GENE THERAPY

Gene therapies (gene transfer technology) involve one or more experimental techniques for correcting or altering genes, including defective genes associated with physiological or psychological disorders. As has historically been the case with many other novel interventions (such as those that depend on drugs or surgery), debates have arisen between those who believe there is a moral obligation to pursue gene transfer research and those who challenge them as illegitimate or unnatural. As yet there is no strong consensus regarding distinctions between what is morally unacceptable, simply permissible, or obligatory.

Technical Aspects

There are a number of approaches to gene alteration including replacing an "abnormal" gene (i.e., DNA sequence) with a "normal" gene through homologous recombination, repairing an "abnormal" gene through selective reverse mutation, and altering the regulation of a particular gene. The term "abnormal" is placed in quotation marks, indicating that there remains room for disagreement about what constitutes a normal gene, is certainly one source of disagreement about these procedures.

Typically, for mostly practical reasons, gene therapy research involves the insertion of a functional gene into a non-specific location in the genome without removal or correction of the disease-causing gene. This can be done in vitro or in vivo. In vitro techniques require cells to be removed from an organism, corrective genetic material added in culture, and the altered cells returned to the organism. The advantages of this approach are twofold. If there is a problem with the genetic manipulation, the altered cells need not be transferred to the organism; also, the risk of unintentionally affecting non-targeted tissues is reduced. Alternatively, the corrective genetic material may be delivered to the targeted cells in vivo using a vector (often a virus that has been altered) to carry the gene into the cells. Retroviruses, adenoviruses, adeno-associated viruses, and herpes simplex viruses are among the viruses altered for vector use.

There are two categories of future gene therapy: somatic cell gene therapy and germ-line gene therapy. Somatic cell therapy involves the genetic alteration of nonfunctioning or malfunctioning somatic (i.e., non-reproductive) cells. These alterations are not passed on to subsequent generations. Germ-line therapy involves the genetic alteration of the germ (i.e., reproductive) cells or the early embryo prior to the development of gonadal tissue. Any resulting genetic changes will be inherited.

Use of gene transfer technology is not limited, however, to therapeutic goals. The technology can also be used for enhancement purposes to improve the functioning of normal genes—for example, the introduction of a growth hormone gene into a person of normal stature.

Ethical Issues

From the beginning, there has been considerable debate about the ethics of future gene therapy (Parens 1995, Walters and Palmer 1997, Stock and Campbell 2000). Some insist that somatic cell gene therapy is a logical extension of available techniques for treating disease; others argue that such genetic interventions are dangerous or inappropriate. Out of this debate emerged a moral demarcation line between somatic and germ-line gene therapy, the latter being widely described as ethically unacceptable because of the risks of physical and social harms (Anderson 1989).

In the late 1980s and early 1990s, with the move to clinical trials involving somatic cell gene transfer (and the possibility of inadvertent germ-line modification), debate about the ethics of germ-line gene transfer resurfaced. Some argued that germ-line gene transfer could be an effective and efficient treatment for diseases that affect many different organs and their cell types (such as cystic fibrosis); for diseases expressed in non-removable or non-dividing cells (such as Lesch-Nyhan syndrome); and for diseases that develop in the very early embryo that could be prevented through germ-line genetic intervention (such as albinism linked to tyrosinase). Indeed, some even argued that in such cases there was a moral obligation to reduce the incidence of disease in subsequent generations using germ-line gene transfer, instead of continuing to treat each successive generation with somatic cell genetic interventions. In opposition, questions have been raised about whether such work is an appropriate use of limited research funds when other efforts might have a more general public benefit, with some also objecting to the pursuit of a kind of biological perfectionism.

Controversial History

The history of gene transfer research in humans is a checkered one, mired in controversy (NRCBL 2002, Johnston and Baylis 2004). Martin Cline of the University of California Los Angeles (UCLA) conducted the first human gene transfer clinical trial in July 1980. The unsuccessful trial involved two patients with thalassemia, one in Israel and the other in Italy. Cline did not inform the UCLA Institutional Review Board (IRB) of his research, and did not fully disclose details of the trial to the Israeli research ethics review committee (at the time, Italy did not have an ethics review system). News of the unauthorized trial became public in a Los Angeles Times story published in October 1980. An internal investigation by UCLA and an external investigation by the U.S. National Institutes of Health (NIH) followed, resulting in significant sanctions for Cline. It would be another decade before an officially approved human gene therapy trial would begin in the United States.

The first federally approved gene transfer into humans in the United States came in 1989. The research involved the autologous transfer of gene-marked lymphocytes into five patients with terminal melanoma. The purpose of this research was to demonstrate safety.

A year later, in 1990, the first gene transfer experiment was approved. This research began with four-year-old Ashanthi DeSilva. DeSilva suffered from an adenosine deaminase (ADA) deficiency (a rare immune defect). She was the first of two children to be injected with her own blood cells that had been altered by a retroviral vector to contain functioning ADA genes. DeSilva and the other child research participant also received a new drug, PEG-ADA (a synthetic form of the ADA enzyme).

Around the same time, a similar trial, also involving two patients with ADA deficiency, was conducted by Italian researchers. In both cases the combined interventions proved successful, although the efficacy of the genetic intervention remains unclear since the children continue to receive PEG-ADA therapy.

The pace of gene transfer research picked up after 1990. As reported on the U.S. Center for Disease Control website, gene transfer clinical trials worldwide jumped from one in 1989 and two in 1990 to sixty-six by 1995. Meanwhile, there was growing concern about the hype surrounding gene therapy. In December of 1995, an NIH-appointed ad hoc committee reported that: "[W]hile the expectations and the promise of gene therapy are great, clinical efficacy has not been definitively demonstrated at this time in any gene therapy protocol" (Orkin and Motulsky 1995). In the same report, concerns were raised about the relationship between gene transfer researchers and industry.

A major setback for gene transfer research came at the end of the 1990s with the death of a small number of research participants in different gene therapy trials. The most widely publicized death was that of Jesse Gelsinger, an eighteen-year-old patient with a rare liver condition who was enrolled in a study at the University of Pennsylvania. In September 1999, Gelsinger received an injection of adenovirus vectors designed to carry corrected ornithine transcarbamylase (OTC) genes to his liver. Four days later, he died of multiple organ failure as a result of the experimental intervention (Raper, Chirmule, Lee, et al. 2003).

A few years later, there was yet another major setback. In October 2002, researchers in France with the first apparently unequivocal success in gene transfer research announced that one of the nine boys in their gene transfer trial for X-linked severe combined immunodeficiency disease (X-SCID) had developed a leukemia-like condition. Three months later, in December 2002, a second X-SCID child in the trial was also showing signs of a leukemia-like disease (Johnston and Baylis 2004).

As of early 2005, there had been no unqualified successes in human gene transfer research. Research continues on ways to improve gene control and targeting, effectively integrate DNA into the genome, limit the risk of stimulating an immune response, and avoid the problems with viral vectors that can result in inflammation and toxicity. Only when these problems are resolved will the promise of gene transfer research begin to be realized—assuming the research is deemed morally acceptable.

FRANÇOISE BAYLIS
JASON SCOTT ROBERT

SEE ALSO Genethics;Genetic Counseling;Genetic Research and Technology;Homosexuality Debate;Playing God.

BIBLIOGRAPHY

Anderson, W. French. (1989). "Human Gene Therapy: Why Draw a Line." Journal of Medicine and Philosophy 14: 682–693.

Johnston, Josephine, and Françoise Baylis. (2004). "What Happened to Gene Therapy? A Review of Recent Events." Clinical Researcher 4: 11–15.

Parens, Eric. (1995). "Should We Hold the (Germ) Line?" Journal of Law, Medicine, and Ethics 23: 173–176.

Raper, Steven E.; Chirmule, Naredra; Lee, Frank S.; et al. (2003). "Fatal Systemic Inflammatory Response Syndrome in a Ornithine Transcarbamylase Deficient Patient Following Adenoviral Gene Transfer." Molecular Genetics and Metabolism 80: 148–58.

Stock, Gregory, and John Campbell, eds. (2000). Engineering the Human Germline: An Exploration of the Science and Ethics of Altering the Genes We Pass to Our Children. New York: Oxford University Press.

Walters, LeRoy, and Julie Gage Palmer. (1997). The Ethics of Human Gene Therapy. New York: Oxford University Press.

INTERNET RESOURCES

National Reference Center for Bioethics Literature (NRCBL). (2002). "Scope Note 24: Human Gene Therapy." Available from http://www.georgetown.edu/research/nrcbl/publications/scopenotes/.

Orkin, Stuart H., and Arno G. Motulsky. (1995). "Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy." National Institutes of Health, 1995. Available from www.nih.gov/news/panelrep.html.