The ethics of human gene transfer

Almost 20 years since the first gene-transfer trial was carried out in humans, the field has made significant advances towards clinical application. Nevertheless, it continues to face numerous unresolved ethical challenges — among them are the question of when to initiate human testing, the acceptability of germline modification and whether the technique should be applied to the enhancement of traits. Although such issues have precedents in other medical contexts, they take on a different character in gene transfer, in part because of the scientific uncertainty and the social context of innovation.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

206,07 € per year

only 17,17 € per issue

Buy this article

Prices may be subject to local taxes which are calculated during checkout

References

  1. Guo, J. & Xin, H. Chinese gene therapy. Splicing out the West? Science314, 1232–1235 (2006). ArticleCASPubMedGoogle Scholar
  2. Booth, C. et al. Management options for adenosine deaminase deficiency; proceedings of the EBMT satellite workshop (Hamburg, March 2006). Clin. Immunol.123, 139–147 (2007). ArticleCASPubMedGoogle Scholar
  3. Branca, M. A. Gene therapy: cursed or inching towards credibility? Nature Biotechnol.23, 519–521 (2005). ArticleCASGoogle Scholar
  4. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. Splicing Life: A Report on the Social and Ethical Issues of Genetic Engineering with Human Beings. (US Government Printing Office, Washington, 1982).
  5. Raper, S. E. et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol. Genet. Metab.80, 148–158 (2003). ArticleCASPubMedGoogle Scholar
  6. Baum, C. What are the consequences of the fourth case? Mol. Ther.15, 1401–1402 (2007). ArticleCASPubMedGoogle Scholar
  7. Kaiser, J. Clinical research. Death prompts a review of gene therapy vector. Science317, 580 (2007). ArticleCASPubMedGoogle Scholar
  8. Horstmann, E. et al. Risks and benefits of Phase 1 oncology trials, 1991 through 2002. N. Engl. J. Med.352, 895–904 (2005). ArticleCASPubMedGoogle Scholar
  9. Kimmelman, J. Recent developments in gene transfer: risk and ethics. BMJ330, 79–82 (2005). ArticleCASPubMedPubMed CentralGoogle Scholar
  10. Dettweiler, U. & Simon, P. Points to consider for ethics committees in human gene therapy trials. Bioethics15, 491–500 (2001). ArticleCASPubMedGoogle Scholar
  11. Gaspar, H. B. et al. Gene therapy of X-linked severe combined immunodeficiency by use of a pseudotyped γ-retroviral vector. Lancet364, 2181–2187 (2004). ArticleCASPubMedGoogle Scholar
  12. Will, E. et al. Importance of murine study design for testing toxicity of retroviral vectors in support of Phase I trials. Mol. Ther.15, 782–791 (2007). ArticleCASPubMedGoogle Scholar
  13. Manno, C. S. et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by host immune response. Nature Med.12, 342–347 (2006). ArticleCASPubMedGoogle Scholar
  14. Freedman, B. Equipoise and the ethics of clinical research. N. Engl. J. Med.317, 141–145 (1987). ArticleCASPubMedGoogle Scholar
  15. Orkin, S. H. & Motulsky, A. G. Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy. (National Institutes of Health, Bethesda, Maryland, 1995). Google Scholar
  16. Kimmelman, J. Stable ethics: enrolling non-treatment-refractory volunteers in novel gene transfer trials. Mol. Ther.15, 1904–1906 (2007). ArticleCASPubMedGoogle Scholar
  17. Evans, J. H. Playing God: Human Genetic Engineering and the Rationalization of Public Debate. (University of Chicago Press, 2002). Google Scholar
  18. King, N. M. RAC oversight of gene transfer research: a model worth extending? J. Law Med. Ethics30, 381–389 (2002). ArticlePubMedGoogle Scholar
  19. Ashcroft, R. E. Gene therapy in the clinic: whose risks? Trends Biotechnol.22, 560–563 (2004). ArticleCASPubMedGoogle Scholar
  20. Danzon, P. & Towze, A. The economics of gene therapy and of pharmacogenetics. Value Health5, 5–13 (2002). ArticlePubMedGoogle Scholar
  21. Danzon, P. & Towze, A. The genomic revolution: is the real risk under-investment rather than bankrupt health care systems? J. Health Serv. Res. Policy5, 253–255 (2000). ArticleCASPubMedGoogle Scholar
  22. National Hemophilia Foundation. Financial and Insurance Issues. [online], (2006).
  23. Herper, M. Avigen Leads Gene Therapy Charge. Forbes[online], (2006). Google Scholar
  24. Ja, H. & Kling, J. China offers alternative gateway for experimental drugs. Nature Biotechnol.24, 117–118 (2006). ArticleGoogle Scholar
  25. Jia, H. Controversial Chinese gene-therapy drug entering unfamiliar territory. Nature Rev. Drug Discov.5, 269–270 (2006). ArticleCASGoogle Scholar
  26. Jia, H. Gene therapy finds welcoming environment in China. Nature Med.12, 263–264 (2006). ArticleCASPubMedGoogle Scholar
  27. Marshall, E. Gene therapy. Panel reviews risks of germ line changes. Science294, 2268–2269 (2001). PubMedGoogle Scholar
  28. Kazazian, H. H. An estimated frequency of endogenous insertional mutations in humans. Nature Genet.22, 130 (1999). ArticleCASPubMedGoogle Scholar
  29. Kaplan, J. & Roy., I. Accidental germ-line modifications through somatic cell gene therapies: Some ethical considerations. Am. J. Bioeth.1, w13 (2001). CASPubMedGoogle Scholar
  30. King, N. M. Accident & desire. Inadvertent germline effects in clinical research. Hastings Cent. Rep.33, 23–30 (2003). ArticlePubMedGoogle Scholar
  31. Cohen, J., Scott, R., Schimmel, T., Levorn, J. & Wiladsen, S. Birth of infant after transfer of anucleate donor oocyte cytoplasm into recipient eggs. Lancet350, 186–187 (1997). ArticleCASPubMedGoogle Scholar
  32. Zoon, K. C. Letter to sponsors/researchers: human cells used in therapy involving the transfer of genetic material by means other than the union of gamete nuclei. FDA Center for Biologies Evaluation and Research. [online], (2001). Google Scholar
  33. Firfer, H. How Far Will Couples Go To Conceive? CNN[online], (2004). Google Scholar
  34. Robertson, J. A. Oocyte cytoplasm transfers and the ethics of germ-line intervention. J. Law Med. Ethics26, 211–220 (1998). ArticleCASPubMedGoogle Scholar
  35. Council of Europe. Convention for the Protection of Human Rights and Dignity of the Human Being with Regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine. European Treaty Series164 (4 Apr 1997).
  36. Hébert, M., Chenier, N. M. & Norris, S. Bill C-6 Assisted Human Reproduction Act. Statutes of Canada, chapter 2 (2004). Available at http://www.parl.gc.ca/common/Bills_ls.asp?Parl=37&Ses=3&ls=C6Google Scholar
  37. Indian Council of Medical Research, New Delhi. Ethical guidelines for biomedical research on human participants. [online], (2006).
  38. Steinbock, B. in Designing Our Descendants: The Promises and Perils of Genetic Modifications. (eds Chapman, A. R. & Frankel, M. S.) 179–198 (Johns Hopkins University Press, Baltimore, 2003). Google Scholar
  39. Genetics and Public Policy Center, Johns Hopkins University. Attitudes about Reproductive Genetics. [online], (2002)
  40. Garber, K. RAC urges changes to retinoblastoma plan. Science284, 2066 (1999). ArticleCASPubMedGoogle Scholar
  41. RAC Department of Health and Human Services National Institutes of Health Recombinant DNA Advisory Committee. Minutes of meeting, June 14 1999 [online], (1999).
  42. Melman, A., Bar-Chama, N., McCullough, A., Davies, K., Christ, G. hMaxi-K gene transfer in males with erectile dysfunction: results of the first human trial. Hum. Gene Ther.17, 1165–1176 (2006). ArticleCASPubMedGoogle Scholar
  43. RAC Department of Health and Human Services National Institutes of Health Recombinant DNA Advisory Committee. Minutes of meeting, March 10 2004 [online], (2004).
  44. Baoutina, A., Alexander, I. E., Rasko, J. E. & Emslie, K. R. Potential use of gene transfer in athletic performance enhancement. Mol. Ther. 15:, 1751–1766 (2007).
  45. Parens, E. Is better always good? The enhancement project. Hastings Cent. Rep.28, S1–S17 (1998) ArticleCASPubMedGoogle Scholar
  46. Sandel, M. J. The Case Against Perfection: Ethics in the Age of Genetic Engineering. (Harvard University Press, Cambridge, 2007) Google Scholar
  47. Buchanan, A., Brock, D. W., Daniels, N. & Wikler, D. From Chance to Choice: Genetics and Justice. (Cambridge University Press, New York, 2001). Google Scholar
  48. Mehlman, M. J. Genetic enhancement: plan now to act later. Kennedy Inst. Ethics J.15, 77–82 (2005). ArticlePubMedGoogle Scholar
  49. Mehlman, M. J. & Rabe, K. M. Any DNA to declare? Regulating offshore access to genetic enhancement. Am. J. Law Med.28, 179–213 (2002). PubMedGoogle Scholar
  50. Parens, E. Should we hold the (germ) line? J. Law Med. Ethics23, 173–176 (1995). ArticleCASPubMedGoogle Scholar
  51. Imperiale, M J. Gene therapy and biosecurity. Mol. Ther.15, 648–649 (2007). ArticleCASPubMedGoogle Scholar
  52. Billings, P. R. In utero gene therapy: the case against. Nature Med.5, 255–256 (1999). ArticleCASPubMedGoogle Scholar
  53. Waddington, S. N. et al. In utero gene therapy: current challenges and perspectives. Mol. Ther.11, 661–676 (2005). ArticleCASPubMedGoogle Scholar
  54. Dresser, R. Genetic modification of preimplantation embryos: toward adequate human research policies. Milbank Q.82, 195–214 (2004). ArticlePubMedPubMed CentralGoogle Scholar
  55. Dennis, M. B. Welfare issues of genetically modified animals. ILAR J.43, 100–108 (2002). ArticleCASPubMedGoogle Scholar
  56. Massiello, S. A. Warning letter to James M. Wilson, Institute for Human Gene Therapy. FDA Freedom of Information[online], (2000). Google Scholar
  57. Munson, R. in Outcome Uncertain: Cases and Contexts in Bioethics. (Munson, R. ed) (Wadsworth, Toronto, 2003). Google Scholar
  58. Cornetta, K. & Smith, F. O. Regulatory issues for clinical gene therapy trials. Hum. Gene Ther.13, 1143–1149 (2002). ArticleCASPubMedGoogle Scholar
  59. Spink J. & Geddes, D. Gene therapy progress and prospects: bringing gene therapy into medical practice: the evolution of international ethics and the regulatory environment. Gene Ther.11, 1611–1616 (2004). ArticleCASPubMedGoogle Scholar

Acknowledgements

I regret that, owing to the brevity of this Perspective, many important contributions to the literature on gene-transfer ethics went unmentioned. The work of the author is funded by a Canadian Institutes of Health Research Maud Menten New Principal Investigator Award.

Author information

Authors and Affiliations

  1. Jonathan Kimmelman is at the Department of Social Studies of Medicine, Biomedical Ethics Unit, McGill University, 3647 Peel Street, Montreal, QB H3A 1X1, Canada. jonathan.kimmelman@mcgill.ca, Jonathan Kimmelman
  1. Jonathan Kimmelman