1999 Genetics, Law and Society Conference, Saint Paul, Minnesota

Research on Prenatal Human Life
by Carol A. Tauer, Ph.D. 
July 28, 1999

Outline

I. Research In Utero
II. Preimplantation Embryo Research
III. The First Attempt to Fund Embryo Research
IV. The Second Attempt to Fund Embryo Research

A. The work of the Human Embryo Research Panel
B. Problems to be addressed by research

1. Inadequacy of current research methodologies
2. Introduction of new procedures without adequate prior testing
3. Risks and harms involved in current routine practices
4. The possibility of genetic diagnosis combined with IVF

3. The outcome: public policy on embryo research

V. Stem Cell Research

A. The approach of the National Bioethics Advisory Commission
B. The approach of the National Institutes of Health

VI. Cloning Research
VII. A New Question: Is It an Embryo?
VIII. References

Research In Utero

On hearing the phrase, "prenatal human life," most people probably think of the fetus inside the uterus of the pregnant woman. This fetus is accessible to observation, medical treatment, and research only through the medium of the pregnant woman. A number of attempts have been made to provide treatment for medical conditions diagnosed in utero. Most of these treatments are considered experimental at present, and are given only after fully informed consent by the parents.

Severe immunodeficiency of the fetus has been treated through intrauterine injection of bone marrow enriched with blood stem cells, and tests after birth indicate that this treatment is promising (Flake et al., 1996). The correction of spina bifida through intrauterine surgery has been reported (Adzick et al., 1998), and in June 1999 surgeons announced that an apparently healthy infant was born following surgical release in utero of fluid buildup from hydrocephalus (Star Tribune, 1999).

While these sorts of experimental procedures raise many ethical questions, they are not the types of things that most people are concerned about. These medical procedures are intended to save the life or improve the health of a fetus that has a diagnosed medical problem. Even though the procedures may be risky and as yet unproven, they offer a chance for helping a severely compromised fetus. While scientists may have mixed motives for offering these experimental procedures, including the hope of advancing scientific knowledge, surely the prospective parents have only the best interests of their offspring at heart.

The potential for in utero genetic therapy or genetic engineering raises more controversial questions. However, because of the limited success of gene therapy in already-born children and adults, it is unlikely that in utero gene transfer will be attempted in the foreseeable future. In fact, the Recombinant DNA Advisory Committee (RAC) of the National Institutes of Health issued the following consensus statement after its March 1999 meeting:

The RAC continues to explore the issues raised by the potential of in utero gene transfer research. However, at present, the members unanimously agree that it is premature to undertake any human in utero gene transfer experiments (RAC, 1999).

Note that the RAC has adopted the language of "gene transfer" rather than "gene therapy" to avoid misleading potential patients or parents as to the prospects for a successful therapeutic outcome.

Preimplantation Embryo Research

Most of the current controversial issues in research with prenatal human life arise from the study of preimplantation embryos. These embryos result from in vitro fertilization (IVF) or, more rarely, from some other procedure such as a cloning procedure. Their existence can be sustained for several days in the embryology laboratory, or their development may be suspended indefinitely through cryopreservation (freezing). Some of these embryos are intended for transfer to a woman, for other embryos that goal has been ruled out because of their unpromising condition, while many embryos – including most of the frozen ones – have an uncertain future.

The success of in vitro fertilization provides scientists with the opportunity to study a very early stage of developing human life, the first few days after fertilization. Previously this period of human embryological development was not available for direct study, and information had to be extrapolated from study of animal embryos. While much can be learned by analogy with animal models, one can never be sure that human reproduction will operate the same way. For example, thalidomide had been shown to be safe in the animals in which it was tested, but it had disastrous results when used during human pregnancy. Thus human studies are necessary in order to validate the safety as well as the effectiveness of a new procedure or treatment.

Research involving preimplantation embryos raises difficult questions for our citizenry. Many people are committed to the position that the IVF embryo is a full human being from the time of fertilization. These people cannot accept any research on the embryo unless it is intended to improve the potential of that embryo to implant in a uterus and to become a healthy fetus and infant. Other people believe that respect for human life does not require such an absolute position. They would allow certain kinds of research directed toward important medical goals, provided it is carefully regulated.

As of July 1999 it has been impossible to develop a political compromise between these two positions. As a result, all preimplantation embryo research in the United States is conducted under private auspices and with private funding. Congress does not regulate this research in any way, even when it is conducted as part of the treatment of infertile couples. Congress also does not permit the National Institutes of Health (NIH) to conduct, sponsor, or fund any research involving preimplantation human embryos, whatever the purpose.

Ordinarily medical research, especially in academic research centers, is heavily funded by Federal grants originating at NIH. NIH funding counteracts the profit-driven motivation of private corporation research by providing support for basic research, a mechanism for setting priorities among public health needs, and a process for ensuring that medical conditions whose treatment is less profitable are not ignored. NIH involvement also provides regulations and structures for the protection of research subjects, such as the Office of Protection from Research Risks and the required Institutional Review Board approval for research protocols. However, with preimplantation embryo research Congress has decided that, because of the controversial nature of the research, Federal agencies should not be involved in sponsoring, funding, or regulating it.

The First Attempt to Fund Embryo Research

In 1978, coincidentally the year the first IVF baby was born in England, an Ethics Advisory Board (EAB) was established in the United States to study in vitro fertilization. The EAB met for two years and issued a report concluding that research on IVF was ethically acceptable for Federal funding. The Board recommended that research be limited to establishing the safety and effectiveness of IVF, that egg and sperm donors be fully informed and consent to the research, and that embryos not be maintained in the laboratory beyond 14 days’ developmental age (Ethics Advisory Board, 1979).

This report, if implemented, would have permitted Federal funding of IVF research at the time when the procedure was first beginning to be used. However, the EAB report elicited an outpouring of letters opposing any such research, and no research was ever funded. The EAB was dissolved in 1980 and its report was simply shelved.

The Second Attempt to Fund Embryo Research

In the NIH Revitalization Act of 1993, Congress authorized NIH to begin to fund research on infertility and in vitro fertilization. The NIH decided to move cautiously and to delay any funding until ethical guidelines were developed by a 19-member board, the Human Embryo Research Panel (HERP). The guidelines would have to be approved by the Advisory Committee to the Director of NIH, and finally accepted by the Director.

The Panel met once a month from February through June 1994. All meetings were open to the public, each meeting included testimony from members of the public, and tens of thousands of written communications were sent to the Panel. As a member of this Panel, I experienced firsthand the deep distress of infertile couples and persons who had genetic diseases in their families, as they submitted strong and often emotional statements in support of research, and on the other hand, the anguished concern of others who believed that NIH was proposing to sacrifice actual human beings for the sake of scientific knowledge or for the benefit of others.

The Panel carefully considered the arguments presented to it and developed discussions of the moral status of the early embryo and other pertinent ethical issues. It finally enunciated this conclusion:

From the perspective of public policy, sufficient arguments exist to support the permissibility of certain areas of research involving the preimplantation embryo within a framework of stringent guidelines (HERP, 1994, p. x).

The Panel provided three rationales to support its conclusion, noting that Panel members differed in the relative weights they attached to the three:

• The promise of human benefit from research is significant, carrying great potential benefit to infertile couples, families with genetic conditions, and individuals and families in need of effective therapies for a variety of diseases.
• Although the preimplantation embryo warrants serious moral consideration as a developing form of human life, it does not have the same moral status as an infant or child. This is because of the absence of developmental individuation in the preimplantation embryo, the lack of even the possibility of sentience and most other qualities considered relevant to the moral status of persons, and the very high rate of natural mortality at this stage.
• In the continued absence of Federal funding and regulation in this area, preimplantation human embryo research that has been and is being conducted without Federal funding and regulation would continue, without consistent ethical and scientific review. It is in the public interest that the availability of Federal funding and regulation should provide consistent ethical and scientific review for this area of research (HERP, 1994, p. x).

Problems to be Addressed by Research

Panel members identified serious problems in the proliferation of assisted reproductive technologies that called for programs of basic and clinic research. Discussion of some of these problems follows.

Inadequacy of current research methodologies. Embryologist Jonathan Van Blerkom characterized the state of science in this area as dismal (Rensberger, 1994). Because of flawed experimental designs, too small sample sizes, lack of control groups, and absence of peer review, results were often confusing and contradictory. As a result, IVF and other reproductive technologies continued to be inefficient (a low success rate), unnecessarily costly, and often associated with health risks to women and prospective children.

Introduction of new procedures in the clinical setting without adequate prior testing. A number of examples were cited. The technique of intracytoplasmic sperm injection (ICSI), where an individual sperm is injected into an egg, was introduced and widely propagated before any data were available as to its safety (White and McClure, 1998). The freezing of unfertilized eggs was introduced into clinical practice while some scientists warned of the risks of chromosomal abnormalities. Fertilization of such eggs through IVF resulted in documented genetic and developmental problems (Trounson, 1990). Zona removal ("assisted hatching") for fertilized eggs that appear inadequate to hatch naturally was introduced into practice although the level of risk was unknown. This procedure may possibly expose the unprotected fertilized egg to contamination through exposure to elements in the culture medium (Van Blerkom, 1994).

Risks and harms involved in current routine practices. Women preparing for assisted reproduction are usually given high doses of hormones to stimulate maturation of eggs in the ovarian follicles. Women who donate eggs to infertile couples also undergo hormonal stimulation in order to provide large numbers of mature eggs that are ready for fertilization. These practices impose short-term risks due to excessive hormonal stimulation. Moreover, recent studies suggest possible long-term risks, including a significantly increased probability of ovarian cancer in women who are exposed to large doses of fertility drugs, particularly if repeated over a number of cycles.

At present scientists do not have reliable measures as to whether a particular woman’s eggs are capable of developing after fertilization, nor tests to determine which fertilized eggs are capable of developing into fetuses. Assisted reproduction is largely based on trial-and-error attempts, and some women may be undergoing strenuous and risky procedures that have no hope of achieving pregnancy for them (Van Blerkom, 1994).

A huge increase in multiple-gestation pregnancies has occurred as a result of infertility treatment. In 1995, 37 percent of births to women using assisted reproductive technologies were multiple births, compared with 2 percent in the general population (Centers for Disease Control, 1999). Given the inefficiency of IVF and the fact that only a small percentage of transferred embryos usually implant in the uterus, the decision as to how many embryos to transfer involves a compromise between risk and effectiveness. But if three or more embryos actually implant, the pregnancy is high-risk by definition. Premature birth is much more likely, with an associated increase in the probability of infant morbidity and mortality. The director of a major IVF clinic states, "The major health risk involved in infertility treatment is premature birth."

A couple with a triplet or higher pregnancy is often presented the option of "selective reduction," whereby one or more fetuses are terminated prenatally for the sake of the others. This option requires the couple to make an excruciating moral choice because of a problem caused by treatment aimed at helping them get pregnant.

The possibility of genetic diagnosis combined with IVF. Advances in genetics are making it possible to diagnose an increasing number of genetic diseases within the first few days after in vitro fertilization. When the preimplantation embryo is at approximately the 8-cell stage, one or two cells may be removed without damage to the remaining embryo. Karyotyping these cells provides a diagnosis of the genetic health or normality of the embryo from which they were taken. Thus if a couple at genetic risk has had a number of eggs fertilized, embryos that are healthy could be distinguished from those that are not. A couple who would not choose to abort an established pregnancy may feel differently about not transferring genetically compromised embryos to the woman two or three days after fertilization.

The Outcome: Public Policy on Embryo Research

The Human Embryo Research Panel submitted its report in September 1994, and on December 2 the Advisory Committee to the Director of NIH approved it. That same day, without previous warning, President Clinton issued a statement:

I do not believe that Federal funds should be used to support the creation of human embryos for research purposes, and I have directed that NIH not allocate any resources for such research.

While this prohibition eliminated some types of research that the Panel considered important, for example, study of the laboratory maturation of oocytes and the freezing of oocytes prior to fertilization, it left most lines of research open. However, in its next appropriations bill (Fiscal Year 1996) Congress reversed its previous stance and once again prohibited NIH from funding any research that might involve damaging or destroying human embryos.

Stem Cell Research

Besides research related to infertility and assisted reproduction, the report of the Human Embryo Research Panel identified the development of embryonic stem cells as one of the most important potential outcomes of embryo research. The Panel described research on mouse stem cells developed from the inner cell mass of the mouse blastocyst, cells that had been coaxed to continue growing and dividing in their undifferentiated state. But a further step had also been taken. These cells had been induced to differentiate into specific types of cells and tissues: skin, blood, cartilage, even neural and heart muscle cells. If similar steps could be taken with cells from human embryos, eventually these human stem cells might provide tissues for a wide variety of therapeutic purposes.

Some critics of the 1994 report argued that its descriptions of potential benefits from embryo research were purely hypothetical and that the report offered no evidence of success. However, in November 1998 researchers announced that they had successfully developed stem cells from human blastocysts and had coaxed them to grow into immortal cell lines. Also in November 1998 a different group of researchers announced that they had developed human stem cells from a different source, the germ cells (precursors of sperm and eggs) of aborted fetuses. Both research projects were funded with private support from the Geron Corporation of Menlo Park, California.

Given the ban on Federal funding of human embryo research, which does not include research using tissue from aborted fetuses, the development of stem cell lines from human blastocysts has caused the most controversy. Scientists and advocates for persons suffering from various diseases point to therapeutic breakthroughs that might be possible. Sufferers from Alzheimer’s and Parkinson’s diseases might be benefited through neural tissue, diabetics through pancreatic cells, heart attack victims through heart muscle tissue. More than 20 advocacy organizations have formed an umbrella lobbying group under the title CURE, the Coalition for Urgent Research, to promote Federal funding of stem cell research.

Opponents argue that Congress has already prohibited Federal funding of research that involves the destruction of embryos, and embryonic stem cells could not be obtained without disaggregating embryos at the blastocyst stage. These opponents maintain that no good end could justify sacrificing living human embryos since, even at 4 to 5 days’ development, they are a form of human life or actual human beings.

Two government bodies have taken up the discussion: the National Bioethics Advisory Commission (NBAC), which was directed to do so by President Clinton, and the National Institutes of Health. The NBAC completed its report in July 1999 after nine months of deliberation and consultation. It found significant differences of opinion among those it consulted, including representative of religious groups and faith traditions. NBAC finally determined that arguments in favor of stem cell research leading to therapies that might save lives and improve the quality of life for chronic sufferers outweighed concerns about the moral status of the blastocysts that would provide the cells. NBAC reiterated the requirement that only embryos donated by couples who had completed their infertility treatment could be used in research; no embryos could be created specifically for research purposes.

In order to implement this conclusion, NBAC recommended that Congress rescind in part its prohibition of Federal funding for embryo research. It asked Congress to allow Federally-funded scientists to use human embryos to develop stem cell lines as well as to work with those cell lines to develop various kinds of therapeutically useful tissues.

NIH took a different approach by requesting its legal counsel to determine whether work with already established cell lines would violate the Congressional prohibition of funding for embryo research. The agency felt that since embryos had already been disaggregated and the cell lines now existed independently of the original embryos, then research with the cells was not "embryo research" and could be permitted. In January 1999 NIH’s legal counsel affirmed this position in a legal opinion that the stem cell lines were neither "embryos" nor "organisms" in the language of the Congressional ban.

As a result NIH moved ahead to form a Working Group to develop guidelines for NIH-funded research on stem cells, whether the cells originated from embryos or from aborted fetal tissue. In both cases the stem cell researchers would be required to keep themselves several steps removed from contact with the patients who donated the embryos or fetal tissue. The treatment of donor patients could not be affected in any way by the goals of research, and patients could be asked to donate embryos or tissues only after their own treatment goals had been fully accomplished.

In a typical case, a couple undergoing in vitro fertilization as part of infertility treatment might have 10 to 20 eggs fertilized. Since it would be imprudent to return more than two or three embryos to the woman for implantation, the rest would customarily be frozen and stored, keeping them available for future attempts to establish pregnancy. But often the couple would achieve their goals and complete their family while some embryos remained – or they might decide to adopt or simply to stop treatment. At this time they would be asked what they wanted done with the remaining embryos. In the United States, a surprisingly small percentage (only 5 percent at some clinics) typically choose to donate embryos to other couples. Most couples prefer either to discard surplus embryos, donate them for research, or simply leave them frozen indefinitely. (British law does not permit the latter, but currently there are no legal restrictions in the U.S.)

Regardless of the recommendations of NBAC or of NIH, Congressional action will determine whether any Federal funding for stem cell research will be permitted. In order to follow the NBAC recommendation, Congress would have to rescind in part its current prohibition on embryo research, thus becoming more permissive. But it could move in the opposite direction and expand its current prohibition to cover research that involves cells originally derived through the destruction of embryos, no matter how far in the past that derivation took place. The latter course would make it impossible for NIH-funded scientists to work with already existing stem cell lines, and would significantly slow progress in this area as well as abdicating control of research policy to an unregulated private sector.

Cloning Research

Before undertaking its investigation of stem cell research, the National Bioethics Advisory Commission had examined the topic of cloning and issued a detail report (NBAC, 1997). The cloning of Dolly the sheep had surprised scientists who generally had doubted that it was possible to clone an offspring from a cell of an adult mammal. While NBAC reviewed a wide range of ethical and religious views on cloning, its report focused on the lack of knowledge regarding the safety of the cloning process. Given the absence of evidence that cloning can be done efficiently and without harms to prospective offspring, NBAC asserted that it would be morally unacceptable to attempt to clone a human child at this time. Not only should Federal funding be prohibited, but the private sector should also avoid such attempts, either through voluntary agreements, or preferably by legal prohibition.

The creation of a child through cloning is characterized as "reproductive cloning." A different application of the cloning procedure is called "therapeutic cloning." In this application a cell of a person who has a medical condition could be fused with an egg cell that has had its nucleus removed in a procedure similar to that used to clone Dolly. But rather than allowing this cloned egg to develop into a fetus, it would be permitted to develop only to the blastocyst stage. At this stage the cells of the inner cell mass would be prevented from beginning normal differentiation and would be coaxed into becoming immortal stem cell lines. These cells might then be induced to differentiate into the type of tissue needed for treatment of the person who provided the original cell. Because the therapeutic cells would be a genetically perfect match for the patient, the problem of immune rejection of someone else's DNA would not arise.

"Therapeutic cloning" thus combines a cloning procedure with stem cell research. Is it embryo research? Some people would say it is not, since an egg was never fertilized. Others would say it is, since the cloned egg has the full human genetic complement of DNA and has the potential to develop to the blastocyst stage and perhaps further.

A New Question: Is It an Embryo?

Both in philosophic discussions and for public policy purposes, the question of what constitutes an embryo is under debate. In previous debates, people have argued about the moral status of the early embryo. Some have considered it a full human being, while others have claimed that it was at most a potential human life. Now there is a new type of disagreement about whether certain kinds of entities should or should not be considered embryos.

Question A: Is the union of an unfertilized enucleated egg with a somatic (body) cell an embryo? In other words, does the process of "therapeutic cloning" involve producing embryos?

Question B: Are stem cells derived from embryos equivalent to embryos? Stem cells apparently have the ability to differentiate into the various tissues and organs of the human body. However, they do not have the potential to develop into a fetus since the cells of the trophoblast, the outer sphere of the blastocyst, are missing. The trophoblast cells not only give rise to the embryonic portion of the placenta, but they are essential for organizing the differentiating cells of the inner cell mass into a fetal body (Hogan, 1999).

Embryonic stem cells are described as "pluripotent," able to become many specific kinds of cells and tissues, but they are not "totipotent," able to give rise to an entire fetus. Unless they are combined with an existing blastocyst, pluripotential stem cells cannot develop into an organized embryo and fetus (Hogan, 1999).

I would argue that the entities described in Question A are embryos, but that the stem cells described in Question B are not. These questions may appear somewhat abstruse, but interest in them is not likely to wane since they are closely connected to deep moral and religious commitments held by our citizens.

References

Adzick, N. Scott et al. Successful fetal surgery for spina bifida. Lancet 352 (November 21, 1998): 1675-76.

Centers for Disease Control. What percentage of clinical pregnancies result in a live birth or multiple births? http://www.cdc.gov/nccdphp/drh/arts/fig8b.htm, July 15, 1999.

Ethics Advisory Board, DHEW. Report and conclusions: HEW support of research involving human in vitro fertilization and embryo transfer. Federal Register 44 (1979): 35033-58.

Fetal brain operation is a success. Star Tribune (Minneapolis), June 19, 1999.

Flake, Alan W. et al. Treatment of X-linked severe combined immunodeficiency by in utero transplantation of paternal bone marrow. New England Journal of Medicine 335 (1996): 1806-10.

Human Embryo Research Panel. Report of the Human Embryo Research Panel, Vol. I. Bethesda, MD: National Institutes of Health, 1994.

Hogan, Brigid L.M. Statement to the National Bioethics Advisory Commission. Meeting transcript, NBAC, February 3, 1999.

National Bioethics Advisory Commission. Cloning Human Beings: Report and Recommendations of the National Bioethics Advisory Commission. Rockville, MD: NBAC, 1997.

Recombinant DNA Advisory Committee (RAC). Meeting summary. Bethesda, MD: National Institutes of Health, March 11-12, 1999.

Rensberger, Boyce. NIH panel looks at ethics, standards for human embryo research. Washington Post, February 7, 1994.

Trounson, Alan. Why do research on human pre-embryos? In Peter Singer et al. (eds.), Embryo Experimentation: Ethical, Legal and Social Issues, pp. 14-25. Cambridge: Cambridge University Press, 1990.

Van Blerkom, Jonathan. The history, current status and future directions of research involving human embryos. In Papers Commissioned by the Human Embryo Research Panel, pp. 1-25. Bethesda, MD: National Institutes of Health, 1994.

White, Gladys B. and McClure, Michael E. Introduction: Introducing innovation into practice: Technical and ethical analyses of PGD and ICSI technologies. Journal of Law, Medicine & Ethics 26 (1998): 5-6.

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