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Recombinant DNA Advisory Committee
National Institutes of Health
Public Health Service
Department of Health and Human Services
(April 1990)
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This page provides basic information for the nonscientific public about experiments intended to cure disease through transplantation of genes into the nonreproductive (somatic) cells of human patients. It includes background material about human gene therapy and its purposes and potential, about supervision of the research, and about why and how the public is involved.
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Preface |
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As a result of recent advances in medical science, researchers believe that a gene can be transplanted into human beings who suffer from severe diseases. Such gene transplants may alleviate or perhaps even cure diseases for which no adequate treatment now exists. The treatment is called human gene therapy and is one of a series of emerging genetic techniques, commonly called genetic engineering, based on new knowledge about how genes work. It is expected that researchers will soon request approval for a human gene therapy experiment. Many benefits are foreseen. However, because of the novelty of the field, concerns about the discriminatory and eugenic misuse of the techniques, and the possible effects on future generations from some types of human gene therapy, important ethical questions will also be raised.
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This document is intended to provide basic information for the general public about the new technique and its significance. It was written at the request of the public representative of the Human Gene Therapy Subcommittee.
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Part 1 - Diseases and Their Treatment |
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The human body is made up of about fifty trillion cells. Inside each cell is information that tells the cell what to do and how to work. This information is contained in genes, which are made up of a chemical called DNA. Through small differences in the structure of the DNA, the information is coded and stored, just as different letters combine to form words which are then stored in books. All the many activities that a cell does start with reading part of the information that is stored in the DNA of the genes. There are approximately one hundred thousand genes in each cell of the human body. Although the genes are the same in every cell, each type of cell reads only certain genes. In this way a muscle cell, for instance, looks and works differently from a skin cell or a liver cell.
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There are two major types of cells in the human body, somatic (non-reproductive) cells and germ line (reproductive) cells. Most cells in the body are somatic. Somatic cells provide all the body structures and perform all the functions except for passing genetic information on to the next generation. Germ cells include eggs in women and sperm in men. The genes in sperm and egg cells store information that will go to the next generation, to one's children. The genetic information in somatic cells is not passed on to the next generation.
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If the DNA information of a particular gene contains mistakes, the gene may not function properly. Sometimes the malfunction will not be serious, but other times it will cause a severe genetic disease. Examples of some genetic diseases are cystic fibrosis, sickle cell anemia, and hemophilia. Hemophilia, for instance, is caused by the malfunctioning of the gene that makes the factor that causes blood to clot. As more is learned about human genetics, it is becoming clear that diseases such as diabetes, cancer, heart disease, and some manic depressive illnesses also result in part from faulty DNA information.
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For some genetic diseases, there are satisfactory therapies that do exist. Drugs, blood transfusions, changes in diet, or transplantation of body organs can often help to compensate for the incorrect information from the malfunctioning gene. For example, clotting factor can be administered to patients with hemophilia.
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Human gene therapy is a possible alternative approach to the treatment of some genetic diseases. The basic idea behind gene therapy is to insert normal genes with correct information into the DNA of the cells that contain malfunctioning genes. Adding genes in this way is called "gene insertion." The added genetic information would allow these cells to function properly and might reduce or eliminate the signs or symptoms of the disease. For example, instead of repeatedly treating a hemophiliac with clotting factor, one could insert the correct genetic information into his cells to allow those cells to make their own clotting factor.
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It seems likely that human gene therapy will also be used to combat certain diseases that may not be genetic. For example, malignancies are usually treated with surgery, radiation and/or chemotherapy. For cancer patients who are not helped by these therapies, researchers are now planning to treat the patients' disease with genetically-altered white blood cells.
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Scientists have developed methods for inserting genes into human somatic cells. The techniques for isolating human genes and making multiple copies of them in the laboratory are well established. Now scientists are studying how to insert those genes into cells and how to make those genes work properly once inside the cells. One method for inserting genes into cells is to link the genes with a virus that has been crippled and rendered harmless. As part of the modification, such a virus, sometimes called a vector or vehicle, has been deliberately altered so that it can carry genes into cells but cannot then escape to infect other cells. After the cells to be treated have been temporarily removed from a patient's body, the virus or vector is used to carry the desired gene into them. The final step will be to return the treated cells, which now contain the correct genetic information, to the patient's body. For example, bone marrow, liver cells, or white blood cells could be removed from the body of a patient, treated in the laboratory, and returned to the patient.
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Whether bone marrow cells or some other type of human cells were used, the added genes would be inserted only into somatic (non-reproductive) cells and not into germ line (reproductive) cells. Therefore, newly inserted genes could not be passed to patients' children. The therapy would be called somatic cell gene therapy and would not attempt to affect the germ line cells, which carry genetic information to the next generation.
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The best outcome of human gene therapy would be a single treatment that would correct enough cells to provide a permanent cure for the patient's disease. This kind of complete success is unlikely in the beginning stages of human gene therapy but will remain the long-term goal of research scientists working in this field.
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Part 2 - Governmental Oversight and Public Participation |
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Oversight of government-funded experiments involving gene therapy for human patients occurs at both the local and national levels.
At the local level, facilities at which experiments would take place are required to have two types of committees. First, hospitals and universities involved in experiments with human subjects are required to have Institutional Review Boards (IRB) to ensure that the research complies with Department of Health and Human Services (DHHS) regulations for protection of human subjects. Second, experiments that involve gene insertion must be approved in advance by an Institutional Biosafety Committee (IBC).
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These local review boards provide an opportunity for the general public to become involved in the decisions made about research involving gene therapy for human patients. The DHHS regulations require that at least one nonscientist serve as a member of each IRB. Further, the NIH Guidelines for Research Involving Recombinant DNA Molecules encourage research facilities to open their IBC meetings to the public.
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At the national level, the Director of the NIH must approve each human gene therapy proposal. In making this decision, the Director seeks advice from the Recombinant DNA Advisory Committee (RAC). The initial review of the proposal is performed by the RAC's Human Gene Therapy Subcommittee, which is guided by the Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA into the Genome of Human Subjects, discussed later in this document.
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The general public is represented on the RAC and the Human Gene Therapy Subcommittee, as well as on the local review boards. The membership of the RAC (25 people), and of the Human Gene Therapy Subcommittee (15 people), includes scientists, physicians, lawyers, ethicists, and several laypeople.
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The NIH Guidelines for Recombinant DNA Molecules require that the NIH Recombinant DNA Advisory Committee (RAC) meetings be given 30 days advance notice in the Federal Register. Federal regulations require all meetings be given 15 days advance notice in the Federal Register (e.g., subcommittee meetings). All meetings are to be open to the press and the public.
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The NIH has authority only over certain federally funded research. However, many private companies that do not receive federal support voluntarily submit proposals to NIH for review. In addition, the Food and Drug Administration (FDA), which has jurisdiction over drug and biological products intended for use in human patients, must also review and approve experiments involving gene therapy for human patients, whether the research is federally funded or not.
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Since the 1970s, general interest in human gene therapy has increased both here and abroad, along with awareness of the need for oversight and regulation. In this country, in 1974, the Secretary, Department of Health, Education, and Welfare (now the DHHS), chartered the Recombinant DNA Advisory Committee (RAC) to develop recommendations for the regulation of recombinant DNA research. The Guidelines for Research Involving Recombinant DNA Molecules were published in 1976. In 1978, the Guidelines were revised, relaxing many of the requirements for recombinant DNA experiments.
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In 1980, at the urging of the three major religious groups in this country, the President requested that the President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research examine the topic of human genetic engineering. In November 1982, one of the Commission's eleven reports, Splicing Life; The Social and Ethical Issues of Genetic Engineering with Human Beings, was submitted to the President and Congress. A subcommittee of the United States House of Representatives held three days of hearings on the report. Congressional interest also resulted in a 1984 background paper entitled, Human Gene Therapy, produced by the Office of Technology Assessment. In response to one recommendation of the President's Commission, the NIH Recombinant DNA Advisory Committee formed a working group in 1984, to specialize in human gene therapy. This is now the Human Gene Therapy Subcommittee. In 1985, the White House Office of Science and Technology Policy created the Biotechnology Science Coordinating Committee (BSCC). The Committee includes federal officials representing the National Institutes of Health, the Environmental Protection Agency, the U.S. Department of Agriculture, the Food and Drug Administration, and the National Science Foundation. The BSCC provides a forum for discussion of biotechnology issues and an opportunity to make recommendations on the federal regulation of biotechnology.
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Legislative interest continues to be expressed through activities of the Subcommittee on Science, Research and Technology of the House Committee on Science and Technology and the Office of Technology Assessment. In 1986, a Congressional Biomedical Ethics Board was formed to oversee research and developments in genetic engineering. This Board is composed of six Senators and six Representatives.
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International interest in human gene therapy has resulted in a number of reports and recommendations submitted by foreign government committees. For example, in 1982, the Parliamentary Assembly of the Council of Europe issued a statement including proposals for oversight and recommendations for certain restrictions on human genetic engineering. (Other reports and statements are listed at the end of this document under Suggestions for Further Study.)
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In summary, research on human gene therapy is being monitored at both the local and national levels, here and abroad. Members of the general public are represented and are encouraged to participate in the public discussion of this new area of biomedical research.
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Part 3 - NIH "Points to Consider" for Gene Therapy Researchers |
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In anticipation of the first request to perform a human gene therapy experiment, the Human Gene Therapy Subcommittee prepared a document called Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA into the Genome of Human Subjects. This document was approved by the NIH Recombinant DNA Advisory Committee and the Director of the NIH in 1986. The "Points to Consider" document provides guidance to physicians and scientists who are planning to submit proposals to the NIH for gene therapy treatment of patients. It describes the considerations that have been identified in the studies and hearings mentioned previously as the most important in evaluating this new mode of treatment.
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In the "Points to Consider," researchers are first asked:
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What disease do you intend to treat with gene therapy?
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Why do you consider this disease to be an appropriate candidate for treatment with this new method?
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In answering these questions, the researcher will discuss the seriousness of the disease, any alternative therapies, and the possible advantages of gene therapy for at least some patients.
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Another part of the "Points to Consider" asks:
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What laboratory studies have been done, with cells and live animals, that make researchers hopeful that gene therapy will help patients rather than harming them?
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Here the researcher will provide the results of studies performed in his/her laboratory or in other laboratories around the world. Especially important will be studies demonstrating that gene therapy does not harm laboratory animals and in fact demonstrates that the desired biological effects occur.
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Even if the preceding questions are satisfactorily answered, important questions about the proposed use of gene therapy in patients will remain. The "Points to Consider" ask the following four questions:
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What are the probable benefits and harms of the proposed treatment, both to the patient and to others?
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If there are several patients who need gene therapy but only one of them can be treated initially, how will selection be made in a way that treats all patients fairly?
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How will patients--or, in the case of young children, the parents of patients--be properly informed about the possible benefits and risks of gene therapy?
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What steps will be taken to protect the privacy of the patient and the patient's family, while at the same time informing the public about the results of gene therapy? In the Introduction to the "Points to Consider," reference is made to two possible undesirable or unintentional consequences of somatic cell gene therapy: transmission of altered genes to a patient's offspring, and viral infection of persons who come in contact with the patient. The Subcommittee requests that researchers describe what actions will be taken to prevent either event from occurring.
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The "Points to Consider" acknowledges the public concern about some aspects of human gene therapy. It reads: "In recognition of the social concern that surrounds the general discussion of human gene therapy, the [Subcommittee] will continue to consider the possible long-range effects of applying knowledge gained from these and related experiments." For the moment, the Subcommittee agrees with the conclusion in the Office of Technology Assessment's report Human Gene Therapy that:
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"Civic, religious, scientific, and medical groups have all accepted, in principle, the appropriateness of gene therapy of somatic cells in humans for specific genetic diseases. Somatic cell gene therapy is seen as an extension of present methods of therapy that might be preferable to other technologies."
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While the RAC and its Subcommittee believe that gene therapy for non-reproductive, or somatic, cells holds promise for patients suffering from certain genetic and other diseases, they will seek to ensure that patients are not subjected to unreasonable risk of harm, excessive discomfort, or unwanted invasion of privacy and that they will receive special care, monitoring, and consideration. The public will be informed about every step that is taken with this new technique.
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