Reproductive & Developmental Sciences
The rationale has never been stronger for advancing our knowledge of human reproductive processes and fetal/neonatal development, in order to improve or control fertility, and to ensure maternal-fetal and neonatal health. Growing recognition of the deleterious effects of environmental factors and clinical therapies for other diseases, combined with intrinsic (genetic or post transcription) defects in cellular mechanisms, broadens the interdisciplinary research needed to understand reproductive processes, and to improve the diagnosis and treatment of reproductive disorders. At the same time, couples continue to experience unintended pregnancies (with many choosing contragestational methods with significant health risk), due in part to lack of access (cost-related or otherwise), non-compliance and non-use due to perceived risks of side-effects. The effects of reproductive health “disorders” on quality of life are personal, but the significant costs on the health care system are societal. It is estimated that the cost of diagnosing and treating infertility in the U.S.A. alone exceeds $5 billion per year; this is an underestimate as it only includes those requesting treatment – which is limited by lack of insurance coverage in many states. If pregnancy occurs, the costs of premature delivery and the lifelong health problems associated with “premie babies” are astronomical - $26 billion annually! Conversely, unintended pregnancies accounting for 51% (> 1 million) of publicly funded births in the U.S., cost over $11 billion annually. Clearly, further advances through state-of-the-art research are needed to improve women’s and child health. For example, there is a renewed effort by both federal (NICHD) and private (e.g., Gates Foundation) agencies to promote development of the next generation of contraceptives for men and women. Likewise, with the development of embryonic stem cells (ESCs) derived from pre-implantation embryos, detailed investigations are needed to characterize and compare ESCs to adult stem cells isolated or derived (induced pluripotent SCs, iPSCs) from various tissues, and to evaluate their use in regenerative medicine to maintain tissue function.
Due to the evolutionary theme of species developing scenarios that optimize reproduction for their environmental niche, differences abound in the structure-function and regulation of reproductive organs between mammals. Notably, many characteristics of and mechanisms controlling reproduction are more comparable in Old World Monkeys, apes and man, and less similar to those in typical laboratory animal models, such as rats and mice. For example, many primates experience long (28 day) ovarian-uterine cycles ending with menstruation, whereas rodents have short (3-4 day) cycles characterized by an estrus interval promoting mating. Likewise, signals for maternal recognition (placental chorionic gonadotropin versus coital neural activity) of pregnancy, maternal-fetal-placental development and function, plus term delivery are much more similar between NHPs and women than rodents. Also, with longer lifespans (including menopause) and metabolisms similar to humans, NHPs are more likely to respond to environmental factors (e.g., dietary restriction or the Western-style, high-fat, high-sugar, diet) in a manner comparable to humans.
Therefore, the mission of the DRDS is to perform basic and applied research on NHPs (primarily macaque species) to increase our understanding of primate reproduction and embryonic/fetal development, and to use this knowledge to control reproductive disorders, fertility and neonatal health. In addition, the Division, as part of the OHSU system and in partnership with other local programs, provides research training for individuals entering science-oriented careers (e.g., pre-and post-doctoral fellows) and a research-oriented knowledge base in primate reproduction and development for others (e.g., K-12, high school teachers, college undergraduates, and the local public). Finally, the Division serves as a regional, national and international resource, especially as it relates to NHP models and research.
The research of the Division focuses on understanding the environmental (e.g., diet, stressors), central (neural) and peripheral (endocrine, paracrine and autocrine) factors controlling NHP reproduction and development, primarily in the female (Fig. 1). Research projects span the continuum of reproductive processes from gamete and embryo development, through pregnancy initiation and maternal-fetal development, to delivery and neonatal health. Research groups utilize rhesus, cynomolgus and Japanese macaques (in order of prevalence) for whole animal, cellular and molecular studies of direct relevance to women’s and child health. Researchers are creating and using NHP models to investigate reproduction and its disorders, with the goal of considering the etiology, diagnosis and treatment of reproductive disorders, as well as developing novel approaches to contraception. There are 14 affiliate and visiting scientistscomprising the Division. Some have primarily appointments in other ONPRC divisions or the Department of Obstetrics & Gynecology, OHSU, but include the reproductive system as a major part of their research. While fostering the individuality of investigator’s research, a theme that emerged in recent years is the formation of interdisciplinary groups performing translational research on key issues in women’s reproductive health. The interdisciplinary groups bringing their expertise to clinical problems include:
1) Infertility disorders and their treatment (e.g., polycystic ovarian syndrome, endometriosis, menstrual irregularities, oocyte quality, and oncofertility) – Drs. J Cameron, P.M. Conn, J. Hennebold, S. Mitalipov, O. Slayden, R. Stouffer, M. Zelinski, J. Xu.
2) Fertility control and contraceptive development (reversible and irreversible methods, specifically targeting the oocyte, follicle or gamete transport prior to fertilization) – Drs. A. Edelman, J. Hennebold, J. Jensen, O. Slayden, R. Stouffer, M. Zelinski
3) Pregnancy disorders and their treatment (including metabolic and environmental disruptors, intrauterine infection and effects on maternal-fetal/neonatal health) – Drs. A. Frias, K. Grove, P. Grigsby, E. Spindel
4) Reproductive aging and its effects (neural-behavioral, ovary-oocyte quality, immune system) – Drs. C. Bethea, I. Messaoudi, H. Urbanski, M. Zelinski
The division also includes a unique research-oriented assisted reproductive technology (ART) program using nonhuman primates. This program has produced several world "firsts" in monkey reproduction. For example, primate embryonic stem cells (ESCs) were produced by reprogramming monkey fibroblasts using somatic cell nuclear transfer into enucleated eggs and culturing cells from resulting blastocysts. This method offers potential for generating immunologically acceptable ESCs for individual animals (and ultimately patients if applicable to humans), which can be evaluated for differentiation into various cell types for treatment of many diseases characterized by loss of cells or cell function (e.g., diabetes, heart failure, neurodegenerative disorders). Recently, world's first chimeric monkeys were generated as proof-of-concept that "pluripotent" cells from primates can be combined to produce healthy tissues and offspring.
In addition, methods were validated for transfer of the meiotic spindle (with its attached chromosomes, and hence all nuclear genes) from a mature primate egg, to another enucleated egg, followed by successful fertilization, pregnancy and healthy offspring. This technique provides a valuable option for preventing the transmission of mitochondrial DNA mutations from the mother, since spindle transfer leaves behind the mitochondria in the cytoplasm. Thus, the offspring following ART would be free of risk of maternal mutations in mitochondrial DNA, but still be the authentic biologic child of the parents. Mitochondrial DNA mutations result in several human diseases that are currently incurable. Spindle transfer, if replicated and proven safe in studies on human eggs, could provide a cure.
The division, in combination with researchers in the Department of Obstetrics and Gynecology at OHSU, is the only program that includes a Specialized Cooperative Center Program in Reproduction and Infertility Research (SCCPIR) and a Contraceptive Development Research Center (CDRC), both sponsored by the NIH, NICHD. Investigative efforts in the centers use nonhuman primates in translational studies seeking to understand the neurologic, endocrine and local mechanisms controlling fertility during the menstrual cycle and to develop novel therapies for treating infertility or to prevent pregnancy in women. Most recently, division scientists joined a NIH-supported consortium of biophysical, biological and clinical researchers to begin an oncofertility program designed to generate therapies for maintaining or restoring fertility in women undergoing treatment for cancer. Division scientists collaborate with research-oriented pharmaceutical companies in these efforts, and actively train the next generation of researchers in women's health through national and international programs.