The Hazards of Developmental Gene Modification

Stuart Newman

About the Author Stuart Newman is a Professor of Cell and at Medical College, Valhalla, NY. He directs a federally funded laboratory in , has contributed to several scientific fields, including the theory of biochemical networks, protein folding and assembly, and mechanisms of the development and of biological form, and has written on the cultural background and social implications of biological research. He is a member of the Board of Directors of the Council for Responsible Genetics (Cambridge, MA), a public interest organization concerned with guarding against misuse of biological science and technology.

About the Article Unlike many contributions to this collection which provide critiques of biotechnology, and biotechnology policy in general, Newman focuses on a specific technology – human developmental gene modification, sometimes (though problematically) termed germ-line gene “therapy”. Newman identifies specific dangers for women and for their children where genetic modification of human embryos or fetuses is pursued. This paper also presents an important gender analysis – pointing out that this kind of genetic experimentation is reliant on the powerful desire and expectation that women will do anything for their children. Further, Newman points to the fact that growing pressures to pursue genetic experiments on developing fetuses and embryos are concurrent (and congruent) with the increasing restrictions on women’s ability to gain access to abortion in the . “Opposition to germline engineering, and to other developmental manipulations such as cloning,” he argues, “clearly has natural affinities to ongoing efforts to promote women’s rights.” Introduction It is important to recognize that many Genetic modification of human embryos or hazards of developmental gene fetuses has been proposed for purposes modification are not eliminated if there is of both prevention of disease and no germline transmission. The biology of enhancement of capacity. The the developing individual will still be development of sophisticated in vitro profoundly altered by the manipulation on fertilization methods, preimplantation DNA his/ her genes at an early stage. analysis, improved techniques for gene Laboratory experience shows that transfer, insertion, or conversion, and miscalculations in where genes are embryo implantation procedures, have incorporated into the chromosomes can made such interventions technically lead to extensive perturbation of feasible. development. The disruption of a normal gene by insertion of foreign DNA in a The hazards of genetic modifications to mouse caused lack of eye development, have usually been discussed in lack of development of the semicircular terms of somatic (body cell) modification, canals of the inner ear, and anomalies of in which only non-reproductive tissues are the olfactory epithelium, the tissue that affected, and germline (egg or sperm cell) mediates the sense of smell (2) modification, in which changes to an individual’s DNA can be passed down to Interactions among genes and their future generations. Indeed, this division products are highly integrated, having has led to the general belief that the only, been refined over evolutionary time or main hazard of developmental scales, and often serve to stabilize modification is the potential of developmental pathways (the sequence of transmission of undesired alterations in structural and biochemical changes that the germline. an embryo passes through on the way to becoming a fully-formed organism) and But genetic modification of early embryos – physiological homeostasis (the normal as well as chromosome and nucleus state of dynamical balance among the transfer techniques, including cloning – body’s many processes) (3-5). In addition, present hazards to the developing the biochemical pathways used by the individual, and in certain cases to the organism and its cells to achieve this mother, even if there is no germline stability and balance are overlapping, transmission to future generations. Genetic rather than discrete or separable (6) manipulation of the human embryo, with or ensuring that any developmental genetic without changes to the germline, is referred alteration will have broad, uncontrolled to as developmental modification. ramifications. Through experimental error, unanticipated interactions among different The hazards of germline transmission of versions of the same gene, or poorly DNA modifications are obvious from a understood regulatory mechanisms such reading of the literature on transgenic as imprinting (the parental source of the . For example, germline gene – mother or father – affecting its introduction of an improperly regulated function), developmental genetic normal gene resulted in progeny with manipulation risks altering sensitive unaffected development but enhanced biological equilibria. Disrupting these tumor incidence during adult life (1). Such interactive systems is likely to have effects may not be recognized for a complex and uncertain biological effects, generation or more. including some which only become

2 apparent during the development or assume such risks for the sake of her functioning of specific cells or tissues (7). baby.

Genetic alterations to the germline are Even if the procedure is to be done in vitro possible even where only body (somatic) rather than in utero, the basis for informed cells are targeted for DNA transfer. This consent remains problematic. Here there represents a hazard in many of the more is no existing person whose life is in than 200 somatic gene therapy protocols jeopardy, but rather an embryo in a petri now in use. For example, the viruses that dish that the egg or sperm donor (or are used to transfer DNA in some somatic whoever else may gain the right to its gene therapy protocols were able to infect disposition) would like to have turn out isolated mouse eggs in laboratory studies, genetically differently. No truly informed leading to germline transmission of a consent on the part of the potential transgene in the progeny (8). Although parents is possible, because no reliable removal of the external “shell” of the egg information would be available when it is was a prerequisite for infection of the eggs first attempted. in vitro, these “shells” are absent in the early development of eggs in the ovaries. It is clear that pressures on women will be These experiments thus raise the growing over the coming years to submit possibility that modification of ova may themselves to experimental genetic occur in women undergoing somatic gene procedures, first to prevent disease, and treatments, with unknown and eventually to enhance the appearance, uncontrolled consequences to their performance, and so forth, of her baby. It progeny. is no accident that there are increasing proposals to use newly obtained genetic In protocols that attempt somatic gene information to “improve” embryos by therapy for life-threatening illnesses, manipulating the embryo (11, 12), rather saving the life of the individual patient is a than for prenatal diagnosis. The new value that must be balanced against genetic research has flourished during a developmental risks, including those to the period in which there have been germline of that individual, and indeed, aggressive attempts to reverse abortion such considerations also pertain to rights in the U.S.; consequently, the use of chemotherapy in cancer patients (9). With prenatal diagnosis as a justification for respect to deliberate developmental public funding of the science has been modifications, the story is quite different. taboo. This period has also been one in Not only is the “patient” (embryo or fetus) which patenting and commercialization of and its progeny at risk from the procedure, genes has been possible for the first time but so is the pregnant woman if the genes (10), and eugenic ideologies, after their are to be introduced in utero, since such post-World War II eclipse, have gained genes can also infect her tissues, new respectability among opinion makers including her own germline, and entail (13). other risks to herself, such as cancer. Clearly she is not in a position to give In evaluating proposals to use the new informed consent on behalf of herself, or genetics to remake human biology, the developing embryo, for a procedure women should be aware of hazards to that has not yet been tested in humans, themselves and their offspring from the and which promises no direct benefits to primitive state of the science and her health (the usual justification for technology, as well as the commercial and experimentation on humans). However, reactionary political agendas behind these she will inevitably be under pressure to efforts. Opposition to germline

3 engineering, and to other developmental manipulations such as cloning, is emerging among public interest advocates (14-16). This new movement clearly has natural affinities to ongoing efforts to promote women’s rights.

References

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