Highlights and Themes
The final part of the conference included summaries of the highlights of each session and discussion of common themes. The field of fetal research carries great promise to alleviate suffering from certain human diseases and to contribute fundamental new knowledge to our understanding of human biology. The political, ethical, and legal controversies elaborated in the first session, however, continue to entangle this field. In the United States, without an Ethics Advisory Board, such controversies resulted in an outright prohibition of most fetal research funded by the federal government. During this period, researchers have obtained support from private sources in the United States, have collaborated with groups outside the United States, and together with these groups and other researchers around the world, have made significant progress. Yet, critical gaps still remain.
The lifting of the U.S. funding moratorium will certainly provide greater resources to investigations of human reproduction, embryogenesis, genetic abnormalities, fetal failure, fetal therapy, and fetal tissue transplantation. Debate continues about whether or not these benefits can be realized only after the reconstitution of an ethics advisory body that can serve as a platform for national discussion and consensus building. While some scientists believe an ethics advisory body should be reconstituted, others do not. Further, it is not yet clear how Congress and the Executive Branch will structure any new ethics advisory body. Thus, although prospects for future federal support are brighter now, additional barriers will continue to exist as a consequence of widely varying state laws. How an ethics advisory body will function and whether or not national guidelines or laws will be established are just two of the many complex questions that await resolution.
All of the speakers in the second session on preembryo research echoed the
theme that progress in this field has been hampered by lack of federal funding in the United States. As a result, much of the U.S. work on technologies related to in vitro fertilization (IVF) has been done in animal models. For example, good predictors of embryologic development have been found in work with oocytes from cows, but this knowledge has not been validated completely with human oocyte research. While the demand has increased for assisted conception technologies, clinics have adapted techniques developed in animals (see Appendix C).
Beyond these difficulties there is a pressing need for greater understanding of developmental failures and abnormalities, particularly genetic abnormalities. It is not known how many of these are normal and occur with equal frequency in natural conception, or how many may be a product of the process of IVF. A related issue is how to predict developmental competency in order to increase the success rates of IVF. Both areas would be served best by research with human oocytes.
Current procedures in IVF carry risks that might be lessened by more research focused on oocyte maturation. The typical procedure now is to give a patient superovulatory or fertility drugs that are implicated in uterine changes and hormone-induced pathologies. Better knowledge of oocyte harvesting, in vitro maturation, and preservation could eliminate the need for fertility drugs in women who require IVF to become pregnant.
A baseline understanding of all the factors involved in human embryo development is still lacking, including cell cycles, secretory products, environmental tolerances, growth factors, differentiation events, and their controls. In vitro embryos produced or donated for research and oocytes derived from aborted fetuses would provide opportunities to shed light on both normal development and the mechanisms of genetic diseases and human cancers. The ability to perform micromanipulations on oocytes and early embryos has allowed the fertilization of oocytes by sperm that could not normally penetrate the zona pellucida. It has also made possible the elegant single-cell assays that are successful in identifying diseases such as cystic fibrosis and Tay-Sachs disease. Thus, preimplantation genetic screening is possible; its use also raises important ethical considerations regarding sex selection, use of screening information and confidentiality, and many other issues.
The third session on fetal research underscored the historic strides that have been made in fetal medicine. A near revolution has occurred in the ability to gain relatively safe access to the fetus from early pregnancy to delivery, opening the way to many avenues of diagnosis and treatment. Techniques we now take for granted, such as amniocentesis and ultrasonography, would not have been possible without the kinds of research that have been restricted in the recent past.
Newer techniques under investigation offer great promise. Embryoscopy is likely to permit earlier diagnosis than other methods. For some fetal conditions, early treatment will be critical. Access to the fetal blood supply through percutaneous umbilical sampling not only can aid in fetal diagnosis, but also can permit
effective interventions for a variety of conditions that threaten the survival of a fetus. Another area needing further attention, however, is methodology for the prenatal detection of certain central nervous system problems, such as cerebral palsy, that arise in seemingly normal babies born of normal pregnancies. New information about nutritional, placental, and environmental factors that impinge on fetal development points to the value of both prenatal and long-term studies in solving birth defects and later health problems. One example from nutritional research is delayed onset of congenital diabetes resulting not from genetic transmission, but rather from unstable glucose levels during fetal life as a consequence of maternal diabetes. Another example comes from studies of the molecular biology of enzymes, which suggest that genetic factors regulating enzyme function may produce important differences from one fetus to another in susceptibility to environmental toxins such as components of cigarette smoke. Postmortem studies are also required in cases of spontaneous abortion to identify the contributions of placental and other pathologies and to diagnose undetected genetic abnormalities that will inevitably compromise a woman's future pregnancies.
In the arena of fetal therapy there have been successes and disappointments. Among the successes is the replacement of fetal blood in Rh disease; work that additionally identified specific risk factors for percutaneous umbilical blood sampling (PUBS) will aid physicians in giving better information to patients considering this procedure. In contrast, attempts at surgical interventions and open fetal surgery have been only partly successful. For example, although placement of shunts to alleviate bladder obstructions in fetuses is frequently successful, later-developing renal disease complicates the usefulness of the procedure in the long-term. Certain other interventions, including the placement of shunts for hydrocephalus, cannot be justified because they alleviate the fluid buildup but do not reverse the severe brain damage. Critical to the evaluation of potential invasive fetal therapies is the degree to which the therapy will increase survival over what would be observed normally and whether or not the therapy results in improved function in the long-term. Nevertheless, research in such areas can lead to better understanding of underlying disease processes and more effective methods for delivering donor cells.
Through both the third and the fourth sessions, the importance of research on stem cells was emphasized. Fetal stem cells, unlike their mature counterparts, lack the cell-surface markers that trigger immune system responses and, especially in the case of neural cells, are multipotent or capable of regeneration and differentiation. Thus, the use of human fetal stem-cell transplants to correct enzymatic deficiencies and neural damage is an active area of research. The research described in the fourth session on fetal tissue transplantation is beginning to provide a foundation for understanding two complex biological systems, the nervous system and the immune system. The major issue for neurobiologists is getting fetal neurons transplanted into patients to perform at sufficient levels to modify disease. The clinical potential of neural transplants is exemplified by
what has already been accomplished with Parkinson's disease. Although optimal results are still in the future, the work to date supports the assertion that we will be able to reduce the immense human costs of certain central nervous system diseases.
Transplant work continues to rely, however, on basic research aimed at defining the precise patterns of neural development, such as the complex patterning of the cerebral cortex that arises from a set of precursor or stem cells controlled by both genetic and environmental mechanisms. Animal experiments have also defined critical time periods during which fetal neurons are most useful for transplant. Such experiments have demonstrated the amazing plasticity of fetal neurons and have shown the potential for manipulation of the local environments of transplant sites to encourage maximal growth of transplanted neurons.
Transplantation research and practice are limited also by adequate sources of stem cells, and for this challenge, basic research may offer great promise. If fetal stem cells are scarce, it makes sense to try to find ways to preserve them in culture until they are needed. For neural stem cells, this is not easily accomplished. One approach has been to ''immortalize'' the stem cells with genetic manipulations, and then to transplant these cells and examine their function. In animal experiments, this technique appears to have produced stable stem-cell lines that, once transplanted, function normally in the host brains.
The primary problem for transplantation in organ systems other than the brain is immune rejection. Current research is seeking the solution to problems of both immune rejection and transplant function largely through studies of hematopoietic stem-cell differentiation in the fetus. After markers were found that identify true hematopoietic stem cells, great strides have been made in experimental bone marrow transplantation because transplantation of a very few fetal stem cells was found to be as successful as the implantation of hundreds of thousands of unsorted cells. The development of the SCID-hu (severe combined immunodeficiency-human model) mouse further expanded this work and it is now possible to study the complete developmental process of a single human stem cell. In addition, because the SCID mouse cannot make lymphocytes, all of the lymphocytes (and many of the other hematopoietic cells including stem cells) harvested from a SCID mouse that has been implanted with human stem cells are human lymphocytes. Thus, the SCID mouse can be used as a "culture environment" to expand the available pool of human stem cells. The SCID-hu mouse also provides an excellent model for studying viral infections. This fact raises the potential for exploring the use of stem cells, which are genetically engineered to block specific pathogenic mechanisms of viral infection, to treat AIDS.
One type of transplantation that is particularly vulnerable to immune rejection is the transplantation of tissue from one species to another, a so-called xenograft. However, if xenografts were more successful, they could offer one solution to the problem of too few organs and tissues being available to meet
existing needs. Research to make xenografts more viable has contributed to the development of techniques to mask antigenic sites on transplanted cells, or to knock them out genetically, thereby disguising the transplanted cells from the host's immune system.
The value of a new technique such as embryoscopy is that it provides access to the fetus before the fetus is immunologically competent. This has the potential of opening up a large array of genetic diseases to fetal therapy.
In summary, then, the conference provided a broad overview of the diversity and direction of current fetal research and a starting point for creating a future research agenda. Examination of the impressive progress that has been made in the face of severe obstacles underscores the need for national guidelines and resolution of the problem of contradictory state regulations. The importance of consensus in the scientific community with regard to ethical considerations surrounding fetal research was a continuing theme throughout the conference. Many participants felt that the scientific community must take a leadership role in partnership with ethicists, policymakers, and others, in helping to frame the debate, develop guidelines, and establish common ground.