pp. 276-284 in Intractable Neurological Disorders, Human Genome Research and Society. Proceedings of the Third International Bioethics Seminar in Fukui, 19-21 November, 1993.

Editors: Norio Fujiki, M.D. & Darryl R.J. Macer, Ph.D.

Copyright 1994, Eubios Ethics Institute All commercial rights reserved. This publication may be reproduced for limited educational or academic use, however please enquire with Eubios Ethics Institute.

Genetic diseases and freedom of faith in life

Yasuo Kagawa
Professor, Jichi Medical School Department of Biochemistry, Tochigi, Japan

1. Summary

Very few molecular biologists want to discuss bioethics. The author is in charge of the Research Project "Genetic Diseases", and a member of the Evaluation Committee of the "Human Genome Project" and "Guidelines for Gene Therapy" of the Ministry of Education, Science and Culture, Japan, and would like to propose practical methods to improve the present state of genetic medicine in Japan.

a) According to the Governmental Survey of Public Opinion on Life Science, public opposition was highest against in vitro fertilization and drugs prepared by recombinant DNA method, yet these are being used in daily clinical practice. On the other hand, the highly supported gene diagnosis has many restrictions on it and is rarely practiced, and not a single gene therapy has been started.

b) There have been great advances in studies on genetic diseases since the last Symposium. Thanks to the YAC contig of human genome and the many genetic markers obtained, the analysis of genetic disease has became much easier. The new concept of trinucleotide repeat expansion diseases has been established.

c) Japanese scholars in bioethics tend to be absorbed in "tatemae" (ideal official concepts) such as "social consensus" and the "fetal right of survival", and neglect "honne" (realistic concepts). Hence they are unable to deal with the reality of the accumulation of genetic diseases, limited medical resources etc., and because patients fail to receive treatment or guidance their health and life suffers.

d) The character of the patient's view of life, which is the foundation of his/her right of self determination, has something in common with that of religion. Thus, there can be no so-called "social consensus" on each medical practice. For this reason, the author proposes that we should recognise a "freedom of faith in life" equivalent to religious freedom. This idea is practical, because it is both constitutional and also well-suited to the custom of the Japanese for compromise.

e) It is essential to establish guidelines for genetic research and gene therapy to indicate that these procedures are safe and appropriate. Both an enlightened attitude to genetic diseases and informed consent for each therapy needed to be in these guidelines. Finally we should leave the choice of medical treatment to be made by the patient according to their faith in life.

2. Expectation and Concern of People on the Study of Genetic Diseases

" Vox populi, vox Dei" (The voice of the people is the voice of God). In order to spread genetic medicine among people, ELSI (ethical, legal and social impact) issues are important (1). The Governmental Survey of Public Opinion on Life Science (2) tells us that 45.3% of respondents in 1985 wanted therapies of cancer and genetic diseases, three times more than the number for the next largest item. It is essential for genetic medicine to obtain public support. But in Japan there are few molecular biologists who discuss bioethics (1). On the other hand, Genethon in France obtained 3.6 billion yen from individual donations of people through a TV appeal, and succeeded in establishing the YAC contig library of the human genome.

As shown in Figure 1, among those questioned concerning the application of the life sciences to the human body, opposition was highest to in vitro fertilization (IVF), while approval was highest for prenatal diagnosis (PD). In particular, 79% of 20-29 year old women, those directly concerned with child rearing, supported PD, and only 15% were against it (2). We discussed these result at the Governmental Special Committee on Recombinant DNA in 1986, and took a cautious attitude to IVF because of the opposition. However, IVF has become an everyday clinical practice. This unexpected result may be attributed to the difference in attitudes between the minority of patients who feel keenly the necessity of IVF, not the majority of people who are indifferent to the special therapy, and may be negative towards change. Some people felt anxious about drugs made by the recombinant DNA method, and over half felt that there was a lack of public education (2). Today, peptide hormones such as tissue plasminogen activator (TPA, an anticoagulant), and various growth factors are produced by the gene technology, and successfully used in hospitals. The amino acid sequences of these proteins are human type being produced from human genes, and thus they are immunologically safer than those extracted from animals. Moreover, many people have been infected with AIDS or hepatitis by conventional human blood products, which are now being replaced with gene technology products, such as vaccines, that are extremely safe.

However, even in 1991, nearly 60% of people were still anxious about IVF and genetic engineering (Macer, in Ref. 1, p.123). Likewise, while most supported PD (76.3% of people, see Ref. 1, p. 129) it has not been popularized yet, because of several difficult problems. Gene therapy which was supported by 56% of 20-29 year old persons in 1986 (2), and more in 1991 (1), and in 1993 (Macer, this book), has not yet been started in Japan. To sum up, "the voice of people" is not always correct, and support by the average of the population has not always led to the general implementation of good new therapies.

From the scholarly point of view, avoidance of the danger of accumulation of genetic diseases is an important problem for modern society. Since mutations are stochastic, and nearly inevitable, patients with genetic diseases will accumulate in the absence of selection in a society where both birth rate and mortality are low. Needless to say, the handicapped can survive only when the majority of those in his society are healthy.

Figure 1: Applications of the fruits of life science directly to the human body (%'s)
(Prime Minister's Office survey on the life sciences, N=7441, over 20 years, December 1985).
3. The Development of the Human Genome Analysis Project

The present bioethical problems occur where customs and ethics hitherto fostered in human society become unable to deal with developments in medical technology (1). For example, the brain death problem was caused by the introduction of artificial respirators, and without PD, there would be no abortion to avoid genetic diseases.

Since the progress in genetic research has already been reported during the last International Seminar (1), the author will briefly summarize the progress over the last two years he has examined as the head of Research Project "Genetic Diseases", and as a member of the Evaluation Committee on the "Human Genome Project" (Table 1, the abbreviations used here are described under the table) (3). Analyses of disease causation and gene function should become very easy when the total nucleotide sequence of the human genome is known. For this purpose, the Human Genome Project is now in progress to elucidate the 3Gbp human nucleotide sequence and determine the structure and character of the 100,000 genes contained therein by at least the year 2006. Considering the universal nature of basic science, the Japanese Human Genome Project should be international. As shown in Table 1, the objectives of the Japanese Project are vague and abstract, while American Project shows definite nucleotide numbers and the target dates for the research, and thus the aims are clear-cut (4). The National Institute of Health has appointed Dr. F. S. Collins, who is noted for pioneering work on positional cloning, and for uncovering the gene responsible for cystic fibrosis, as Director of the National Center for Human Genome Research.

a) From Functional Cloning to Positional Cloning: To cope with the rapid elucidation of innumerable genetic diseases, new journals such as Nature Genetics have been started. The classical genetic diseases have been mainly classified as inborn errors of metabolism. This is because in the case of the phenylketonuria, the mutated gene has been identified with the accumulated metabolite of the responsible enzyme. This method is called functional cloning. However, the present method for isolation of genes is called positional cloning, because it starts directly by locating the gene locus using linkage analysis. This method has revealed the cause of diseases that cannot be explained by enzyme deficiencies. Diseases such as muscular dystrophy, malignant hyperthermia, cystic fibrosis, Zellweger syndrome, etc. are caused by genetic abnormalities of biomembranes. These genetic diseases have been illustrated in a monograph (5). Carcinomas, inflammation, cardiovascular diseases, diabetes mellitus, endocrine diseases etc. are also caused by abnormal biomembranes predisposed by genetic mutation (5).

Table 1: The Goals of the Japanese and U.S. Human Genome Projects

Final Goals:
Japanese Human Genome Project
Genome Structure & Functions. Development of Bioscience.
U.S. Human Genome Project
3 Gbp DNA sequence by 2006. Elucidation of all 100,000 genes.

1st Stage 1991-6 Goals:
Japanese Human Genome Project
Analytical improvements. Sequencing of ca. 10,000 cDNA. Routine automation of sequencing and FISH improvements. Model species, Data bases.
U.S. Human Genome Project
Genetic map: STS at 2-5cM. Physical map: STS at 100,000bp. 2Mbp length of contig DNA. Cost down: $0.5/base, 30Mbp. Model species, 20Mbp seq.

Results up to August 1993. From DNA data of GenBank, DDBJ & EMBL totals
Japanese Human Genome Project
Technical advances in mapping of 3,6,8,11,14,21,X,Y chr. P1 micromap, HLA, Ig sequencing; International Fukui Bioethics Seminar; Tissue cDNA library; Analysis of gene expression; Technical teaching meetings; C. elegans, yeast, B. subtilis micromaps, databases
U.S. Human Genome Project
YAC contig for Y and 21 chr.* (*France), each 200 STS 16,19 chr. contig 80% length etc. for whole genome contig; DNA 28Mbp (93.3% of the goal); 71,3922 DNA loci determined BACs. Single band FISH <1kbp; ELSI developments; mouse, C. elegans, yeast models; Non-gel sequencing by mass

Contribution in the world (/100%)
Japanese Human Genome Project
cDNA 22%, Disease group. EST 10%, Matsubara's group marker 20%, Nakamura's group DNA bp 5%, (+marker)
U.S. Human Genome Project
Leading HUGO & Technology. brain EST=3,400 (Venter 35%). Chrom.5,6,11,15,16,17,19,22. GenBank; 59.6% =16.8Mbp

Japanese Human Genome Project
Support to Researchers on 1 yr basis
U.S. Human Genome Project
Grantee-Contractor contracts

Abbreviations used: BACs: Bacterial Artificial Chromosome using F-factor. cM: centimorgan (A unit of measure of recombination frequency, One cM is equal to a 1 % chance that a marker at one genetic locus will be separated from a marker at a second locus due to crossing over per generation. contigs: Groups of clones representing overlapping regions of a genome. DOE: Department of Energy of U.S. Federal government. ELSI: Ethical, Legal, and Social Issues supported by grants from HUGO. EST: Expressed Sequence Tag (STS derived from cDNA). FISH: Fluorescence in situ Hybridization (A physical mapping approach that uses fluorescein tags to detect hybridization of probes with chromosomes.

b) Advances in Methods in Gene Analysis; PCR, FISH, Microsatellite Polymorphism: Even in daily clinical diagnosis, patient's mutations and chromosome aberrations can be detected easily due to the introduction of polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH), respectively (6). As shown in Figure 2, today clinical testing companies now test more than 2,600 aberrant chromosomes (50 % are aberrant) a year under the complete privacy of the report format as shown in Fig. 2. Microsatellite (dinucleotide repeat polymorphism) is an excellent marker. Utilizing this, the locus of Machado-Joseph disease was located at 14q, the disease was found in a remote area, where the limited chance of marriage results in the accumulation of genetic diseases in the large families (Figure 3).
Figure 2: Chromosome Analysis Report (SRL: Science Reference Laboratory) G-banding

Figure 3: Pedigree of a Japanese Machado-Joseph Disease Family

Jichi Medical School specialises in medical care for remote villages, where such large pedigrees are found. This is an autosomal dominant neuro-degenerative cerebellar disease. The blood samples were taken with written informed consent from each family member and from unrelated normal persons, and lymphoblastoid cell lines were established. A total of 90 microsatellite DNA polymorphism markers were used. Analyses of microsatellite DNA polymorphisms were performed by the polymerase chain reaction. Two-point LOD scores were performed by the PCR. Two-point LOD scores were calculated using the MLINK program of the LINKAGE package. This gene is mapped to chromosome 14q24.3-q32.2 (From Takiyama Y., et al. Nature Genetics 4, 300 (1993)).

Figure 4: Maternal inheritance of mutated mitochondrial DNA in MELAS (Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes).

The severity of the disease depends on the amount of mutated mitochondrial DNA (305bp, the lower band, ApaI fragment) inherited (ref. 8). This mutation also causes diabetes melltius of tens of thousands of people.

c) Genetic Diseases showing Varied Severity: The discovery of the trinucleotide repeat diseases such as myotonic dystrophy, spinal and bulbar atrophy and Huntington's disease which have variations in individuals at age of onset and in severity of symptoms had a large impact. The genes contain a polymorphic trinucleotide repeat, an unstable DNA segment in which the sequence is copied many more times than normal. The number of repeats correlates with the severity of the disease and the age at which it becomes apparent: the longer the repeat, the earlier the onset of symptoms. Mitochondrial encephalomyopathies are also genetic diseases showing varied severity of symptoms, in this case because the thousands of mitochondrial DNA are transferred cytoplasmically, severity increases with the amount of the mutated DNA inherited from the mother (Figure 4) (7, 8). These patients with a continuous variation in severity have changed the old Mendelian concept that there are only three categories of progeny: mutant homozygote, heterozygote and normal homozygote, and the diseases themselves have been established as having an unclear boundary between sufferer and non-sufferer.

e) The Contig of the Whole Human Genome: The target of the first stage of the Human Genome Project is the mapping of the genome. Dr. D. Cohen's group succeeded in constructing the contig map using YAC (yeast artificial chromosome), and the whole human genome is expected to be covered by the contig during this year (6,9). Thus, classical linkage analysis has greatly improved.

f) The Amount of Genome Sequenced and the Contribution of Japan: The total length of human genome sequenced as recorded by databases by August 1, 1993 was 28,035,789bp, and the total entry was 25,879, so it had reached about 93% of the initial US goal of the first stage of 30 Mbp (Table 1). The contribution of Japanese to sequencing was 6.22% (data from DDBJ, DNA Data Bank of Japan) or 4.8% (data from Riken). Of course this includes the length sequenced under other projects, and as a whole, the Japanese contribution was estimated to be about 5%. Of the approximately 100,000 human genes, those whose total cDNAs had been sequenced were 5,274, of which 1157 were in the National Genetics Research Institute's DDBJ. The high Japanese contribution of 22% was attributed to the contribution of researchers concentrating on genetic diseases etc (3, 10). The ESTs (expression sequence tags) of the 3' terminal region of cDNA, mainly sequenced by the Matsubara-Ohkubo group, are registered separately. The world total of EST sequences was 9,781, with 983 from Japan (about 10%). As for mapping markers the contribution of Dr. Yusuke Nakamura (Cancer Institute) was ranked first internationally, and made up about 20 % of the world total (10).

g) Inauguration of the Gene Therapy: In various foreign countries, gene therapy against adenosine deaminase deficiency and cancers has been started, with good results in some areas. There is a good review of this (11).

4. "Tatemae (Ideal)" and "Honne (Real Intention)" in Genetic Diseases

The role that bioethics (ELSI) plays in the Human Genome Project is large (1, 11, 12). Heart transplantation is not possible and abortion based on PD is not commonly available in Japan, though these applications of the fruits of life science are technically feasible and widely utilised in foreign countries. Elucidating the real cause of this difference is an important theme for bioethics. It is attributed to the Japanese dual attitude of "tatemae (ideal, official opinion)" and "honne (real, practical intention)". In an official open meeting, "tatemae" manifests itself and "honne" is concealed, only heard among friends or in closed meetings, where for example doctors and politicians make many important decisions in Japan. In bioethical debate, a formal "tatemae" based on humanism is always strongly stressed, without considering existing limitations in medical science, and medical and financial resources and expenses. However, as usual, everybody has their own "honne", the reduction of the tax burden, insurance premiums and service necessary to support the gigantic medical bill. "One life is weightier than the earth" is hyperbole. In reality, 5 billion people have only one earth that can never be for the convenience of a single person. If "tatemae" is not feasible, it is nothing but hypocrisy. It is the responsibility of scholars of bioethics to look for responsible methods and to correct these superficial wrong opinions of hypocrites. The examples of these opposing "tatemae" vs. "honne" are summarized in Table 2.

a) Social Consensus and the pros and cons of each Therapeutic Method of Genetic Medicine: It is wrong that a genetic therapeutic method should be prohibited until social consensus is established, because each individual has their own opinion of life. Actually this idea may result in an eternal ban of the therapy.

b) Enlightened Education for Prenatal Diagnosis (PD): There are some groups who oppose prenatal diagnosis as a eugenic idea and ignoring fetal life. Thus, the prefectural efforts to enlighten people about prenatal diagnosis have been interrupted, and the Japanese Society of Obstetrics and Gynecology condemns abortion after PD. However, the parents are unable to take care of and be responsible for their handicapped children throughout their lives. If we leave this situation as it is, disabled patients will increase in our modern society where there is no selection, and then the ban of PD will bankrupt. If prefectural efforts to enlighten people about PD are cancelled because of the opposition of a small minority, many patient's families will be deprived of their rights.

Table 2: "Tatemae" and "Honne" in Japanese Genetic Medicine

Example: Tatemae (Official Ideal); Honne (Real intention);

Application of genetics treatment: Social consensus is essential; Patient's free choice

Abortion after prenatal diagnosis: No: the fetus has an absolute right to survival; Yes: The child, his family and society will suffer

Applications for insurance: Yes: There should be no discrimination against the patient; No: The insurance company will become bankrupt

Experiments on the human body: No: It endangers life and is unethical; Yes: No safe drugs or therapies without such testing

Patents on human genome: No: non-profit-making in humanistic science; yes; without industrialisation the supply of drugs is difficult

Going abroad for new medicine: No: This treatment is still forbidden at home; Yes: This situation is caused by the defective system

Exclusion from the workplace: No: No discrimination for the disadvantaged; Yes: Employers should seek to exclude the susceptible

c) Application for Life and Disability Insurance Contracts: "Tatemae" prohibits any discrimination, but Japanese life insurance companies will start blood testing prospective clients to check for HIV from October, 1994. A contract with a patient known to have a fatal genetic disease is a serious operating problem for a company. According to an editorial in the Journal Nature (13),"if it is fair to weight insurance premiums against those who smoke cigarettes, should not the same apply to those with an aberrant gene?"

d) Experiments on the Human Body: "Tatemae" prohibits any experiment on the human body because they may be unethical and dangerous. However, as shown in Fig. 5, testing on individuals after informed consent, is essential to the development of a new drug, vaccine or therapy. In fact, a number of gene marking protocols using human subjects have already been reported in the development of gene therapy in the USA (ref. 11, p. 194).

e) Patenting the Human Genome: "Tatemae" is that patents on the human genome to force economical burdens on the patient and slow the advance of genetic science by restricting information flow. However, industrialization of gene technology is impossible without some patents on the human genome (14). In fact, in Japan the annual sales of interferon to treat hepatitis C are 240 billion yen. But NIH's patent application for 4000 ESTs (partial cDNA sequences without known function) is questionable and unacceptable.

f) Advanced Medical Treatments in Foreign Countries: "Tatemae" prohibits receiving any medical treatment not approved in Japan, even abroad. But as in the case of heart transplantation, patients will go abroad to survive if gene therapy proves effective. The legislative delays and intolerant "bioethics" in Japan must be corrected.

g) Discrimination of Patients in Employment: "Tatemae" prohibits any discrimination, and the law says that companies must employ a certain number of handicapped people. However, again according to the same editorial of Nature "If it emerges that there are occupations in which people's susceptibility to unavoidable hazards is genetically determined, does it not make good and even humane sense that employers seek to exclude those who are susceptible?"(13). However it is certainly not discrimination to select on the basis of severity of disease, but rather a means of maintaining safety and protecting human rights. Tests for human susceptibility to unavoidable work hazards are permitted abroad.

Figure 5: Letters on the requirement for informed consent

Mr. Norio Masuzawa 27 July, 1992
Chairman, Ethics Committee for Teachers

Dear Mr Masuzawa,
The members of the Research Material Examination Committee approved unanimously the conditions* listed in the application, "Functions and genetic structure of human adenosine triphosphate synthesizing enzyme" (Paper I), submitted by Prof. Yasuo Kagawa of the Biochemistry Dept. (researcher: Prof. Kagawa). Attached to the application is my statement (Paper II). We would be grateful if you could review the application and report the result to Prof. Kagawa.

The reason we put* to the conditions was that one of our members suggested it is appropriate to put "informed consent" in written form, if there is any risk of hepatitis B, tuberculosis, etc., at the time of obtaining samples for biopsy. On the other hand, there was an opinion that we should avoid complicated explanations as no sample will be obtained without consent. The risk in the former case is not to the individual patient, therefore we believe written consent is not necessary.
Tsunao Tetsuka

Mr. Tsunao Tetsuka 4 August, 1992
Member of Ethics Committee for Teachers

Dear Mr Tetsuka,
I am happy to inform you that the research theme reviewed by the Ethics Committee for Teachers, "Functions and genetic structure of human adenosine triphosphate synthesizing enzyme" (Paper I), submitted by Prof. Yasuo Kagawa of the Biochemistry Dept., was approved. The approval has been sent to the applicant as shown in the attached paper.
Norio Masuzawa

5. Freedom of Faith in Life and the Cultural Background of the Japanese

Let us recall the proposition "Vox populi, vox Dei" again. Since genetic medicine is being developed for mankind, the desires of the people seem to be the best guide to its implementation. However, as shown in Figure 1 (2), their opinions are never unanimous. The conservative majority of the general population, who must bear some economical burden to save patients, can have quite different opinions from those of the patients and their families, who want to treat their disease even if it risks their own life.

It can be said that the official opinion that a "national consensus" or "social consensus" is needed for each genetic medical treatment, and that medical specialists should educate people in order to attain this goal (Ref.1, many chapters). However, as discussed in the previous section, this "tatemae" idea is wrong. Even if time and effort is put into education, such a consensus will never be reached, because each person has their own "faith in life" which has something in common with religious belief. There are fundamental disagreements and it is not a character of these problems. It is also wrong to force people to have a unified "national consensus" by the majority rule of democracy, and trying to educate people into making such a consensus is dangerous because it violates the constitutional freedom of faith.

Hence, instead of "social consensus", it is rather the coexistence of people with different senses of values that will open the way to the future and will solve the difficulty. The "social consensus" needed here is only to guarantee the patient's own right of self-determination to choose the medical treatment. For example, there is certainly no definite consensus on the right of survival of the fetus as peoples views of life are different. The author proposes we recognise a "freedom of faith in life" as a right equivalent to the freedom of religion guarantied by constitution. Provided the rationale for the diagnosis and treatment satisfies the guidelines described in the next section, the informed consent of the patient and/or his family is the only requirement for the therapy. To put matters concretely, in the case of most genetic diseases after prenatal diagnosis they can choose the path to be taken according to their right of self-determination. If they want to select a healthy child by their own responsibility, the abortion is approved. On the other hand, if they want, it is also possible for them to live with the handicapped child who was given to them by God. Society will extend and raise outstretched arms to these handicapped children, even while bearing the economical burden, and we must not forget these children in return will contribute to the development of medicine through the treatment and nursing they receive.

Is this kind of "freedom of faith in life" really practical in Japan? As Dr Yonemoto pointed out in the last Seminar (1), "the acceptance of genetic medicine in a society depends to a large extent on their cultural background". There are narrow-minded, intolerant religious and nationalistic conflicts in and between foreign countries. In contrast, the Japanese are vague and compromising, and peaceful, an attitude which may be beyond the imagination of Western scholars in bioethics who believe in a monotheistic religion. For example, the largest Buddhist sect in Japan is called "Jodo Shinshu", which dispensed with inhuman precepts and prohibits criticizing other religions. The average Japanese celebrate the New Year and marriage according to Shintoism, attends Buddhist funerals, observes Confucian ethics, and also enjoys Christmas with their children. This very religious, and yet nonreligious coexistence of varied sense of values is suited to the Japanese. In general, the intolerant bioethics is the result of Western influence. True bioethics requires a tolerant attitude to "honne".

6. Guidelines on Genetic Research

There have been many symposia on genetic medicine where different opinions and foreign examples concerning bioethics have been discussed, mainly as tatemae. However, mere reports on different ideas will not show the doctors and patients what way they should proceed (1). In particular, according to the strong criticism (15) of the last International Seminar (1), the most important scientists "left before the talk turned to ethics", and "Japanese scientists are reluctant to discuss ethical issues."

Someone conversant with research must take responsibility and construct guidelines, in other words, guidance on behaviour, for the patient's best. Based on these guidelines, patients will have no need to receive treatment should they not desire it. Because of the lack of suitable guidelines, there is the possibility that the patient rights will be unjustly lost due to accusations by a third party, even if the treatment is rational and grounded in the patient's rights of self determination and the doctor's conscience. There is strong opinion by some that as genes are largely not understood, abortion after prenatal diagnosis is premature (1). However, diseases caused by a single gene, such as those likely to be associated with abortion dilemmas, are based on a clear mutation, and it is medical common sense that should a genetically defective child be born it will be handicapped. After humbly admitting there is still much we don't know about genetics, the guidelines will recognise what kind of genetic diseases are suitable subjects for treatment.

Genetic research is not regulated by law but by the guidelines "Recombinant DNA experiments in Universities etc.", and when there is any fear of danger, approval by the Minister of Education, Science and Culture is required. Grant applications for genetic research require internal approval by authorized university committees, or in some case, by those outside. The Guideline was revised in 1992, because there has not been a single accident caused by the recombinant DNA experiments in Japan.

The largest issue, the use of human subjects, was excluded from the revised Guideline. This can be partly attributed to the absence of any medical doctors, except the author, in the members of the 12th Recombinant DNA Committee. The other reason is the bureaucratic system in Japan has no organisation equivalent to NIH where both the research subsidising function of the Ministry of Education and the medical administration of the Ministry of Health and Welfare are unified. For example, there are two Guidelines for Gene Therapy, one by the Ministry of Health and Welfare, the other by the Ministry of Education, Science and Culture. Thus, for example, it is still not certain whether "the head of the institution for gene therapy" is the president of the university or the director of the university hospital. If the ethics committee of the university contains a subcommittee for gene therapy, this "head" may be the president, but the responsibility of therapy should be taken by the hospital director.

We still do not have a guideline for genetic diagnosis equivalent to the "Guidelines for Gene Screening" of the American Association of Human Genetics. In the U.S. Human Genome Project, the ELSI program placed special emphasis on defining privacy and confidentiality issues (12). In Japan, the research on human samples are permitted after permission is received by the bioethics committee, or its subcommittee, in each university, and there may be a special committee for this issue as shown in Figures 5, and 6. The Japanese Guidelines for Gene Therapy contains a definite format concerning procedures for applications related to gene therapy.

Gene therapy in Japan, according to the Ministry of Health and Welfare Guidelines, is confined to the fatal diseases, and requires the agreement of patient and family. This informed consent is a notification of death, which is against the "right of not receiving information" widely spread among Japanese cancer patients. Of course, in Japan, according to the new legislation on disclosure of information, the patient can now look into their own clinical records, if they so wish. However, the ability to predict future serious or fatal illnesses well before any symptoms or medical therapy exists. In this case, a patient's hope in their future life may be lost. The consultation system for genetic diseases and the consultants training is still imperfect. Informed consent and guarantee of the patient's human right as provided for in the Japanese Guideline for Gene Therapy will be more complete if the "Patient's Self Determination Law" of America (federal law) of December 1991 (16) is taken into consideration.

In conclusion, the author recommends recognising the "freedom of faith in life" accompanying patient's self determination, and the consideration not of bureaucratic "tatemae" but of realistic "honne" in implementing genetic medicine.

Figure 6: Format for Informed Consent of a Volunteer (an Example)

(Written format used by a doctor testing a new drug, to explain it to a volunteer)

1. Objectives and Methods of the Test
KW-4679 was developed in Japan, and its effectiveness against chronicle A has been proved by animal and human tests. We are asking many patients to use the drug in order to further research on its effect and safety. We ask you if it is possible to use the drug in your treatment.
You will take 2 doses a day, one after breakfast and one before you go to be, one tablet and one capsule, for two weeks. Tablets and capsules contain either the new antiallergic drug called KW-4679 or an antiallergic drug (Zaziden) which is now in commercial use. By comparing the two types of drug, we can examine how effective the new drug is.

2. Possible effects and side effects
It is expected that an improvement/cure in B will be seen, as both drugs are very effective. Our experience in using the new antiallergic drug shows that drowsiness and fluctuation of test value may occur, but these are not serious, and other side effects are not different from those of conventional antiallergic drugs.
Please inform your doctor as soon as possible if your condition worsens. we will give appropriate treatment immediately.

3. Effect and contents of other treatments for the disease
There are several drugs such as Antihistamine or antiallergic drugs, therefore, treatment using these will be conducted in the case that consent to the test is not given.

4. No disadvantages due to refusing consent
It is your own free decision whether to volunteer for the test. There will be no disadvantages for your treatment, even if you refuse to volunteer.

5. Withdrawal from the test
You can refuse to continue the test for any reason, even if you have already given consent to the use of the drug. The doctor in charge will do their utmost best for your treatment.

6. Protection of the rights of the patient
Information on the patient's disease and treatment obtained through participation in the drug test will be confidential. The privacy of the patient will be strictly protected on the basis of respecting human rights. In addition, please do not hesitate to ask if you have any doubts about the test, or need explanations. We will do our best to explain fully, and to continue the test.


1. Fujiki, N. & Macer, D.R.J. eds, Human Genome Research and Society. Proceedings of the 2nd International Bioethics Seminar in Fukui, (Christchurch: N.Z.; Tsukuba, Japan: Eubios Ethics Institute, 1992) .
2. The Prime Minister's Office, "Life science", Monthly Public Opinion Survey April 1986, 53-99 (in Japanese).
3. Okada, Y. & Kagawa, Y. (1993) Report on Evaluation of "Human Genome Analysis Project". Ministry of Education, Science and Culture. pp. 1-11.
4. United States Department of Energy (1992) Human Genome Program Report, 248pp.
5. Kagawa, Y. (1993) Illustrative Molecular Biology of Biomembranes and Diseases, 560pp., (Tokyo: Nanzando, 1993)
6. Matsubara, K. & Sakaki, Y. (1993) Genome Analysis Research. Protein, Nucleic Acid, Enzyme 38, (3) 203-720 (in Japanese).
7. Kagawa, Y. et al. (1993) Multiple deletions of mitochondrial DNA in patients with familial mitochondrial myopathy. Progr. Neuropathol. Vol. 7, pp. 129-151 (New York: Raven Press 1993)
8. Kagawa, Y. (1992) Mitochondrial Gene and its Diseases. Cell Technology 11 (1) 1.
9. Chumakov, L. et al (1992) (34 researchers): Nature 237, 336.
10. Kagawa, Y. (1993) Ministry of Education Special Research Program "Genetic Diseases" Chairman's Report, News Letter No. 3.
11. Morgan, R. A. & Anderson, F. A. (1993) Annu. Rev. Biochem. 62, 191.
12. United States NIH and DOE. Human Genome News 5, (1-3).
13. Editorial (1992) Genetics and public interest. Nature 356, 365.
14. Anderson, C. (1993) Genome project goes commercial. Science 259, 300.
15. Swinbanks, D. (1992) Japan Bioethics. When silence isn't golden. Nature 356, 368.
16. Oki, T. (1992) The suggestion of "Patient's self determination law. Japan Society for Dying with Dignity News Letter (65) 10.

To next chapter
To contents list
To book list
To Eubios Ethics Institute home page