What quality is most in demand in today's medical researchers? "We have to be translational,"answers Thaddeus (Ted) Golos, Ph.D. "The scientific and health community today demands that researchers be well educated and experienced in both the clinical and laboratory aspects of our fields." Golos himself has brought a wealth of experience in both clinical and basic research settings to our Center over the past nine years. This experience was instrumental in Interim Director Joseph Kemnitz's decision to appoint him as chair of our Reproduction and Development Research Group last December, to succeed John Hearn, who accepted a consultancy position elsewhere in November.
Golos, also an assistant professor of obstetrics and gynecology at UW-Madison, and his colleagues, led by core investigators Barry Bavister, Ph.D., Jerry Schatten, Ph.D., James Thomson, Ph.D., D.V.M., and David Watkins, Ph.D., study infertility, contraception and early prenatal development. The group is also involved with university plans to develop an environmental toxicology center.
The group's investigators use non human primate models to investigate aspects of human reproduction that cannot be addressed in clinical settings.
Bavister's group is examining the role of oviduct secretions in promoting successful oocyte maturation and fertilization. Schatten is studying the sperm centrosome, a critical structure in the reorganization that occurs after the sperm enters the oocyte. ''Understanding the basic biology of this reorganization would help us learn whether there are functional problems with some instances of male infertility, and help us possibly explore novel ways to disrupt that reorganization and prevent fertilization or implantation,Ó Golos says.
Understanding the basic biology of fertilization? Didn't we learn all about that in high school?
''We understand it in mice, and in other laboratory or domestic species," Golos says. ''But, in fact, there's minimal understanding of early events in fertilization at such intricate levels in humans." The group's work, especially that of investigators in Jerry Schatten's lab, indicates that the early embryonic development of primates is in many ways very different from that of rodents.
In addition to contraception, researchers are spending more energy these days studying natural infertility. With more women delaying childbirth, the successful fertilization of their older, lower quality eggs is perceived as a growing problem. Barry Bavister is studying chromosomal abnormalities and developmental impairments in oocytes from older rhesus monkeys; these simian counterparts of women over 35 are in their teens. Rhesus monkeys begin regular reproductive cycles at around age three or four years and undergo menopause in their late 20s.
The project interfaces with Dr. Bavister's other major research effort involving rhesus monkeysÑthe optimization of methods to mature and fertilize primate oocytes in culture, which may translate directly into new in vitro fertilization methods for clinical use. An early milestone in this effort occurred in 1984, when the world's first ''test-tube" monkey, Petri, was created in Bavister's lab. Petri still resides at the Center. He came onto the scene after the world's first in vitro human baby, Louise Browne, was conceived. "So many women have been treated for fertility problems that clinicians have worked out many of the mechanics without the use of experimental models to really understand why things worked when they did," Golos says.
"We must remember, however," he adds, "that the average success rate of in vitro fertilization in women remains at around 25 percent and has stayed that way for several years," Golos says. "Taking it to the next level of success will require a greater understanding of the cellular and molecular events in the earliest stages of human development. The primate work in Wisconsin is on the cutting edge in these pursuits."
Another topic the group is concerned about is contraception. "It's a hot-button issue in the United States, but also an incredible problem worldwide in terms of overpopulation and starvation," Golos says. "John Hearn, Barry Bavister and Jerry Schatten have a grant from the Mellon Foundation to work on early embryonic development for new directions in contraception research." The project addresses prefertilization through preimplantation development, primarily in the rhesus monkey. Hearn's lab is investigating the role that a placental hormone, gonadotropin releasing hormone (GnRH), may play in blastocyst implantation; and whether specific agonists or antagonists may prove useful in promoting or interfering with the establishment of pregnancy.
Studying early placental formation is important if we are to learn the causes of early miscarriage. The placenta serves two roles: to establish and maintain pregnancy, and to nurture and sustain the fetus. Problems with placental development and the interaction between the placenta and the mother's uterus may be the most significant contribution to spontaneous pregnancy failure. The Thomson lab is intensely interested in developing genetic approaches to controlling the molecular switches that direct an ES cell to differentiate into a specific cell type. A better understanding of how tissues are generated could not only unlock the mysteries of early pregnancy loss, but could also someday lead to gene therapies to either prevent, or to later treat, an array of diseases, such as diabetes or cancer.
"Yet the placenta does a lot of extraordinary things to hide from the mother's immune system, as well as to control it so the mother can tolerate her fetus," Golos explains. In collaboration with the David Watkins lab, Golos and his colleagues are examining the placental surface cell proteins that direct the immune system to recognize the placenta as self. These proteins are encoded by the major histocompatibility class I complex (MHC Class I). In other tissues of the body, these proteins are called transplantation antigens.
"The Watkins team is expert in the evolution and function of these molecules," Golos describes, "particularly regarding how they function in the immune system to respond to diseases, or how their normal function can go awry, as with the auto immune diseases."
The Golos and Watkins labs are studying the monkey placenta to learn more about how a molecule found in human placentasÑleucocyte antigen-g (HLA-G)Ñoperates. Golos explains that HLA-G may not only allow the mother's immune system to recognize the placenta as self, but may also act locally in the uterus to inhibit other "attackers" from the mother's immune system (e.g., the "natural killer" cells). Interestingly, he says, the placenta molecule in the monkey resembles HLA-G, but is not directly evolutionary to it.
"There's something very important here," Golos emphasizes. "The monkeys likely wouldn''t have developed a separate family of genes that shared a number of the characteristics with the human gene if they didn't have a specific and important function. If we can find that function in monkeys, it would bring us closer to understanding the actual role of the HLA-G in human pregnancyÑin the initiation and maintenance of pregnancy, and perhaps in placental function and protection of the fetus throughout gestation."
Golos's lab has received 10 years of NIH support to study how the transcription of this gene, the placental growth hormone variant (mGH-V), is specifically targeted to the placenta. So far, studies have found cellular signalling pathways unique to the trophoblast, the cell layer through which the embryo receives nourishment from the mother.
"We hope that learning more about the specific molecules that control transcription of the mGH-V gene will give us broader insight into the control of placental cell differentiation," Golos says. To this end, collaborating investigators in Belgium are characterizing potential antibodies to the hormone. Our researchers can then measure the hormone in the blood of pregnant monkeys and study its secretion under a variety of conditions.
Copyright 1997. Wisconsin Regional Primate Research Center.