these contributions have been technologic advances in diagnostic ultrasound, amniocentesis, chorionic villus sampling, fetal blood and tissue sampling, and even fetal surgery. A fifth, and related, area in which fundamental and clinical research have both contributed to clinical care and, in turn, been stimulated by it, is that of neonatal intensive care and survival of the sick premature infant. Mildred Stahlman eloquently addressed these issues in her Child Health Day address last year. 31 To avoid duplication, I will summarize some key contributions." A quarter of a century ago the survival of a l 000 gm infant born at 28 weeks' gestation was only about 10%. Today that figure approaches nearly 95%. In those
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early years, survival rates for yet smaller infants were essentially nil. Today, about half of 600 gm premature newborns born at 26 weeks' gestation survive. 33 Interest in these "ex utero fetuses," so to speak, has stimulated a wealth of vital research in understanding the physiology of development of the cardiovascular, respiratory, and endocrine systems. For instance, fundamental and clinical studies have demonstrated the necessity of temperature and humidity control, nuances of fetal metabolism, and a better understanding of metabolic needs from parenteral alimentation, the physiology of the ductus arteriosus and blood flow to the brain and other vital organs, and the pathogenesis of retrolental fibroplasia. Understanding of these physiologic systems and their pathophysiology has led to clinical advances such as continuous positive airway pressure, the use of prostaglandin synthetase inhibitors to close the ductus (and perhaps stabilize the cerebral circulation), and improved management of pulmonary hypertension, altered acid-base balance, and respiratory distress. Each of these individual "bits" and "bytes" has contributed to the overall "program" of lower infant morbidity and mortality. Of course, these miraculous improvements in survival could not have occurred without concomitant technologic advances such as the development of improved incubators and respirators, the Clark oxygen electrode, microtechniques of blood sampling, transcutaneous and pulse oximetry, electronic monitoring, and other items. Nonetheless, we are not there yet! Many other examples of the productive interplay between fundamental and clinical research and improved health care for mothers and children could be cited. Advances in developmental biology, the use of Rho(D) immune globulin and intrauterine intravascular transfusion to treat erythroblastosis fetalis, exquisitely sensitive pregnancy tests to monitor early reproductive wastage, and an understanding of the roles of the maternal use of cigarettes, alcohol, and other drugs in the genesis of infant morbidity and mortality are just a few of these. During the life span of this Institute these and other advances have played a not inconsequential role in the lowering of perinatal mortality by almost 60%, from about 34 per l 000 births in 1962 to about 15 today. This same period has seen maternal mortality drop almost 80%, from more than 36 per l 00,000 live-births in 1962 to about 8 today."' A remarkable record, but not yet good enough. This is but a sampling of the magnificent achievements in reproductive medicine in the past quarter century. Nonetheless, there is much yet to accomplish. As Norman Kretchmer (1923-) noted, "Every year thousands upon thousands of children die or are crippled by disorders that we have neither the knowledge to treat nor the wisdom to prevent.""
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Lessons to be learned
Recitation of these advances makes one almost gasp in wonderment. What can there be left to do? How can the spectacular achievements of this past quartercentury possibly be matched in the next? What lessons can be learned from this seemingly unparalleled success? Making no pretense at being a prophet, I shall leave to others a vision of the future. Nonetheless, without seeming gratuitous, I believe that several points bear consideration. First, clinicians, scientific investigators, and the public must understand that reproductive medicine is the future of the human genome. Many of the key discoveries that played a major role in clinical advances were in fundamental science or technology with little promise of immediate application. For instance, much of the research in reproductive endocrinology was undertaken to understand at a deeper level the nuances of neurohormonal communication in the brain, and yet this work has proved to be of great practical value. Similarly, the increased understanding of uterine muscle physiology is contributing to a decreased incidence of premature labor, and the development of techniques in subcellular biology promise future improvements in diagnosis and treatment of a host of molecular diseases. It is almost as though there were giant positive feedback loops going from a "cell" at one institution to a "cell" at another, perhaps thousands of miles away-one discovery stimulating others. One simply cannot predict which advances in cell biology, molecular genetics, or some other science will be just the key to unlock a conundrum in a totally unrelated basic or clinical field. Of course, that is what this Institution is all about, stimulating the positive feedback circuitry. Another lesson is that although the scientific and clinical advances I have enumerated might appear to have proceeded in sequence-one triumph building on another-that is hardly the case. Although today we see further because we stand on the shoulders of giants, the way of science is not linear. There have been many digressions, paths that led nowhere, and downright erroneous conclusions from poorly designed studies. Most of the "breakthroughs" have come neither quickly nor easily. Thus occasionally there are "short circuits" or "misfirings" in this great information network. A better appreciation of the history of medical science and practice can help to protect us from the deadly sin of hubris, which assigns value only to the experience of the moment or a single lifetime. An additional lesson to ponder is the ultimate relationship between progress in science (e.g., improved maternal and child health) and adequate research monies. This is perhaps self evident, but the Republic's biomedical research enterprise is a national resourceif you please, the "crown jewels" and stately "royal trea-
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sures" of our democracy. As with the maintenance of a militia for our defense, the development and maintenance of even more accurate standards in weights and measures, and the surveillance of the continent's weather, fundamental research in the biomedical sciences is a federal responsibility. This being the case, to a great extent it is dependent on governmental leaders who appreciate its worth. Private industry, of course, also has made notable contributions (and, in turn, has benefited greatly from government-supported studies). Nonetheless, with few exceptions, only a federally supported program such as exists on this campus can mount the intensive and expensive programs required for research of complex problems and for the common good, but with perhaps little apparent immediate payoff. Unfortunately, some economists would have us believe that all governmental programs are inefficient and create more problems than they solve. Although there may be an element of truth in that, the National Institutes of Health, including the National Institute of Child Health and Human Development, have certainly been a glorious exception. The task of science is to identify problems and their solutions. In reproductive medicine the payoff has been the relief of human suffering and improved health for mothers and children. As a corollary of this, those of us whose work has been supported these many years owe a great debt to the visionary leaders in the legislative branch of our government (the John E. Fogarty's, the Lister Hill's, the Warren G. Magnuson's, and others) who authorize and appropriate the funds; to the executive branch of the government; to the Mary Woodard Lasker's and other private citizens who translate their visions of better health into activism; and to the citizens of the Republic who pay the taxes. These individuals support what at times must seem like rather arcane studies with unclear goals. We are in their debt for their faith and commitment to this glorious enterprise. A further lesson is the need to rely on the wits of individual investigators for progress in maternal and child health. Scientific research is a peculiarly human experience that probably comes as close to intended action as any human effort can, and is par excellence an expression of purpose. We may recall the words of Francis Bacon ( 1561-1626), who counseled": "Reduce things to the first institution, and observe ... [and] ask ... what is best, ... and what is fittest." It is the first institution of science to serve the human condition, and the task of those of us in reproductive research to serve women and children. How to achieve most fittingly that first institution at this time is a continuing challenge to the probity and wit of individual scientists as well as of our Society.
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As an aside, to the leaders of this institution and to individual investigators, sometimes those of us who are extramural are viewed as supplicants, cup in hand, begging for a handout; or worse, we are viewed as adversaries rather than as partners in the symbiotic relationship of this enterprise. We all recognize that as investigators our studies must be hypothesis oriented and carefully planned, and that our grant applications must be carefully detailed as to what we plan to accomplish. Nonetheless, many of the greatest achievements were unforeseen by the investigator when preparing his or her application or by the peer review group that critiqued it. By their nature, important discoveries and the development of new paradigms are a somewhat stochastic process, and we need to trust investigators, a bit at least, even though their ideas may be unorthodox. Our scientific destiny is being shaped by forces and discoveries beyond our control. Today reproductive medicine would appear to be on the verge of a new "golden age" of knowledge at the cellular and molecular level. The key will be to see that the most able and imaginative scientists can follow their intuition and let their minds run free. An additional lesson is the importance of research training for physicians, in the instance at hand, for young obstetricians and gynecologists. Almost without exception, the present generation of clinical and basic biomedical scientists are "graduates" of the National Institutes of Health system. Nonetheless, reproductive medicine faces a critical period with a need to nurture physician investigators, the "endangered species" of academic medicine. Even among academically committed obstetrician-gynecologists there exists a profound illiteracy regarding the new biology. One of the critical needs of our specialty is a research training program for such individuals in cellular and molecular biology, the key to the future in reproductive biology, as in most other areas of medicine. Another lesson is that concern for the mother must go hand in hand with that for the child. Early in this century the realization developed that the well-being of the infant critically depended on that of the mother. Somehow in the intervening decades this verity seems to have been forgotten, but the evidence is there. A healthy mother produces a healthy baby, whereas an unwell mother more often than not has a very sick infant. Finally, we cannot forget that vast seas of ignorance surround our small islands of scientific knowledge. A subtitle for this presentation could have been "whither the National Institute of Child Health and Human Development?" For this institute the challenge for the next 25 years-and the next century-will be to enlarge these isles into yet larger islands, from which grow whole continents of understanding. As the "wise man"
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admonished, "Wisdom is the principal thing; therefore get wisdom; and with all thy getting get understanding.""" But this is not a new challenge. Just over a century ago at this nation's first centennial, five of our most respected physicians described the medical achievements of the prior century.' 7 In closing his essay, John Shaw Billings (1838-1913), developer of the Surgeon General's Library (now National Library of Medicine) and initiator of the Library's Index Catalogue (now Index Medicus), observed, "It is better to have a future than a past."'" History assures us that if our Society permits continued scientific investigation, it will bear fruit in important new knowledge. Thus the challenge that lies before us and this Institute is to not rest on past achievements, but to look to the future. The problems we face are to use the future wisely, to use our time wisely, to use our talents wisely, and to use our funds wisely. We can be certain that, as Jack Masur pointed out, the continued exploration at both the fundamental and clinical levels, combined with technologic advances, will give promise to continued enlargement of our understanding and the satisfaction of achievements in the care of mothers and children. I am grateful to Drs. Norman Kretchmer, Joyce L. Peabody, and Steven M. Yellon for discussing with me some of the issues presented in this essay. REFERENCES I. Virchow RLK. Die Cellularpathologie in ihrer Begriindung auf physiologische und pathologische (~ewebelehre. Berlin: A Hirschwald, 1858. 2. Pasteur L. Oeuvres de Pasteur, reunies par Pasteur Vallery-Radot. 7 vols. Paris: Masson, 1922-39. 3. Koch R. Gesammelte Werke, 2 vols. Leipzig: G Thieme, 1912. 4. Table of contents. Trans Am Gynecol Soc 1887; 12:7-8. 5. Index. AmJ Dis Women Child 1887;20:1313-40. 6. Longo LO. The rise and fall of Battey's operation: a fashion in surgery. Bull Hist Med I 979;53:244-67. 7. Longo LO. Electrotherapy in gynecology: the American experience. Bull Hist Med I 986;60:343-66. 8. Starling EH. The Croonian Lectures on the chemical correlation of the functions of the bodv. Lancet I 905;2:33941, 423-5, 501-3, 579-83. , 9. Bayliss W~I. Starling EH. The chemical regulation of the secretory process. Proc R Soc Lond [BJ 1904;73:210322. 10. Battey R. Normal ovariotomy. Atlanta Med Surg .J 1872; 10:321-39. 11. Crowe SJ. Experimental hypophysectomy. Johns I lopkins Hosp Bull 1910;21:127-69. 12. Dale HH. The action of extracts of the pituitary b()(h. Biochem J I 909;4:427-47. 13. Hitschman F, Adler L. Der Bau der Uterusschleimhaut des geschlechtsreifen Weibes besonderer Berucksichtigung der Menstruation. Monatschr Geburtshilfe Gynakol 1908;27:1-82. 14. Lane-Claypon JE, Starling EH. An experimental enquiry into the factors which determine the growth and activitv of the mammary glands. Proc R Soc Lond [BJ 190506;77:505-22.
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15. Ballantyne JW. Manual of antenatal pathology and hygiene, 2 vols. Edinburgh: William Green & Sons, 190204. 16. Williams JW. What the obstetrician can do to prevent infantile mortality. Trans Am Assoc Stud Prevention Infant Mortal 1910;1:190-201. 17. Williams JW. Obstetrics: a textbook for the use of students and practitioners. New York: D Appleton, 1903. 18. Longo LD, Thompson C. The evolution of prenatal care in America. In: Proceedings of the Symposium, Childbirth: the beginnings of motherhood. Women's Study Program. Madison, Wis: University of Wisconsin, 1981. 19. Aschheim S, Zondek B. Schwangerschaftsdiagnose aus dem Harn (durch Hormonnachweis). Klin Wochenschr 1928;7:8-9, 1404-11, 1453-7. 20. Zondek B, Aschheim S. Des Hormon des Hypophysenvorderlappens. Klin Wochenschr I 928;6:348-52, 1927:7: 831-5. 21. Allen E, Doisy EA. An ovarian hormone. JAMA 1923; 81 :819-21. 22. Corner GW, Allen W'.\1. Physiology of the corpus luteum. Am J Physiol I 929;88:326-46. 23. Marrian GF. The chemistry of oestrin. I. Preparation from urine and separation from an unidentified solid alcohol. BiochemJ 1929;23:1090-8. 24. Marrian GF. The chemistry of oestrin. Ill. An improved method of preparation and the isolation of active crystalline material. Biochem J I 930;24:435-45. 25. Butenandt AFJ. Neuere Ergebnisse auf dem Gebiet der Sexualhormone. Wien Klin Wochenschr I 934;47:89790 I, 924-36. 26. Butenandt AF.J. Ueber die chemische Untersuchung der Sexualhormone. Z Angew Chem 1931 ;44:905-8.
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27. Bush V. Science-the endless frontier: A report to the president. Washington, DC: United States Government Printing Office, 1945. 28. Longo LD. A short history of the Society for Gynecologic Investigation, 1953-1983. Los Angeles: 1983. 29. Program and abstracts of the ninth annual meeting of the Society for Gynecologic Investigation, Chicago, Illinois, 1962. 30. Table of contents. AM J 0BSTET GY:>;ECOL 1962;83: 1-4. 31. Stahlman M. The interrelationship of research and care in neonatal intensive care units. Address given on Child Health Day, Oct 7, 1985, Bethesda, Md. 32. ComroeJHJr. Retrospectroscope. Menlo Park, Calif: Von Gehr Press, 1977. 33. Pritchard JA, MacDonald PC, Gant NF. Williams' obstetrics. 17th ed. Norwalk, Conn: AppletonCentury-Crofts, 1985:3-4. 34. Kretchmer N. In: Child health and human development. An overview and strategy for a five-year research plan. Washington, DC: United States Department of Health and Human Services, Public Health Service, 1981: iii (NIH Publication no 82-2303). 35. Bacon F. Of great place. In: Essays and ancient fables of Francis Bacon. New York: Walter J Black, Inc, 1932:37. 36. Proverbs 4:7. 37. Clarke EH, Bigelow HJ, Gross SD, Thomas TG, Billings JS, eds. A century of American medicine, 1776-1876. Philadelphia: Henry C Lea, 1876:3-72. 38. Billings JS. Literature and institutions. In: Clarke EH, Bigelow HJ, Gross SD, Thomas TG, Billings JS, eds. A century of American medicine, 1776-1876. Philadelphia: Henry C Lea, 1876:291-366.
Key words: Investigation, basic science, clinical care, mother, child, National Institute of Child Health and Human Development I am honored to participate in Child Health Day, this twenty-fifth anniversary of the National Institute of Child Health and Human Development, and this centennial observance of the founding of the National Institutes of Health. Chiseled on the portals of this clinical center are the words of Jack Masur (1908-1969), designer and first director of the Clinical Center from 1948 to 1951: "Hospitals with long traditions of excellence have demonstrated abundantly that Research enhances the vitality of teaching. Teaching lifts the standards of service, and Service opens new avenues of investigation." This credo, which encapsulates the essence of this institution, serves as the theme of my remarks; that is, that in reproductive science, as in most everything else in medicine, fundamental research complements clinical research to improve patient care. In turn, observations at the bedside stimulate the search for key scientific discoveries. I have been given the astonishing task of herein summarizing a century of progress in reproductive medicine, and the role of obstetrics and gynecology in child health, particularly as it relates to the National Institute of Child Health and Human DeFrom the Division of Perinatal Biology, Departments of Physiology and Obstetrics and Gynecology, School of Medicine, Loma Linda University. Supported by United States Public Health Service Grant No. HD-03807. Presented at the celebration of Child Health Day, Clinical Research Center, National Institutes of Health, Bethesda, Md., October 2, 1987, on the occasion of the twenty-fifth anniversary of the National Institute of Child Health and Human Development and the one hundredth anniversary of the National Institutes of Health. Reprint requests: Lawrence D. Longo, MD, Division of Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA 92350.
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velopment. Because of time constraints, I shall consider only a few highlights in this rich heritage.
1887 and the Laboratory of Hygiene The forerunner of the National Institutes of Health, the Laboratory of Hygiene, opened in 1887 as a oneroom attic laboratory at the Marine Health Service Hospital, Staten Island, N.Y. It came into existence largely through the influence of Surgeon General John Brown Hamilton (1847-1898) and under the direction of Joseph James Kinyoun (1860-1919). By that year medicine had advanced considerably in the century since the founding of the Republic. Rudolph Ludwig Karl Virchow's (1821-1902) cellular pathology' gave a rational basis for understanding many disease states, while Louis Pasteur's (1822-1895) 2 and Robert Koch's (18431910)' microbiology gave hope to the elimination of infectious disease. It was just a few years before this that one of America's first major contributions to medicine, the discovery of ether anesthesia, had lessened the terror of surgery and childbirth. With the development of women's hospitals gynecology developed as a specialty, and with the rise of lying-in hospitals obstetrics moved out of the home. The year this great institution was founded ( 1887) saw gynecologists considering topics such as the proper treatment of uterine ftexions and displacements, advancements in pelvic surgery for tumors of the ovaries and uterus, the proper treatment of salpingitis and pelvic abscess, and the role of uterine disease as a cause of severe neurosis, so-called hysteroneuroses. They also were considering the proper treatment of typhoid fever in pregnancy and eclampsia, the course of labor in the woman with a deformed pelvis, the best method for reducing an inverted puerperal uterus, the
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treatment of puerperal endometritis, and the use of electrotherapy in the treatment of numerous disorders, gynecologic as well as obstetric.1·1 The first journal exclusively devoted to the field of women's diseases, The American Journal of Obstetrics and Diseases of Women and Children, appeared in 1868 and by 1876 the American
Gynecological Society was well established. The diseases of children were still a branch of obstetrics and gynecology. This, then, was the background of the specialty just a century ago. 1912 and the child welfare movement
By 1912 when the Hygienic Laboratory had reached the maturity of a quarter of a century, it had moved to new facilities at 25th and E Streets in this nation's capitol. Its name had been changed to the Public Health Service Laboratory and its research programs had expanded to include diseases other than those that were communicable. Reproductive medicine at this time was in its embryonic stage. Ernest Henry Starling ( 1866-1927) had coined the term hormone just a few years earlier8 and with William Maddock Bayliss (1860-1924) had developed the theory of endocrine control of internal secretions.9 Experiments had demonstrated the ovarian dependence of the menstrual cycle, 10 that experimental hypophysectomy profoundly affected the reproductive system, 11 and the oxytocic action of posterior pituitary injection. 12 Additional contributions to reproductive endocrinology at this time included the first definite description of the cyclic changes in the endometrium" and the attribution of pregnancy-induced changes in the mammary glands to the developing fetus and placenta.11 However, most of these contributions were English or German in origin, rather than American. Reproductive medicine also began to advance in the field of maternal and child health, initially as a social movement and only later in original research. During the first decade of this century a veritable crusade developed for the improved care of pregnant women and their newborn infants. Initially this movement had its roots in concern for the astonishingly high death rates of young children. Pediatricians, obstetricians, nurses, public health workers, and women's groups strove to establish well-baby clinics, assure clean milk supplies, and eliminate the waves of epidemic infections that accounted for a huge loss of life. Soon it was realized, however, that without properly managed pregnancy, the benefits of pure milk were limited. Concurrently the works of John William Ballantyne (1861-1923) 15 and John Whitridge Williams (1866-1931)' 6 • 17 helped focus attention on several facts: (1) the enormous numbers of mothers who died of pregnancy-related disorders and other conditions, (2) that to a great extent diseases of young children had their origin during fetal
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life, and (3) that the fetus could be treated by correcting the underlying pathologic condition in the pregnant mother. These ideas contributed greatly to an increased interest in the care of children and their mothers. In addition, they led to the organization of the Association for the Study and Prevention of Infant Mortality, which promoted numerous studies in maternal and child care. As a consequence of recommendations of a White House Conference on Child Welfare Standards, the Children's Bureau of the Department of Labor was established in 1912 for the purpose of" ... investigating and reporting on all matters pertaining to the welfare of children and child life among all classes of people." Under the leadership of Julia Clifford Lathrop ( 1858-1932), the Bureau conducted numerous early studies relating to maternal and child health.'" 1937 and the National Institutes of Health
By 1937 the Public Health Service Research Program was 50 years old and had been reorganized into the National Institutes of Health, largely as a result of Louisiana Senator Joseph Ransdell ( 1858-1954), whose bill to create the Institutes to focus on the fundamental problems of the diseases of man was passed by Congress in 1930 and signed by President Herbert Hoover (18741964). The following year the National Institutes of Health moved to the Bethesda campus on land donated by Mr. and Mrs. Luke I. Wilson. At the urging of then Surgeon General Thomas Parran (1892-1968), President Franklin D. Roosevelt ( 1882-1945) allocated funds to construct the three original buildings on this campus. In reproductive research the 1930s were a time of ferment. Selmar Aschheim ( 1878-1965) and Bernhard Zondek ( 1891-1966) had announced their test for diagnosing pregnancy'• and had also isolated pituitary gonadotrophic hormone!" Steroid hormones were also under active investigation. Edgar Allen ( 1892-1943) and Edward Adelbert Doisy ( 1893-1986) had isolated estrogen 21 and George Washington Corner ( 1889-1981) and Willard Myron Allen (1904-) had discovered progesterone. 22 Guy Frederick Marrian (1904-1981) had isolated both pregnanediol 23 and estriol, 21 and Adolf Friedrich Johann Butenandt ( 1903-) had crystalized both progesterone 25 and androsterone. 26 Also, by the mid- l 930s obstetrics and gynecology had matured as a specialty, with the joining together of most departments of gynecology and obstetrics. The American Board of Obstetrics and Gynecology was established (1930) and a few departments conducted original research. 1962 and the National Institute of Child Health and Human Development In 1945 at the end of World War II, Vannevar Bush (1890-1974), the President's Science Advisor, outlined
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his visionary policies for the federal support of peacetime health research in his "Science-The Endless Frontier." 27 Bush foresaw both the vital need for fundamental biomedical research and the key role that the nation's universities and colleges could play in advancing knowledge in the health sciences by letting minds explore. By 1961 a Center for Research in Child Health had been established in the Division of General Medical Sciences. In addition, a task force had reported that year to President John F. Kennedy (1917-1963) that research into the physical, intellectual, and emotional growth of children was severely handicapped by not having a centralized organizational structure. The group called for a new institute to launch a concentrated attack against disorders of development. Because at that time, by law, each institute had as its mission to increase understanding and to develop treatments for specific diseases, new laws had to be written and enacted. Thus on October 17, 1962, near the seventy-fifth birthday of the (by then designated) National Institutes of Health, Public Law 87-838 was passed, which authorized creation of the National Institute of Child Health and Human Development (and the National Institute of General Medical Sciences). A few months later the National Institute of Child Health and Human Development was physically established, with authorization to conduct research and training relating to maternal health, child health, and human development. By the year this Institute was founded, the American College of Obstetricians and Gynecologists ( 1951) had been organized and reproductive investigators had banded into the Society for Gynecologic Investigation ( 1953).28 At this time reproductive problems of interest included metabolic alterations in diabetes in pregnancy and pregnancy-induced hypertension, urinary estriol excretion in the pregnant woman with diabetes, the pathogenesis of disseminated intravascular coagulation, the use of veratrim and hydralazine in the treatment of pregnancy-induced hypertension, electronic monitoring of fetal heart rate patterns and the meaning of bradycardia, diagnosis of the inadequate luteal phase, Stein-Leventhal syndrome, the hormonal activity of ovarian tumors, testicular feminization, urethral suspension procedures for stress incontinence, and the optimal surgical treatment of pelvic lymph node metastasis from carcinoma of the cervix.2 9 • ' 0 Many of these problems are still with us today. Fundamental versus clinical research
To many individuals, physicians as well as laymen, the word "research" connotes an activity conducted by a rather aloof, or at least dispassionate, scientist in an "ivory tower" with little or no relevance to problems of the real world. Others would make a rather arbitrary
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and sometimes specious distinction between those studies designated as "basic" and those that are "applied." A unique endowment of the National Institutes of Health has been the support of both fundamental and clinical research for the amelioration of disease and improvement in patient care. For reproductive medicine the National Institute of Child Health and Human Development has singularly advanced this ideal in many areas; allow me to recite just five examples. (Because so many outstanding workers have played a role in these advances, with few exceptions I shall not cite individual names.) First, the two sides of the coin of fertility are contraception and infertility. At the time of the National Institute of Child Health and Human Development's founding, the "population explosion" was emerging as a major issue, while at the same time the infertility rate in our society was 10% to 15% (where it remains). Clinical trials were first demonstrating the efficacy of "the Pill," spurring new developments in basic reproductive endocrinology. For instance, determination of the chemical composition of luteinizing hormonereleasing hormone (gonadotropin-releasing hormone) gave impetus to an enormous amount of work that has helped to unravel the mysteries of the normal hypothalamic-pituitary-ovarian relationships, and to gain a deeper understanding of the mechanisms by which polypeptide and steroid hormones act. In turn, this fundamental work has led to the development of a number of analogs and blocking compounds for clinical use. Just one example is the use of gonadotropinreleasing hormone analogs that show great promise in the treatment of endometriosis and precocious puberty, as well as in fertility regulation and the management of other conditions. In addition, the deeper understanding of fundamental reproductive endocrinology and technologic advances has literally sparked a new "industry" of in vitro fertilization and the transfer of embryos and gametes in patients with infertility. Recent discoveries in cell and molecular biology promise to save our intellectual souls, giving hope of even more powerful tools to manage the yin of infertility and the yang of contraception. Another example of the interactions between fundamental and clinical research and patient care is in the area of prematurity and the initiation of parturition. Roughly 7% of infants are born too soon, and prematurity is the major factor accounting for newborn morbidity and mortality. Indeed, if one were to judge from the patient population in most of this nation's tertiary care centers, premature labor and its sequelae have reached epidemic proportions. To a great extent this clinical problem has stimulated important research into the elegantly orchestrated regulation of hormones in the fetus and mother that eventuates in parturition.
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To date much of this effort has focused on the myometrium, decidua, chorioamnion, and the fetal adrenal gland. To arrive at a more complete understanding, present and future studies must elucidate the roles of the fetal pituitary gland, hypothalamus, and, perhaps, higher centers. In concert with this fundamental work is a two-pronged attack both to prevent prematurity by the identification of mothers at high risk and to improve the treatment of such women with (3-mimetic and other uterolytic drugs. A related area in which enormous advances have occurred is that of antenatal testing of lung maturity and the prevention and treatment of hyaline membrane disease-respiratory distress syndrome. The challenge of understanding the role of pulmonary surfactant, as well as more accurate diagnosis of fetal development, sparked fundamental research into surfactant biochemistry and metabolism. This, in turn, led to more precise evaluation of maturational state by the "profiles" of lung phospholipids and, almost incidentally, establishment of the relative safety of amniocentesis. An exciting topic of research in this field is the use of surfactant (human, animal, and synthetic) in the prevention and treatment of respiratory distress in the newborn. Another example of the interdependence of clinical obstetrics and pediatrics and both fundamental and "applied" research is in the field of antenatal diagnosis. More than a quarter of a million infants in this nation are affected by fetal abnormalities. Fundamental research in birth defects has progressed on several fronts. For example, advances in genetics have led to more accurate diagnosis of trisomy and other chromosomal abnormalities. In turn, this has led to rather startling advances in molecular genetics that allow in utero screening for numerous conditions. An example of this is the diagnosis of phenylketonuria, an enzyme deficiency that if left untreated results in severe mental retardation but that can be controlled by a special diet during childhood. The in utero diagnosis of neural tube defects and congenital hypothyroidism is also a reality. Complementing these contributions have been technologic advances in diagnostic ultrasound, amniocentesis, chorionic villus sampling, fetal blood and tissue sampling, and even fetal surgery. A fifth, and related, area in which fundamental and clinical research have both contributed to clinical care and, in turn, been stimulated by it, is that of neonatal intensive care and survival of the sick premature infant. Mildred Stahlman eloquently addressed these issues in her Child Health Day address last year. 31 To avoid duplication, I will summarize some key contributions." A quarter of a century ago the survival of a l 000 gm infant born at 28 weeks' gestation was only about 10%. Today that figure approaches nearly 95%. In those
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early years, survival rates for yet smaller infants were essentially nil. Today, about half of 600 gm premature newborns born at 26 weeks' gestation survive. 33 Interest in these "ex utero fetuses," so to speak, has stimulated a wealth of vital research in understanding the physiology of development of the cardiovascular, respiratory, and endocrine systems. For instance, fundamental and clinical studies have demonstrated the necessity of temperature and humidity control, nuances of fetal metabolism, and a better understanding of metabolic needs from parenteral alimentation, the physiology of the ductus arteriosus and blood flow to the brain and other vital organs, and the pathogenesis of retrolental fibroplasia. Understanding of these physiologic systems and their pathophysiology has led to clinical advances such as continuous positive airway pressure, the use of prostaglandin synthetase inhibitors to close the ductus (and perhaps stabilize the cerebral circulation), and improved management of pulmonary hypertension, altered acid-base balance, and respiratory distress. Each of these individual "bits" and "bytes" has contributed to the overall "program" of lower infant morbidity and mortality. Of course, these miraculous improvements in survival could not have occurred without concomitant technologic advances such as the development of improved incubators and respirators, the Clark oxygen electrode, microtechniques of blood sampling, transcutaneous and pulse oximetry, electronic monitoring, and other items. Nonetheless, we are not there yet! Many other examples of the productive interplay between fundamental and clinical research and improved health care for mothers and children could be cited. Advances in developmental biology, the use of Rho(D) immune globulin and intrauterine intravascular transfusion to treat erythroblastosis fetalis, exquisitely sensitive pregnancy tests to monitor early reproductive wastage, and an understanding of the roles of the maternal use of cigarettes, alcohol, and other drugs in the genesis of infant morbidity and mortality are just a few of these. During the life span of this Institute these and other advances have played a not inconsequential role in the lowering of perinatal mortality by almost 60%, from about 34 per l 000 births in 1962 to about 15 today. This same period has seen maternal mortality drop almost 80%, from more than 36 per l 00,000 live-births in 1962 to about 8 today."' A remarkable record, but not yet good enough. This is but a sampling of the magnificent achievements in reproductive medicine in the past quarter century. Nonetheless, there is much yet to accomplish. As Norman Kretchmer (1923-) noted, "Every year thousands upon thousands of children die or are crippled by disorders that we have neither the knowledge to treat nor the wisdom to prevent.""
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Lessons to be learned
Recitation of these advances makes one almost gasp in wonderment. What can there be left to do? How can the spectacular achievements of this past quartercentury possibly be matched in the next? What lessons can be learned from this seemingly unparalleled success? Making no pretense at being a prophet, I shall leave to others a vision of the future. Nonetheless, without seeming gratuitous, I believe that several points bear consideration. First, clinicians, scientific investigators, and the public must understand that reproductive medicine is the future of the human genome. Many of the key discoveries that played a major role in clinical advances were in fundamental science or technology with little promise of immediate application. For instance, much of the research in reproductive endocrinology was undertaken to understand at a deeper level the nuances of neurohormonal communication in the brain, and yet this work has proved to be of great practical value. Similarly, the increased understanding of uterine muscle physiology is contributing to a decreased incidence of premature labor, and the development of techniques in subcellular biology promise future improvements in diagnosis and treatment of a host of molecular diseases. It is almost as though there were giant positive feedback loops going from a "cell" at one institution to a "cell" at another, perhaps thousands of miles away-one discovery stimulating others. One simply cannot predict which advances in cell biology, molecular genetics, or some other science will be just the key to unlock a conundrum in a totally unrelated basic or clinical field. Of course, that is what this Institution is all about, stimulating the positive feedback circuitry. Another lesson is that although the scientific and clinical advances I have enumerated might appear to have proceeded in sequence-one triumph building on another-that is hardly the case. Although today we see further because we stand on the shoulders of giants, the way of science is not linear. There have been many digressions, paths that led nowhere, and downright erroneous conclusions from poorly designed studies. Most of the "breakthroughs" have come neither quickly nor easily. Thus occasionally there are "short circuits" or "misfirings" in this great information network. A better appreciation of the history of medical science and practice can help to protect us from the deadly sin of hubris, which assigns value only to the experience of the moment or a single lifetime. An additional lesson to ponder is the ultimate relationship between progress in science (e.g., improved maternal and child health) and adequate research monies. This is perhaps self evident, but the Republic's biomedical research enterprise is a national resourceif you please, the "crown jewels" and stately "royal trea-
July 1988 Am J Obstet Gynecol
sures" of our democracy. As with the maintenance of a militia for our defense, the development and maintenance of even more accurate standards in weights and measures, and the surveillance of the continent's weather, fundamental research in the biomedical sciences is a federal responsibility. This being the case, to a great extent it is dependent on governmental leaders who appreciate its worth. Private industry, of course, also has made notable contributions (and, in turn, has benefited greatly from government-supported studies). Nonetheless, with few exceptions, only a federally supported program such as exists on this campus can mount the intensive and expensive programs required for research of complex problems and for the common good, but with perhaps little apparent immediate payoff. Unfortunately, some economists would have us believe that all governmental programs are inefficient and create more problems than they solve. Although there may be an element of truth in that, the National Institutes of Health, including the National Institute of Child Health and Human Development, have certainly been a glorious exception. The task of science is to identify problems and their solutions. In reproductive medicine the payoff has been the relief of human suffering and improved health for mothers and children. As a corollary of this, those of us whose work has been supported these many years owe a great debt to the visionary leaders in the legislative branch of our government (the John E. Fogarty's, the Lister Hill's, the Warren G. Magnuson's, and others) who authorize and appropriate the funds; to the executive branch of the government; to the Mary Woodard Lasker's and other private citizens who translate their visions of better health into activism; and to the citizens of the Republic who pay the taxes. These individuals support what at times must seem like rather arcane studies with unclear goals. We are in their debt for their faith and commitment to this glorious enterprise. A further lesson is the need to rely on the wits of individual investigators for progress in maternal and child health. Scientific research is a peculiarly human experience that probably comes as close to intended action as any human effort can, and is par excellence an expression of purpose. We may recall the words of Francis Bacon ( 1561-1626), who counseled": "Reduce things to the first institution, and observe ... [and] ask ... what is best, ... and what is fittest." It is the first institution of science to serve the human condition, and the task of those of us in reproductive research to serve women and children. How to achieve most fittingly that first institution at this time is a continuing challenge to the probity and wit of individual scientists as well as of our Society.
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As an aside, to the leaders of this institution and to individual investigators, sometimes those of us who are extramural are viewed as supplicants, cup in hand, begging for a handout; or worse, we are viewed as adversaries rather than as partners in the symbiotic relationship of this enterprise. We all recognize that as investigators our studies must be hypothesis oriented and carefully planned, and that our grant applications must be carefully detailed as to what we plan to accomplish. Nonetheless, many of the greatest achievements were unforeseen by the investigator when preparing his or her application or by the peer review group that critiqued it. By their nature, important discoveries and the development of new paradigms are a somewhat stochastic process, and we need to trust investigators, a bit at least, even though their ideas may be unorthodox. Our scientific destiny is being shaped by forces and discoveries beyond our control. Today reproductive medicine would appear to be on the verge of a new "golden age" of knowledge at the cellular and molecular level. The key will be to see that the most able and imaginative scientists can follow their intuition and let their minds run free. An additional lesson is the importance of research training for physicians, in the instance at hand, for young obstetricians and gynecologists. Almost without exception, the present generation of clinical and basic biomedical scientists are "graduates" of the National Institutes of Health system. Nonetheless, reproductive medicine faces a critical period with a need to nurture physician investigators, the "endangered species" of academic medicine. Even among academically committed obstetrician-gynecologists there exists a profound illiteracy regarding the new biology. One of the critical needs of our specialty is a research training program for such individuals in cellular and molecular biology, the key to the future in reproductive biology, as in most other areas of medicine. Another lesson is that concern for the mother must go hand in hand with that for the child. Early in this century the realization developed that the well-being of the infant critically depended on that of the mother. Somehow in the intervening decades this verity seems to have been forgotten, but the evidence is there. A healthy mother produces a healthy baby, whereas an unwell mother more often than not has a very sick infant. Finally, we cannot forget that vast seas of ignorance surround our small islands of scientific knowledge. A subtitle for this presentation could have been "whither the National Institute of Child Health and Human Development?" For this institute the challenge for the next 25 years-and the next century-will be to enlarge these isles into yet larger islands, from which grow whole continents of understanding. As the "wise man"
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admonished, "Wisdom is the principal thing; therefore get wisdom; and with all thy getting get understanding.""" But this is not a new challenge. Just over a century ago at this nation's first centennial, five of our most respected physicians described the medical achievements of the prior century.' 7 In closing his essay, John Shaw Billings (1838-1913), developer of the Surgeon General's Library (now National Library of Medicine) and initiator of the Library's Index Catalogue (now Index Medicus), observed, "It is better to have a future than a past."'" History assures us that if our Society permits continued scientific investigation, it will bear fruit in important new knowledge. Thus the challenge that lies before us and this Institute is to not rest on past achievements, but to look to the future. The problems we face are to use the future wisely, to use our time wisely, to use our talents wisely, and to use our funds wisely. We can be certain that, as Jack Masur pointed out, the continued exploration at both the fundamental and clinical levels, combined with technologic advances, will give promise to continued enlargement of our understanding and the satisfaction of achievements in the care of mothers and children. I am grateful to Drs. Norman Kretchmer, Joyce L. Peabody, and Steven M. Yellon for discussing with me some of the issues presented in this essay. REFERENCES I. Virchow RLK. Die Cellularpathologie in ihrer Begriindung auf physiologische und pathologische (~ewebelehre. Berlin: A Hirschwald, 1858. 2. Pasteur L. Oeuvres de Pasteur, reunies par Pasteur Vallery-Radot. 7 vols. Paris: Masson, 1922-39. 3. Koch R. Gesammelte Werke, 2 vols. Leipzig: G Thieme, 1912. 4. Table of contents. Trans Am Gynecol Soc 1887; 12:7-8. 5. Index. AmJ Dis Women Child 1887;20:1313-40. 6. Longo LO. The rise and fall of Battey's operation: a fashion in surgery. Bull Hist Med I 979;53:244-67. 7. Longo LO. Electrotherapy in gynecology: the American experience. Bull Hist Med I 986;60:343-66. 8. Starling EH. The Croonian Lectures on the chemical correlation of the functions of the bodv. Lancet I 905;2:33941, 423-5, 501-3, 579-83. , 9. Bayliss W~I. Starling EH. The chemical regulation of the secretory process. Proc R Soc Lond [BJ 1904;73:210322. 10. Battey R. Normal ovariotomy. Atlanta Med Surg .J 1872; 10:321-39. 11. Crowe SJ. Experimental hypophysectomy. Johns I lopkins Hosp Bull 1910;21:127-69. 12. Dale HH. The action of extracts of the pituitary b()(h. Biochem J I 909;4:427-47. 13. Hitschman F, Adler L. Der Bau der Uterusschleimhaut des geschlechtsreifen Weibes besonderer Berucksichtigung der Menstruation. Monatschr Geburtshilfe Gynakol 1908;27:1-82. 14. Lane-Claypon JE, Starling EH. An experimental enquiry into the factors which determine the growth and activitv of the mammary glands. Proc R Soc Lond [BJ 190506;77:505-22.
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15. Ballantyne JW. Manual of antenatal pathology and hygiene, 2 vols. Edinburgh: William Green & Sons, 190204. 16. Williams JW. What the obstetrician can do to prevent infantile mortality. Trans Am Assoc Stud Prevention Infant Mortal 1910;1:190-201. 17. Williams JW. Obstetrics: a textbook for the use of students and practitioners. New York: D Appleton, 1903. 18. Longo LD, Thompson C. The evolution of prenatal care in America. In: Proceedings of the Symposium, Childbirth: the beginnings of motherhood. Women's Study Program. Madison, Wis: University of Wisconsin, 1981. 19. Aschheim S, Zondek B. Schwangerschaftsdiagnose aus dem Harn (durch Hormonnachweis). Klin Wochenschr 1928;7:8-9, 1404-11, 1453-7. 20. Zondek B, Aschheim S. Des Hormon des Hypophysenvorderlappens. Klin Wochenschr I 928;6:348-52, 1927:7: 831-5. 21. Allen E, Doisy EA. An ovarian hormone. JAMA 1923; 81 :819-21. 22. Corner GW, Allen W'.\1. Physiology of the corpus luteum. Am J Physiol I 929;88:326-46. 23. Marrian GF. The chemistry of oestrin. I. Preparation from urine and separation from an unidentified solid alcohol. BiochemJ 1929;23:1090-8. 24. Marrian GF. The chemistry of oestrin. Ill. An improved method of preparation and the isolation of active crystalline material. Biochem J I 930;24:435-45. 25. Butenandt AFJ. Neuere Ergebnisse auf dem Gebiet der Sexualhormone. Wien Klin Wochenschr I 934;47:89790 I, 924-36. 26. Butenandt AF.J. Ueber die chemische Untersuchung der Sexualhormone. Z Angew Chem 1931 ;44:905-8.
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27. Bush V. Science-the endless frontier: A report to the president. Washington, DC: United States Government Printing Office, 1945. 28. Longo LD. A short history of the Society for Gynecologic Investigation, 1953-1983. Los Angeles: 1983. 29. Program and abstracts of the ninth annual meeting of the Society for Gynecologic Investigation, Chicago, Illinois, 1962. 30. Table of contents. AM J 0BSTET GY:>;ECOL 1962;83: 1-4. 31. Stahlman M. The interrelationship of research and care in neonatal intensive care units. Address given on Child Health Day, Oct 7, 1985, Bethesda, Md. 32. ComroeJHJr. Retrospectroscope. Menlo Park, Calif: Von Gehr Press, 1977. 33. Pritchard JA, MacDonald PC, Gant NF. Williams' obstetrics. 17th ed. Norwalk, Conn: AppletonCentury-Crofts, 1985:3-4. 34. Kretchmer N. In: Child health and human development. An overview and strategy for a five-year research plan. Washington, DC: United States Department of Health and Human Services, Public Health Service, 1981: iii (NIH Publication no 82-2303). 35. Bacon F. Of great place. In: Essays and ancient fables of Francis Bacon. New York: Walter J Black, Inc, 1932:37. 36. Proverbs 4:7. 37. Clarke EH, Bigelow HJ, Gross SD, Thomas TG, Billings JS, eds. A century of American medicine, 1776-1876. Philadelphia: Henry C Lea, 1876:3-72. 38. Billings JS. Literature and institutions. In: Clarke EH, Bigelow HJ, Gross SD, Thomas TG, Billings JS, eds. A century of American medicine, 1776-1876. Philadelphia: Henry C Lea, 1876:291-366.