pp. 42-52 in Protection of the Human Genome and Scientific Responsibility

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

Copyright 1996, 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.

Fukui Session: Fourth International Bioethics Seminar in Fukui

Welcome Address

Masami Sudo(
President, Fukui Medical School


It is a real honour and privilege for me to welcome all of you, especially Mme Lenoir, President of the IBC of UNESCO, and the panelists from various countries, to the Fourth International Bioethics Seminar in Fukui, as well as the MURS Japan / IBC, UNESCO joint seminar.

Eight years have passed since the first Bioethics Seminar in Fukui entitled "Human Dignity and Medicine" was held in 1987, with the keynote lecture by Prof. Jean Bernard, the former president of the French National Academy of Science. The second seminar "Human Genome Research and Society" was held in 1992, the third seminar "Intractable Neurological Disorders, Human Genome Research and Society" in 1993.

In those seminars, we discussed how to protect human dignity from the ethical, legal and social point of view, while promoting application of rapidly developing biotechnology to the diagnosis, treatment and prevention of genetically related diseases, to the supply of bioactive substances.

In 1993, Prof. F. Mayor, Director-General of UNESCO, has invited Mme. Lenoir to establish the IBC for protection of the human genome and human dignity, in addition to educational, scientific and cultural backgrounds. At the visit of Mme. Lenoir to Japan, we are most happy to have her as an honourable guest speaker in this fourth Bioethics Seminar in Fukui, following the meetings in Tokyo, Nagoya and Kyoto, as MURS Japan / IBC UNESCO Joint Seminars, which were organized by Emeritus Prof. Norio Fujiki, vice-president of IBC, UNESCO and secretary general of MURS Japan.

In this seminar, we will have two lectures and one panel discussion. The first lecture on "Medical Geneticist's Responsibility" will be given by Prof. Fujiki and the second lecture on UNESCO and Bioethics by Mme. Lenoir. In the panel discussion on "Science and Society in Different Countries", we will have five distinguished panelists from various countries.

In closing this address, I hope that this seminar improves the understanding of bioethics and the role and activity of IBC, UNESCO. I also hope that participants from abroad will enjoy the Japanese traditional culture and the beauties of nature in Fukui.


Medical Geneticist's Responsibility

Norio Fujiki(
Emeritus Professor, Fukui Medical School; Vice President, IBC, UNESCO Paris, France;
with the cooperation of M. Kuriyama, M. Hirayama, T. Azuma, K. Mano, S. Nakazaki, and K. Hashimoto


Introduction

The application of new biotechnology has developed with tremendous speed and DNA technology has created ethical problems needing some guidelines on medical genetic practices, such as DNA diagnosis, mass screening, prenatal diagnosis, carrier detection of genetic disease, as well as prediction for genetic combinations on susceptibility to common diseases, I, as Vice President of the International Bioethics Committee of UNESCO, would like to report the bioethical aspects of medical genetics, especially on human genome research, which become more and more important in our social lives.

Since 1960, we have made every effort to solve the suffering and anxiety of patients with birth defects, through human genetics, learned under the guidance of my respected tutor Professor Emeritus Komai for human genetics. Also I have tried to develop my clinical medical practice with medical and ethical considerations taught by another respected tutor, Professor Emeritus Masuda who passed away from lung cancer after 6 years.

Bioethics concerns many problems of birth and death as well as quality of life. In summary, we emphasize internationally moral norms not specifically concerning how we, as human beings, should survive in this rapidly developing biotechnological period, but rather concerning the multidisciplinary process not only within but also between specified areas of biology and medicine with such allied fields as philosophy, sociology, psychology, law and economics. In Japan, development of this is still immature, but the Japan Society of Bioethics has been concerned among its activities during 5 years, we had over 10 international conferences and dialogues on bioethics.

We have recognized the importance of the dignity of human life in our discussions. We held the First International Bioethics Seminar in Fukui 1987, welcoming Prof. Bernard, former President of the French National Academy of Science. After this First Seminar , we had the Second and Third International Bioethics Seminar's in Fukui in 1992 and 1993, as well as the CIOMS Conference on Genetics, Ethics and Human Values in Tokyo & Inuyama in 1990, International Association of Human Biologists-Japan Society of Human Genetics Joint Symposium on Medical Genetics and Society in Fukui in 1990, and published their proceedings, respectively, as Human Dignity and Medicine, Human Genome Research and Society, Intractable Neurological Disorders, Human Genome Research and Society as well as Medical Genetics and Society. By developing bioethics in medical genetics, we have drawn attention internationally to the ethical, legal & social issues (ELSI), especially in DNA diagnosis in the area of medical genetics, as below described, in order to bridge the cultural differences between the East & West as well as South & North (Appendix 1).

Bioethics in Medical Genetics

From the standpoints of medical genetics, the existence of eugenic movements must be taken into considerations. There have been recent examples in which solutions of problems from screening or testing have sometimes achieved unintended or unwanted outcomes: the involvement of human geneticists and psychiatrists in the crimes committed in Nazi Germany, led to a taboo for several decades, appeared to be a nightmare, and many scientist could get out from this nightmare only to plunge into the deep sleep of amnesia. And more recently, we have the unpleasant experience of the leakage of genetic information in sickle cell anemia screening surveys and the disturbance of the employment and insurance of the patients themselves. Nobody could imagine the fear of nuclear contaminations, when famous physicists discovered the nuclear reaction, which was at that time thought wonderful. Although we have had hot discussions with surgeons over withholding the heart operation on Down's infants, not only I myself but also many physicians have been tought from severely handicapped children the facts that even physically or mentally handicapped have respectful human dignity, which we have never forgotten.

Concerning the ELSI of medical genetics, we should emphasize the need to think separately about diagnosis, presymptomatic diagnosis, carier detection and prenatal diagnosis for high risk persons with a given hereditary disease by the one hand, and neonatal mass screening, genetic testing in the workshop general population screening for occupational disease, and common disease on the other hand. As described before, we, as medical geneticists or genetic counsellors, have faced difficulties and suffered from the conflicts, and have responed to such ELSI raise by Human Genome Research for the resolution of various fields of medical genetics (Appendix 2).

Concerning genetic medicine, including gene therapy and other applications, such as purification of gene products, hormones and vaccine, it is absolutely necessary to obtain informed consent, before and after genetic counselling and application for the purpose, aims, follow up studies. Confidentiality, the moral justification, collection of genetic information and self-decision-making, should all be respected. Why should this information be linked to genetic discrimination? We should work hard at the self-assessment and education of our medical and paramedical staff and also make every effort to remove misunderstandings and prejudices of the general public.

We have succeeded with carrier detection and presymptomatic diagnosis in Huntington disease, and predictive diagnosis in cancer and coronary sclerosis. However, we should discuss more whether we should tell the diagnosis of diseases, such as Huntington disease, and clarify the significance of polygenic susceptibility, such as p53, ApoE4 genes, and environmental agents, such as diet and exercise and also emphasize the importance of the global ecosystem, as Nobel Laureate Prof. Gajdusek did.


Figure 1: Genetic counseling;

Figure 2: Cases of genetic counseling: Kyoto, Aichi and Fukui (9/1961-7/1992); 2470 Counseling Cases, 3344 Accumulated Cases

Figure 3: Followup Study of Genetic Counseling

Figure 4: Consensus Survey on the Handicapped and Heredity


International Opinion Survey

For 40 years, we have continued genetic counselling services in 3 different units in Kyoto, Nagoya & Fukui and collected over 3500 cases with follow up studies, based upon the recommendation of Guidebook on Genetic Counselling by Ministry of Heath & Welfare, Japan (Figure 1 & 2).

We carried out the follow up study to see how those receiving counselling responded our advice; to the majority of families seeking advice accepted our advice and acted accordingly. The results showed some difference regarding evaluation of genetic risk; risks were excessively underestimated in urban areas compared with overestimated in rural area (Figure 3).

Our domestic opinion survey told that the limited knowledge of the handicapped and heredity might lead to misunderstanding, prejudice and lesser recognition even among medical students. We also made an opinion survey on prenatal diagnosis, selective abortion and on new insight on the tremendous development of biotechnology, illustrated by human thalassemia, supremacy over animals, as well as withholding treatment to severely handicapped infant, in order to show applications of new technology (Figure 4).

Our international opinion survey was conducted in 1993 with the support of WHO, UNESCO, IUBS, CIOMS, Japan ELSI on HGR supported by Ministry of Education. This compared attituds in many different countries against backgrounds in religion and culture. The topics covered various issues of genetics, the handicapped, biotechnology, medical genetics and even attitudes to the environment. Some international opinion surveys had already done it all over the world for the counsellor and clinical geneticist by Weltz and Fletcher, but our survey included interests of the general public. In order to develop cross cultural ethics, we examined the reasoning that people have, which is a useful addition to the instruments that are available to examine international bioethics as UNESCO IBC stated. Most of the respondents had misunderstanding and prejudice, their ethical & emotional conclusions were common to their countries, while dependence on their society was different such as following selective abortion. It is the duty of the clinical geneticist as special advisor to cooperate with people in the mass media and to provide information that is accurate & easy to understand by the general public (Table 1, 2, 3).


Table 1: Bioethical Opinion Survey in Asian Countries - General Information

%'s Across page: India 1991; Thailand 1991; Japan 1982
N 1212 500 624
Sex (Male/Female) % 23/77 78/22 40/60
Age range (years) 20-60 20-50 20-50
Religion % Hindu 75; Muslim 8; Christian 5; Sikh 9 Buddhism 100 Buddhism >90

Married 77 - 40
No Education 9 - -
Primary School or less 9 1 10
High School 31 43 40
College 44 50 40
Professional 14 6 10

Occupation
Student 19 - 50
Housewife 46 7 40
Service 32 - 10
Business 2 49 -
Official - 44 -

Table 2: Bioethical Opinion Survey in Asian Countries - "What do you think of genetic disorders?"

%'s across page: India; Thailand; Japan
Prefer prenatal diagnosis in General 80 65 80
Prefer prenatal diagnosis for sex selection 30 12 10
Selective abortion of abnormal fetus 72 65 71
Abnormal fetus has a right to survive 32 24 25
Because life is given by God 58 2 10
Because life should be respected 47 46 30
Shocked very much if you were a carrier 62 55 46
2% frequency seems to be very high 59 65 50
How to evaluate the risk - severity 51 75 60
How to evaluate the risk - socio-economics 10 72 40
How to evaluate the risk - treatment 40 80 40

Table 3: Bioethical Opinion Survey in Asian Countries - "What do you think of the handicapped?"

%'s across page: India; Thailand; Japan
Who should take care of the handicapped - Government
42 24 70
Who should take care of the handicapped - Family
86 53 60
Spend money on both the healthy and handicapped
82 85 60
Image of Genetics - Good / Bad
42/32 40/60 20/40
Image of Genetics -Scientific / Mysterious
61/14 40/60 20/30
Get married if fiance's family has a handicapped person
76 32 (42 - No comment) 67


UNESCO International Bioethics Committee (IBC)

Director General of UNESCO Mayor decided to set up this committee and invited Mm. Lenoir as chairlady to lay down the intellectual framework and practical program, in order to reply to the ethical concern raised by advances in the life science. She prepared a report on the ethical and juridical problems raised by research on the human genome and its application and invited 40 members from all over the world in 1993, in view of the complexity of these problems she emphasized the necessity of the committies triple roles as 1) a forum for the exchange of ideas and experiences 2) an initiating role in giving practical effects to field work with a view to the better informing the public by health and research workers and decision makers 3) identifiying values common to human kind, which could bring scientific and biological progress. These tasks are basic to the reflection necessary to the elaboration of an international instrument for the protection of the human genome.

The debate is no longer one of relation of science and society but of human relationship with nature in its biological diversity, emphasized at IUBS, and our IBESF. Description of the IBC is given in Mme Lenoir's paper in this book.

Third International Bioethics Seminar In Fukui (IBESF)

This concerned the impact of human genome research on the intractable neurological disorders, such as Parkinson's disease & schizophrenia which have genetic susceptibility with environmental risk factors and are recognized as polygenic diseases, as well as disease like Huntington disease and progressive muscular dystrophy which are recognized as monogenic disease. Such neurological disorders raise a number of ELSI because of their intractability.

During the first 2 days, each of these four sessions -sociological aspects, diagnosis and counselling, genetic testing, prevention & treatment -had six multidisciplinary speakers and extensive discussion including comments and papers by the chairpersons. The ELSI as well as scientific issues were discussed, with consideration of social consequences in a range of different countries. The economic aspects may also be important in the choice of medical care systems that are adopted and attitudes people have to those suffering from disease. Later we discussed possible therapeutic approaches, including gene therapy. Topics including the philosophy of eugenics and examples of nursing experiences with such patients were also covered. After these sessions, we had a joint session with the Japanese Branch of the Universal Movement of Scientific Responsibility (MURS Japan), chaired by both President in France and Japan, Profs. Dausset and Okamoto.

On the last day, we had a Workshop on the International Bioethics Survey as described before and a final Workshop on Genetics and Bioethics in Global Society. We developed the Fukui Statement that reflected much of the spiritor different cultures and its understanding, international standards and guidelines, diversity and universality, ELSI on human genome research, genetic screening and therapy, its availability, and public education etc.

Discussion

We have made every effort for early diagnosis, treatment and prevention of heredity disease, using genetic counselling techniques, although it makes a rather small contribution in our preventive measures. The early presymptomatic diagnosis in Huntington disease, carrier detection in thalassemia and also genetic susceptibility of common disease, such as APOE4 as a marker for coronary heart disease, and Alzheimer disease would now be discussed from the ethical standpoint. As we described before, we concluded after our follow up study of over 3000 genetic counselling cases for 35 years and consensus survey in 2000 public cases. Now there have been so many prejudices and misunderstandings on heredity and handicapped. Therefore new bioethical problems, as the justification of presymptomatic gene diagnosis for Huntington disease, possibility for the discrimination of patients with adult disease psychiatric disease using predictive markers, as well as the availability of impairment of health welfare for handicapped children by these misunderstandings and prejudices, should be further discussed. Although recent studies on mapping & screening of human genome are leading to detection and diagnosis of genetic disease, the long range goal goes beyond this to providing improved treatment, prevention and ultimately cure. The interim phase is the one in which the most deleterious consequences can occur, as above mentioned, such as discrimination against gene carriers, loss of employment or insurance, and also stigmatization, ostracism, labelling and the individual psychological response, including impact on the self-image.

Here, an essential distinction must be made between the gene therapy of patients and the hereditary modification of the genetic information of mankind. Indeed, if a gene were introduced in a somatic cell of patients it could correct the disease, but not inherited. Such treatment can be compared to simple graft, such as bone marrow transplantation. Considerable efforts are currently being made to develop this perfectly ethical therapeutic approach the only hope for many patients and their families. But this contrasts with the modification of genes in the germ cell of an early embryo, which would modify the genes in the next several generations. Fortunately, until now, all scientific bodies have prohibited the insertion of foreign genes into human germ cells. In the future, if progress gives us the freedom to help families hosting a deleterious gene, perhaps this could be acceptable but only with the agreement of the highest international ethical and scientific authorities, and only after a large public debate based on completely objective and intelligible information showing full consensus among human communities.

This is the reason why MURS, a movement with no political, ethical and religious link, has undertaken an important initiative by Prof. Dausset, Nobel Laureate, to propose an additional article to the Universal Declaration of Human Right. We have now commenced the MURS Japan, under the presidency of Prof. Emeritus Okamoto, Director of International Institute for Advanced Study, as seen in this book (See the Progress Report at the beginning of this book).

From these considerations, we should provide the knowledge of science and technology, in order to protect the future biosphere and human dignity equally on the global scale, not only for developed but also developing countries. This is our proposal on the scientist's responsibility for our whole human species and environment.

Medical genetics is the science itself for the study of individuality and variability. The fact that DNA sequences of each person on the greatly varied has important imprications for the evolutionary processes of human species, respecting the human dignity. If some want to standardize some combinations of genotypes, which are regarded at present as the most suitable for present evolution, the human species would disappear within 100 years. Thus such great diversity must be respected in order to preserve the dignity of mankind.

In order to educate the general public for their understanding of individual and social problems we should remove the boundaries between the developed and developing countries, the professional and non-professional fields and assign more time in the medical and postgraduate curriculum for medical genetics, with bioethics and the scientists responsibility in our own society.

Summary

Through the clinical application of human genetic knowledge, early diagnosis, neonatal mass screening, prenatal diagnosis followed by selective abortion, carrier detection for genetic disease, genetic counselling, together with such preventive measures as the prohibition of inbreeding in eugenic law and promotion of family planning, have been mostly effective, as shown in WHO thalassemia eradication strategy (Table 4, Figure 5).

We should not open Pandora's Box, which might cause the destruction of whole world, through the misuse, misunderstanding and temptations of biotechnology. Also we should consider our programs in both professional and non-professional fields.

We should make every effort to educate the general public and medical profession as part of scientist's responsibility, which we have emphasized in the MURS Campaign, in order to incorporate bioethical and genetic considerations into medical & postgraduate curriculum, as well as into public education.

Finally, we with MURS, agree to adda new article to the United Nations Universal Declaration of Human Rights, our scientific knowledge should be used only to promote human dignity and preserve the integrity of scientific knowledge and the future of man. I close this presentation with the message of Spinoza's Ethica: the souls of men are not conquered by arms but only by love and generosity.


Table 4: Prevention of genetic disease and its consequences

Diagnosis
1) Early diagnosis - appropriate treatment and welfare
2) Mass screening survey - treatable disease
3) Prenatal diagnosis - selective abortion
4) Carrier detection - public opinion

Guidance
5) Consanguinity reduction - homozygote reduction
6) Eugenic law - birth control, sterilisation and abortion
7) Family planning - family size reduction, aged pregnancy reduction
8) Genetic counseling - public and professional education

Treatment
9) Biochemical application - substrate reduction, cofactor supplements, metabolite replacement, removal of toxic substances, dietary supplement, enzyme replacement
10) Symptomatic therapy - welfare and technology development
11) Pharmacogenetics - monitoring drug side effects
12) Genetic engineering and genetic surgery - technology assessment, bioethics

Public Policy
13) Natural selection and relaxed selection - genetic hygeine
14) Avoidance of nuclear weapons and pollution - monitoring mutagens
15) Genetic registry - record linkage and polymorphism
16) Guidance and education of genetic knowledge

Figure 5: Fall in Thalassemia Major Birth Rate in five Control Programmes


Acknowledgements

The authors sincerely thank Mme N. Lenoir, President of IBC, UNESCO, Prof. K. Matsubara, Chairman of Study Group on Human Genome Research, and Dr. G. Vilaldell, President of CIOMS for having this opportunity to talk of our research projects here, and Prof. Verma I.C. Prof. Ratanakul P, and other Japanese & Asian coworkers for collecting the data of opinion survey in Asia. This study was supported in part by Ministry of Health & Welfare (1973-1982) of Education (1973-1976, 1982-1983, & 1991-1994), NIGMS USPHS (1964-1970), WHO (1976,1982,1987), UNESCO IBC(1993-1995)

References

1. Bernard J. Fujiki N. et al(Eds): Human Dignity & Medicine, (ICS778) Amsterdam, Experpta med. 1988.
2. Fujiki N., Macer D.R.J.(Eds): Human Genome Research & Society. Tsukuba, Eubios Ethics Inst. 1992.
3. Fujiki N., Macer D.R.J.(Eds): Intractable Neurological Disorders, Human Genome Research & Society. Tsukuba, Eubios Ethics Inst. 1994.
4. Fujiki N., Bulyzhenkov V. et al(Eds): Medical Genetics & Society. Amsterdam, Kugler 1991.
5. Bankowski Z, & Capron A.(Eds): Genetics, Ethics and Human Values. Geneva, CIOMS 1991.
6. Fujiki N. et al: Clinical application of human genetic knowledge-Genetic counselling. Jap. J. Const. Med. 49(1/2):20-38,1985(J)
7. Sakamoto S., Fujiki N. et al(Eds): Guidebook on Genetics Counselling. Tokyo, Ministry of Health & Welfare, 1982.(J)
8. President's Commission for the Study of Ethics Problems in Medicine & Biomedical and Behavioral Research: Screening & counselling for genetic conditions. Washington D.C.,US Government Printing Office 1983.
9. Mano K., Fujiki N, et al: International opinion survey for bioethics and medical genetics. Coll. Anthropol. 17(20):191-198,1993.
10. Yesley M.(ed): ELSI Bibliography. Bethesda, USDOE, 1992,1993.
11. Fujiki N. Bioethics in gene analysis. Pediat. Med. 25(12):1801-1807,1993.(J)
12. Wertz D. & Fletcher J.(Ed): Ethics and Human Genetics. N.Y. Springer Verlag, 1989.
13. Lenoir N.: IBC Report to Director General of UNESCO on Human Genome Projects. S7S-93/conf. 015/3 Paris, UNESCO, 1993.
14. Dausset J.: Science and the future of man. Science et Devenir de l'Homme 4(18):34-41,1989.
15. Fujiki N.: Naissance announce du MURS Japon Les Cahiers du MURS 26:74- 82,1991.
16. Berg P., Fujiki N. et al(Eds): Control of Hereditary Diseases. WHO TRS, Geneva WHO 1994.
17. Matsubara K.,(Ed): Annual Report on Human Genome Research, Tokyo, Ministry of Education 1993.(J)
18. Bernard J.: De la Biologie a l'Ethique. Paris, Buchet Chastel 1991.(F) (J)


Appendix I: Activities in Bioethics

Appendix II: Ethical, Legal and Social Issues of Medical Genetics

A. Basic concepts of bioethics in genetic counselling services.
Informed consent, non-directive counseling, self-decision making, confidentiality, follow-up care.

B. DNA diagnosis (thalassemia)
Definite diagnosis by selective probe for genetic heterogeneity (variable gene loci) ; Cost-benefit analysis (prevalence vs. expense) ; Possible treatment & prevention.

C. Presymptomatic diagnosis (Huntington's disease)
Restriction fragment length polymorphism (linkage in a family, genetic heterogeneity); Environmental risks (no effective treatment, improved risk)

D. Carrier detection (Tay-Sachs' disease)
Genetic heterogeneity (high prevalence of carrier in populations); Explanation of significance (misunderstanding & prejudice); Follow up for prenatal diagnosis (Informed consent)

E. Prenatal diagnosis (Down's syndrome, Hemophilia)
Schedules (maternal screening, amniocentesis, chorionic villi sampling); Process (in utero and perinatal diet treatment, selective abortion)

F. Neonatal mass screening (PKU)
Early treatment (cost-benefit analysis) ; Confidentiality (genetic discrimination)

G. Genetic testing in workplace (sickle cell anemia)
Drug monitoring (pharmacogenetic traits)
Avoidance of hypersensitivity (leakage of genetic information); Loss of employment (genetic discrimination); Voluntary testing (informed consent)

H. Genetic testing for insurance and employment (coronary disease)
Early diagnosis of genetic susceptibility (avoid high risk); Prevention of common diseases (reducing medical cost); Predictive medicine (susceptibility and environment); Variable candidate genes (genetic heterogeneity, further family registration); Loss of health insurance and employment (genetic discrimination); Voluntary testing (informed consent)

I. Gene Therapy (ADA deficiency, cancer immunotherapy)
Somatic cell gene therapy not germ-line gene therapy including preimplantation therapy; Severe disease, No effective treatment (informed consent); Guidelines committee (responsibility for quality control, selection, medical cost assistance, adverse effect monitoring, technical assessment)

J. Other Human Genome Project Issues
Pharmaceutical development (HGH, vaccine); Genetic registration and data bank protection (privacy); Fingerprinting for judicial use (international exchange); Intellectual property and patent protection


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