MacDonald Years — Research
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During his career, Paul C. MacDonald, M.D., published more than 300 scientific papers, 96 percent of which came during his years as the Green Center Director. Among the publications was a series of articles on the subject of initiation of parturition (human labor and delivery).
Although methods have been available to induce human labor for many years, information concerning the biochemical and endocrinological basis for the onset of normal labor is still not fully understood.
Infants born prematurely have a high incidence of complications such as respiratory distress due hyaline membrane disease. This disease makes the exchange of gas in the lungs difficult and breathing labored. Respiratory distress occurs when the lungs have not had sufficient time to mature in utero, and the production of a protective molecule, surfactant, is inadequate.
Convinced that preventing prematurity was key to an infant’s survivability and quality of life, Dr. MacDonald and the faculty of the Green Center set about to define the mechanism(s) that resulted in normal human labor. It became a life-long quest of discovery.
Research was by no means confined to parturition. Other investigations included studies of male infertility, the mechanisms which result in problems of sexual differentiation in utero, and studies to explain problems of sexual precosity and gynecomastia (breast formation in men).
Dr. MacDonald described the research being done by the faculty of the Green Center in the excerpts below: Kinetics of Steroid Metabolism, Mechanisms of Hormone Action, Molecular Biology, Neuroendocrinology, and Lipid Metabolism.
Kinetics of Steroid Metabolism
For many years, the mechanisms of steroid hormone formation that involve metabolic transformations of circulating precursors have been studied by faculty of the Center.
Among their discoveries have been:
- That dehydroisoandrosterone sulfate, secreted by fetal and maternal adrenal glands, is the major precursor for placental estrogen biosynthesis
- That estrogen formation in postmenopausal women, in children, in men, and in anovulatory women occurs in extraglandular sites, principally adipose tissue
- That extraglandular estrogen formation is not a static process but is affected by a variety of metabolic processes
- That deoxycorticosterone, the mineralocorticosteroid, is formed from circulating progesterone in extraglandular sites of mineralocorticosteroid action
- That a number of biologically active steroid hormones are formed from plasma precursors in situ in tissue sites of action
Center faculty have pioneered studies in defining the role of plasma lipoproteins, especially low-density lipoprotein, in providing the precursor, cholesterol, for the formation of steroids in human steroidogenic tissues, namely, placenta, fetal and adult adrenal, and corpus luteum.
Mechanisms of Hormone Action
A major goal of the faculty of the Center is to define the hormonal mechanisms that are involved in selected reproductive processes.
In the conduct of these studies, specific problems of great importance are addressed:
- The role of growth factors in the regulation of fetal lipid metabolism and prostaglandin formation during parturition
- The mechanisms by which hormones control the biosynthesis of surfactant in fetal lung
- The mechanisms by which tropic hormones and growth factors regulate steroid hormone biosynthesis in steroidogenic tissues, namely, the placenta, fetal and adult adrenals, testes, and ovaries.
Molecular Biology
In the investigation of the nature of specific biochemical mechanisms that are involved in reproductive and developmental processes, the faculty of the Center make use of the full range of techniques of modern molecular biology. Antibodies prepared against specific enzymes or other proteins are used to immunoisolate the proteins of interest; mRNA is isolated, translated in vitro, and cDNA sequences complementary to the mRNA encoding the proteins of interest are isolated and cloned.
Full length cDNA inserts are sequenced; the amino acid sequences of proteins encoded for by the specific DNA are deduced, and regulatory sequences of the genes are identified.
Thereby, the fundamental nature of the mechanisms by which gene transcription is regulated in selected processes of reproduction is investigated.
Faculty and trainees of the Center have applied these techniques to the study of mechanisms whereby tropic hormones regulate the expression of genes that encode enzymes involved in steroid hormone biosynthesis, as well as the mechanisms whereby cortisol, insulin, and prolactin regulate surfactant apoprotein biosynthesis in the human fetal lung.
Neuroendocrinology
Basic studies are conducted on neurosecretory functions of neurons of the brain, especially the hypothalamus.
By directly sampling the blood of the hypophysial portal vasculature, the rates of secretion of various hypothalamic neurons are assessed, and the role of these neurohormones on pituitary function is elucidated.
Molecular changes associated with the biosynthesis and regulation of the activity of enzymes of neurons involved in the secretion of specialized neurohormones in the young as well as aged brain are major areas of emphasis.
The faculty of the Division of Neuroendocrinology are particularly interested in hormone dynamics and cellular responses that occur with development and maturation and with aging. Such events are believed to be of importance in the development of aging-dependent impairments of neurons that lead to memory loss and defective mentational processes.
Radioimmunoassay, monoclonal antibodies, cell and organ culture, molecular biology, microsurgery, and microsampling are among the many experimental procedures that are used in the conduct of research designed to address questions of signal importance in reproductive biology.
Lipid Metabolism
Faculty of the Center are conducting fundamental studies to define the regulation of prostaglandin biosynthesis, especially the mechanism(s) of arachidonic acid release and metabolism in the initiation of parturition, and the regulation of surfactant biosynthesis in the process of fetal lung maturation.
Studies in experimental animals and in humans are performed by use of cells and tissue explants maintained in culture, analyses of the kinetics of enzyme activities, protein isolation and purification, as well as immunological and molecular biological procedures.
Faculty and trainees seek to define the “ideal” hormonal milieu of pregnancy, especially that of the fetus that serves to promote lung maturation and to ensure a timely birth.
Green Center Faculty: MacDonald Years
A few of the Green Center Faculty who contributed to these investigations and the Green Center’s success during the MacDonald years are pictured below.
2nd Row (l-r): John C. Porter, Ph.D.; Jeanne Snyder, Ph.D.; Michael Waterman, Ph.D.
2nd Row (l-r): William E. Rainey, II, Ph.D., Evan R. Simpson, Ph.D., Associate Director, 1985-1997; Carole R. Mendelson, Ph.D.; Ann Word, M.D.