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CHAPTER 4 - RESEARCH AGENDA AND REOIMENDATIONS â¢mis chapter lists the areas of research that, in the view of the committee and workshop participants, hold particular promise in advancing the knowledge base and efficacy of medically assisted conception for humans and other animals. In addition, this chapter outlines the conclusions and specific recommendations that were made by the committee following the workshop. The research agenda items are organized into three main categories. The first and largest category includes promising areas of basic scientific investigation. The second category encompasses areas in which improvements in technology are needed. The third category includes questions that can be approached by cooperative agreements among clinical centers involved in IVFET. In addition to organizing the research agenda into common areas, these categories also generally reflect the different funding mechanisms that might be required to support such investigations. Research grants to support basic science projects could be obtained through competitive grant programs at the National Institutes of Health or the National Science Foundation. Formula funds and competitive grants can be obtained from the United States Department of Agriculture. Technological development, however, could be supported by contracts from projects already supported by the NIH or other agencies. Coordination of information from IVFET clinics could be accomplished by any one of a number of agencies or professional societies. Research Agenda The topics listed below are areas in which further research was recommended by workshop participants and committee members. It therefore reflects the areas of investigation considered to be promising by the committee. Work in these areas is expected to increase understanding of the biology of reproduction with the hope that increased knowledge will eventually lead to improvements in practice of IVFET in humans or other animals, or to advances in the area of contraception. Research areas are listed here in summary form and apply both to lower animals and human beings unless specifically noted. â¢The reader should refer to Chapter 2 for detailed discussion of these areas. Basic Science Male Garoetogenesis o Definition of the role of cell adhesion molecules in interactions between Sertoli cells and developing sperm cells. - 86 -
o Understanding the function of differential protein synthesis in different stages of sperm development. o Determination of the role of paracrine factors including fibroblast growth factor, â¢rjimf-rmmtin c, q?i<V>'rm*1 growth factor, and interleukin-1 on the development and differentiation of male gametes. o Structural analysis to identify normal and abnormal sperm and the development of markers for abnormal sperm. o understanding of the biochemistry of sperm capacitation. Female Gametcoenesis o Analysis of the effects of superovulation or hormonal stimulation protocols on oocyte development and maturation. This work should also examine differences among species. o Development of ways to mature oocytes in vitro. o Investigation of ways to naturally stimulate oocyte and follicular development. o Investigation into the biochemistry of meiotic arrest and the factors, such as cyclic AMP, purines, calcium, and naturation-promoting factor, that may mediate this process. o Development of ways to produce or synthesize hormones from non-human primates to be used in ovarian stimulation. o Definition of the role of ovarian estrogen in oocyte maturation and ovulation and the interactions between estrogen and paracrine factors including fibroblast and epidermal growth factors, insulin-like growth factor, transforming growth factor, and inhibin. o Definition of the point at which oocytes become sensitive to factors that influence their development. o Elucidation of the processes that underlie oocyte depletion, to determine why oocytes are lost at a predictable rate throughout life. o Investigation into ways to augment natural hormone release. o Investigation into the biochemistry of protein synthesis and modification in ovarian cells. - 87 -
Fterfcilization o Investigation into the biophysics of cell membranes as it relates to sperm and egg interactions at fertilization. o Continued investigation to identify the genes for zona proteins in various species, especially humans. o Further delineation of the role of zona proteins, especially ZF2 and ZP3, in sperm binding. o Understanding of the biochemistry of the modification of zona proteins in preventing polyspermy. o Elucidation of the molecular determinants of antibody formation to zona proteins and their possible role in contraceptive strategies. o Definition of the biochemical mechanisms of the cortical reaction in the egg and the effects of this reaction on zona proteins. o Determination of the physiological significance of germinal vesicle breakdown and the biochemistry of sperm chromatin decondensation. o Definition of the molecular events associated with formation of the male and female pronuclei. o Definition of the molecular events during zygote formation and the first cleavage. Preinplantation Development o Definition of the metabolic requirements of early embryos at different stages. o Determination of embryonic gene expression. o Assessing the potential of individual embryonic cells and defining the point at which embryonic cells are committed to particular fates. o Identification of substances produced by early embryos that signal changes in the uterus prior to implantation. o Improvements in embryo multiplication and embryo splitting, especially for food-producing animals. - 88 -
o Definition of the biochemical events that make the uterus permissive to implantation. o Definition of the factors released by embryos that cause endcmetrial changes at the site of implanation. o Identification of the role of embryo-released factors in suppressing the imnune responses of the mother. o Isolation and analysis of substances released by endometrial cells and their effects on embryos. o Continued work with in vitro models of human implantation to study the biochemistry and mechanisms of embryo-endcmetrial interactions, especially the role of extracellular matrix proteins and the biochemistry of trophoblast invasion of the endonetrium. Technological Advances o Improved cryopreservation techniques, including freezing and thawing protocols for eggs and embryos. o Improved resolution of ultrasonography for localization and noninvasive harvest of cocytes, eggs, and embryosâwould have particular usefulness for non-human primates and food-producing animals. o Development of new culture media and methods for in vitro maturation of oocytes. o Development of safe methods of biopsy of early embryos for preimplantation diagnosis of genetic ftintvnen. Clinical Research Opportunities The following areas are those in which a coordinated data collection effort across IVFET clinical centers would improve the quality and success rates of TVFET nationally and, possibly, internationally. o Evaluation of hormonal stimulation protocols in terms of number of oocytes harvested, quality of oocytes, and rate of fertilization o Documentation on the incidence of abnormal implantation rates in IVFET practice and correlation of incidence with particular stimulation protocol used. - 89 -
o Collection of information regarding the incidence of abnormal eggs and embryos, failed fertilization, and developmental arrest of embryos. o Analysis of data pertaining to synchronization of embryonic stage with endonetrial stage and development of methods to improve synchronization. o Collection of information on sharing of spare oocytes and arrested embryos for research purposes. Conclusions and RBcannendations Developing Research Policy The lack of a mechanism for dealing with ethical disagreement over the use of embryos in research has slowed the rate of progress in research by, in effect, placing a moratorium on the use of federal funds for eight years. This has had undesirable results: the human clinical practice of IVFET is less effective than it might have been had research progressed at a faster pace; other socially desirable goals such as improved contraception, better techniques to preserve endangered species, and more cost-effective methods of producing food have developed at a pace slower than is optimal. The recent appointment of the Biomedical Advisory Committee by the Biomedical Ethics Board, to report to Congress by November 1990 on embryo research issues, could be a step toward a solution. The committee also applauds the intention to revive the Ethics Advisory Board of the Department of Health and Human Services to rule on the ethical acceptability of research relating to human embryos, which is required before federal funding of such a research grant can be considered. However, until these groups become fully functional and show evidence of progress, their impact must remain in question. If these groups can assume leadership roles in resolving the difficult issues of reproductive research, and develop guidelines for research that are based on information provided by science, as well as on concepts that are ethically acceptable to society, research in reproduction will be able to move forward. But if these groups become paralyzed because of political considerations or an inability to develop a framework for the resolution of differences of opinion, another organization should take over the role. The committee recxiiiiiends that, if row*" urtentl being fonff5*^ o come to riffr'n<s conce estabshed to develop cpi the most advanced knowledge that science can muster, and with serious consideration of the expressed value*5 of society. The grou - 90 -
fit scientific ni ?j*1-inn shrill ri ho ethical and social in an for such activities can be found in the Voluntary Licensing Authority of Great Britain. This group was established after a governmental committee reoaanended a statutory licensing authority. Recognizing that it would be some time before legislation would be completed, the Medical Research Council and the Royal College of Obstetricians jointly sponsored the voluntary body. Five of its 13 members are lay people. The group has a mandate to undertake five major activities: o to approve a code of practice on research related to human fertilization and embryology; o to invite all centers, clinicians and scientists engaged in research on IVF to submit their work for approval and licensing; o to visit each center before it is granted a license; o to report to the sponsoring organizations; and o to make known publicly the details of both approved and unapproved work. Basic Science Foundations The number and range of topics included in this chapter's research agenda indicate the exciting potential for productive scientific exploration. Funding that would allow investigation of the areas targeted in the research agenda would allow significant advances to be made in understanding reproductive processes. The committee believes that fundamental research to enhance the basic science foundations of reproductive biology should be stimulated and supported. This includes studies of human beings, laboratory animal models, and food-producing animals. The knowledge that would be generated is fundamental to an understanding of how to reverse infertility, to new approaches in the area of contraception, and to increasing the world's food supply. This report attempts to define not only the state of knowledge in reproductive science relating to IVFET, but to aaseso and highlight some research opportunities. It is important that aspects of male as well as female reproductive biology be studied. It is also important that investigators make use of some opportunities that are largely ignored today. These opportunities occur as a result of clinical activities as - 91 -
well as research activities. For example, eggs that have failed to become fertilized can become material for studies seeking chrcnoscnal abnormalities. Fertilized eggs that fail to develop nay be used to investigate the reasons for developmental failure, and to answer questions about the natural wastage that occurs in pregnancy. Research of this type would generally be funded by the grant mechanisms of the National Institutes of Health and by the United States Department of Agriculture. For adequate attention to a research agenda, however, administrators of NIH need mechanisms to insure that studies on a variety of these topics are being funded. For this an RFP or a contract mechanism might be necessary to insure adequate coverage of the various aspects of reproductive biology. Foundations are also encouraged to consider increased support for basic studies in reproduction. A stable funding base for reproductive research will encourage young, well-trained scientists to pursue research in reproductive biology. basic science agenda in reproductive biology be maintained in a coordinated fashion bv an amrooriate office in the National Institutes of Health. Applied Research Research needs to be stimulated concerning technologies used in medically assisted conception in food producing animals and in human beings. lack of support in these areas is leading to inadequate scientific underpinnings for safe and effective clinical practice. An example of a technique used, but not carefully evaluated for possible detrimental effects, is freezing eggs or zygotes. Further experiments should be conducted to assess the effects on safety and viability of this technology which is standard practice in many IVFET clinics. Other areas of technology that need to be developed include less invasive ways to retrieve oocytes, ways to mature occytes in vitro, and ways to assess the quality of spermatozoa or oocytes to be used for fertilization. Since these studies would be technology driven, it is unlikely that the research will be funded by a grant mechanism, therefore a contract mechanism should be used. P>e conini' foundation for the find effective practice of in vitro fertilization appropriate office at the of Health. - 92 -
Clinical Research Opportunities Perhaps the most obvious missed opportunity is the failure to learn from the diverse experiences of the approximately 160 clinical programs that provide human IVFET. In addition to scientific questions, there are questions to do with the organization of clinics and the outcomes of procedures. The answers to these questions would enable practitioners to work more effectively, and enable policy makers to make decisions on the basis of the best available information. Such questions include; Who provides the quality assurance for facilities and procedures used (including the training of those providing services)? How are protocols developed? How standard are they? What are the outcomes for each protocol? What is the role of Institutional Review Boards in the establishment and maintenance of clinical facilities? Some specific questions to be answered from data that could be collected from clinics include: What ovarian stimulation protocols are the most successful? Is chromosomal damage associated with any of the procedures used? What indicates whether a zygote will implant successfully? Much data relating to these questions already exist in the centers. Other questions may require a cooperative prospective study to be undertaken. Clinical IVFET centers can also provide unique opportunities for important studies. For example, human eggs that fail to fertilize in vitro are material that could be used to investigate the phenomenon of failed fertilization. Improved understanding of reasons for failure has implications for reversing infertility and ensuring conception. Another area for investigation for which the IVFET centers are particularly suited is arrested zygotic development. In producing embryos by in vitro fertilization, it has been noted that certain zygotes stop dividing. The reasons for such arrested zygotic development are unknown. Have these cells died? Can one tell from studying the newly dividing zygotes which ones will be most likely to initiate a successful pregnancy? Failed fertilization in the peri-implantation period in both the natural situation and during the procedures of IVFET is an important area to be understood. Developmental failure in the early stages of embryonic development appears to be a normal event for the human species. Whether this loss results from lethal genetic defects, chromosomal anomalies, biochemical or structural abnormalities, or technical difficulties needs further elucidation. Research that seeks to understand the basis of reproductive failure, and its relationship to hyperstimulation should be encouraged. Coordinated studies utilizing the mass of material and experience from IVFET centers could begin to answer these and other questions. In addition, the experience of centers performing IVFET for farm animals could provide valuable information. - 93 -
The committee applauds the activities of the various professional societies that have issued non-binding statements about the quality of practice of IVF. The American Fertility Society has also provided a voluntary registry for centers. On the animal side, The American Embryo Transfer Society has started to establish some quality measures for commercial bovine embryo transfer. States in general get involved by licensing physicians, hospitals, and clinics, and as yet have not played a dominant role in assuring quality of care. The committee believes that a mechanism is needed to monitor and evaluate clinical practice so that existing information that is relatively easy and inexpensive to collect can be disseminated. This would enable clinicians to build on the broadly based experience of the comnunity and help ensure that patients have access to information about developments in IVFET and to well-informed physicians. The conmittee recommends that a mechanism for multi-centered data collection be «>gfr-jiKi i chart to monitor and human and veterinary prdcLJcftg of medically Assisted conception in order to inrove the safet, effectiveness, and oM1 it of clinical practice. societies A cooerative rou of the relevant professional to fund and initiate ^*" *llection under of an inter-society council cxmxmed of representivtives of each participating organization. Improving Connunications The ICM Workshop on Medically Assisted Conception brought together researchers from basic science, clinical practice, and animal sciences. The resulting interaction was viewed as extremely helpful by investigators from each of these cxnttunitd.es. The coronittee reccninerK^ that a (or multiple mechanisms) be found for fostering contirMed connunication between r^^^^rtrchers in diverse *r*>3s of CTrochy^tive science. Tne initiative should coroe both from SDonsor additional tunities and from the professional societ lividuallv or tt :iety council. - 94 -
