HUMAN GENE TRANSFER RESEARCH

Human gene transfer research (HGTR) involves the deliberate transfer of genetic material (naturally-occurring, genetically-modified, or synthetic DNA or RNA) into human subjects. Clinical success has come more slowly than was first predicted, but HGTR remains a fundamentally novel approach to medical practice. It may one day enable clinicians to cure genetic disorders at their source, as well as provide oncologists with tools designed to disable or cure specific cancers. Nonetheless, HGTR differs from other clinical modalities in a number of ways. It involves creating genetically novel organisms that are potentially both transmissible and pathogenic, and there is a risk that this could modify the human genome. Human gene transfer techniques may also be extended beyond therapy into other, more controversial, areas (Verma). Consequently, while HGTR continues to capture the public's imagination, it has received an unparalleled level of public oversight. However, only when HGTR finally achieves success will ethical concerns become real issues.

Basic Terminology and Methods

Two distinctions shape the analysis and practice of human gene transfer: between therapy and enhancement, and between somatic and germline cells. The first refers to the transfer's intended outcome. Researchers may seek to prevent or cure disease (therapy), or they may want to alter an individual's characteristics or capabilities (enhancement). The second refers to whether researchers, in order to achieve these ends, seek to alter nonreproductive (somatic) cells or reproductive (germline) cells. Somatic alteration would affect only the individual subject, while germline alteration would change genes passed on to an individual's offspring. As of 2003, federal regulatory bodies will only entertain somatic-cell gene transfer protocols conducted for preventing diseases or developing treatments (U.S. NIH).

Genetic material can be transferred to human subjects in different ways, but most methods share certain similarities. Many protocols can be classified as either ex vivo or in vivo. Ex vivo protocols obtain tissue cells from the subject, genetically modify them in the lab, and return them to the subject's body. In vivo protocols employ different techniques to introduce genetic material into a subject's body, hoping that it will reach the appropriate tissues. Most protocols to date have used disabled viruses as the vector for transferring genetic material, though other vectors are also under development. Information on how frequently different methods are used can be obtained from the "Human Gene Transfer Protocol List" compiled by the National Institutes of Health (NIH) Office of Biotechnology Activities (OBA).

Clinical Successes and Setbacks

Certain milestones and setbacks mark the progress of HGTR from 1989 through 2003. Within this period, over 545 human gene transfer protocols, involving over 4,000 patients, were registered with the OBA. The field was launched on May 22, 1989, when Steven A. Rosenberg, Michael Blaese, and W. French Anderson injected genetically modified white blood cells into a male subject with advanced skin cancer. This protocol was not designed to intervene in his disease, but rather to track where the "marked" cells went in his body. The first protocol that sought a therapeutic outcome began on September 14, 1990, when W. French Anderson and colleagues transferred genetically modified white blood cells to Ashanti DeSilva, a four-year-old girl with severe combined immune deficiency (SCID). Ashanti's immune system was strengthened, but her underlying condition was not cured. Throughout the 1990s no other protocol was able to report clinical efficacy.

The first unambiguous clinical successes were reported in the spring of 2000. In April 2000 the French researchers Marina Cavazzano-Calvo and Alain Fischer reported that two baby boys (a number later raised to nine) with a version of SCID had normal immune systems ten months after receiving cells that were genetically modified to replace a missing gene. In March 2000 Katherine A. High and Mark A. Kay reported that subjects with hemophilia B experienced an increase in factor IX protein activity for at least six months after the gene transfer.

Yet this long awaited clinical progress has been tempered by setbacks. In December 2002 a subject in the hemophilia-B study developed signs of liver injury, halting the trial. The same trial was briefly halted in December 2001 when the gene-carrying virus was found in subjects' semen, raising the specter of inadvertent germline gene transfer. And in January 2003 the second of the nine boys treated in France developed a leukemia-like illness.

More troubling for the field was the death of Jesse Gelsinger. On September 17, 1999, Gelsinger, an 18-year-old subject, died from a gene transfer experiment being conducted at the University of Pennsylvania's Institute for Human Gene Therapy. Gelsinger was affected by ornithine transcarbamylase (OTC) deficiency. Patients with OTC deficiency lack an enzyme needed for processing nitrogen with the result that toxic levels of ammonia accumulate in their bloodstreams, leading to severe mental impairment and even death. But Gelsinger's symptoms were manageable so that, unlike subjects in other gene transfer trials, he approximated a healthy volunteer. The viral vector used in this protocol was an adenovirus—a virus that usually causes the common cold. Although used in many protocols prior to Gelsinger's death, in his case the vector triggered a deadly immune response. An inquiry into his death resulted in severe sanctions against the University of Pennsylvania and the researchers involved, and it revealed major problems with HGTR oversight and conduct nationwide.

Public Oversight of Human Gene Transfer Research

HGTR is overseen in the United States by two agencies within the Department of Health and Human Services: the NIH and the Food and Drug Administration (FDA). While FDA review is "public" insofar as it involves federal oversight, NIH review through the Recombinant DNA Advisory Committee (RAC) is truly a forum open to the public. This aspect is unique to HGTR and reflects its historical development.

EARLY CONCERNS ABOUT "GENETIC ENGINEERING." Serious debate about human gene transfer began in the 1960s, when scientists, theologians, and philosophers raised many concerns about genetic engineering, or genetic manipulation. Theoretical concerns evolved into real possibilities in 1972 when scientists discovered how to combine genetic material from different organisms. Recognizing that biologically novel organisms created through these techniques could, if inadvertently released, imperil the environment, individuals, or society, the scientific community called for a voluntary moratorium on this research—referred to as recombinant DNA research or rDNA—until safety issues could be assessed (Berg et al., 1974). The 1974 moratorium was lifted after leading scientists met in Asilomar, California, and issued strict guidelines for the safe conduct of rDNA in 1975 (Berg et al., 1975).

The self-imposed scientific moratorium on rDNA research unnerved the public, who were already disenchanted by a decade of research scandals. In response to these scientific and public concerns, the NIH established the RAC, on October 7, 1974. The RAC embodied a novel approach to federal oversight of a novel biotechnology. Because concerns about rDNA were societal as well as scientific, the RAC was staffed by both scientists and nonscientists, and its meetings were open to the public. In 1976 the RAC issued its first set of guidelines. These guidelines focused on laboratory safety and containment, required federally funded institutions conducting rDNA research to establish an Institutional Biosafety Committee (IBC), and required all rDNA research to be reviewed first by the local IBC and then by the RAC.

HGTR OVERSIGHT. The RAC's early work focused on laboratory research that created recombinant organisms, and on work with animals and plants. As safety concerns raised by specific novel techniques were allayed, the RAC regularly shifted oversight responsibility to the IBCs.

By 1983 the RAC's attention had turned to HGTR. This shift was catalyzed by a number of events that captured public attention, including two unauthorized and scientifically ill-founded human gene transfer experiments (the 1970 case of Dr. Stanfield Rogers and the 1980 case of Dr. Martin Cline) as well as the controversial decision in Diamond v. Chakrabarty, allowing the patenting of genetically engineered organisms (for further information on these cases, see Walters and Palmer). One of the most important outcomes of these events was the 1982 publication of Splicing Life, a report on human gene transfer issued by the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research. The commission argued that only transfer into somatic tissues to prevent or treat disease could be justified.

The President's Commission also recommended that the RAC broaden its responsibilities to include HGTR—and to attend to ethical and social implications as well as safety concerns. In 1983 the RAC created the Working Group on Human Gene Therapy (later renamed the Human Gene Therapy Subcommittee) to develop guidelines for human rDNA research and to review protocols (Walters, 1991). By 1985, this working group had produced "Points to Consider," the first version of the guidelines that would eventually govern HGTR.

CLINICAL TRIALS AND CHALLENGES TO PUBLIC OVERSIGHT. In April 1988 the RAC received its first actual human gene transfer protocol, and federal oversight of HGTR began. The field grew cautiously at first, and then exponentially, moving quickly from work with single-gene disorders to cancer research (Ross et al.).

By 1995 the NIH was spending $200 million per year (2% of its budget) on HGTR. Harold Varmus, the director of NIH, commissioned two reports on the state of the field. The first, coauthored by Stuart H. Orkin and Arno G. Motulsky, criticized researchers for exaggerating prospects for therapeutic success. They argued that more basic research was needed before moving to and investing in clinical trials. The second assessed the work of the RAC and concluded that the committee continued to serve important functions (Verma).

From the outset, RAC oversight of HGTR was contested. As early as 1990, RAC review was assailed for delaying vital medical research (U.S. NIH-RAC; Culliton). Biotech companies objected to the public nature of RAC review, while researchers felt that RAC review unnecessarily duplicated FDA review, which holds statutory authority for such approval. Human gene transfer protocols, unlike other areas of research, must be reviewed both by the RAC and by the FDA, either simultaneously or sequentially. At the FDA, responsibility for human gene transfer lies with the Center for Biologics Evaluation and Research (CBER), and review focuses on the safety and efficacy of rDNA products, the safety of the manufacturing process, and the control of the final product (Coutts). To protect proprietary interests, CBER review is closed, and it cannot, by charter, address the ethical or social implications of research. The FDA has developed its own "Points to Consider" document to advise investigators (U.S. FDA, 1998).

In 1996, with the urging of biotech lobbyists, researchers, and politically powerful patient activists, Varmus proposed to abolish the RAC, and only overwhelming public support for the RAC averted its demise. Although not abolished, the RAC was downsized and could no longer recommend approval or disapproval of specific protocols. From 1996 through 2000, the RAC reviewed approximately 10 percent of the HGTR proposals submitted to the NIH (those proposing novel methodologies) and convened occasional Gene Therapy Policy Conferences.

THE AFTERMATH OF THE GELSINGER CASE. The Gelsinger case revealed major problems with the oversight of HGTR. A primary finding concerned the reporting of adverse events (bad reactions or deaths during a human gene transfer experiment). According to the NIH Guidelines, all adverse events must be reported in a timely fashion to the RAC, but Gelsinger's investigators failed to report three adverse events to the FDA in a timely manner. Moreover, only 37 of 970 adverse events that occurred between 1993 and 1999 in trials using the adenovirus vector (approximately 25% of the HGT protocols underway at that time) were properly reported to the NIH (Walters, 2000)—these adverse events were reported to the FDA, but not relayed to the RAC.

The inquiry also uncovered problems in the informedconsent process. The informed-consent document given to subjects in Gelsinger's protocol differed from the one approved by the RAC and FDA, and it did not mention adverse events in animal studies. Public reporting about HGTR had led the Gelsingers to believe that patients had been cured by "gene therapy," and they reported that the investigators had led them to believe subjects in their particular protocol had experienced clinical benefit. Finally, adverse events experienced by other subjects in the protocol were not communicated to the Gelsingers, as required by federal guidelines (Stolberg). Ironically, the RAC's attention to informed consent was one reason given by Varmus for abolishing it (Marshall).

The Gelsinger case led to Congressional inquiries, multiple hearings, and soul-searching at the NIH and FDA. The RAC provided a unique and crucial forum for gathering, analyzing, and publicizing information relevant to this crisis. This resulted in two notable outcomes: (1) the FDA formally agreed to inform the NIH of all adverse events reports it received, and (2) the Advisory Committee to the Director of the NIH recommended that the RAC receive novel protocols at an earlier stage in their development—namely, prior to submission to the IRB and FDA.

Ethical Issues in Human Gene Transfer Research

Early ethical and social concerns surrounding HGTR were outlined in 1985 in the NIH's "Points to Consider." Since then, broader public and commercial contexts of HGTR have raised additional concerns, especially involving subject recruitment and economic conflicts of interest. These issues become increasingly important as HGTR moves toward new applications and methods.

THE ETHICAL COMMITMENTS OF THE "POINTS TO CONSIDER." The "Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA Molecules into One or More Human Subjects" consists of over 100 specific questions that HGTR investigators must address for RAC approval (U.S. NIH, Appendix M). The RAC Working Group on Human Gene Therapy tested the document and developed its process of protocol review by working through a prototype HGTR protocol submitted in April 1987 by a team led by W. French Anderson (Walters and Palmer).

The ethical commitments of the "Points to Consider" reflect its historical context. The document reflects both the RAC's involvement with debates surrounding rDNA and a decade of national deliberations on the use of human subjects in biomedical research (Juengst). Its ethical framework hinges on six moral concerns. The first three derive from specific concerns about rDNA technology:

• 1. the need for special biosafety precautions;
• 2. the need for public participation in genetic research policy; and
• 3. potential broad and long-range research consequences (Juengst).

The final three concerns reflect the Belmont Report's three central principles (beneficence, respect for the person, and justice) and the federal guidelines for the protection of human subjects issued in 1981:

• 4. clinical benefit to subjects;
• 5. free and informed consent by subjects; and
• 6. fair subject selection (Walters and Palmer; Juengst).

The RAC deliberations based on the "Points to Consider" tended to focus primarily on issues of safety and informed consent. Biosafety concerns focused on whether genetically modified viral vectors might be shed, or infect others who come into contact with research subjects. There was concern that viral vectors might revert to wild-type strains and become replication competent—that is, capable of replicating and infecting subjects or others in unanticipated ways. Further, might transferred genetic material integrate into the wrong place in the subject's genome, thus causing cancer (a hypothesized cause for the illnesses seen in the French SCID boys)? Might it inadvertently integrate into the subjects' germline tissues and be transmitted to their descendants? Scientific and clinical questions further attended to the risks particular protocols might present to subjects themselves. Nonscientific members (patient advocates, ethicists, attorneys) consistently raised concerns about informed consent and subject recruitment.

THE CHALLENGE OF RECRUITMENT. There are also important concerns about subject recruitment. HGTR initially targeted only life-threatening, incurable conditions for which no other effective therapy existed. Theoretical benefits to these subjects were believed to outweigh any possible risks. Initially, disease candidates included only single-gene disorders. By 2002, however, the pool of disease candidates had expanded to include cancers (64% of all protocols), HIV, peripheral artery disease, rheumatoid arthritis, and erectile dysfunction (U.S. NIH-OBA).

Subjects with life-threatening, incurable conditions are often in desperate straits, and it is not clear that consent can be truly voluntary in such situations? Too often, subjects misunderstand experimental protocols as their last or only hope, or as therapy, when in fact most human gene transfer trials are designed only to test safety, not efficacy. Subjects are aided in this misunderstanding by informed-consent documents that describe experimental interventions as treatment, or that mention a possible benefit. This, coupled with the misleading label of gene therapy, has led the field to be redescribed more accurately as "human gene transfer research" (Churchill et al.)

Misunderstanding gene transfer as therapy has led to questions about fair access to protocols. Before the first protocol was launched, concerns were raised about how to decide which members of even a limited subject pool would have access to the potential benefits of the research. Such thinking climaxed in 1993 when, in response to political pressure, Bernadine Healy, then the director of the NIH, allowed researchers to enroll a subject in an unapproved human gene transfer protocol as a last-chance therapy on the basis of "compassionate use." This would not be the last time the RAC faced political pressure to alter protocol approval (Lysaught).

COMMERCIAL INTERESTS AND "ORPHAN DISEASES." Another important issue is that of rare diseases and commercial interests. Early advocates of HGTR emphasized that this novel methodology promised, at long last, to provide cures for some 4,000 single-gene disorders. Ashanti DeSilva was afflicted with just such a disorder. But investigators quickly began applying human gene transfer techniques to clearly non-Mendelian disorders (e.g., cancer). As of 2002 only 10 percent of human gene transfer protocols approved by the RAC involved monogenic disorders. Most monogenic disorders are quite rare, with a small market for eventual therapies, and those involved in HGTR have been accused of abandoning persons with genetic disorders in order to cash in on big market payoffs (Meyers; Anderson).

The Orkin-Motulsky panel raised concerns about economic incentives surrounding human gene transfer in 1995. Due to these incentives, they noted, virtually every NIH institute had created a gene transfer program, whether equipped to do so or not, and they cautioned that the rush to find the gold in HGTR might lead investigators to ignore the pursuit of other, easier-to-achieve, conventional treatments.

Commercial interests, and the potential for conflicts of interest, also emerged in the Gelsinger case and led to a renewed examination of the relationship between academic research and industry. In Gelsinger's case, the University of Pennsylvania's Institute for Human Gene Therapy received one-fifth of its $25 million annual budget from a company founded by the Institute's director, James M. Wilson. In return, the company had exclusive commercial rights to Wilson's discoveries. None of the subjects in the study had been informed of this relationship or this arrangement. In 2000 the American Society of Gene Therapy established a policy that its researchers should be free of significant financial involvement with companies that sponsor their studies.

FRONTIER ISSUES. Although HGTR has yet to achieve unambiguous clinical success, "frontier issues" such as prenatal gene transfer, nonrecombinant methods of DNA transfer, and the likelihood of enhancement merit mention.

Prenatal gene transfer might offer certain advantages, as early intervention might prevent the devastating effects of some conditions. The prenatal environment may provide better conditions for gene transfer and facilitate sustained gene expression. It could also offer parents at risk for conceiving a child with a genetic disorder an actual therapeutic alternative to selective abortion or preimplantation genetic diagnosis. However, in utero research entails unknown risks to the fetus and mother and raises the real possibility of germline modification (Fletcher and Richter). In January 1999 the RAC concluded (based on a Gene Therapy Policy Conference) that allowing prenatal gene transfer research would be premature. However, the RAC indicated its willingness to entertain in utero gene transfer protocols if current scientific questions were to be addressed (U.S. NIH-RAC).

Jesse Gelsinger's death and setbacks in the French SCID and hemophilia trials raised anew concerns about the risks of viral vectors. Researchers are therefore pursuing alternative methods of DNA transfer, including approaches that do not involve DNA recombination. Microinjection, where DNA or RNA is directly injected into a cell's nucleus using a glass pipette, is currently used for germline modification in animal research. A similar approach involves the injection of naked DNA (DNA not contained within a vector) directly into tissues. Another protocol uses high pressure to push short DNA sequences into graft tissue. Others suggest attaching DNA to other macromolecules, such as liposomes. These complexes can navigate cell membranes without the risks posed by viral vectors. And yet others are developing methods of inserting not just genes but entire artificial chromosomes. While these approaches may reduce certain safety concerns, they may also introduce others. For example, transmission of artificial chromosomes to offspring via germline integration raises questions about the creation of individuals with more than the standard complement of forty-six chromosomes. How does this challenge our understanding of what it means to be human? Moreover, given our limited knowledge of chromosomal interaction and gene mutation, the long-term consequences of such modifications cannot be known.

Finally, researchers clearly have an interest in pursuing gene transfer for enhancement purposes. The same techniques used for legitimate medical therapies could be used for decidedly non-therapeutic purposes by athletes for example, looking for a competitive advantage. Somatic-cell interventions might be able to strengthen muscles and bones or boost oxygen efficiency, while germline enhancements could provide a way for parents to engineer children with superior athletic skill. Researchers further anticipate developing techniques that will enable inserted genes to be "turned off" by an additional intervention if necessary. While such developments might prove therapeutically useful, they could also allow a mechanism for avoiding detection of genetic modifications. What responsibilities do researchers and physicians have with regard to such practices? Although clearly decades away at best, the World Anti-Doping Agency is taking this possibility quite seriously. With the advent of stem cell and cloning techniques, the prospect of gene transfer being used for enhancement purposes becomes increasingly probable. Certainly such applications of gene transfer technology raise serious questions about the just allocation of resources in a world where over 2 million people each year die from a lack of adequate sanitation and clean water and 44 million people in the U.S. remain without adequate health insurance.

Conclusion

The possibilities of prenatal or germline gene transfer and genetic enhancement suggest that the need for public oversight of HGTR is far from over. Initial safety and societal concerns surrounding rDNA research and HGTR have not materialized, in part because the research has received careful scrutiny and oversight in a public forum that has earned respect through hard work and responsiveness to changes in its social and scientific contexts. Unlike other biotech developments, HGTR is not perceived as being driven solely by the momentum of the market, with technology racing ahead of society's moral compass. Nor has it become intractably polarized. Public oversight has provided both a forum for discussing ethically controversial applications of human gene transfer and a mechanism for exercising prudence and caution.

Public oversight of HGTR also provides a unique venue for addressing concerns that are not unique to HGTR, but are applicable to the practice of scientific research in general. These include concerns about the commercial influence on scientific research, the practice of informed consent, and about vulnerable patients. But because it proceeds in public view, HGTR may serendipitously lead to significant improvements in the conduct of human-subjects research in the United States and throughout the world.

m. therese lysaught

SEE ALSO: Genetic Engineering, Human; Genetics and Human Self-Understanding; Public Policy and Bioethics

BIBLIOGRAPHY

Anderson, W. French. 1994. "Yes, Abbey, You Are Right." Human Gene Therapy 5(October): 1199–1200.

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Berg, Paul R.; Baltimore, David S.; Brenner, Sidney; et al. 1975. "Summary Statement of the Asilomar Conference on Recombinant DNA Molecules." Proceedings of the National Academy of Sciences U.S.A. 72(6): 1981–1984.

Churchill, Larry R.; Collins, Myra L.; King, Nancy M. P.; et al. 1998. "Genetic Research as Therapy: Implications of 'Gene Therapy' for Informed Consent." Journal of Law, Medicine, and Ethics 26(1): 38–47.

Coutts, Mary Carrington. 1994. "Scope Note 24: Human Gene Therapy." Kennedy Institute of Ethics Journal 4: 63–83.

Culliton, Barbara J. 1990. "Conflict at the RAC." Science 248(4952): 159.

Fletcher, John C., and Richter, Gerd. 1996. "Human Fetal Gene Therapy: Moral and Ethical Questions." Human Gene Therapy 7(13): 1605–1614.

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

Lysaught, M. Therese. 1998. "Reconstruing Genetic Research as Research." Journal of Law, Medicine, and Ethics 26(1): 48–54.

Marshall, Eliot. 1996. "Varmus Proposes to Scrap the RAC" Science 272(5264): 94.

Meyers, Abbey S. 1994. "Gene Therapy and Genetic Diseases: Revisiting the Promise." Human Gene Therapy 5: 1201–1202.

Ross, Gail; Erickson, Robert; Knorr, Debra; et al. 1996. "Gene Therapy in the United States: A Five-Year Status Report." Human Gene Therapy 7(14): 1781–1790.

Stolberg, Sheryl Gay. 2000. "Youth's Death Shaking Up Field of Gene Experiments on Humans." New York Times, 27 January.

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INTERNET RESOURCES

American Society of Gene Therapy. 2000. "Policy of The American Society of Gene Therapy on Financial Conflict of Interest in Clinical Research (Adopted April 5, 2000)." Available from <http://www.asgt.org>.

Orkin, Stuart H., and Motulsky, Arno G. 1995. "Report and Recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy, December 7, 1995." NIH Office of Biotechnology Activities. Available from <http://www4.od.nih.gov/oba>.

U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. 1998. "Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy." Available from <http://www.fda.gov/cber>.

U.S. Food and Drug Administration, Center for Biologics Evaluation and Research. 2000. "Human Gene Therapy and The Role of the Food and Drug Administration, September 2000." Available from <http://www.fda.gov/cber>.

U.S. National Institutes of Health. 2002. "Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines, April 2002)." NIH Office of Biotechnology Activities. Available from <http://www4.od.nih.gov/oba>.

U.S. National Institutes of Health, Office of Biotechnology Activities. 2002. "Human Gene Transfer Protocol List." Available from <http://www4.od.nih.gov/oba>.

Verma, Inder 1995. "Report of the Ad Hoc Review Committee: The Recombinant DNA Advisory Committee, September 8,199." NIH Office of Biotechnology Activities. Available from <http://www4.od.nih.gov/oba>.