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 optimal maternal-fetal and neonatal health. Growing recognition of the deleterious effects of environmental factors and clinical therapies for other diseases, combined with intrinsic 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, unintended pregnancy rates have remained high (50-60%) over the last three decades, due in part to lack of access (cost-related or otherwise), as well as non-compliance and non-use due to perceived risks of side-effects. These reproductive health “issues” impact quality of life and place a significant financial burden on the health care system. 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. Lastly, advances in the derivation of embryonic stem cells (ESCs) from pre-implantation embryos, transferring nuclear material from somatic cells to healthy donor oocytes (somatic cell nuclear transfer; SCNT), as well as the potential to edit and, more importantly, correct mutations in zygotes using newly developed genome editing techniques have cleared a path to treating diseases that were recently thought to be incurable.
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 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) as well as metabolic rates and activities that are 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. 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 and cynomolgus macaques, as well as baboons 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 reproductive physiology and pathologies, with the goal of considering the etiology, diagnosis and treatment of reproductive disorders, as well as developing novel approaches to contraception. There are 14 scientists comprising the Division. Some have primary 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/embryo quality, and oncofertility) – Drs. S. Chavez, 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. 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. Spindel4) Reproductive aging and its effects (neural-behavioral, ovary-oocyte quality) – Drs. C. Bethea, H. Urbanski, M. Zelinski.5) Embryonic development, stem cell biology and regenerative medicine (aneuploidy and fetal loss, embryonic and induced-pluripotent stem cells, mitochondrial disease and mitochondrial replacement) – Drs. S. Chavez, S. Mitalipov.
The division also includes a unique research-oriented Assisted Reproductive Technology (ART) program using nonhuman primates. This program contributed to several "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, the 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 would be free of risk of maternal mutations in mitochondrial DNA. 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. Recent advances in non-invasive time-lapse imaging have allowed for the identification of cell division kinetics in embryos following in vitro fertilization that are predictive of successful implantation that leads to a normal term pregnancy. Moreover, abnormalities in embryonic cell division and cytokinesis detected by real-time imaging are indicative of abnormal chromosome segregation and offer a means to identify embryos that would likely fail to implant, develop to term, or result in offspring with birth defects due to aneuploidy. Use of NHP ARTs to further characterize the causes of embryonic aneuploidy and develop preventative or curative therapies is necessary to establish safety and efficacy prior to application to humans.
The division, in combination with researchers in the Department of Obstetrics and Gynecology at OHSU, is the only program that includes a National Center for Translational Research in Reproduction and Infertility (NCTRI) 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 were instrumental in forming the Oregon Permanent Contraception Research Center (OPERM), which is supported by a generous gift from the Bill and Melinda Gates Foundation and aims to develop a highly effective, safe, low cost, nonsurgical and highly portable method of permanent contraception to meet the unmet needs of women around the world who desire to have no additional children.