SCOPE NOTE 24

National Reference Center for Bioethics Literature The Joseph and Rose Kennedy Institute of Ethics Box 571212, Georgetown University Washington, DC 20057-1212 888-BIO-ETHX; 202-687-3885; fax: 202-687-6770 e-mail: bioethics@georgetown.edu http://bioethics.georgetown.edu Human Gene Therapy

First published in March 1994, Scope Note 24 is an annotated bibliography with links to electronic texts where possible.  It is updated on a periodic basis.

I. Background

On September 14, 1990 researchers at the U.S. National Institutes of Health performed the first (approved) gene therapy procedure on four-year old Ashanti DeSilva. Born with a rare genetic disease called severe combined immune deficiency (SCID), she lacked a healthy immune system, and was vulnerable to every passing germ. Children with this illness usually develop overwhelming infections and rarely survive to adulthood; a common childhood illness like chickenpox is life-threatening. Ashanti led a cloistered existence--avoiding contact with people outside her family, remaining in the sterile environment of her home, and battling frequent illnesses with massive amounts of antibiotics.

In Ashanti's gene therapy procedure, doctors removed white blood cells from the child's body, let the cells grow in the lab, inserted the missing gene into the cells, and then infused the genetically modified blood cells back into the patient's bloodstream. Laboratory tests have shown that the therapy strengthened Ashanti's immune system; she no longer has recurrent colds, she has been allowed to attend school, and she was immunized against whooping cough. This procedure was not a cure; the white blood cells treated genetically only work for a few months, and the process must be repeated every few months. (VII, Thompson [First] 1993).

Although this simplified explanation of a gene therapy procedure sounds like a happy ending, it is little more than an optimistic first chapter in a long story; the road to the first approved gene therapy procedure was rocky and fraught with controversy. The biology of human gene therapy is very complex, and there are many techniques that still need to be developed and diseases that need to be understood more fully before gene therapy can be used appropriately. The public policy debate surrounding the possible use of genetically engineered material in human subjects has been equally complex. Major participants in the debate have come from the fields of biology, government, law, medicine, philosophy, politics, and religion, each bringing different views to the discussion.

In studying the ethics of gene therapy, one should make a distinction between therapy on the somatic (non reproductive) cells and the germ (reproductive) cells of an individual. Only the germ cells carry the genes that will be passed on to the next generation. Some commentators on gene therapy have objected to any form of genetic manipulation, no matter how well-intentioned (VII, Rifkin 1983). Many others approve of the use of somatic cell therapy, but hesitate to allow the use of germ-line gene therapy that could have an unforeseeable effect on future generations. Still others have argued that with proper regulation and safeguards, germ-line gene therapy is a logical extension of the progress made to date, and an ethically acceptable procedure.

Techniques

The first somatic cell gene therapy procedure inserted a normal gene into the DNA of cells in order to compensate for the nonfunctioning defective gene. This technique involves obtaining blood cells from a person afflicted with a genetic disease and then introducing a normal gene into the defective cell. This can be done by directly introducing the new DNA into the cells or by using domesticated viruses. It is important that the DNA be inserted in the correct cell and at the correct place in the cell's genome.

Germ-line gene therapy is technically more difficult, and as noted, raises more ethical challenges. The two main methods of performing germ-line gene therapy would be: 1) to treat a pre-embryo that carries a serious genetic defect before implantation in the mother (this necessitates the use of in vitro fertilization techniques); or 2) to treat the germ cells (sperm or egg cells) of afflicted adults so that their genetic defects would not be passed on to their offspring. This approach requires the technical expertise to delete the defective gene and insert a properly functioning replacement.

Candidate Diseases for Gene Therapy

Gene therapy is likely to have the greatest success with diseases that are cause by single gene defects. By the end of 1993, gene therapy had been approved for use on such diseases as severe combined immune deficiency, familial hypercholesterolemia, cystic fibrosis, and Gaucher's disease. Most protocols to date are aimed toward the treatment of cancer; a few are also targeted toward AIDS. Numerous disorders are discussed as candidates for gene therapy: Parkinson's and Alzheimer's diseases, arthritis, and heart disease (VII, Wolff 1993).

Eve Nichols describes the criteria for selection of disease candidates for human gene therapy: 1) the disease is an incurable, life-threatening disease; 2) organ, tissue and cell types affected by the disease have been identified; 3) the normal counterpart of the defective gene has been isolated and cloned; 4) the normal gene can be introduced into a substantial subfraction of the cells from the affected tissue; or that introduction of the gene into the available target tissue, such as bone marrow, will somehow alter the disease process in the tissue affected by the disease; 5) the gene can be expressed adequately (it will direct the production of enough normal protein to make a difference); and 6) techniques are available to verify the safety of the procedure. (III, Nichols 1988, p. 18)

Information about genetic research and disease can be obtained through the Web site MedlinePlus: Genes and Gene Therapy, an online directory coordinated by the U.S. National Library of Medicine (NLM), National Institutes of Health (NIH).

Brief History of Gene Therapy in the United States

John Fletcher cites 1967 as the threshold of the gene therapy debate, when Nobelist Marshall Nirenberg wrote of programming cells with synthetic messages, and recognized the promise and danger of this scientific procedure. (III, Fletcher 1990, p. 57)

A seminal event in the history of gene therapy occurred when an American doctor, Stanfield Rogers, collaborated with a German physician to treat two sisters suffering from hyperargininemia with Shope papilloma virus (SPV) between 1970 and 1973. It was erroneously believed that the virus would cause expression of the gene that regulated the production of arginine in the children.

In 1974 the National Institutes of Health (NIH) took the lead in regulating recombinant DNA (rDNA) research. The Recombinant DNA Advisory Committee (RAC) to the NIH Director was created. The RAC first approved all research projects involving recombinant DNA in laboratories in the United States, then handled gene marking research, and finally reviewed all gene therapy protocols in conjunction with the Food and Drug Administration (FDA). The FDA would focus on the safety and efficacy of the genetically altered products, on the safety of the manufacturing process, and on control of the final product. The FDA published its own "Points to Consider in Human Somatic Cell Therapy and Gene Therapy" in 1991 (VII, U.S. Food and Drug Administration 1991) and later clarified its regulations in 1993 (VII, U.S. Food and Drug Administration 1993). Current information about the RAC can be found on NIH's Office of Biotechnology Activities' Recombinant DNA and Gene Transfer Web site. The document "Points to Consider" continues to be updated, and can be found as Appendix M of NIH's Guidelines on recombinant DNA research.

The work of the RAC and the FDA embodies the guidelines on human experimentation that had emanated from the work of the National Commission for the Protection of Human Subjects, and its Belmont Report in 1978. Regulations were established whereby research proposals went through a review process (VII, U.S. Office of Science and Technology Policy 1991). Preliminary approval was required by the home institution's institutional biosafety committee (IBC) and institutional review board (IRB); final approval was then required by the RAC. These regulations were applied to all federally funded institutions performing rDNA research, regardless of the funding for the specific project, and regardless of whether or not the research took place in the United States.

The first attempt at human gene therapy was performed under questionable circumstances by University of California at Los Angeles (UCLA) researcher, Dr. Martin Cline. Without the approval of his UCLA IRB, Cline performed a recombinant DNA transfer into cells of the bone marrow of two patients with hereditary blood disorders in Italy and Israel. At the time, Italy did not have IRBs, and Dr. Cline did not disclose fully to the Israeli IRB the exact nature of the gene transfers he proposed. In October 1980, the Los Angeles Times published details of Dr. Cline's activities (VII, Jacobs 1980). Dr. Cline suffered grave consequences for his overexuberance. He was forced to resign his department chairmanship at UCLA, he lost some grants, and for a period of three years, all of his applications for grant support were accompanied by a report of the investigations into his activities in 1979-1980.

In light of Dr. Cline's experiment, and at the prompting of the National Council of Churches, the Synagogue Council of America and the United States Catholic Conference, the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research became involved with the issue of gene therapy and released a landmark study called Splicing Life in 1982. (II, United States 1982). The President's Commission vigorously defended the continuation of gene therapy research. Splicing Life responded to the concern that scientists were playing God, concluding that we can distinguish between acceptable and unacceptable consequences of gene therapy research. The Commission suggested the RAC broaden the scope of its review to include the ethical and social implications of gene therapy.

In 1984 the RAC created a new group, called the Human Gene Therapy Working Group (later called the Human Gene Therapy Subcommittee (HGTS)) specifically to review gene therapy protocols (V, Walters 1991). The first task of the Working Group was to produce the "Points to Consider for Protocols for the Transfer of Recombinant DNA into the Genome of Human Subjects" document as a guide for those applying for RAC approval of gene therapy protocols (V, National Institutes of Health (United States) 1990).

Another outcome of the hearing was the 1984 U.S. Office of Technology Assessment (OTA) background paper Human Gene Therapy, which stressed the difference between somatic and germ-line gene therapy. (VII, U.S. Congress. Office of Technology Assessment 1984) The OTA also issued an important survey on public opinion regarding genetic technologies, New Developments in Biotechnology, Volume 2: Background Paper: Public Perceptions of Biotechnology (III, U.S. Congress. Office of Technology Assessment 1987).

Other attempts by Congress to participate in the public debate on gene therapy have been less effective. Emanating from the hearings chaired by then Congressman Al Gore, was legislation to create a federal commission to study the ethical, legal and social issues of genetic engineering (VII, U.S Congress 1983), but the bill never passed. The Biomedical Ethics Advisory Committee briefly studied the issue of gene therapy, but its mandates to study issues relating to death and fetal tissue research led it to become embroiled in abortion politics, and the Committee collapsed before taking action (V, Cook-Deegan 1990).

By late 1985 the RAC Subcommittee had its "Points to Consider" document ready and waited for gene therapy protocols to be presented. The first protocol it received, in 1988, was actually for gene marking. Steven Rosenberg proposed using gene marking techniques to track the movements of tumour infiltrating blood cells in cancer patients; no actual therapy was proposed. After several months of discussion among the HGTS members, and the gathering of additional information, the protocol was approved by a mail ballot in December 1988. The experiment was briefly stalled by a lawsuit filed by the Foundation on Economic Trends questioning the validity of the review process (V, Foundation on Economic Trends 1991). Eventually Rosenberg did perform the experiment, with fruitful results (VII, Rosenberg 1990).

In 1990 the HGTS received two protocols to review. One was from Michael Blaese and French Anderson for gene therapy on children like Ashanti DeSilva who suffered from SCID; the other was from Steven Rosenberg and colleagues who wanted to use the same tumour-infiltrating blood cells, now genetically altered, to deliver a tumor necrosis factor designed to kill tumor cells. Both protocols were approved, and the results of the SCID study were related above.

In December 1992 Dr. Bernadine Healy, then Director of the NIH, approved a compassionate use exemption from the regular review process, to allow a critically ill patient to receive gene therapy. This circumvention of the regular approval process proved very controversial and set off a series of meetings aimed at creating procedures for dealing with expedited review of single patient protocols in the future (V, National Institutes of Health 1993).

In October 1999, the death of Jesse Gelsinger, the first fatality in a gene therapy experiment, was reported in Nature (V, Lehrman 1999). Subsequent investigations revealed that the deaths of six gene therapy patients had not received the usual public disclosure that has characterized gene therapy research (V, Nelson and Weiss November 3, 1999). Gelsinger's death also raised questions about researcher entrepreneurial activities and conflict-of-interest, and about government oversight procedures (V, Nelson and Weiss November 21, 1999). The United States Senate held hearings on this topic on February 2, 2000. (V, United States Congress 2000), and the heightened scrutiny has resulted in increased reporting of adverse effects and renewed oversight by both NIH and FDA. (V, Smith and Byers 2002) Gelsinger's death also resulted in federal charges being brought against the clinical trial researchers and their institutions who reached a settlement with the U.S. Office of the Attorney General in February, 2005. (V. United States. Attorney 2005)

The success of a multi-center trial for treating children with SCID held from 2000 and 2002 was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily, but resumed after regulatory review of the protocol in the United States, the United Kingdom, France, Italy, and Germany. (V. Cavazzana-Calvo, Thrasher and Mavilio 2004)

Arguments in Favor of Gene Therapy

The central argument in favor of gene therapy is that it can be used to treat desperately ill patients, or to prevent the onset of horrible illnesses. Conventional treatment has failed for the candidate diseases for gene therapy, and for these patients, gene therapy is the only hope for a future. Many commentators liken somatic cell gene therapy to other new medical technologies, and argue that we have an obligation to treat patients if we can. Authors may use the term "human gene transfer research" (HGTR) to emphasize the current nontherapeutic nature of genetic research. (IV. Churchill et al.1998;  III. Lysaught 2004)

Eric Juengst summarized the arguments in favor of and against human germ-line gene therapy in 1991: 1) germ-line gene therapy offers a true cure, and not simply palliative or symptomatic treatment; 2) germ-line gene therapy may be the only effective way of addressing some genetic diseases; 3) by preventing the transmission of disease genes, the expense and risk of somatic cell therapy for multiple generations is avoided; 4) medicine should respond to the reproductive health needs of prospective parents at risk for transmitting serious genetic diseases; and 5) the scientific community has a right to free inquiry, within the bounds of acceptable human research. (IV, Juengst, 1991, p. 588-89)

Arguments Against Gene Therapy

Many persons who voice concerns about somatic cell gene therapy use a "slippery slope" argument against it. They wonder whether it is possible to distinguish between "good" and "bad" uses of the gene modification techniques, and whether the potential for harmful abuse of the technology should keep us from developing more techniques (VII, Hubbard and Wald 1993, p. 116). Other commentators have pointed to the difficulty of following up with patients in long-term clinical research. Gene therapy patients would need to be under surveillance for decades to monitor long-term effects of the therapy on future generations (VII, Ledley 1992). Some are troubled that many gene therapy candidates are children too young to understand the ramifications of gene therapy treatment.

Others have pointed to potential conflict of interest problems pitting an individual's reproductive liberties and privacy interests against the interests of insurance companies, or society not to bear the financial burden of caring for a child with serious genetic defects (VII, Leenen, 1988). Issues of justice and resource allocation have also been raised: in a time of strain on our health care system, can we afford such expensive therapy? Who should receive gene therapy? If it is made available only to those who can afford it, "the distribution of desirable biological traits among different socioeconomic and ethnic groups would become badly skewed" (Zimmerman, see IV, Juengst et al. 1991).

Arguments specifically against the development of germ-line gene therapy techniques include: 1) germ-line gene therapy experiments would involve too much scientific uncertainty and clinical risks, and the long term effects of such therapy are unknown; 2) such gene therapy would open the door to attempts at altering human traits not associated with disease, which could exacerbate problems of social discrimination; 3) as germ-line gene therapy involves research on early embryos and effects their offspring, such research essentially creates generations of unconsenting research subjects; 4) gene therapy is very expensive, and will never be cost effective enough to merit high social priority; 5) germ-line gene therapy would violate the rights of subsequent generations to inherit a genetic endowment that has not been intentionally modified (IV, Juengst 1991, p. 590).

The ethical issues posed by both somatic and germ-line gene therapies are international in scope. The documents listed below serve to demonstrate the variety of reactions to gene therapy, and to illuminate the complexity of this continuing public debate.

II. Organizational Statements/Policies

American Medical Association. Council on Ethical and Judicial Affairs. Opinions of the Council on Ethical and Judicial Affairs: Gene Therapy and Surrogate Mothers. Report E (I-88). Chicago: The Association, 1988. 3 p.

The American Medical Association approves of the use of somatic and germ-line gene therapy provided: 1) that the research conforms to its Council on Ethical and Judicial Affairs' guidelines on clinical investigations; 2) that it adheres to stringent safety considerations; and 3) that gene therapy only be utilized for therapeutic purposes in the treatment of human disorders, and not for enhancement or eugenic purposes.

Australia. National Health and Medical Research Council. Medical Research Ethics Committee. Ethical Aspects of Research on Human Gene Therapy: Report to the NHMRC by the Medical Research Ethics Committee of NHMRC. Canberra: Australian Government Publishing Service, 1987. 39 p.

The Committee concluded that certain forms of somatic cell gene therapy are ethically acceptable, but recommended that researchers in Australia not undertake germ-line gene therapy either in the laboratory or in human subjects.

Canada. Medical Research Council. Guidelines for Research on Somatic Cell Gene Therapy in Humans. Ottawa: Minister of Supply and Services, 1990. 44 p.

The Council approved the use of somatic cell theory for single-gene diseases with no other successful therapies. For the foreseeable future, only germ-line gene therapy on animal models may proceed.

Catholic Bishops. Joint Committee on Bioethical Issues. Genetic Intervention on Human Subjects: The Report of a Working Party. London: The Committee, 1996. 80 p.

Intended to be of use to the general public as well as to professionals in law, medicine, and pastoral counseling, this report on the moral problems raised by gene therapy is a product of a four-year collaboration by Roman Catholic clergy, physicians, lawyers, and philosophers in the United Kingdom. Chapters include a general review of the scientific aspects of gene therapy, a discussion of "genetic responsibility" and the value of human life, and recommendations on permissible forms of genetic intervention. Excerpts from papal documents relating to gene therapy are included as an appendix.

Catholic Health Association of the United States (CHA). Research Group on Ethical Issues in Early Human Development and Genetics. Human Genetics: Ethical Issues in Genetic Testing, Counseling, and Therapy. St. Louis, Mo.: Catholic Health Association of the United States; 1990. 58 p.

The CHA focuses on germ-line gene therapy and research on gametes and pre-embryos. It sees the development of "gonadal cell" therapy as an "especially important good to be sought insofar as therapies will provide a positive solution to a negative diagnosis." Because such therapy helps to avoid selective abortion for genetic defects, the CHA supports it.

Council for International Organizations of Medical Sciences (CIOMS). The Declaration of Inuyama and Reports of the Working Groups. Human Gene Therapy 2(2): 123-129, Summer 1991.

At a 1990 conference held in Tokyo and Inuyama, Japan, the Council adopted a policy statement on human genetics. Somatic cell gene therapy should be evaluated like other innovative therapies. It requires independent review and interventions should only be limited to conditions that cause significant disability, and not enhance or suppress cosmetic, behavioral or cognitive defects unrelated to a disease. Before germ-line gene therapy is undertaken, its safety must be very well established.

Council for Responsible Genetics. Position Paper on Human Germ Line Manipulation Presented by Council for Responsible Genetics, Human Genetics Committee Fall, 1992. Human Gene Therapy 4(1): 35-37, February 1993.

The Council unconditionally opposes germ-line gene therapy. Problems of obligations to future generations and social discrimination against those who do not submit to genetic engineering make such therapy intolerable.

Council of Europe. Parliamentary Assembly. Recommendation 934 (1982) on Genetic Engineering. Human Gene Therapy 2(4) 327-328, Winter 1991.

Based on its support of the right to life and to human dignity, the Council rejects germ-line genetic engineering because it would violate the implied right to a inherit a genetic pattern which has not been artificially changed. Somatic cell therapy is acceptable provided researchers follow standard guidelines for informed consent and for oversight by research ethics committees.

European Medical Research Councils. Gene Therapy in Man: Recommendations of European Medical Research Councils. Lancet 2 (8597): 1271-1272, 4 June 1988.

The Medical Research Councils of Austria, Denmark, Finland, France, The Netherlands, Norway, Spain, Sweden, Switzerland, the United Kingdom and West Germany agreed not to allow germ-line gene therapy.

France. National Ethics Advisory Committee (Comité Consultatif National d'Ethique). Announcement on Gene Therapy. Human Gene Therapy 2(4): 329, Winter 1991.

While approving research on gene therapy in France, the Committee placed some stringent constraints on such research. First, only somatic cell research is permitted; germ-line gene therapy is banned. The use of viral vectors to transfer genes is prohibited out of fear of damaging germ cells. Only monogenic(single gene) defects are candidates for gene therapy in France.

Glover, Jonathan, et al. Ethics of New Reproductive Technologies: The Glover Report to the European Commission. DeKalb: Northern Illinois University Press, 1989. 159 p.

Somatic gene therapy does not raise ethical questions significantly different from those raised by organ transplantation; the patient, with relatively low risk, may gain significant benefit from the procedure. However germ-line gene therapy should not be undertaken at this time due to concerns over the safety and concerns regarding our obligations to future generations.

Great Britain. Committee on the Ethics of Gene Therapy (Chairman: Cecil Clothier). Report of the Committee on the Ethics of Gene Therapy: Recommendations. [partial report] Human Gene Therapy 3(5): 519-523, October 1992. [Full report available from: London: Her Majesty's Stationery Office, 1992 January. 41 p. Command paper number: Cm 1788]

While the Clothier Committee recommended that germ-line gene therapy should not yet be undertaken, it approved continued study of somatic cell gene therapy. The Committee further recommended the establishment of a government supervisory body to provide scientific and medical advice on the safety and efficacy of human gene modification, and its use.

Netherlands. Health Council. Committee [on Genetic Testing and Gene Therapy]. Heredity: Science and Society -- On the Possibilities and Limits of Genetic Testing and Gene Therapy. The Hague: Health Council of the Netherlands, 1989 December 29. 196 p.

The Dutch Health Council approved of somatic cell gene therapy and urged a voluntary moratorium on germ-line gene therapy.

Sweden. Ministry of Health and Social Affairs. Swedish Act Concerning Use of Gene Technology on Human Beings and Experiments with Fertilised Ova. Stockholm: The Ministry, 1991. 17 p.

Research and experiments aimed at performing gene therapy on human somatic cells are ethically acceptable. When doing gene therapy experiments on such cells, steps must be taken to prevent the simultaneous occurrence of undesirable effects on gametes. Gene therapy on human gametes(sperm and ova) presents concerns over "human upgrading," which is deemed unethical and thus, prohibited.

United States. 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. Washington, DC: The Commission, 1982 November. 115 p.

In this first report by a government body, the Commission proposed new agencies to continue oversight of human gene therapy research, and defended research on gene therapy in the United States. The Commission concluded that somatic cell therapy was similar to other standard medical treatment, and is ethically acceptable. Germ-line gene therapy was not rejected, but indefinitely delayed due to technical and ethical barriers.

West Germany. Enquête Commission. An Extract from Prospects and Risks of Gene Technology: The Report of the Enquête Commission to the Bundestag of the Federal Republic of Germany. Bioethics 2(3): 254-275, July 1988.(Published in full as: German Federal Republic, Tenth Bundestag, Enquête-Kommission. Chancen und Risiken der Gentechnologie. Bonn: Referat Öffentlichkeitsarbeit, 1987).

This English translation of the crucial section on germ-line gene therapy from the Report of the Enquête Commission raises specific questions relating to germ-line gene therapy within the context of human embryo research. The Commission recommended that germ-line gene therapy be made a criminal offense. A previous section of the Report deals with somatic gene therapy which is ethically acceptable. Published with a critique by Hans-Martin Sass.

World Council of Churches. Subunit on Church and Society. Biotechnology: Its Challenge to the Churches and the World. Geneva: The Council, 1989. 34 p.

The Council calls for a ban on germ-line gene therapy and recommends strict control over somatic cell gene therapy, bearing in mind the potential misuse of the technology to discriminate against those held to be defective.

World Medical Association. World Medical Association Statement on Genetic Counseling and Genetic Engineering. No. 17.S. Available from the World Medical Association, 28 Avenue des Alpes, 01210 Ferney-Voltaire, France. 1987 October. 2 p.

The Association makes general recommendations regarding gene therapy. It suggests that such research on human subjects adhere to guidelines posed in the Declaration of Helsinki, and that full informed consent be obtained. No hazardous or unwanted virus can be inserted into patients. Evaluation of the effectiveness of the therapy should be made. Human gene therapy should not be performed if simpler or safer treatment exists for a disease.

III. General

Anderson, W. French. Human Gene Therapy. Science 256(5058): 808-813, 8 May 1992.

Hematologist and gene therapist Anderson describes the first 11 clinical protocols dealing with gene therapy or gene marking. He briefly surveys ethical and social considerations of gene therapy.

Anderson, W. French, and Theodore Friedmann. Gene Therapy: I. Strategies for Gene Therapy. In Encyclopedia of Bioethics. Revised Edition, pp. 907-914. Warren T. Reich, ed. New York: Simon & Schuster Macmillan, 1995.

The authors describe three different types of somatic cell gene therapy - ex vivo, in situ, and in vivo - and the methods by which genes are transferred to an individual. They detail the criteria necessary for the development of germ-line(reproductive cell) therapy and explain the potential impact of such procedures on society and future generations.

Berger, Edward M. Ethics of Gene Therapy. In his Morality and the New Genetics: A Guide for Students and Health Care Providers, with Bernard Gert, et al., pp. 209-223. Sudbury, MA: Jones and Bartlett Publishers, 1996.

This textbook chapter reviews the pros and cons of gene therapy and describes the biological basis for concerns raised about the potential effects of germ-line interventions on future generations.

Fletcher, John C. Evolution of Ethical Debate about Human Gene Therapy. Human Gene Therapy 1(1): 55-68, Spring 1990.

Bioethicist Fletcher traces the development of the acceptance of somatic cell gene therapy in the United States, beginning with Nirenberg, Cline, Rogers, and culminating in gradual acceptance of genetic treatment.

Fletcher, John C., and Anderson, W. French. Germ-Line Gene Therapy: A New Stage of Debate. Law, Medicine and Health Care 20(1-2): 26-39, Spring-Summer 1992.

Fletcher and Anderson present an ethical argument that supports the approval of pre-embryo experiments, and compares ethical and social priorities of research in germ-line gene therapy to other human subjects research.

Gura, Trisha. After a Setback, Gene Therapy Progresses ... Gingerly. Science 291(5509): 1692-1695, 1697, March 2 2001

After noting that gene therapy research is "...a field in which hype has far outstripped payoffs," Gura provides a history of genetic research in hemophilia, and describes the current climate of clinical trials using human subjects after the field's first death [Jesse Gelsinger.]

Howell, Joel D. The History of Eugenics and the Future of Gene Therapy. Journal of Clinical Ethics 2(4): 274-278, Winter 1991.

Howell surveys the recent history of eugenics including the Immigration Restriction Act of 1924, the sterilization of Carrie Buck, and Nazi eugenics. Pointing to history's relevance for those contemplating germ-line gene therapy, he believes that scientists, physicians, and the public ought to be aware of the slippery slope on which we as a society have embarked.

Kimmelman, Jonathan. Recent Developments in Gene Transfer: Risk and Ethics. BMJ: British Medical Journal 330(7482): 79-82, January 8, 2005. [Online]. Available: http://bmj.bmjjournals.com/cgi/content/full/330/7482/79

Noting that "[s]ince the early 1990s, investigators have toiled to establish the transfer of genes to human somatic cells as a valid therapy", Kimmelman describes the difference between using regular drugs and gene transfer agents in a clinical trial, summarizes the unusual ethical issues raised by these differences, and details the risk factors unique to gene transfer trials.

Juengst, Eric, and Walters, LeRoy. Gene Therapy: II. Ethical and Social Issues. In Encyclopedia of Bioethics. Revised Edition, pp. 914-922. Warren T. Reich, ed. New York: Simon & Schuster Macmillan, 1995.

Reviewing early commentaries on the social implications of genetic intervention by such authors as Hermann J. Muller, Paul Ramsey, and Karl Rahner, Juengst and Walters chronicle the responses of both professional organizations and governments to the advent of genetic research. They note that the intense public debate about the potential abuses of genetic technologies has resulted in a high level of public confidence about the ability of the parties involved to work for the good of all, and that previous biomedical developments could have benefited for such a comprehensive dialogue.

Krimsky, Sheldon. Human Gene Therapy: Must We Know Where to Stop Before We Start? Human Gene Therapy 1(2): 171-173, Summer 1990.

University professor Krimsky criticizes the common distinctions used for gene therapy: somatic v. germ cells, and therapeutic use v. enhancement, because the distinctions are too easy to blur. He argues that we should only allow somatic cell therapy for life-threatening or severely debilitating disease until we can find better moral rules.

Ledley, Fred D. Are Contemporary Methods for Somatic Gene Therapy Suitable for Clinical Applications? Clinical and Investigative Medicine 16(1): 78-88, February 1993.

Biologist Ledley raises the question of whether current clinical trials gained approval prematurely. He suggests that gene therapy can be performed in select clinical trials safely and with public acceptance, and while there is still much to be learned, existing methods may be employed fairly in clinical trials.

Lyon, Jeff, and Gorner, Peter. Altered Fates: Gene Therapy and the Retooling of Human Life. New York: W.W. Norton, 1995. 636 p.

These Chicago Tribune writers covered the developments in genetic research for over a decade and expanded their articles into a journalistic history of gene therapy. They report on the initial gene therapy experiments, the scientists involved in the research, the patients selected for treatment, and the oversight activities of the federal government. Various opinions on whether the potential benefits of gene therapy have been "oversold" are presented along with differing views of appropriate government regulation.

Lysaught, M. Therese. Human Gene Transfer Research. In: Encyclopedia of Bioethics, 3rd edition, Volume 2. New York : Macmillan Reference, 2004, p. 1204-1209.

The author reviews basic terminology for genetic clinical protocols, outcomes of clinical trials to date, and oversight of human gene transfer research (HGTR). Lysaught also discusses economic incentives for "orphan disease" drug development as it applies to HGTR.

Macer, Darryl; Akiyama, Shiro; Alora, Angeles Tan; Asada, Yukiko, et al. International Perceptions and Approval of Gene Therapy. Human Gene Therapy 6: 791-803, June 1995.

The authors describe a survey conducted in Asia and Australasia that gathered data on public attitudes toward gene therapy. They discovered that the "diversity of comments was generally found to be the same in different countries, suggesting that reasoning about these issues goes deeper than cultures, or religions..." The authors discuss the implications of their findings for the development of international guidelines for gene therapy.

Macer, Darryl R.J. Public Acceptance of Human Gene Therapy and Perceptions of Human Genetic Manipulation. Human Gene Therapy 3(5): 511-518, October 1992.

Bioethicist Macer compares attitudes and general public acceptance of the use of gene therapy in humans. Macer details reactions in Japan to gene therapy experiments, which are basically favorable, and compares Japanese reactions to European and American public opinion.

Marcel, T., and Grausz, David. The TMC Worldwide Gene Therapy Enrollment Report. Human Gene Therapy 7(16): 2025-2046, October 20, 1996; and 8(6): 775-800, April 10 1997.

When the Recombinant DNA Advisory Committee's (RAC) duties were revised and it was no longer reviewing each gene therapy protocol, the RAC's "Appendix M" listing the particulars of all existing trials ceased to exist. A European consulting firm, TMC Development, took on the task of compiling a similar list of data provided to them on a voluntary basis. Their chart includes information on the number of participants in each trial and the disease from which they suffer, the gene and vector used, the type of procedure(in vivo/ex vivo) employed, and the country of origin.

Marshall, Eliot. Less Hype, More Biology Needed for Gene Therapy. Science 270(5243): 1751, December 15, 1995.

A summary of the findings of NIH's Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy is followed by an elaboration on the panel's fear that "basic science [is] being neglected as enthusiasts race to join the gene therapy club". This article also reports on responses to the recommendations by geneticists involved in gene therapy research.

National Institutes of Health (United States) Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy. December 7, 1995. Bulletin of Medical Ethics 116: 10-11, March 1996 [Executive Summary]. Available: online. NIH. http://www.nih.gov/news/panelrep.html [Full report]

The panel, chaired by geneticist Arno Motulsky and hematologist Stuart Orkin, reviews the status of gene therapy after 5 years of experimentation and notes that, despite positive anecdotal reports, "...significant problems remain in all basic aspects of gene therapy", and "[e]xpectations of current gene therapy have been oversold." The panel's recommendations focus on funding limitations, project coordination, basic science/clinical research combinations, and study evaluations.

National Institutes of Health (Unites States). Recombinant DNA Advisory Committee. Human Gene Therapy Subcommittee. Gene Therapy for Human Patients: Information for the General Public. Bethesda, MD: National Institutes of Health, 1990 April. 13 p.

While this brochure does not specifically address ethical questions pertaining to human gene therapy, it does provide a concise explanation of how one variety of gene therapy works, highlights the regulatory process for such research and provides an outline of the "Points to Consider" document.

Nichols, Eve K. Institute of Medicine; National Academy of Sciences. Human Gene Therapy. Cambridge, MA: Harvard University Press, 1988. 251 p.

Following a segment on the technical and clinical aspects of human gene therapy are sections on ethical and economics issues, Federal oversight, and prospects for the future of human gene therapy. The text of the "Points to Consider" document, and a glossary of genetics terms are included.

Ross, Gail; Erickson, Robert; Knoor, Debra; Motulsky, Arno G.; Parkman, Robertson; Samulski, Jude; Straus, Stephen E.; and Smith, Brian R. Gene Therapy in the United States: A Five-Year Status Report. Human Gene Therapy 7(14) 1781-1790, September 10, 1996.

This summary of progress report data submitted to the Recombinant DNA Advisory Committee through June, 1995, by the principal investigators of existing gene therapy studies provides an overview of gene therapy clinical trials in the United States. In addition to describing individual projects, the article contains charts on number of protocols/patients by disease and protocol type, and the number of vectors used and their advantages/disadvantages.

Rubanyi, Gabor M., and Yia-Herttuala, Seppo, eds. Human Gene Therapy: Current Opportunities and Future Trends. New York: Springer-Verlag, 2003. 252 p.

This volume contains the proceedings of the Ernst Schering Research Foundation Workshop No. 43 on human gene therapy held in Berkeley, California on October 2-4, 2002. Discussions focus on four themes: 1) cardiovascular diseases; 2) cancer; 3) CNS diseases; and 4) novel technologies.

Rubenstein, Donald S.; Thomasma, David C.; Schon, Eric A.; and Zinaman, Michael J. Germ-Line Therapy to Cure Mitochondrial Disease: Protocol and Ethics of In Vitro Ovum Nuclear Transplantation. Cambridge Quarterly of Healthcare Ethics 4(3): 316-339, Summer 1995.

The authors describe what they term "the first germ-line therapy protocol developed" - IVONT(in vitro ovum nuclear transplantation) - in vitro fertilization of an egg which has had its abnormal mitrochondria replaced. This protocol is proposed to eliminate degenerative neuromuscular abnormalities in children born to those suffering from MELAS(mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes). The authors address fears and ethical quandaries concerning germ-line therapy generally, such as whether "by removing certain diseases we destroy a flexibility in the genome that would be a benefit to future generations, just as sickle-cell anemia is thought to be a benefit in people faced with malaria." While they recommend caution in the use of germ-line therapy, the authors point out that "the skills developed in intervening in the germ line will stand us in good stead for further interventions down the line should problems later be revealed." They call for "a collective, world-wide effort of cooperation and discussion" on germ-line interventions since the issue lies "not just along an ethical or scientific axis, but also along the axis of the power of human healing."

Symposium on Biomedical Technology and Health Care: Social and Conceptual Transformations. Southern California Law Review 1(65): 1-735, November 1991.

Devoted to ethical and social issues in biotechnology, the issue includes articles by Robertson Parkman on "Gene Therapy in the 1990s;" Alexander Capron on "Biomedical Technology and Health Care;" Michael Shapiro on "The Technology of Perfection;" and Daniel Kevles on "Vital Essences and Human Wholeness."

Thompson, Larry. Correcting the Code: Inventing the Genetic Cure for the Human Body. New York: Simon & Schuster, 1994. 378 p.

A journalist for the Washington Post, Thompson traces the development of gene therapy and reports on the establishment of federal guidelines and administrative procedures to protect those involved in the experiments. He concludes with an epilogue on genetically altered stem cells and the hopes of researchers and patients for the perfection of this treatment.

U.S. Congress. Office of Technology Assessment. New Developments in Biotechnology, Volume 2: Background Paper: Public Perceptions of Biotechnology. Washington, DC: OTA, 1987. 127 p.

The report contains the result of a nationwide survey of public knowledge and attitudes about genetics and the future of technology, including a section on gene therapy.

Walters, LeRoy, and Palmer, Julie Gage. The Ethics of Human Gene Therapy. New York: Oxford University Press, 1997. 209 p.

In their preface, the authors note that this book is published "at an appropriate moment for appraising the first stage of gene therapy research with human patients." Even though more than 100 gene therapy protocols have been developed since the first approved study in 1990, "...many researchers in the field are pausing to catch their breath... [as] diseases that plague human beings have proven to be much more difficult to defeat than some researchers had anticipated." Chapters focus on the biology of gene function, somatic and germ-line therapies, enhancement genetic engineering, and public policy for gene therapy. The NIH Recombinant DNA Advisory Committee's "Points to Consider" are included as an appendix along with brief overviews of cell function, Mendelian inheritance, methods for transferring genes to cells, and homologous recombination.

Weiner, Jonathan. His Brother's Keeper: A Story from the Edge of Medicine. New York: Ecco/HarperCollins, 2004. 356 p.

When his brother Stephen was diagnosed with amyotrophic lateral sclerosis (also known as ALS, Lou Gehrig's disease, or Charcot's disease) at the age of 29, Jamie Heywood formed a biotech company to find a cure for ALS utilizing gene therapy. In his chronicle, Weiner interweaves personal narratives and discussions of the emerging ethical issues with descriptions of the business and scientific milieux of the time.

Wivel, Nelson, and Walters, LeRoy. Germ-Line Gene Modification and Disease Prevention: Some Medical and Ethical Perspectives. Science 262(5133): 533-538, 22 October 1993.

The head of the Office of Recombinant DNA Activities at the NIH and the chair of the RAC summarize the technical obstacles that must be overcome before human germ-line gene therapy can be considered for approval, and encourage public debate over the ethical considerations that will likely be faced by the RAC sometime in the future.

IV. Philosophical Aspects

Churchill, Larry R.; Collins, Myra L.; King, Nancy M. P.; Pemberton, Stephen G.; and Wailoo, Keith A. Genetic Research as Therapy: Implications of "Gene Therapy" for Informed Consent. Journal of Law, Medicine and Ethics 1998 Spring; 26(1): 38-47.

The authors discuss the ease with which genetic research is misnamed "therapy", and provide an historical background for this misnomer. While noting that "...the persistent failure to distinguish clearly between research and therapy in medical science" is not limited to genetic protocols, the authors suggest that the term "gene transfer research" be used to highlight its experimental nature and deemphasize its therapeutic potential.

Engelhardt, H. Tristram. Germ-Line Genetic Engineering and Moral Diversity: Moral Controversies in a Post-Christian World. Social Philosophy and Policy 13(2): 47-62, Summer 1996.

The author maintains that "absent a religious or culturally normative understanding of human nature and given the availability of germ-line genetic engineering, there is a plurality of possibilities for refashioning our nature." While elimination of deadly diseases is one aspect of genetic engineering's moral significance, another is "the possibility that numerous possible future alternatives may be chosen, fracturing mankind into numerous different species of humans." Given that there are no content-full norms for guidance, the author concludes that the decision to undergo germ-line gene therapy would rest with the individual.

Fowler, Gregory; Juengst, Eric T.; and Zimmerman, Burke Z. Germ-Line Gene Therapy and the Clinical Ethos of Medical Genetics. Theoretical Medicine 10: 151-165, June 1989.

Three sets of arguments against developing gene therapy are discussed, concentrating on the clinical risks, social dangers and better alternatives. Those arguments are evaluated from the perspective of the client-centered ethos that traditionally governs practice in medical genetics. This vantage point suggests useful new directions for the professional discussion of germ-line gene therapy and suggests that germ-line therapy in human pre-embryos may always be more problematic for medical genetics than adult germ-line interventions despite greater technical difficulties.

Goering, Sara. Gene Therapies and the Pursuit of a Better Human. Cambridge Quarterly of Healthcare Ethics 9(3): 330- 41, Summer 2000.

Goering explores the "treatment vs. enhancement" distinction in genetic medicine, and suggests using a decision-making model based on Rawls' "veil of ignorance" as a first step in determining what would constitute a justifiable genetic improvement. Speculating that the designation of a trait as a "disability" may in fact devalue the lives of those currently living with that trait, the author points out that any discussion of what constitutes treatment or enhancement is based primarily on how society defines disease.

Grey, William. Design Constraints for the Post-human Future. Monash Bioethics Review 24(2): 10-19, April 2005.

Grey examines the conundrum where..."the difficulty in identifying the individuals who might be adversely affected by [germ-line gene therapy is that] the identity of the individuals is determined, at least in part, by the choices made." The author proposes that these future individuals be safeguarded by limiting germ-line research to those traits that would enrich but not change basic human characteristics.

Hughes, James J. Embracing Change with All Four Arms: A Post-Humanist Defense of Genetic Engineering. Eubios: Journal of Asian and International Bioethics 6(4): 94-101, July 1996.

Describing his journey from gentle Luddite to democratic post-humanist in regard to germline intervention, Hughes addresses critiques ("bio-luddisms") and concerns ("gene angst"), including the "geneticization" of life and the value of genetic diversity. He concludes that "...the relations between new genetic communities will hopefully be mediated by the same institutions, courts and legislatures, minority rights and majority rule. The real challenge faced by a post-human ethic is to define new parameters for which forms of life should be considered property...".

Juengst, Eric T., et al. Human Germ-Line Engineering. Journal of Medicine and Philosophy 16(6): 587-694, December 1991.

This entire issue of the Journal is on germ-line gene therapy, and includes many oft-cited articles. In the introductory article, Germ-Line Gene Therapy: Back to the Basics, Juengst outlines the arguments in favor of and against human germ-line gene therapy. Burke K. Zimmerman discusses risks and uncertainty in Human Germ-Line Gene Therapy: The Case for Its Development and Use. In How Do We Think about the Ethics of Human Germ-Line Genetic Therapy? Kathleen Nolan addresses the persistent questions as to who is the patient in germ-line therapy and how much discretion should be left to potential parents and/or researchers. Marc Lappé focuses on intergenerational equity and secondary germ-line effects in Ethical Issues in Manipulating the Human Germ-Line. In Maintaining the Somatic/Germ-Line Distinction Ray Moseley challenges the conventional wisdom that while somatic therapy may be ethically acceptable, germ-line therapy is not. Swiss authors Alex Mauron and Jean-Marie Thévoz report on European reaction to human germ-line gene therapy in Germ-Line Engineering: A Few European Voices. And finally, in Genetic Disorders and the Ethical Statues of Germ-Line Gene Therapy, Edward M. Berger and Bernard M. Gert discuss evolutionary concerns and iatrogenic dangers of gene therapy, and express their reluctance to approve of germ-line gene therapy based on slippery slope arguments.

Keenan, James F. What is Morally New in Genetic Manipulation? Human Gene Therapy 1(3): 289-298, Fall 1990.

Theologian Keenan argues that an act-oriented ethics is inadequate and that only a virtue-oriented ethics enables us to recognize and resolve problems caused by genetic manipulation. He expresses concerns that through genetics we will be in danger of objectifying the human subject.

Lysaught, M. Therese. Gene "Therapy": A Test Case for Research With Children. In: Genetics and Ethics: An Interdisciplinary Study, Gerard Magill, ed. St. Louis, Missouri: Saint Louis University Press, 2004, pp. 216-252.

Beginning her chapter with the statement "[t]he cultural face of gene therapy is that of a child", Lysaught argues that this iconic status functions to "...forestall critique, to displace argument, to garner public support - and public monies - for human gene transfer research." Drawing from her experience as a reviewer of a gene transfer protocol for HIV-positive children, the author examines the ways in which uncertainty about what constitutes "minimal risks" and "prospects for benefit" in research with children generally are intensified when gene transfer research is considered to be "gene therapy".

McGee, Glenn. The Not-So-Deadly Sins of Genetic Enhancement. In his The Perfect Baby: A Pragmatic Approach to Genetics, pp. 111-133. London: Rowman & Littlefield, 1997.

The author suggests that the distinction between gene therapy as cure versus genetic intervention for enhancement is a false one. McGee reminds us that the desire for self-improvement predates genetic experimentation, and notes that "our current cultural focus on the moral issues associated with 'enhancement' depends on a... cultural faith in a particular and deceptively clear description of the limits of human nature and the territory of clinical medicine... When new interventions are proposed, the correct question is not 'Is this medicine or enhancement?' but rather 'Will this approach to this issue work better than others?" The author critiques Norman Daniels' notion of "species-typical functioning"(as it pertains to the cure versus enhancement debate) as an inappropriate exercise in specifying norms.

McGleenan, Tony. Human Gene Therapy and Slippery Slope Arguments. Journal of Medical Ethics 21(6): 350-355, December 1995.

After discussing the distinction between logical and rhetorical slippery slope arguments, the author reviews the application of both types to gene therapy. McGleenan points out that the clear conceptual and biological differences between somatic cell and germ-line therapy seriously undermine the use of slippery slope arguments when evaluating these procedures(ie., if somatic cell therapy is permitted, germ-line therapy doesn't necessarily follow because it is distinctly different). The author goes on to note that the "rhetorical force [of slippery slope arguments] can obscure the arguments' obvious philosophical flaws. Detailed analysis of the weakness of slippery slope claims should help to displace such claims from their prominent position in ethical debates and allow attention to be focused on the demanding and important aspects of moral line-drawing in the new genetic technologies."

Munson, Ronald, and Davis, Lawrence H. Germ-Line Gene Therapy and the Medical Imperative. Kennedy Institute of Ethics Journal 2(2): 137-158, June 1992.

Munson and Davis argue that medicine has a prima facie moral obligation to continue developing gene therapy techniques, and that germ-line gene therapy is not morally unacceptable.

Parens, Erik. The Goodness of Fragility: On the Prospect of Genetic Technologies Aimed at the Enhancement of Human Capacities. Kennedy Institute of Ethics Journal 5(2): 141-152, June 1995.

The author ponders "what might be lost if, to an unprecedented extent, we could reduce our vulnerability to change and chance" through gene therapy. He contrasts the work of philosopher Francis Bacon "...[who] thinks that nature is ours to use in whatever ways conduce to our desires..." with that of theologian Hans Jonas "...[who] thinks that because nature is in an important sense not ours - 'being [is] strictly on loan'- we ought not to use it." While he asserts that gene therapy should be used to heal the sick and that attempts to control genetic enhancement would be foolish, Parens calls for us to "think more deeply about how attempts at control and alteration that truly enhance life are different from those that impoverish it" for "it would be profoundly tragic if the virtue that is our capacity for self-transformation became a vice."

Rosenkranz, E. Joshua. Custom Kids and the Moral Duty to Genetically Engineer Our Children. High Technology Law Journal 2(1): 1-53, Spring 1987.

Attorney Rosenkranz argues that we have a duty of "genetic rescue," and that human germ-line gene therapy is morally acceptable so long as: 1) the redesigned person is "still the same;" and 2) the intervention is beneficial.

Shickle, Darren. Are "Genetic Enhancements" Really Enhancements? Cambridge Quarterly of Healthcare Ethics 9(3): 342- 352, Summer 2000.

Shickle discusses genetic enhancements in the context of cosmetic and pharmacological ones, and notes that the high percentage of side effects in the latter calls into question the "progressive" nature of enhancements. Noting that all decisions about biotechnology are based on some concept of the "good," the author describes "enhancement" as a normative concept rather than as a cost-benefit ratio to be analyzed.

Stock, Gregory. Ethics and Ideology. In his Redesigning Humans: Our Inevitable Genetic Future. New York: Houghton Mifflan 2002, pp. 124 - 152.

An enthusiastic supporter of germinal choice technology (GCT), the author rebuts the stock arguments against modifying our biology. Claiming that genetic enhancement is "...more like a slippery sidewalk than a slippery slope", Stock suggests that we "...concentrate on the specific choices parents can make about their children's genes and try to discourage those practices that seem damaging" rather than follow our current approach "...to worry about the technicalities of the procedure itself" which hinge "...on philosophical abstractions far removed from dangers to present or future humans."

Tauer, Carol A. Does Human Gene Therapy Raise New Ethical Questions? Human Gene Therapy 1(4): 411-418, Winter 1990.

Tauer concludes that most of the ethical concerns expressed about gene therapy have appeared in the bioethical literature already in other contexts. She revisits concerns about tampering with "human nature," our obligations to future generations and the status of early human embryos. Tauer sees subtle changes in our attitudes to risk and human experimentation, in publicity and public perceptions of biotechnology, and in our attitudes toward "defective" individuals.

van Tongeren, Paul J.M. Ethical Manipulations: An Ethical Evaluation of the Debate Surrounding Genetic Engineering. Human Gene Therapy 2(1): 71-75, Spring 1991.

Dutch philosopher van Tongeren argues that we need to be careful that science and politics not lead the discussion of the morality of genetic engineering. The crucial question is: When and how are we allowed to manipulate?

Walters, LeRoy. Ethical Issues in Human Gene Therapy. Journal of Clinical Ethics 2(4): 267-274, Winter 1991.

Bioethicist Walters begins by tracking the early history of gene therapy from the unauthorized experiments of Martin Cline, through the creation of the RAC's Human Gene Therapy Working Group/Subcommittee, and ending with details on the review process for the first gene transfer experiment in 1989 and the first gene therapy protocol in 1990. The second half on the article delineates some ethical arguments relating to germ-line gene therapy.

Zohar, Noam J. Prospects for "Genetic Therapy" -- Can a Person Benefit from Being Altered? Bioethics 5(4): 275-288, October 1991.

Zohar argues that persistence of the human genotype is necessary to maintain the personal identity, and the essence of the individual, including preembryos. We must not use prenatal genetic intervention unless an embryo is at risk for some deadly illness.

V. Regulation and Public Policy

Anderson, W. French. Human Gene Therapy: Why Draw a Line? Journal of Medicine and Philosophy 14(6): 681-693, December 1989.

Anderson believes we should draw a moral line at gene therapy for enhancement purposes. The basis for our uneasiness over enhancement therapy lies with the fear that genetic engineering could lead to changes in "human nature."

Areen, Judith. The Greatest Rewards and the Heaviest Penalties. Human Gene Therapy 3(3): 277-78, June 1992.

In a brief essay, law professor Areen outlines the reasons for ethics review panels and emphasizes the necessity of carrying out RAC deliberations in public. Ethics review panels can 1) educate the public; 2) lead to protocols that are more scientifically rigorous; and 3) are the requisite safeguards imposed by democratic government.

Baruch, Susannah; Huang, Audrey; Pritchard, Daryl; Kalfoglou, Andrea; Javitt, Gail; Borchelt, Rick; Scott, Joan; and Hudson, Kathy. Genetics and Public Policy Center. Human Germline Genetic Modification: Issues and Options for Policymakers. Washington, DC: The Center, 2005 May; 63 p. [Online] Available: http://tools-content.labvelocity.com/pdfs/6/68176.pdf

Noting that public opinion concerning human germline genetic modification (HGGM) "...has come from Hollywood in the form of disquieting, sometimes horrific portrayals of the results of irresponsible scientific tampering or accidental mishaps", the authors conducted focus groups across the country to collect data regarding what Americans really think about HGGM. This report provides a summary of their research, a review of current regulatory oversight, and suggestions for future government policies that could foster innovation within an ethical environment.

Bonnicksen, Andrea L. National and International Approaches to Human Germ-Line Gene Therapy. Politics and the Life Sciences 13(1): 39-49, February 1994.

After reviewing the guidelines of various countries for genetic screening and therapy, the author critiques the goal of "transnational harmonization" for genetic intervention as reflecting "...the assumption that genes are public resources, like the sea and air, and that deliberations must represent all humans." She concludes that international normative codes should develop from empirical evidence gathered in diverse communities rather than from abstract principles imposed in a hierarchical fashion.

Carmen, Ira H. Human Gene Therapy: A Biopolitical Overview and Analysis. Human Gene Therapy 4(2): 187-193, April 1993.

Carmen argues that political science offers the best methodology with which to evaluate decisions regarding the future of human gene therapy research. He focuses on the track record of the RAC in directing the procedures by which human gene therapy protocols are approved.

Cavazzana-Calvo, Marina; Thrasher, Adrian; and Mavilio, Fulvio. The Future of Gene Therapy. Nature 2004 February 26; 427(6977): 779-781.

After providing the history of a multi-center clinical trial for treating SCID in which two patients developed leukemia, the authors discuss the ethical dilemma posed by technological advances that both improve treatment success rates and increase the risk for adverse effects.

Cook-Deegan, Robert Mullan. Human Gene Therapy and Congress. Human Gene Therapy 1(2): 163-170, Summer 1990.

Cook-Deegan unfolds the developments of the 1980s with regard to the regulation and politics of human gene therapy. As a staff member of the Office of Technology Assessment, and the Director of the abortive Biomedical Ethics Advisory Committee, he provides an insider's overview of the political complexities surrounding human gene therapy.

deWachter, Maurice A.M. Ethical Aspects of Human Germ-Line Gene Therapy. Bioethics 7(3): 166-177, April 1993.

DeWachter highlights the stands taken by various government commissions and independent organizations in Europe on human gene therapy.

Epstein, Suzanne L. Regulatory Concerns in Human Gene Therapy. Human Gene Therapy 2(3): 243-249, Fall 1991.

Epstein explains the regulatory responsibilities of the United States Food and Drug Agency (FDA) and its interaction with the RAC in evaluating protocols for human gene therapy. The RAC focuses on basic sciences, clinical medicine, law, ethics, theology and preclinical testing in regularly scheduled, public meetings. The FDA studies basic science, clinical medicine, regulatory issues, manufacturing processes, quality control and preclinical testing in confidential meetings scheduled on an as-needed basis. The scientific and regulatory basis for the requests for data in the FDA "Points to Consider" document are also discussed.

Foundation on Economic Trends. Petition to Amend the National Institutes of Health Guidelines for Research Involving Recombinant DNA Molecules to Establish a Public Policy Advisory Committee, 18 September 1990 [and] Proposed Amendment to the National Institutes of Health Guidelines for Research Involving Recombinant DNA Molecules to Establish a Public Policy Advisory Committee. Human Gene Therapy 2(2): 131-134, Summer 1991.

The Foundation proposes to establish a Public Policy Advisory Committee, parallel to the RAC to advise the NIH on matters relating to public policy and genetic research. Foundation President Jeremy Rifkin seeks to give more voice to public policy concerns in the approval process for such genetic research. Citing the SCID protocol approved by the NIH in 1990, the Foundation opposes gene therapy on the basis that "the therapy violates the general ethical rule that the benefits to an individual from an experimental therapy should equal or exceed the potential harm."

Gardner, William. Can Human Genetic Enhancement Be Prohibited? Journal of Medicine and Philosophy 20(1): 65-84, February 1995.

The author maintains that banning gene therapies that enhance human capabilities not only would be unenforceable but also could lead to "DNA audits" that "would violate other principles prized in liberal societies, including the privacy of reproductive decision-making and the autonomy of families in choices about the development and rearing of children."

Gene Therapy Advisory Committee, Health Departments of the United Kingdom. Second Annual Report: January 1995-December 1995 (May 1996). Human Gene Therapy 7(15): 1915-1922, October 1, 1996.

This report gives information on gene therapy research in the United Kingdom, including the number of approved clinical trials by disease, the status of those trials, exemptions and guidance issues, and a list of committee members and their addresses.

Juengst, Eric T. The NIH "Points to Consider" and the Limits of Human Gene Therapy. Human Gene Therapy 1(4): 425-433, Winter 1990.

Juengst examines the basis for the "Points to Consider" document: the ethical discussion of research with human subjects and the recombinant DNA debate. Such precedents provided six criteria by which to evaluate human gene therapy proposals. Juengst writes that the criteria have not provided a principled basis for our banning the development of these forms of genetic intervention. "Points to Consider" will facilitate the discussion of gene therapy in terms its moral limits and the professional policy question about the goals of medicine, instead of seeing the gene therapy debate as a social policy question about the public good.

Kaiser, Jocelyn. Panel Urges Limits on X-SCID Trials. Science 307(5715): 1544-1545, March 11, 2005.

While gene therapy trials for X-linked severe combined immunodeficiency (X-SCID) had resumed following a review of two trial participants who had developed leukemia, an additional case of a different form of leukemia occurring in another child prompted a recommendation that only patients for whom conventional treatment has failed should be enrolled in X-SCID trials.

Larson, Edward J. Human Gene Therapy and the Law: An Introduction to the Literature. Emory Law Journal 39(3): 855-874, Summer 1990.

In an entire issue devoted to the Genetics and the Law Symposium, law professor Larson provides a highly readable survey of the varied literature on gene therapy. Additional articles germaine to gene therapy include: Alexander Capron on Which Ills to Bear?; John Robertson on Procreative Liberty and Human Genetics; and John Fletcher and Dorothy Wertz on Ethics, Law, and Medical Genetics.

Lehrman, Sally. Virus Treatment Questioned After Gene Therapy Death. Nature 401(6753): 517-8, October 7, 1999.

National Institutes of Health (United States) [NIH]. Office of Biotechnology Activities [OBA]. NIH Guidelines for Research Involving Recombinant DNA Molecules. Appendix M: Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA Molecules into One or More Human Research Participants. Bethesda, MD: National Institutes of Health [NIH], April 2002. 16 p.

National Institutes of Health (United States) [NIH]. Office of Biotechnology Activities [OBA]. Recombinant DNA and Gene Transfer [Web Site].

OBA'sWeb site for rDNA research contains current information about the Recombinant DNA Advisory Committee, fact sheets, and links to the NIH guidelines for rDNA research and gene transfer.

National Institutes of Health (United States). Recombinant DNA Research; Actions Under Guidelines; Notice -- E. Points to Consider for Protocols for the Transfer of Recombinant DNA into the Genome of Human Subjects. Federal Register 55(41): 7443-7447, 1 March 1990.

This document provides researchers with a framework against which to evaluate their proposals for human gene therapy. It includes technical questions as well as ethical ones.

National Institutes of Health (United States). Recombinant DNA Advisory Committee. Minutes of Meeting, January 14, 1993. Human Gene Therapy 4(4): 529-544, August 1993.

The minutes of this important meeting of the RAC relate the story of Bernadine Healy's compassionate use exemption, and the subsequent turmoil caused within the RAC.

Nelson, Deborah, and Weiss, Rick. Hasty Decisions in the Race to a Cure? Gene Therapy Study Proceeded Despite Safety, Ethics Concerns. Washington Post November 21, 1999: A1, A26-A27.

Nelson, Deborah, and Weiss, Rick. NIH Not Told of Deaths in Gene Studies. Washington Post November 3, 1999: A1, A6-A7.

Palmer, Julie Gage. Liability Considerations Presented by Human Gene Therapy. Human Gene Therapy 2(3): 235-242, Fall 1991.

Using a hypothetical case of a human gene therapy experiment gone awry, attorney Palmer discusses legal liability associated with gene therapy. Basic negligence principles are applied to the case, including its prior governmental review and its potential effect on future generations. Palmer expresses concerns about the limits of liability and the effects of gene therapy on future generations.

Singer, Peter, and Wells, Deane. Genetic Engineering. In Ethical Issues in Scientific Research: An Anthology, Erwin Edward, Sidney Gendin, and Lowell Kleiman, eds., pp. 307-320. New York: Garland Publishing, 1994.

Although the authors assert that "therapeutic" genetic enhancement(that which enables one to live a full and healthy life) is desirable, they caution that regulating such therapies should not be left solely to either the government or to individuals. Rather, "...the genetic endowment of children should be in the same hands it has always been in - the hands of parents. But parents who wish to use genetic engineering to bring about a characteristic that had not previously been sanctioned by society through its government should have to apply for permission...[a] broadly based government body could be set up to approve or reject particular parents' proposals..." For those who are skeptical of any plan where the state can interfere with individual choice, the authors refer to immigration law and the right of society to choose its members based on certain criteria.

Smith, Lynne and Byers, Jacqueline Fowler. Gene Therapy in the Post-Gelsinger Era. JONA'S Healthcare Law, Ethics, and Regulation 4(4): 104-110, December 2002.

After reviewing the history of gene therapy in the United States, the authors discuss the effects on the field brought about by the death of volunteer research subject Jesse Gelsinger.

United States. Attorney. Pennsylvania, Eastern District. U.S. Settles Case of Gene Therapy Study That Ended With Teen's Death [press release]. Washington, D.C.: Office of the Attorney General, 2005 February 9; 4 p. [Online]. Available: http://www.usdoj.gov/usao/pae/News/Pr/2005/feb/UofPSettlement%20release.html

After the death of Jesse Gelsinger in a gene therapy clinical trial, the U.S. Department of Justice brought charges against both the researchers involved (James Wilson, Mark Batshaw, and Steven Raper) and their institutions (University of Pennsylvania and Children's National Medical Center) for misrepresenting the findings of research supported with federal funds. These misrepresentations resulted in the failure to obtain properly informed consent from Gelsinger. The press release discusses the terms of the settlements and contains links to the agreement documents.

United States. Food and Drug Administration. Addendum to The Points to Consider in Human Somatic Cell and Gene Therapy. Human Gene Therapy 7(9): 1181-1190, June 1996.

When the FDA issued it's first set of guidelines for gene therapy in 1991(Points to Consider in Human Somatic Cell Therapy and Gene Therapy, Recombinant DNA Technical Bulletin 15(1): 43-56, March 1992), the majority of gene therapy protocols involved ex vivo procedures(where the patient's cells are removed and a normal gene added before reinsertion). With the addition of new methods for gene transfer(vectors) and increasing utilization of in vivo procedures(where the therapeutic gene is injected directly into the bloodstream), the FDA needed to evaluate safety concerns for recombinant vectors and cord blood stem cells. This document reviews preclinical issues for in vivo safety, guidance for cell banking systems, and the use of different types of viruses as vectors in gene therapy.

United States. National Institutes of Health, Ad Hoc Review Committee. Executive Summary of Findings and Recommendations [on the Role of the Recombinant DNA Advisory Committee], September 8, 1996. Available: Online. NIH. http://www.nih.gov:80/od/orda/adhoc-re.htm

This report recommends shifting the review of individual gene therapy protocols from the Recombinant DNA Advisory Committee(RAC) to the Food and Drug Administration(FDA). The RAC would continue to review protocols that "represent a significant degree of departure from familiar practices" and to recommend changes to current regulations based on the new techniques.

United States Congress. Senate. Committee on Health, Education, Labor, and Pensions. Subcommittee on Public Health. Gene Therapy: Is There Oversight for Patient Safety?: Public Hearing. Washington, D.C.: Unpublished testimonies and documents from the hearing, February 2, 2000. 69 p.

Chaired by Senator Bill Frist (R Tenn.), this hearing features testimony from Paul Gelsinger, the father of Jesse Gelsinger, a research subject who died while taking part in a gene therapy experiment at the University of Pennsylvania; Eric Kast, a frequent participant in gene therapy trials for cystic fibrosis; Amy Patterson, M.D., Director of the Office of Biotechnology Activities at the U.S.National Institutes of Health; Jay Siegel, M.D., Director, Office of Therapeutics Research and Review, U.S. Food and Drug Administration; Inder Verma, Ph.D., Professor of Molecular Biology, Laboratory of Genetics, Salk Institute; LeRoy Walters, Ph.D., Director, Kennedy Institute of Ethics, Georgetown University; and H. Stewart Parker, representing the Biotechnology Industry Organization.

Walters, LeRoy. Human Gene Therapy: Ethics and Public Policy. Human Gene Therapy 2(2): 115-122, Summer 1991.

Walters provides an insider's review of the early discussion of the ethics of gene therapy, the actions of the RAC and the approval of the first gene therapy protocols. He summarizes public opinion and international policy statements on gene therapy, and promotes a formal public process for the ethical assessment of germ-line gene therapy.

VI. Religious Aspects

Demy, Timothy J. and Stewart, Gary P., eds. Genetic Engineering: A Christian Response. The Christian Response Series. Grand Rapids, MI: Kregel Publications, 1999. 320 p.

The editors divide the work into three parts: "Genetic Engineering and Society" with eight essays concerned with gene therapy and its relation to religion, justice, and human rights; "Genetic Engineering the Family" containing six essays including discussions of genetic testing and counseling, neonatal intensive care, and reproductive issues; and "Genetic Engineering and the Individual" with six essays, among them two on cloning. The introduction notes that the essays point out the need for responsibility and opportunity applied to genetics in the "light of the Christian faith."

Dunstan, G.R. Gene Therapy, Human Nature and the Churches. International Journal of Bioethics 2(4): 235-240, December 1991.

Moral theologian Dunstan asks whether gene therapy affects human nature, whether we have a right to inherit a non-manipulated genome, and whether churches should have a definite position on gene therapy. He concludes that truly therapeutic gene therapy could not change human nature, a product of the distinctively human cerebral cortex. Dunstan rejects the legalistic approach to the second question, though he does agree that parents have a duty to safeguard and to serve the interests of their potential child. The role of churches is to be faithful to their theological principles.

Golinkin, David. Does Jewish Law Permit Genetic Engineering on Humans? Moment 19(4): 28-29, 67, August 1994.

Although finding support for somatic cell gene therapy in the halachah, Golinkin calls for a rabbinic enactment to forbid genetic enhancement as it is not in keeping with Jewish theological teachings.

Gustafson, James M. A Christian Perspective on Genetic Engineering. Human Gene Therapy 5(6): 747-754, June 1994.

Observing that, for scientists, "...the naturally normal in a biological sense is the basis for a moral norm," theologian Gustafson stresses that "God, the ultimate power, is ordering life in the world through the patterns and processes of interdependence of life." He does not see his theocentric perspective as necessarily contradicting that of scientists, and calls for "'communities of moral discourse' in which the scientific medical, ethical and political issues are engaged by informed and intelligent persons who represent both different interests and different perspectives on the nature of humanness and human well-being."

Gustafson, James M. Genetic Therapy: Ethical and Religious Reflections. Journal of Contemporary Health Law and Policy 8: 183-200, Spring 1992.

Professor Gustafson critiques the writings of French Anderson and poses some questions of his own on humanness, and what is distinctly human, and what ought we value in the human? He studies the implications of the biblical teaching that man is made in the image of God and the moral status of the natural human life.

Moraczewski, Albert S. The Human Genome Project and the Catholic Church. International Journal of Bioethics 2(4): 229-234, December 1991.

Gene therapy directed at the correction or amelioration of a disorder is acceptable to the Catholic Church, provided it promotes the personal well being of the individual being treated. Germ-line interventions are of dubious moral probity, but are not totally rejected. To be morally acceptable germ-line intervention should include due respect for the psychological nature of each individual human being. In addition, no harm should be inflicted on the process of human generation, and its fundamental design should not be altered, nor should any new species be created.

National Council of Churches of Christ/U.S.A. Panel on Bioethical Concerns. Genetic Engineering: Social and Ethical Consequences. New York: Pilgrim Press, 1984. 81 p.

Though this document states explicitly that it is not a policy statement on genetics for the Council, it raises some religious questions, and encourages further discussion.

Nelson, J. Robert. The Role of Religions in the Analysis of the Ethical Issues of Human Gene Therapy. Human Gene Therapy 1(1): 43-48, Spring 1990.

Theologian Nelson outlines the participation of religious scholars in the gene therapy debate, and the notable impact theology has had on public policy formation.

Perlin, Elliott. Jewish Bioethics and Medical Genetics. Journal of Religion and Health 33(4): 333-340, Winter 1994.

Perlin places questions of genetic intervention within the broader context of Jewish medical ethics. While somatic cell gene therapy is permissible because it may cure someone(pikuach nefesh), germline intervention possibly would be discouraged because "Judaism prohibits mating between diverse kinds of animals, different kinds of seeds, as well as the blending of linen and wool in a garment."

Peters, Ted. "Playing God" and Germline Intervention. Journal of Medicine and Philosophy 20(4): 365-386, August 1995.

The author discusses germ-line gene therapy in light of the Christian concept of Imago Die (that man is created in the image and likeness of God). Peters refers to the work of Philip Hefner when describing human beings as "created co-creators", and suggests that as such, we "play human" by seeking a better future, "as God intends us to." Emphasizing God's ongoing creative work, the author asserts that "...realism about technological limits and risks is insufficient warrant for prematurely shutting the door against possibilities for an improved human future."

Peterson, James C. Genetic Turning Points: The Ethics of Human Genetic Intervention. Critical Issues in Bioethics Series. Grand Rapids, MI: William B. Eerdmans Publishing Company, 2001. 364 p.

Written to meet the need of thinking through the "ethical challenges of human genetic intervention," the work is presented from the perspective of the Christian tradition and provides a framework for a semester course. The author moves from genetic research to "genetic testing, genetically created pharmaceuticals, and finally genetic surgery that directly alters a person's genes." Peterson describes the need in genetic engineering for clarity, especially in terminology, the need for careful reflection, and the need to think and plan ahead.

Rifkin, Jeremy. The Theological Letter Concerning Moral Arguments Against Genetic Engineering of the Human Germline Cells. Washington, DC: Foundation on Economic Trends, 1983. 13 p.

This letter, signed by over 50 religious leaders from a vast array of religious traditions, and a few scientists concludes that efforts to engineer specific genetic traits into the germ-line of the human species should not be attempted. The body of an accompanying paper discusses gene therapy in the context of Nazi eugenics and public policy making.

Stig Hansen, John-Erik. The Significance of the Human Genome. America 171(12): 15-17, October 22, 1994.

In discussing the Roman Catholic position that a complete human being is present at fertilization, the author examines the misconception(citing twinning) that this position has a scientific basis in genetics. He notes that spirituality "evolve[s] in concert with...biological development" and goes on to suggest that "[s]ince human consciousness already intervenes in an indirect and uncontrolled way in the evolutionary process, it may be time to consider a more rational and designed intervention in the evolution of Homo sapiens." Stig Hansen calls for a thorough discussion of gene therapy by both scientists and moral theologians, a dialogue that should include consideration of "...the goal of evolution and what blueprint of the human serves this purpose best."

Sutton, Agneta. The New Genetics: Facts, Fictions and Fears. Linacre Quarterly 62(3): 76-87, August 1995.

Sutton finds somatic cell gene therapy to raise the same moral issues as conventional medicine - i.e. questions of risks/benefits to individual patients. However, she finds that germ-line intervention is "...an offense to human dignity, because [it] means treating children as commodities ...ignor[ing] the inherent dignity and worth of each..."

Additional Citations for the Original Essay