Gene Therapy: Ethical Issues

Gene therapy introduces or alters genetic material to compensate for a genetic mistake that causes disease. It is hoped that gene therapy can treat or cure diseases for which no other effective treatments are available. However, many unique technical and ethical considerations have been raised by this new form of treatment, and several levels of regulatory committees have been established to review each gene therapy clinical trial prior to its initiation in human subjects. Ethical considerations include deciding which cells should be used, how gene therapy can be safely tested and evaluated in humans, what components are necessary for informed consent, and which diseases and/or traits are eligible for gene therapy research.

Germ Line versus Somatic Cell Gene Therapy

Virtually all cells in the human body contain genes, making them potential targets for gene therapy. However, these cells can be divided into two major categories: germ line cells (which include sperm and eggs) and somatic cells. There are fundamental differences between these cell types, and these differences have profound ethical implications.

Gene therapy using germ line cells results in permanent changes that are passed down to subsequent generations. If done early in embryologic development, such as during preimplantation diagnosis and in vitro fertilization, the gene transfer could also occur in all cells of the developing embryo. The appeal of germ line gene therapy is its potential for offering a permanent therapeutic effect for all who inherit the target gene. Successful germ line therapies introduce the possibility of eliminating some diseases from a particular family, and ultimately from the population, forever. However, this also raises controversy. Some people view this type of therapy as unnatural, and liken it to "playing God." Others have concerns about the technical aspects. They worry that the genetic change propagated by germ line gene therapy may actually be deleterious and harmful, with the potential for unforeseen negative effects on future generations.

Somatic cells are nonreproductive. Somatic cell therapy is viewed as a more conservative, safer approach because it affects only the targeted cells in the patient, and is not passed on to future generations. In other words, the therapeutic effect ends with the individual who receives the therapy. However, this type of therapy presents unique problems of its own. Often the effects of somatic cell therapy are short-lived. Because the cells of most tissues ultimately die and are replaced by new cells, repeated treatments over the course of the individual's life span are required to maintain the therapeutic effect. Transporting the gene to the target cells or tissue is also problematic. Regardless of these difficulties, however, somatic cell gene therapy is appropriate and acceptable for many disorders, including cystic fibrosis, muscular dystrophy, cancer, and certain infectious diseases. Clinicians can even perform this therapy in utero , potentially correcting or treating a life-threatening disorder that may significantly impair a baby's health or development if not treated before birth.

Research Issues

Scientific and ethical discussions about gene therapy began many years ago, but it was not until 1990 that the first approved human gene therapy clinical trial was initiated. This clinical trial was conducted on a rare autoimmune disorder called severe combined immune deficiency. This therapy was considered successful because it greatly improved the health and well-being of the few individuals who were treated during the trial. However, the success of the therapy was tentative, because along with the gene therapy the patients also continued receiving their traditional drug therapy. This made it difficult to determine the true effectiveness of the gene therapy on its own, as distinct from the effects of the more traditional therapy.

Measuring the success of treatment is just one challenge of gene therapy. Research is fraught with practical and ethical challenges. As with clinical trials for drugs, the purpose of human gene therapy clinical trials is to determine if the therapy is safe, what dose is effective, how the therapy should be administered, and if the therapy works. Diseases are chosen for research based on the severity of the disorder (the more severe the disorder, the more likely it is that it will be a good candidate for experimentation), the feasibility of treatment, and predicted success of treatment based on animal models. This sounds reasonable. However, imagine you or your child has a serious condition for which no other treatment is available. How objective would your decision be about participating in the research?

Informed Consent

A hallmark of ethical medical research is informed consent. The informed consent process educates potential research subjects about the purpose of the gene therapy clinical trial, its risks and benefits, and what is involved in participation. The process should provide enough information for the potential research subjects to decide if they want to participate. It is important both to consider the safety of the experimental treatment and to understand the risks and benefits to the subjects. In utero gene therapy has the added complexity of posing risks not only to the fetus, but also to the pregnant woman. Further, voluntary consent is imperative. Gene therapy may be the only possible treatment, or the treatment of last resort, for some individuals. In such cases, it becomes questionable whether the patient can truly be said to make a voluntary decision to participate in the trial.

Gene therapy clinical trials came under scrutiny in September 1999, after the highly publicized death of a gene therapy clinical trial participant several days after he received the experimental treatment. This case raised concerns about the overall protection of human subjects in clinical testing, and specifically about the reliability of the informed consent process. In this case, it was alleged that information about potential risks to the patient was not fully disclosed to the patient and his family. It was further alleged that full information regarding adverse events (serious side effects or deaths) that occurred in animals receiving experimental treatment had not been adequately disclosed. Adverse events should be disclosed in a timely manner not only to the participants in these trials, but also to the regulatory bodies overseeing gene therapy clinical trials. Furthermore, participants had not been told of a conflict of interest posed by a financial relationship between the university researchers and the company supporting the research. Obviously, any conflicts of interests could interfere with the objectivity of researchers in evaluating the effectiveness of the clinical trials and should be disclosed during the informed consent process.

Appropriate Uses of Gene Therapy

How do researchers determine which disorders or traits warrant gene therapy? Unfortunately, the distinction between gene therapy for disease genes and gene therapy to enhance desired traits, such as height or eye color, is not clear-cut. No one would argue that diseases that cause suffering, disability, and, potentially, death are good candidates for gene therapy. However, there is a fine line between what is considered a "disease" (such as the dwarfism disorder achondroplasia) and what is considered a "trait" in an otherwise healthy individual (such as short stature). Even though gene therapy for the correction of potentially socially unacceptable traits, or the enhancement of desirable ones, may improve the quality of life for an individual, some ethicists fear gene therapy for trait enhancement could negatively impact what society considers "normal" and thus promote increased discrimination toward those with the "undesirable" traits. As the function of many genes continue to be discovered, it may become increasingly difficult to define which gene traits are considered to be diseases versus those that should be classified as physical, mental, or psychological traits.

To date, acceptable gene therapy clinical trials involve somatic cell therapies using genes that cause diseases. However, many ethicists worry that, as the feasibility of germ line gene therapy improves and more genes causing different traits are discovered, there could be a "slippery slope" effect in regard to which genes are used in future gene therapy experiments. Specifically, it is feared that the acceptance of germ line gene therapy could lead to the acceptance of gene therapy for genetic enhancement. Public debate about the issues revolving around germ line gene therapy and gene therapy for trait enhancement must continue as science advances to fully appreciate the appropriateness of these newer therapies and to lead to ethical guidelines for advances in gene therapy research.

Promise of Gene Therapy

There was extensive media coverage and public excitement about the promise of gene therapy as the first clinical trials commenced in 1990. In fact, many individuals and families with genetic disorders expected an imminent cure for their diseases. Unfortunately, there are as yet few successes to report, even though hundreds of somatic cell gene therapy clinical trials for many different diseases have been attempted. The early hype of gene therapy might have been avoided with more open and honest communication about gene therapy and its expectations between the researchers, physicians, patients, and the public. The death of the participant in 1999 and deficiencies in the protocol (study design) used for that trial underscore the need for continued public discourse on gene therapy.

The promise of gene therapy has not diminished, even though its full therapeutic potential is not yet known. Scientists, physicians, patients, and families continue to look forward to many future successes for gene therapy. With the completion of the Human Genome Project and the accelerated discovery of human disease genes, the potential number of diseases for which gene therapy could be beneficial continues to increase. With further research into the technical aspects of gene therapy and continued public debate about the ethical issues involved in such treatments, it is hoped gene therapies will become standard, effective treatments in the next few decades.

see also Cystic Fibrosis; Eugenics; Gene Therapy; Growth Disorders; Muscular Dystrophy; Prenatal Diagnosis; Severe Combined Immune Deficiency.

Elizabeth C. Melvin