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Slide 1. Advances in reproductive genetic technologies offer prospective parents the possibility of influencing the health of the children they bring into the world, or preventing the birth of children with hereditary diseases. Although these technologies have enormous potential for preventing human disease and increasing parental choices, they also raise difficult ethical issues.
Slide 2. One of the predominant ethical questions raised by reproductive genetics research is whether it is morally acceptable for researchers to develop technologies that assist parents in "designing" their babies by selecting or altering an embryo they wish to bring to term.
Consider the following real cases:
Slide 3a. Mrs. Jones is a carrier of Duchenne muscular dystrophy (DMD), a progressive, neuromuscular disease from which boys usually die by their mid-twenties. Mrs. Jones had three brothers who died of DMD.
Slide 3b. DMD is an X-linked disorder, which means that the gene is passed down only from mothers to sons. Mrs. Jones and her husband want to have a child but they also want to make sure they do not have a son with DMD. One morning over coffee, the couple sees the following ad:
Slide 4. "A multi-center clinical trial is
being launched to study the safety and efficacy of a new technology for sex
selection. Based on evidence of success from recent animal studies, this technology
has been approved for study in humans. Anyone interested in selecting the gender
of their next child can participate in this study. Please call..."
What ethical issues does this case raise?
Slide 5. Mrs. Smith is 35 years old and very eager to become
a mother. However, she has had three miscarriages, and her doctors suspect
that a fetal abnormality called aneuploidy is
responsible for her pregnancy losses. She is referred to a multi-center study
designed to assess the use of preimplantation genetic diagnosis (PGD) to screen
out embryos with this genetic abnormality.[1-3]
Slide 6. Several prestigious groups have deliberated on the ethical issues raised by cases such as these. Included are the President's Council on Bioethics[4], the New York State Task Force on Life and the Law[5], the Hastings Center Working Group on Reprogenetics[6], and the Ethics Committee of the American Society of Reproductive Medicine.[7]
Slide 7. The objectives of this module are to sensitize learners to (1) the ethical issues raised by reproductive genetics research, and (2) ways of minimizing possible harms associated with this research. The emphasis in this module is on ethics, not the related legal and regulatory considerations.
Slide 8. Although we are focusing on cases that involve research
rather than clinical practice, it is important to bear in mind that many of
these technologies have not been subjected to rigorous testing, but have been
implemented as "innovative clinical practices". Therefore, the distinction
between reproductive genetics research and clinical applications of reproductive
genetic technologies is particularly fuzzy.[6, 8-9]
Slide 9a. In this module, we first define the range of reproductive genetic technologies and provide a historical context in which to understand the evolution of the ethical issues associated with each.
Slide 9b. Then we focus on the ethical issues raised by recent studies of reproductive genetic technologies and explore the ethical implications of research results.
Slide 10. There are three broad categories of technologies included under the rubric of reproductive genetics (www.dnapolicy.org) : genetic testing technologies used in reproductive decision making, gene transfer technologies intended to modify characteristics of children, and cloning. Of these, only genetic testing technologies are currently available.
Slide 11. Since the 1950s individuals and couples have been undergoing "carrier screening" to determine their risk of having a child with a recessive genetic disease such as Tay-Sachs or sickle cell anemia. Pregnant women have also been undergoing prenatal testing to determine if they were carrying a fetus with a genetic abnormality.[10-12]
In the mid- to late 1990s, genetic testing technology was coupled with artificial reproductive technology to enable genetic screening and testing to take place in vitro, or outside the womb.
At some point in the future it is likely that clinical trials involving genetic modification or cloning of human embryos for reproductive purposes will be proposed. Some have coined the term "reprogenetics" to refer to these two categories of reproductive genetic technologies.
Slide 12. From the mid-1970s to the mid-1990s, reproductive genetic testing took place at the intersection of predictive genetics research in general and research involving pregnant women and fetuses. Because pregnant women and fetuses are considered vulnerable research populations, federal guidelines afford them special protections (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm#subpartb). Since the mid-1990s and into the foreseeable future, reproductive genetics has been taking place at the intersection of predictive genetics research and assisted reproductive technologies which, as yet, are largely unregulated.
Slide 13. There is a wealth of literature on the ethical issues raised by the reproductive genetic testing technologies that have been in widespread use since the 1970s and 1980s.[13-16](See Supplementary Information, Slide 13, a-d.)
Most of this module will be devoted to the ethical issues raised by the second category of reproductive genetics research. Because genetic modification and cloning are technologies of the future, only brief mention will be made of them.
Slide 14a. Most prominent among the newer genetic testing technologies, all of which occur outside the womb, is pre-implantation genetic diagnosis, or PGD. PGD is a very early form of prenatal diagnosis in which embryos are created using assisted reproductive technologies and analyzed for well-defined genetic defects. Only those free of disease are implanted back in the uterus.
Slide 14b. Researchers are also trying to test and screen gametes (ova and sperm) before fertilization. One form of gamete screening is sperm sorting. These technologies enable couples to avoid passing on a genetic disease without having to undergo prenatal diagnosis and abortion.[4, 23]
Slide 15a. These recent advances in reproductive genetic technologies highlight several new ethical concerns which, unlike the more traditional forms of prenatal diagnosis, do not explicitly involve abortion.[4, 6] Rather, in vitro techniques, by definition, rely on assisted reproductive technologies (ART), which raise ethical issues of their own.[4, 24-26]
Slide 15b. In vitro genetic tests also shift the target population from pregnant women and fetuses to "pre-pregnant" women and embryos. This shift raises moral questions about the value placed on human embryos, whether there should be any restrictions on the use of human embryos in research, and what to do with excess embryos that are produced in the course of this research.
Slide 15c. The availability of these techniques also means that, in the near future, they can be used for a broader range of purposes than simply preventing genetic disease. In vitro genetic technologies can be used for genetic enhancement and trait selection.
Let's return to the cases described earlier and analyze the ethical issues raised by such research.
Slide 16a. There are several ethical considerations in any type of reproductive genetics research: (1) the purpose or goal of the research; (2) the population being studied, including the criteria for subject selection and whether subjects are vulnerable in any particular way;
Slide 16b. (3) risks and benefits to participants, including concerns about safety and well-being; (4) informed consent;
Slide 16c. (5) the potential impact of research results on social values, clinical practice, and health policy.
Slide 17a. In the sperm sorting study described earlier in
this module (Case #1), the purpose of the research is to establish a safe and
effective way of selecting the sex of a baby. In the aneuploidy screening case
(Case #2), the purpose is to screen out embryos with a genetic abnormality
that predisposes them to miscarriage once they are implanted. Some might argue
that the development of expensive technologies for sex selection or for preventing
miscarriages is not a morally justifiable way to spend scarce research dollars.
Would it matter if the purpose of the research was to screen embryos for high-risk
diseases? These could be lethal diseases with onset in early childhood or complex
adult-onset diseases.
Slide 17b. What about picking an embryo for its specific traits
or manipulating the embryo's genetic makeup for therapeutic or cosmetic reasons?
In short, it is important to ask when and whether the intention of such research
is ethically defensible.
Slide 18a. What is the population being studied? Are they adults who have not yet conceived, as is true in the cases of sperm sorting and aneuploidy screening described in this module? If so, are they women who have to undergo in vitro fertilization in order to retrieve their eggs? Or are they men, from whom procurement of gametes is far simpler and safer? Would it matter if the prospective participants are carriers of a genetic disease? For example, in the sperm sorting study, research subjects might be women who are carriers of X-linked diseases, like Mrs. Jones, or they might be couples who already have had three daughters and want to "balance" their family by having a son. Arguably, adults who are themselves carriers of a genetic disease might be more vulnerable because of an overriding sense of responsibility for transmission of the disease in their families.
Slide 18b. The population might instead be pregnant women or fetuses, as in a study of prenatal
diagnosis, or they might be human embryos.
Slide 18c. The research might want to target
certain ethnic or racial minorities. For example, there might be a study attempting
to screen embryos for sickle cell disease, which is more prevalent among African-Americans,
or there may be a study using PGD to screen embryos for inherited susceptibility
to adult-onset diseases such as cancer[28], in which certain genetic
mutations have been found to be more prevalent among Ashkenazi Jews.[29-30] If so, special attention will have to be paid to how the group
is selected and recruited, and special precautions will have to be taken to guard
against stigma and discrimination. (See module #1, slide 15 - selecting the group.)
Slide 19. As is true of any research involving human subjects, or any clinical or experimental application of a new technology, the ethical obligations involve an assessment of risks and benefits to the individual, so that risks can be minimized and benefits maximized. In addition, it is essential that the potential benefits of the proposed research outweigh its risks. Risks and benefits can be physical, psychological, social, or economic.
Slide 20a. In the case of research involving pre-implantation genetic diagnosis or sperm sorting, potential physical harms usually relate to the safety and efficacy of the procedures themselves. In addition to the physiological effects of the in vitro fertilization procedure, there are several stages at which an embryo can be harmed. PGD usually involves removing one or two cells from a 6-8 cell embryo. It is not known whether this biopsy affects the development of the child that will be born. There are also concerns about the accuracy and validity of the genetic tests to which the embryo is subjected. If a genetic test yields a false negative result, the embryo that is implanted would carry the disease that the woman intended to prevent, which some see as a harm. Because of the possibility of misdiagnosis, it is often recommended that PGD be confirmed by subsequent chorionic villi sampling (CVS) or amniocentesis.
Slide 20b. Also, as with IVF generally, there is no certainty that a pregnancy will occur after the embryo is implanted (see www.dnapolicy.org). Therefore, at least at the present time, there are significant questions about the efficacy of this technique for the mother and the safety of the technique for the embryo and the developing child.
Slide 21. What about the safety and efficacy of sperm sorting? Obtaining sperm from male subjects is usually physically safe and easy. However, little is known about the safety of sperm sorting for the resultant embryos. Moreover, most techniques for sorting sperm have been unreliable. Although one particular technique, MicroSort, has proven somewhat effective, success rates are lower for conceiving male children than for female children. This means that, by participating in the trial described in Case 1, research subjects like Mrs. Jones and her husband still run a substantial risk of conceiving a male child with muscular dystrophy. They would be more successful undergoing PGD and selecting for implantation only female embryos or male embryos unaffected with DMD. For this reason, recruiting carriers of lethal X-linked diseases into sperm sorting research raises ethical concerns that would need to be addressed in the design of the trial.
Slide 22a. In vitro genetics research also requires an assessment of risks and benefits with regard to well-being, given concerns about psychological and social risks to children and their families. For example, by giving prospective parents the capacity to screen and select for specific genetic traits in their children, will children be more likely to be treated as commodities or as the property of their parents? Will use of these technologies serve the parents' interests at the expense of the child's? Will the attitudes of parents toward their children change from acceptance to judgment and criticism - increasing pressure on children to meet their parents' expectations? For example, if a couple participates in reproductive genetics research for the purpose of preventing the birth of a child with a genetic disease, and the experimental technique fails, will the child that results from this research feel that he or she has "failed" the parents?
Slide 22b. Would the widespread availability of PGD create societal pressure on parents to use the technology as a condition of being "good parents"?
Slide 23. PGD research might also influence psychological and social well-being in positive ways. By preventing the need for abortion, PGD may give enormous benefit and reassurance to families that want to avoid the birth of an affected child but are opposed to abortion.
Slide 24a. These questions about safety, efficacy, and well-being
need to be well described and understood as part of the informed consent process.
Informed consent provides a means of respecting the autonomy of prospective
research participants (see Module #1, slide 20).
Slide 24b. A valid informed consent process
requires that participants 1) possess sufficient decision-making capacity;
2) be given relevant information about the purpose, procedures, risks, and
benefits of the research, as well as the alternatives to participation; 3)
demonstrate an understanding of that information; and 4) are in a position
to make a voluntary decision about participating.
Slide 25a. Although decision-making capacity is rarely a problem
for participants in reproductive genetics research, challenges to information
disclosure and understanding do exist. As is true for informed consent in any
type of genetics research[32], one major concern is that the
information is complex and several questions remain unanswered. For example,
how can couples considering participation in PGD research make truly informed
decisions without knowledge of what will be done with their left-over embryos?
Moreover, the weighing of benefits and risks is greatly influenced by personal
values. For example, some carriers of X-linked diseases may be willing to participate
in sperm sorting research despite the failure rate, while others may prefer
to undergo PGD for sex selection despite the physical risks of the IVF procedure.
Slide 25b. A further concern for the ability to obtain valid informed consent is the potential
proliferation of new reproductive genetic tests among those with limited education
or time for discussion.
Slide 26. Challenges to voluntariness also exist. Prospective research participants may feel pressure from either their own sense of guilt, as in the case of carriers of genetic diseases, or from their partner or other family members who hope that they will participate in research that holds the promise of preventing the birth of a child with a genetic disorder. Ultimately, there may be societal pressure to create the "perfect child," particularly if prospective parents are concerned about how an "abnormal" child would be treated.
Slide 27a. It is also important to consider what impact the results of reproductive genetics research will have on society at large. Who will have access to the technologies? Will access be equitably distributed? Should there be ethical and legal limits to parental power to identify, select, or modify the genetic characteristics of children?
Slide 27b. What effects will the development and use of these technologies have on individuals, family, society, the species?
Slide 27c. How are diverse views on the moral status of the human embryo to be accommodated in reproductive genetics policy?
If these questions are morally vexing, the reproductive genetic technologies of the future will complicate matters further.
Slide 28. These technologies are of two types: gene transfer and cloning.
Slide 29. Gene transfer is sometimes called genetic modification because the technique is intended to modify characteristics of an individual. There are two broad categories of gene transfer: somatic gene transfer and germ-line gene transfer. It is likely that the first round of gene transfer protocols involving embryos or developing fetuses will be restricted to somatic gene transfer for therapeutic purposes, or so-called "gene therapy." Eventually, however, it is likely that somatic gene transfer for purposes of enhancement or germ line gene transfer will be proposed.[4]
Slide 30. The third broad category of reproductive genetics involves cloning, which also is of two types. Therapeutic cloning involves harvesting stem cells from embryos for the purpose of treating disease. One of the questions raised by therapeutic cloning is whether there is a morally relevant difference between creating embryos strictly for research purposes and using embryos left over from IVF procedures.[36]
Reproductive cloning would involve creating an exact replica of another human
being by placing a sample of DNA - available from any cell of the person's body
- in the nucleus of an egg which would then be implanted in the uterus and brought
to term like any other child.[26] Much has been written, both here
and abroad, about the ethics of therapeutic and reproductive cloning.[4, 37-40] Most have endorsed therapeutic cloning and not reproductive cloning,
although cloning for research purposes is taking place. The ethical issues raised
by the prospect of stem cell research and cloning are beyond the scope of this
module.
Slide 31a. However, human embryo research involving somatic cell transfer for therapeutic or enhancement purposes is around the corner. It carries with it many of the same ethical concerns raised by PGD.[4, 41-42] First, there is the potential for physical and psychological harm. Tampering with the human genetic structure might actually have unintended and unpredictable damaging consequences. Second, these technologies might alter the relationship between parent and child and could interfere with the unconditional love that one hopes accompanies parenthood.
Slide 31b. Third, the resulting child may be robbed of the opportunity for an open future. By enabling parents to choose a child's genetic makeup, the parents might perceive that the child's fate is determined, giving the child less freedom to create a life of his or her own making.[43]
Slide 31c. There are potential harms to societal values about equality and access. Eugenic goals could propagate notions about the sorts of people who are desirable and those who are dispensable. This could result in the creation of a genetic "superclass."
Although it remains to be seen whether these potential concerns are realized, they are voiced by a sizable percentage of the general public.[33-34]
Slide 32a. There are, however, some strategies that could be implemented to reduce the potential adverse impact of reproductive genetics research. First, genetic counseling could be included as part of the consent process to improve understanding and informed decision making.
Slide 32b. Second, professional guidelines developed to deal with the diffusion of these technologies into clinical practice should address the possibility of coercion so that potential users of this technology do not feel compelled to do so for fear of subjecting the children who are born the "natural way" to undue stigma.
Slide 32c. Third, effort should be made to ensure equitable access and distribution of technologies shown to be medically valuable. At the very least, this would require third party payers to cover the use of such technologies. However, the rampant problem of health and economic disparities in society has complex roots and is unlikely to be solved by insurance reimbursement alone. Attention also needs to be paid to reducing discrimination against marginalized subgroups of the population, including the disabled.
Slide 32d. This may require government intervention. Relevant government agencies should develop regulations and guidelines on appropriate use of reproductive genetic technologies and restricting discrimination and stigma on the basis of genetic makeup. Development of these guidelines should be informed by public input and debate.[39, 44-45]
Slide 33a. In summary, reproductive genetic technologies may benefit society by enabling future children to live healthier, longer lives and by decreasing the social and economic burden associated with genetic disease.
Slide 33b. However, these technologies and the research needed to develop them raise many ethical concerns. We need to ensure that embryos, future children, prospective parents, and families are protected from harm, and to guard against health and economic disparities.
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