Hostname: page-component-848d4c4894-nr4z6 Total loading time: 0 Render date: 2024-06-04T21:30:53.526Z Has data issue: false hasContentIssue false

Germ-line Gene Therapy: A New Stage of Debate

Published online by Cambridge University Press:  29 April 2021

Extract

Ethical debate on human germ-line gene therapy is in a new stage. After an era when only individual convictions could be examined, technology is on a threshold of real possibilities. Germ-line gene therapy can conceivably be carried out in either of two practical ways: 1) insertion of a gene into a pre-embryo, which is the subject of this paper, or 2) insertion of a gene into the germ cells of an individual.

Transgenic animal research and pre-implantation embryo diagnosis have implications for human embryonic germ-line experiments to correct single gene disorders. When would such experiments be feasible and ethically acceptable? If further animal research supports it, we argue for a moral obligation to learn if human germ-line experiments are feasible and safe to attempt. The obligation is grounded in several social-ethical principles that lead society and researchers to set gods for studies that promisc to relieve and to prevent human suffering and premature death. These principles also shape the practices and restrictions of biomedical research.

Type
Article
Copyright
Copyright © American Society of Law, Medicine and Ethics 1992

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Council for Science and Society. Human Procreation (Oxford: Oxford University Press, 1984), 7.Google Scholar
Kass, Leon, “New Beginnings in Life,” in Hamilton, M., ed., The New Genetics and the Future of Man (Grand Rapids, Eerdmans, 1972), 61.Google Scholar
Ramsey, Paul, “Genetic Therapy. A Theologian's Response,” in Hamilton, supra note 2, at 175.Google Scholar
Fletcher, Joseph, The Ethics of Genetic Control (Garden City: Doubleday Anchor, 1974), 1415.Google Scholar
Capron, Alexander M., “Unsplicing the Gordian Knot: Legal and Ethical Issues in the New Genetics,” in Milunsky, A. and Annas, G.J., eds. Genetics and the Law III (New York: Plenum, 1985), 24.Google Scholar
President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Splicing Life (Washington, DC: US Government Printing Office, 1982).Google Scholar
Norman, Colin, “Clergymen Urge Ban on Altering Germ-line Cells,” Science 220 (1983), 1360–61; Capron, Alexander M., “Don't Ban Genetic Engineering,” Washington Post, June 26, 1983, p. A-3.CrossRefGoogle Scholar
Capron, Alexander M., “Historical Perspective. The Impact of the Report, Spiking Life,” Human Gene Therapy, 1 (Spring, 1990:6971.Google Scholar
Fletcher, John C., “Moral Problems and Ethical Issues in Prospective Human Gene Therapy,” Virginia Law Review 69 (1983), 515–46; Capron, Alexander M., “Human Genetic Engineering,” Technology in Society 6 (1984), 23-35; Glover, Jonathan, What Sort of People Should There Be? (Harmondsworth: Penguin, 1984); Walters, LeRoy, “The Ethics of Human Gene Therapy,” Nature 320 (1986), 225–27; Anderson, W. French, “Human Gene Therapy: Scientific and Ethical Considerations,” Journal of Medicine and Philosophy 10(1985), 275–291.Google Scholar
Regulatory Issues. “The Revised ‘Points to Consider’ Document,” Human Gene Therapy 1 (1990), 95.Google Scholar
Sixth Report of the Interim Licensing Authority for Human In Vitro Fertilisation and Embryology, “Guidelines for both Clinical and Research Applications of Human In Vitro Fertilisation,” (ILA Secretariat, Clements House, Gresham St., London EC2V 7JE, 1991), 65.Google Scholar
Parliamentary Assembly of the Council of Europe, Fortieth Ordinary Session, “Recommendation 1100 (1989), On the Use of Human Embryos and foetuses in Scientific Research,” 67000 Strausbourg, France.Google Scholar
Parliamentary Assembly of the Council of Europe, Thirty-Third Ordinary Session, “Recommendation 934 (1982), On Genetic Engineering,” 67000 Strausbourg, France.Google Scholar
Parliamentary Assembly of the Council of Europe, Thirty-Eighth Ordinary Session, “Recommendation 1046 (1986), “On the Use of Human Embryos and Foetuses for Diagnostic, Therapeutic, Scientific, Industrial, and Commercial Purposes,” 67000 Strausbourg, France.Google Scholar
Official Statements, “German Law Protects Embryos.” Bulletin of Medical Ethics, No. 64, (Dec., 1990), 911; David Kirk, “West Germany moving to make IVF research a crime,” Science 241 (1988) 406; Hans-Martin Sass, “Biomedical Ethics in the Federal Republic of Germany,” Theoretical Medicine 9 (1988), 291–97.Google Scholar
Juengst, Eric T., “Germ-line Gene Therapy: Back to Basics,” The Journal of Medicine and Philosophy, 16 (1991), 587–92.Google Scholar
Fowler, Gregory, Juengst, Eric T. and Zimmerman, Burke K., “Germ-line Gene Therapy and the Clinical Ethos of Medical Genetics,” Theoretical Medicine 10 (1989), 151165; Tauer, Carol A., “Does Human Gene Therapy Raise New Ethical Questions?” Human Gene Therapy 1 (1990), 411–418; John Maddox, “The Case for the Human Genome,” Nature 352 (1991), 11-14; a current journal issue, edited by Juengst, Eric T., supra note 20, contains these articles: Burke K. Zimmerman, “Human Germ-line Therapy: The Case for its Development and Use,” 593-612; Nolan, Kathleen, “Commentary: How Do We Think About the Ethics of Human Germ-line Genetic Therapy,” 613-619; Lappe, Marc, “Ethical Issues in Manipulating the Human Germ-line,” 621-639; Mosely, Ray, “Commentary: Maintaining the Somatic/Germ-line Distinction: Some Ethical Drawbacks,” 641–647; Mauron, Alex and Thevoz, Jean-Marie, “Germ-line Engineering: A Few European Voices,” 648–665; Berger, Edward M. and Gert, Bernard M., “Genetic Disorders and the Ethical Status of Germ-line Gene Therapy,” 667-683.Google Scholar
Walters, LeRoy, “Human Gene Therapy: Ethics and Public Policy,” Human Gene Therapy, 1 (1991), 115–22. This article takes on importance because the Human Gene Therapy Subcommittee of the Senate has decided to make a special study of prospects for and issues in human germ-line gene therapy.Google Scholar
Stone, Richard, “Germ Cell Gene Panel,” Science, 253 (1991) August 23, 841.Google Scholar
Bankowski, Zbigniew, Capron, Alexander M., eds., Genetics, Ethics, and Human Values. Proceedings of the XXIVth CIOMS Round Table Conference (Geneva, CIOMS, 1991)Google Scholar
Gregorius, Paul, “Ethical Reflections on Human Gene Therapy,” in Bankowski, Z., Capron, A.M., eds., Genetics, Ethics, and Human Values. Proceedings of the XXIVth CIOMS Round Table Conference (Geneva, CIOMS, 1991), 143–53.Google Scholar
Anderson, W. French and Fletcher, John C., “Gene Therapy in Human Beings: When Is It Ethical to Begin?” New England Journal of Medicine 303 (Nov. 1980):1293–97.Google Scholar
Anderson, W. French, supra note 9, 285–86.Google Scholar
Culver, Kenneth W., Anderson, W. French and Blaese, R. Michael, “Lymphocyte Gene Therapy,” Human Gene Therapy 2 (1991), 107–9.Google Scholar
Anderson, W. French, “September 14, 1990: The Beginning,” Human Gene Therapy 1 (1990), 371–2.Google Scholar
Zimmerman, , supra note 17, 600–1.Google Scholar
The term pre-implantation embryo describes the earliest stage of the fertilized ovum prior to implantation. One could also use “pre-embryo” following the United Kingdom's Interim Licensing Authority cited below, or two other important sources: McLaren, Anne, “Prelude to Embryogenesis,” in Ciba Foundation, Embryo Research: Yes or No? (London: Tavistock Publications, 1986), 517; Ethics Committee of the American Fertility Society, “Ethical Considerations of the New Reproductive Technologies,” Fertility and Sterility, 46 (1986), Supplement, 26S31S. Until implantation, which occurs from six to 13 days after fertilization, it is unknown how many embryos will develop from a pre-embryo. For an excellent discussion of the issues in this area, see John A. Robertson, “Ethical and Legal Issues in Pre-Implantation Genetic Screening, Fertility and Sterility 57 (1992), 1–11.Google Scholar
Handyside, Alan H., Pattinson, J. K., Penketh, Richard J.A., et al., “Biopsy of Human Pre-implantation Embryos sexed by Y-specific DNA Amplification,” Lancet 1 (1989), 347–49.Google Scholar
Handyside, Alan H., Kontogianni, E.H., Hardy, K., et al., “Pregnancies From Biopsied Human Pre-implantation Embryos Sexed by Y-specific DNA Amplification,” Nature 344 (1990), 768–70.Google Scholar
Sixth Report, supra, note 11, p. 40.Google Scholar
Coutelle, Charles, Williams, Carolyn, Handyside, Alan H., et al., “Genetic Diagnosis of DNA from Single Human Oocytes—A Model for Pre-implantation Diagnosis of Cystic Fibrosis,” British Medical Journal 299 (1989), 2224.Google Scholar
Lesko, J., Snabes, M., Handyside, A., Hughes, M., “Amplification of the Cystic Fibrosis Delta 508 Mutation from Single Cells: Application Toward Genetic Diagnosis of the Preimplantation Embryo,” Proceedings of the 8th International Congress of Human Genetics, Abstract 1210, The American Journal of Human Genetics 49 (No. 4, October 1991), Supplement, 223; Handyside reported the single pregnancy in a session on reproductive genetics, October 8, 1991.Google Scholar
Monk, Marilyn and Holding, G., “Amplification of a Beta Haemoglobin Sequence in Individual Human Oocytes and Polar Bodies,” Lancet 335 (1990), 985–88.Google Scholar
Gladwell, Malcolm, “Gene-Defect Tests Planned,” Washington Post, December 31, 1990, p. A-1.Google Scholar
Cook-Deegan, Robert M., “Human Gene Therapy and Congress,” Human Gene Therapy 1 (1990), 163–70.Google Scholar
Zimmerman, , supra note 17, p. 595.Google Scholar
Zimmerman, , supra note 17, 608; also, personal communication from Golbus, Mitchell S. M.D., June 28, 1991.Google Scholar
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, The Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects of Research, April 18, 1979, (Washington, DC: US Government Printing Office: 1986 181296:41238).Google Scholar
Beauchamp, Tom L., Childress, James F., Principles of Biomedical Ethics, 3rd ed. (New York: Oxford University Press, 1989), 120193.Google Scholar
The Belmont Report discussed three tasks in the protection of human subjects: informed consent, risk-benefit assessment, and selection of subjects. We have added two new tasks, selection of goals for research and protection of the freedom of the pursuit of important biomedical knowledge by research. The Belmont Report focused primarily on protection of human subjects and its drafters assumed that freedom of research was not a major issue. We believe that the by-products of the conflict on abortion, especially in the federal sector, include policies, practices, and moratoria that unfairly restrict the pursuit of important biomedical knowledge.Google Scholar
There is much evidence that genetic abortions cause serious emotional trauma to both parents. More research freedom will increase a trend in earlier prenatal diagnosis that has already reduced: 1) complications of second trimester abortion to the pregnant woman, and 2) emotional harms of mid- trimester genetic abortion. Black's study documented a need for support and caring following abortion or pregnancy loss after first trimester chorionic villus sampling. In prenatal diagnosis, women who suffer pregnancy loss at any time benefit from intervention and supportive care by clinicians and companionship of persons close to them; Bernard Adler, Theodore Kushnick, “Genetic Counseling in Prenatally Diagnosed Trisomy 18 and 21: Psychological Aspects,” Pediatrics 69 (1982):94–101; Blumberg, Bruce D., Golbus, Mitchell S. and Hanson, Karl H., “The Psychological Sequelae of Abortion Performed for a Genetic Indication,” American Journal of Obstetrics and Gynecology, 122 (1975):799802; Donnai, Patricia, Charles, Nora, Harris, Rodney, “Attitudes of Patients After ‘Genetic’ Termination of Pregnancy.” Br Med J 1981;282:621–23; Leschot, N.J., Verjaal, M., Treffers, P.E., “Therapeutic Abortion on Genetic Indications. A Detailed Follow-up Study of 20 Patients” in Verjaal, M., Leschot, J.H. eds. On Prenatal Diagnosis. (Amsterdam: Rodopi, 1982):85-110; Jones, O.W., Penn, Nolan E., Schucter, Stephen, et al., “Parental Response to Mid-Trimester Therapeutic Abortion Following Amniocentesis,” Prenatal Diagnosis, 4 (1984):249–55; Marteau, T.M., Johnston, M., Shaw, R.W., et al., “The Impact of Prenatal Screening and Diagnostic Testing upon the Cognitions, Emotions, and Behavior of Pregnant Women,” Journal of Psychosomatic Research, 33 (1989): 7–21; Black, Rita B., “A 1 and 6 Month Follow-up of Prenatal Diagnosis Patients Who Lost Pregnancies,” Prenatal Diagnosis, 9 (1989):795–99; Van Mourik, White M.C.A., Connor, H.M., Ferguson-Smith, Malcomb A., “Patient Care before and after Termination of Pregnancy for Neural Tube Defects,” Prenatal Diagnosis, 10 (1990):497-502; Elder, S.H., Laurence, K.M., “The Impact of Supportive Intervention after Second Trimester Termination of Pregnancy for Fetal Abnormality,” Prenatal Diagnosis, 11 (1991):47-51.CrossRefGoogle Scholar
Galjaard, Hans, “Early Diagnosis and Prevention of Genetic Disease,” in Galjaard, H., ed., Aspects of Genetic Disease, (Basel: Karger, 1984), 115.Google Scholar
Brent, Robert L., “The Magnitude of the Problem of Congenital Malformations,” in Prevention of Physical and Mental Congenital Defects. Part A: The Scope of the Problem, (New York, Alan R. Liss, 1985), 55.Google Scholar
Hall, J.M., et al., “Linkage of Early-Onset Familial Breast Cancer to Chromosome 17q21,” Science 250 (1990), 1684–89; Joan Marx, “Genetic Defect Identified in Rare Cancer Syndrome,” Science 250 (1990), 1209; Malkin, D., et al., “Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms,” Science 250 (1990), 1233–38.CrossRefGoogle Scholar
Warburton, Dorothy, “Reproductive Loss: How Much is Preventable?” New England Journal of Medicine 316 (1987), 158–60; Harlap, S., Shiono, P.H. and Ramcharan, S., “A Life Table of Spontaneous Abortions and the Effects of Age, Parity, and Other Variables,” in Porter, I.H. and Hook, E.B., eds., Embryonic and Fetal Death, (New York, Academic Press, 1980), 148.Google Scholar
Krimsky, Sheldon, “Human Gene Therapy: Must We Know Where to Stop Before We Start?” Human Gene Therapy 1 (1990), 171–73; Lappe, supra note 17, 637; Agius, E., “Germ-line Cells — Our Responsibilities for Future Generations,” Concilium 223 (1989), 127–38; Ruh, Hans, “Ethische Aspekte der Biologie,” Bulletin des Medicins Suisses 70 (1989), 2080–83.Google Scholar
Anderson, W. French, “Human Gene Therapy: Why Draw A Line,” The Journal of Medicine and Philosophy 14 (1989), 681–93.Google Scholar
Krimsky, , supra note 46, 173.Google Scholar
Culver, Charles C., Gert, Bernard M., Philosophy in Medicine (New York, Oxford University Press, 1982).Google Scholar
Berger, and Gert, , supra note 17, 671–74.Google Scholar
Fletcher, John C., “Controversies in Research Ethics Affecting the Future of Human Gene Therapy,” Human Gene Therapy 1 (1990), 307324.Google Scholar
Gordon, Jon W., “Transgenic Animals,” International Review of Cytology, 115 (1989), 171229; Church, Robert B., ed., Transgenic Models in Medicine and Agriculture, (New York, Wiley-Liss, 1990).Google Scholar
Palmiter, Richard D., Brinster, Ralph L., “Germ-line Transformation of Mice,” Annual Review of Genetics 20 (1986), 465–99.Google Scholar
van der Putten, Herman, Botteri, Florence M., Miller, A. Dusty, et al., “Efficient Insertion of Genes Into the Mouse Germ Line Via Retroviral Vectors.” Proceedings of the National Academy of Sciences USA 82 (1985), 6148–52.Google Scholar
Kuehn, Michael R., Bradley, Allan, Robertson, Elizabeth J., et al., “A Potential Animal Model for Lesch-Nyhan Syndrome Through Introduction of HPRT Mutations into Mice,” Nature 326 (1987), 295–98.CrossRefGoogle Scholar
Hammer, Robert E., Palmiter, Richard D., Brinster, Ralph L., “Partial Correction of Murine Hereditary Growth Disorder by Germ-line Incorporation of a New Gene,” Nature 311 (1984), 65–7.CrossRefGoogle Scholar
Constantini, Frank, Chada, Kiran, Magram, Jeanne, “Correction of Murine Beta-thalassemia by Gene Transfer Into the Germ Line,” Science 233 (1986), 1192–94.Google Scholar
Readhead, Carol, Popko, Brian Takahashi, Naoki, et al., “Expression of a Myelin Basic Protein Gene in Transgenic Shiverer Mice: Correction of the Dysmyelinating Phenotype,” Cell 48 (1987), 703–12.Google Scholar
Mason, Anthony J., Pitts, Sharon L., Nikolics, Karoly, et al., “The Hypogonadal Mouse: Reproductive Functions Restored by Gene Therapy,” Science 234 (1986), 1372–78.Google Scholar
Moolten, Frederick L., Wells, John M., Heyman, Richard A., et al., “Lymphoma Regression Induced by Ganciclovir in Mice Bearing a Herpes Thymidine Kinase Transgene,” Human Gene Therapy 1 (1990), 125–34.Google Scholar
Kyle, J.W., Birkenmeier, E.H., Gwynn, B., et al., “Correction of Murine Mucopolysaccharidosis VII by a Human Beta-glucuronidase Transgene,” Proceedings of the National Academy of Sciences USA 87 (1990), 3914–18.Google Scholar
Yamamura, K., Ebihara, T., Kamino, K., et al., “Restoration of Immune Response by Gene Therapy in Mice,” Acta Paediatrica Japanese Overseas Edition 29 (1987), 519–21.Google Scholar
Cavard, Catherine, Grimber, Gisele, Dubois, Nathalie, et al., “Correction of Mouse Ornithine Transcarbamylase Deficiency by Gene Transfer into the Germ Line,” Nucleic Acids Research 16 (1988), 2099–110.Google Scholar
Lund, Torben, O'Reilly, Lorraine, Hutchings, Patricia, et al., “Prevention of Insulin-Dependent Diabetes Mellitus in Non-Obese Diabetic Mice by Transgenes Encoding Modified I-A Beta-Chain or Normal I-F. Alpha Chain,” Nature 345 (1990), 727–9.Google Scholar
Zimmerman, , supra note 17, 601.Google Scholar
Mansour, Suzanne, et al., “Disruption of the Proto-Oncogene in Int-2 Mouse Embryo-derived Stem Cells: A General Strategy for Targeting Mutations to Non-selectable Genes,” Nature 336 (1988), 348352.Google Scholar
Thomas, Kirk R. and Capecchi, Mario R., “Site-Directed Mutagenesis by Gene Targeting in Mouse Embryo-Derived Stem Cells,” Cell 51 (1987), 503–12.CrossRefGoogle Scholar
We are unsure whether fetal gene thetapy experiments could be approved by the Human Gene Therapy Subcommittee and the RAC alone, or whether a recommendation would also be necessary from an Ethics Advisory Board required by federal regulation but unchartered since 1980. There is precedent for review of federally supported fetal research by an Ethical Advisory Board. Technically, such projects would not require any use of the “waiver of minimal risk,” which applies to investigative fetal research, especially that conducted in the context of elective abortion. This research is therapeutic in intent, designed to “meet the health needs of…the particular fetus” [45 Code of Federal Regulations 46.206]. However, the Secretary, HHS, can request advice from an Ethical Advisory Board about ethical issues raised by individual applications or proposals [46.204 (b)].Google Scholar
Fletcher, John C., supra note 51, at 307f; Fletcher, John C., “Fetal Tissue Transplantation Research and Federal Policy: A Growing Wall of Separation,” Fetal Diagnosis and Therapy 5 (1990), 211225.Google Scholar
Furman, Wayne L., Pratt, Charles B. and Rivera, Gaston K., “Mortality in Pediatric Phase I Clinical Trials,” Journal of the National Cancer Institute, 81 (1989): 11931194.Google Scholar
U.S. Department of Health and Human Services, Understanding Our Genetic Inheritance. The U.S. Human Genome Project: The First Five Years FY 1991–1995 (Washington, DC: US Government Printing Office, 1990) 266863.Google Scholar
Mason, James O., “Should the Fetal Tissue Research Ban Be Lifted?” Journal of NIH Research, 2 (1990), 1718.Google Scholar