Editors: Michio Okamoto, M.D., Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.
President, Japanese Society for Gene Diagnosis and Therapy; Professor, Department of Laboratory Medicine, Kyoto University School of Medicine
At the time of genetic testing the medical staff should give sufficient information about the tests and what information is likely to come to light as a result of the test, and the testee should be able to invoke their 'Right to know' or 'Right to not know'; the medical staff does not have the right to withhold information. Written informed consent is indispensable. Further, to prevent any unauthorized access to genetic information, it is necessary to have a confidential information management system independent of the general information system in the hospital. As for gene therapy, in addition to the central evaluation system and in-hospital ethics committees, it is desirable to have a practical in-hospital monitoring and guidance system. To achieve all these ends, a new division for gene diagnosis and therapy is being planned for Kyoto University Hospital. This division would be comprised of 3 sections, one dealing with genetic consultation and education, another confidentially dealing with genetic tests and information management, and the other for monitoring and guidance of gene therapy. In addition, there are serious ethical problems in the application of prenatal or pre-gestational gene diagnosis and the handling of these results; we are planning to discuss these issues in detail to establish guide lines for the Ethics Committee of the Japanese Society of Gene Diagnosis and Therapy. Through such facilities it is our hope to promote gene diagnosis and therapy that is not only effective but also ethical.
The origin of life is now considered go back to 3.5 billion years ago as based on fossil DNA analysis. Before this, however, there most likely was a period of RNA virus, which probably originated 5 billion years ago. RNA and DNA contain the entire genetic code, and the gradual accumulation of mutations of the genes has resulted in evolutionary development of the various living things seen at the present time.
Mutational changes of the genes can be induced by physiological (radiation), chemical (oncogenic substances) and biological (viral infection) factors. DNA, which contains all of the life information, has a stable double strand structure and can repair most of the derangement caused by the above factors.
Nevertheless, some unrepaired mutations remained. When the damage is great, it induces cell-|death or the death of organism. While in the case of minor damage which is not as hazardous to living things, the damage, known as DNA polymorphism, can be inherited by the offspring, this process seems to have induced different phenotypes among races and even among individuals. In the case of intermediate damage the cell and organism survive but variable dysfunction is seen; this is called disease.
Medicine until now has dealt mostly with patients having pathological manifestations. Disease diagnosis is based on the observation of pathological physical findings and measurements of proteins or enzymes which are the resulting products of the disease, and moreover, treatment is also based for the most part on indirect means. Gene diagnosis and therapy are essentially different from previously used methods in medicine, and are directed at elucidating the cause of disease and remedying the fundamental error causing the disease. Up to now more than 6000 diseased have been identified as genetic disorders. Therefore the clinical access to information about genetic abnormality is extremely important, especially in the prediction and prevention of diseases.
At the same time, the prediction of and the application of gene therapy for genetic diseases have also raised various ethical problems. We consider that the clinical application of gene-related techniques has now entered the practical stage, and to foster an ethical transition, we founded the Japanese Society for Gene Diagnosis and Therapy in April 1994. We realized that the associated ethical problems are among the most important issues that will need to be addressed by our society. I would like to present a discussion of the bio- and socio-ethical problems related with gene diagnosis and therapy, and I hope that through this discussion I will stimulate future thoughtful debated.
1. Diseases Related With Gene Diagnosis and Therapy
Human diseases develop due to variable contributions of genetic and environmental factors. Inherited diseases due to a single gene defect develop due to only genetic factors, while infectious diseases and trauma are totally due to environmental factors. From the perspective of gene diagnosis we can classify diseases into congenital and acquired ones and we can further divide them into 4 categories, as follows:
1.1. Diseases due to Congenital Genetic Disorders
1.1a. Diseases due to a single gene defect
These diseases are caused by a specific single gene abnormality and the epidemiology in most of them follows Mendelian law. However, there are several diseases showing the mode of non-Mendelian inheritance, such as maternal inheritance or gene imprinting. All of these are totally related to the gene abnormality and the diagnosis should be directed at detecting the underlying abnormality. In some of these diseases gene therapy to induce normal genes has already been performed. The treatment of these diseases raises serious problems ethically as will be discussed later.
1.1b. Genetic abnormalities as contributory genes in common diseases
Recently there have been quite a few reports on genetic analyses in patients with various common diseases such as atherosclerois, diabetes, hypertension, autoimmune disease, hereditary cancer, Alzheimer's disease, and osteoporosis. In these common diseases genetic disorders by themselves alone are not the causative factor but they may play contributory roles in the development of disease. It is likely to be the case that in the near future much more attention will come to be focused on the genetic approaches to the diagnosis and even treatment of these common diseases.
1.2. Diseases Associated With Acquired Genetic Abnormalities
Cancer developed in a specific tissue cell resulting from oncogenic mutations. Such transformed cells grow in an uncontrollable manner, and finally leading to the death of the organism. Various physiological, chemical and biological factors can induce oncogenic activations either alone and together with damage in the DNA repair mechanisms, and the affected cells show unusual replication either by tumor promotion or by disturbance of tumor suppression, sometimes by both. The genetic mutations seen in cancer have two characteristic features, one being localized somatic mutations restricted only to the tumor cells and the other multi-step mutations. Cancer can be induced by a single mutation but for the development and wide expansion to occur an increasing number and grade of mutations appear to be necessary. In these particulars, the gene (DNA) diagnosis and therapy for cancer have certain aspects differing from those in other diseases.
1.2b. Infectious Disease
As described previously, infectious diseases are not associated with endogenous genetic abnormality. However, exogenous genes can be transported and detection of such genes is highly specific, rapid and sensitive for the diagnosis. In Japan gene diagnosis for many infections is increasingly covered by health insurance and its clinical applications are gradually expanding. Such information is likely to be of value in most of cases, but there are some infectious diseases, such as HIV, HTLV or HCV infections, that are associated with profound social and medical problems.
2. Ethical Problems Related to Gene Diagnosis and Testing
2.1. The Right Not To Know
As is well known, the patient's 'Right to know' and the conflicting medical staff's discretionary 'discretion not to divulge' have been the topics of heated debates in the case of cancer notification. However, it is our opinion that results indicating a genetic abnormality be unconditionally available to the patient or testee, and that the discretion not to divulge this information should not be invoked by medical staff under any circumstances. On the other hand, information as to gene abnormality may also indicate the future likelihood of certain genetic diseases. To be made aware of such information without recourse to any effective means of prevention or treatment would not be of any use to the testee but would in fact serve only to increase anxiety, confusion and even despair. In this regard, I think that the client's decision to elect not to know should be respected.
In any event, it is absolutely indispensable to prepare a written informed consent for signature at the time of genetic testing except in most infectious diseases and perhaps in some cancers. The medical staff in charge should explain the purposes of the test and what will become known as a result. They are required to have enough knowledge to be competent in explaining these specifics in detail. The testee at this time can elect to undergo the test or not, and also to be informed of the test results or not.
It should be strictly prohibited for the medical authorities to perform genetic test simply because of their perceived need to know. For example, information about the HIV, HTLV, HCV and MRSA status of hospitalized patients is very important in protecting the health of the medical staff and moreover in preventing intra-hospital transmission. These diseases can be tested for by microbiology also, but I assert that medical facilities should not perform these tests without any notifying the patient or obtaining informed consent of the patient. Patients should be given the right or refuse, and if the patient invokes this right, the medical staff should take as if the patient is infected. Of course, the necessity for patient management in this fashion would be quite expensive but it is unavoidable.
In order to curb such ethically dubious testing and to help in understanding genetic testing both medical staff and patients or testes, I think that it is necessary to establish a new division for gene diagnosis and therapy in hospitals equipped with facilities to perform gene diagnosis and therapy. This division should be constructed in 3 sections, one of which would be devoted to genetic consultation from the aspect of education and increasing the awareness on the part of the testees and general medical staff by special geneticists. At present this aspect is considered to be very important, because general medical staff do not appear to have enough knowledge to present proper genetic information to the testees.
2.2. Management of Genetic Information
There has been established a data registration system for any novel findings on genetic abnormalities. Utilization of the data-base for general medical information is also becoming widely available. This may include information on the genetic abnormalities of specific individuals. However, as described previously, the individual genetic data should be provided only to the individual having such abnormality, and should not be made available without permission. This is absolutely necessary to protect the human rights of the patient. However, if these data were managed within the general computer system of a hospital they could surely be accessed by general unauthorized medical staff or even by outsiders, as is the case for general medical information. To prevent this unauthorized access, genetic information should be managed within a closed and independent system. In this regard, my proposal would include a second section for genetic test and information control within the division for gene diagnosis and therapy. All the samples for genetic testing would be sent to this division with an order form and informed consent. The staff of this division would assign new code numbers to the samples to make identification of the individual testees impossible. Then the samples would be distributed for genetic testing either in the clinical laboratories of the hospital or to special institutes outside of the hospital. When the test results are sent back, the staff would reconvert the assigned number to the ID number for the person and the results would be reported to the individual testees by attending physicians. All such genetic information would be kept confidential in this division, and no one but a quite limited number of authorized geneticists would have access to them. Even the attending physicians who ordered the test would not be allowed to see the information by themselves. In some day, I think, we should discuss for establishing a certification system for qualification of special clinical geneticists.
2.3. Prenatal Gene Diagnosis and Screening for Inherited Genetic Disorders
As reported in the January 17, 1994 issue of Time magazine, half (50%) of the citizens of the United States would be willing to accept a genetic test that could tell them what diseases they are likely to suffer from later in life. If they or their spouse were pregnant, 58% of them would allow prenatal genetic tests to screen for possible genetic disorders of the neonate, while 39% of them would not. Inherited inborn errors of metabolism are very serious and distressing to the parents, and other family members or even to the society as a whole. Therefore prenatal gene diagnosis of disorders for which effective prevention and treatment are available is of very great value. In the absence of any effective way of addressing the disease, prenatal gene diagnosis may be of no use at all. The pre-gestational gene diagnosis that has recently become available should not be introduced by the time when preventive abortions of disordered embryos will be legally permitted or when application of safe and stable gene therapies will become possible. In the near future we will have to consider these matters very seriously.
3. Ethical Problems Related to Gene Therapy
Since the first gene therapy, for a girl with ADA deficiency, was performed in September, 1990, approximately 600 cases of various diseases have been treated by DNA preparations. In Japan, the first case was treated very recently. As for the basic considerations concerning gene therapy, similar and very clear guidelines have been presented by both the Ministry Health and Welfare as well as the Ministry of Education, Science and Culture. These guidelines prohibit any genetic manipulation of germ-lines, and very stringently restrict the categories of disorders for which they are to be applied. Further, the Ministry of Health and Welfare has set-up the Central Evaluating Committee for Gene Therapy to carefully review the validity of all proposals. Agencies in the United States and many European countries have been working already in the same direction, in attempts to exclude any inappropriate gene therapies. However, the gene therapies currently available are still in the experimental or trial stage. There are many unresolved issues to be clarified further, including: the safety and stability of vectors used for the insertion of genes; the duration of the life span of gene-transfected cells or their possible pathogenic behaviors in the recipient's body; useful means of regulating the extent of gene expression or cell replication after the therapy. On the other hand, if the pre-gestational gene diagnosis were admitted, there would be some possibility of controlling birth based on the results or of performing gene therapies on the premature embryonal cells. So when most of the other problems may be solved in the future, this latter issue will need to be discussed once again.
Gene therapy appears to be less mired in ethical problems than is gene diagnosis. Nevertheless, every medical institute planning to institute a gene therapy program is required to have its own ethics committee to evaluate individual therapy proposals. Such evaluation based solely on the written proposal materials may not be adequate, and in addition to ethics committees, the third section of the proposed division of gene diagnosis and therapy would deal with practical guidance and detailed monitoring of therapy.
In summary, I hope I have demonstrated several critical points in my presentation or current ethical considerations related to gene diagnosis and therapy. These are, the right to not know, the inadmissibility of the right to not divulge, protection of human rights, with the necessity of a confidential management system for genetic information, the ideas that genetic information is essentially the property of the testee and not of the medical authorities and that informed consent is required for the testing also, and current and future considerations in the prenatal or pre-gestational application of gene diagnosis and embryonal treatment. In order to resolve these problems practically, I proposed the necessity for a division of gene diagnosis and therapy and for in-hospital ethics committees devoted solely to issues in genetics in any hospital performing gene diagnosis and therapy. The clinical division would be comprised of the 3 sections of genetic consultation and education, genetic testing and management of gene information, and gene therapy guidance and monitoring.
Gene diagnosis and therapy has now reached a stage with grave implications for clinical practice. It is imperative that we develop guidelines and implement system that promote not only effective but also ethical practices.