Germ-Line Gene Therapy: A New Stage of Debate

Council for Science and Society. Human Procreation (Oxford: Oxford University Press, 1984), 7.

Kass Leon , “New Beginnings in Life,” in Hamilton M. , ed., The New Genetics and the Future of Man (Grand Rapids, Eerdmans, 1972), 61.

Ramsey Paul , “Genetic Therapy. A Theologian's Response,” in Hamilton, supra note 2, at 175.

Fletcher Joseph , The Ethics of Genetic Control (Garden City: Doubleday Anchor, 1974), 14–15.

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.

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).

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.

Capron Alexander M. , “Historical Perspective. The Impact of the Report, Spiking Life,” Human Gene Therapy, 1 (Spring, 19901:69–71.

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.

Regulatory Issues. “The Revised ‘Points to Consider’ Document,” Human Gene Therapy 1 (1990), 95.

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.

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.

Parliamentary Assembly of the Council of Europe, Thirty-Third Ordinary Session, “Recommendarion 934 (1982), On Genetic Engineering,” 67000 Strausbourg, France.

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.

Official Statements, “German Law Protects Embryos.” Bulletin of Medical Ethics, No. 64, (Dec., 1990), 9–11; 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), 191–97.

Juengst Eric T. , “Germ-line Gene Therapy: Back to Basics,” The Journal of Medicine and Philosophy, 16 (1991), 587–92.

Fowler Gregory Juengst Eric T. and Zimmerman Burke K. , “Germ-line Gene Therapy and the Clinical Ethos of Medical Genetics,” Theoretical Medicine 10 (1989), 151–165; 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.

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.

Stone Richard , “Germ Cell Gene Panel,” Science, 253 (1991) August 23, 841.

Bankowski Zbigniew Capron Alexander M. , eds., Genetics, Ethics, and Human Values. Proceedings of the XXIVth CIOMS Round Table Conference (Geneva, CIOMS, 1991)

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.

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.

Anderson W. French , supra note 9, 285–86.

Culver Kenneth W. Anderson W. French and Blaese R. Michael , “Lymphocyte Gene Therapy,” Human Gene Therapy 2 (1991), 107–9.

Anderson W. French , “September 14, 1990: The Beginning,” Human Gene Therapy 1 (1990), 371–2.

Zimmerman , supra note 17, 600–1.

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), 5–17; Ethics Committee of the American Fertility Society, “Ethical Considerations of the New Reproductive Technologies,” Fertility and Sterility, 46 (1986), Supplement, 26S–31S. 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.

Handyside Alan H. Pattinson J. K. Penketh Richard J.A. , “Biopsy of Human Pre-implantation Embryos sexed by Y-specific DNA Amplification,” Lancet 1 (1989), 347–49.

Handyside Alan H. Kontogianni E.H. Hardy K. , “Pregnancies From Biopsied Human Pre-implantation Embryos Sexed by Y-specific DNA Amplification,” Nature 344 (1990), 768–70.

Sixth Report, supra, note 11, p. 40.

Coutelle Charles Williams Carolyn Handyside Alan H. , “Genetic Diagnosis of DNA from Single Human Oocytes—A Model for Pre-implantation Diagnosis of Cystic Fibrosis,” British Medical Journal 299 (1989), 22–24.

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.

Monk Marilyn and Holding G. , “Amplification of a Beta Haemoglobin Sequence in Individual Human Oocytes and Polar Bodies,” Lancet 335 (1990), 985–88.

Gladwell Malcolm , “Gene-Defect Tests Planned,” Washington Post, December 31, 1990, p. A-1.

Cook-Deegan Robert M. , “Human Gene Therapy and Congress,” Human Gene Therapy 1 (1990), 163–70.

Zimmerman , supra note 17, p. 595.

Zimmerman , supra note 17, 608; also, personal communication from Golbus Mitchell S. M.D., June 28, 1991.

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 181–296:41238).

Beauchamp Tom L. Childress James F. , Principles of Biomedical Ethics, 3rd ed. (New York: Oxford University Press, 1989), 120–193.

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.

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):799–802; 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 , “Parental Response to Mid-Trimester Therapeutic Abortion Following Amniocentesis,” Prenatal Diagnosis, 4 (1984):249–55; Marteau T.M. Johnston M. Shaw R.W. , “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.

Galjaard Hans , “Early Diagnosis and Prevention of Genetic Disease,” in Galjaard H. , ed., Aspects of Genetic Disease, (Basel: Karger, 1984), 1–15.

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.

Hall J.M. , “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. , “Germ Line p53 Mutations in a Familial Syndrome of Breast Cancer, Sarcomas, and Other Neoplasms,” Science 250 (1990), 1233–38.

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.

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.

Anderson W. French , “Human Gene Therapy: Why Draw A Line,” The Journal of Medicine and Philosophy 14 (1989), 681–93.

Krimsky , supra note 46, 173.

Culver Charles C. Gert Bernard M. , Philosophy in Medicine (New York, Oxford University Press, 1982).

Berger and Gert , supra note 17, 671–74.

Fletcher John C. , “Controversies in Research Ethics Affecting the Future of Human Gene Therapy,” Human Gene Therapy 1 (1990), 307–324.

Gordon Jon W. , “Transgenic Animals,” International Review of Cytology, 115 (1989), 171–229; Church Robert B. , ed., Transgenic Models in Medicine and Agriculture, (New York, Wiley-Liss, 1990).

Palmiter Richard D. Brinster Ralph L. , “Germ-line Transformation of Mice,” Annual Review of Genetics 20 (1986), 465–99.

van der Putten Herman Botteri Florence M. Miller A. Dusty , “Efficient Insertion of Genes Into the Mouse Germ Line Via Retroviral Vectors.” Proceedings of the National Academy of Sciences USA 82 (1985), 6148–52.

Kuehn Michael R. Bradley Allan Robertson Elizabeth J. , “A Potential Animal Model for Lesch-Nyhan Syndrome Through Introduction of HPRT Mutations into Mice,” Nature 326 (1987), 295–98.

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.

Constantini Frank Chada Kiran Magram Jeanne , “Correction of Murine Beta-thalassemia by Gene Transfer Into the Germ Line,” Science 233 (1986), 1192–94.

Readhead Carol Popko Brian Takahashi Naoki , “Expression of a Myelin Basic Protein Gene in Transgenic Shiverer Mice: Correction of the Dysmyelinating Phenotype,” Cell 48 (1987), 703–12.

Mason Anthony J. Pitts Sharon L. Nikolics Karoly , “The Hypogonadal Mouse: Reproductive Functions Restored by Gene Therapy,” Science 234 (1986), 1372–78.

Moolten Frederick L. Wells John M. Heyman Richard A. , “Lymphoma Regression Induced by Ganciclovir in Mice Bearing a Herpes Thymidine Kinase Transgene,” Human Gene Therapy 1 (1990), 125–34.

Kyle J.W. Birkenmeier E.H. Gwynn B. , “Correction of Murine Mucopolysaccharidosis VII by a Human Beta-glucuronidase Transgene,” Proceedings of the National Academy of Sciences USA 87 (1990), 3914–18.

Yamamura K. Ebihara T. Kamino K. , “Restoration of Immune Response by Gene Therapy in Mice,” Acta Paediatrica Japanese Overseas Edition 29 (1987), 519–21.

Cavard Catherine Grimber Gisele Dubois Nathalie , “Correction of Mouse Ornithine Transcarbamylase Deficiency by Gene Transfer into the Germ Line,” Nucleic Acids Research 16 (1988), 2099–110.

Lund Torben O'Reilly Lorraine Hutchings Patricia , “Prevention of Insulin-Dependent Diabetes Mellitus in Non-Obese Diabetic Mice by Transgenes Encoding Modified 1-A Beta-Chain or Normal I-F. Alpha Chain,” Nature 345 (1990), 727–9.

Zimmerman , supra note 17, 601.

Mansour Suzanne , “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), 348–352.

Thomas Kirk R. and Capecchi Mario R. , “Site-Directed Mutagenesis by Gene Targeting in Mouse Embryo-Derived Stem Cells,” Cell 51 (1987), 503–12.

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)].

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), 211–225.

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): 1193–1194.

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) 266–863.

Mason James O. , “Should the Fetal Tissue Research Ban Be Lifted?” Journal of NIH Research, 2 (1990), 17–18.