HTML> Bioethics in Asia pp. 254-262 in Bioethics in Asia

Editors: Norio Fujiki and Darryl R. J. Macer, Ph.D.
Eubios Ethics Institute

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7.5. The Recent Trends in Bioethics in Medical Genetics and Cloning

Norio Fujiki.

Emeritus Professor, Fukui Medical University; Secretary General, UNESCO ABC’97

Through my genetic counseling services in Kyoto Prefectural University of Medicine, Aichi Prefectural Colony for the Mentally & Physically Handicapped and Fukui Medical University since 1960, we have tried to make a hybridoma between science, technology and humanity, at our successive International Bioethics Seminars in Fukui since 1987 (1-5), after reading Taylor's book "Biological Timed-bomb and Last Doomsday" about the fears of social consequences of scientific developments and translating Bernard's book "De la Biologie a l'Ethique" (6), which emphasized human dignity.

We have made every effort to solve the suffering and anxiety of patients with birth defects, and their families, by the knowledge of medical genetics, under the guidance of my respectful tutor, late Emeritus Professor, T. Komai and also have developed clinical medical practices following the medical and ethical considerations taught by another respectful tutor, late Emeritus Professor, M.Masuda, who passed away from lung cancer 6 years ago. Since then, I have worked at the Institute for Developmental Research, Aichi Prefectural Colony for Mentally & Physically Handicapped for 10 years, where I have learned much about human dignity through communications with handicapped children, and after that, genetic counseling services at Fukui Medical University has continued until today.

Genetic Counseling Practices

The heredity clinic has come to be recognized as a useful service unit in our society. Since 1960 (7) we have performed over 3500 cases and reported at numerous international meetings (8), emphasizing informed consent, non-directive counseling, good doctor-patient or counselor-counselee relationship. These are also emphasized in our Guidebook on Genetic Counseling (9), as well as the recently in compiled Guidebook of Genetic Counseling, Prenatal Diagnosis (10) and Gene Diagnosis of the Japanese Society of Human Genetics.

The most relevant data (11) required for genetic counseling, are drawing the exact pedigree and precise diagnosis. Therefore, we attempt to make a pedigree chart as comprehensive as possible, usually dating back 3 generations, including birth order, gender, present age and age at death, consanguinity, diseases and abortion history. We calculate theoretical and empirical risk factors, taking into account genetic heterogeneity and diversity. The counseling techniques are important through training courses on recurring psychological conflict such as anxiety and false complaints, using the perspective of medical psychology. Training is also given on the bio-psycho-social and environmental factors, that can impact a counselee's life. We provide information in a multiple choice format, keeping in mind the above-mentioned principle of genetic counseling, while also taking account of the client's level of understanding of gene diagnosis, prenatal diagnosis, carrier detection, and determine feasible preventive measures based on the counselee, social resources and family support. We then summarize the content of the counseling session, with the client's level of understanding and if necessary, we provide continuous support, counseling and follow up. We also describe the updated data on incidence, distribution, natural history, recurrence risk, feasibility of prenatal and presymptomatic and carrier diagnosis and DNA diagnosis, into counseling charts. We follow McKusick's Mendelian Inheritance in Man (12) and other catalogues. Records are kept in files in the counseling unit, as evidence of informed consent (13), and for further evaluation of the counselor’s training.

As shown in the brilliant strategy for thalassemia eradication by WHO (Figure 1, 14), clinical applications of human genetic knowledge, -diagnosis, neonatal mass screening, prenatal diagnosis followed by the option of selective abortion, and carrier detection, as well as genetic counseling -together with such preventive measures as prohibition of inbreeding, eugenic law, family planning and treatment, has been most effective (Appendix 1).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 1
: Fall in the Thalassemia Major Birth Rate (WHO)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 2
: Content of Genetic Counseling Figure 4: Followup study of genetic counseling

Figure 3: Disease categories of genetic counseling in Kyoto, Nagoya and Fukui during 1961-1994

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

We counseled over 3500 cases in Kyoto, Nagoya and Fukui during over 35 years (Figure 2, 3). We have reported the trends of genetic counseling and its followup study. After the followup study, we have strongly emphasized the necessity of option survey on the recent developments of genetic knowledge in general public and the Japanese concepts of heredity and handicapped, compared with medical geneticist's one (Figure 4) (15).

Public Opinion Surveys

Previously we have conducted opinion surveys on heredity and handicapped to students and general public in different areas in Japan. In summary, younger, more educated, more male, and those with longer profession with handicapped care, show more interest for the handicapped. However, concerning the more practical question than theoretical understanding, the counselee themselves or professionals for handicapped care show much better understanding and interests (16).

At the first stage, our Japanese survey has found out many misunderstandings and prejudices that birth defects are thought to be quite rare and almost all of genetic origin and incurable. So that they don't have any interests or sympathies. There are also differences in their responses with the amount of information available or the interests they have on specific genetic disease problems. However, data suggests improvement year by year, and handicapped children maintain human dignity and are not discriminated, due to having deleterious genes (Figure 5).

Since 1992, international opinion surveys (17) have been extended into other Asian countries, especially in India, Thailand, China and Korea, then compared with USA and Europe, by the support of UNESCO, WHO and the Japanese Human Genome Project. The topics cover various issues of heredity, handicap, biotechnology, medical genetics and even the environment. In order to develop cross-cultural ethics, we have to examine the reasoning that people have (Figure 6).

Most of the respondents in each country have misunderstandings and prejudices even in modern society. Education of general public seems to be most effective and impact through the mass media, especially television programs and student debates in university festivals. Differences in bioethical decision may be affected by religion, economics and cultures, and are common to all countries with various social influences.

Concerning the questionnaires, some agree, others disagree, but some say they don't know. Some believe in the progress of the sciences but also that it may have adverse effects, therefore, are not able to answer yes or no. Other people can't access enough critical information and say they don't know. Therefore, we should discuss very carefully the moral norm and make our decisions from a common understanding on both newly developed and old traditional evaluations. We should have more on medical genetics and bioethics in the curriculum for medical students and professionals, in order to educate the general public. We are talking about how people misunderstand and have prejudice, not talking of the reality. We should be important to think about their ethical problems, when the general public has been asked to answer these questionnaires.

Bioethics and DNA Diagnosis

From the ethical viewpoint of medical genetics, the existence of the eugenic movement must be taken into consideration. There have been examples arising from screening and testing, that have sometimes achieved unintended or unwanted outcomes, such as involvement of human geneticists or psychiatrists in the crime of Nazi Germany. More recently we have had unpleasant experiences, with the leakage of individual genetic information in sickle cell anemia screening, disturbing employment or insurance of the patients. Nobody could imagine the fear of nuclear contamination after the rapid development of nuclear physics. Discussing the withholding of a heart operation for a Down's infant, not only myself but also many physicians have been taught by severe handicapped children the fact that even physically and mentally handicapped children have human dignity that should be respected.

We have discussed ethical considerations (18) of :1) early diagnosis 2) presymptomatic diagnosis 3) carrier diagnosis 4)prenatal diagnosis and following selective abortion,5) preimplantation diagnosis 6) genetic testing in the workplace,7) genetic testing for common diseases,8) gene therapy (19) as well as, 9) medicinal developments and patent problems (Appendix 2).

We should emphasize the need to think separately about diagnosis, presymptomatic, prenatal diagnosis and carrier detection for high risk persons with given genetic diseases, and neonatal mass screening, genetic testing in the workplace for occupational diseases or common diseases. Concerning genetic counseling, including gene therapy and other applications, it is absolutely necessary to obtain informed consent, before and after counseling services, for the purpose, aims and followup study. Confidentiality, moral justification, collection and storage of genetic information, and self-decision making should be all respected. We also discuss presymptomatic diagnosis in Huntington diseases, and predictive diagnosis in cancer and coronary heart disease. However, we should discuss more whether we should tell diagnosis for Huntington diseases and clarify the significance of polygenic susceptibility, such as APOE4 and P53, with environmental agents, such as diet and exercise, and also emphasize the importance of the global ecosystems.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 5: Consensus survey on the handicapped and heredity

Figure 6: Bioethics opinion survey in Asian countries - general information; religion; and thoughts about genetic disorders.

Reproductive Medicine and Cloning Experiments

I would like to discuss recent trends on reproductive medicine especially in vitro fertilization and embryo transfer (IVF-ET) as well as transgenic and cloning experiments (20-21). The situation of development of in vitro fertilization exists de facto in scientific and medical institutions, which endeavor to meet the wishes of unhappy couples and resort to experiences and knowledge acquired in animal research. The application to human beings in practice for the improvement of scientific and technical control of reproduction, is still in its immature stages. Rapid progress is now opening new avenues for research, on human embryo or application to medically assisted procreation techniques, already applied for certain animals, such as gender determination and selective breeding. The human embryo can also be used for fundamental research, not yet related to a personal procreative projects, such as fetal brain transplants for treatment of Parkinson disease (Appendix 3).

The use of cloning techniques for the replication of human individuals seems to be ethically unacceptable, as it would violate some basic principles, given in medically assisted procreation. Medical genetics as a science is the study of individuality and variability. The fact that the DNA sequences of each individual are unique and varied, has a important implication for the evolutionary process of the human species. Such great variability and diversity must be respected, in order to preserve the dignity of the human being and protection of the security of the human genome and rights.

However, animal cloning offers the opportunity to advance biomedical research on diagnosis and treatment of disease affecting human beings, besides improvement in agricultural products (gender, selection purposes). The availability of genetically identical organisms, clones, can help to elucidate the etiology of diseases and interactions of gene and environmental factors, which account for the clinical variations. Nuclear transfer may be used to study the processes of aging, its consequences for the function of the genomes, the onset age dependent diseases. It should also make it possible to explore the so far completely unknown influences of cytoplasmic factors, to investigate interactions between the nuclear and mitochondrial genomes.

Other potential interactions of cloning techniques might relate to the development and use of animals, in which human genes have been introduced transgenic techniques to produce tissues and organs for transplantation. Transgenic sheep have already been used to produce human clotting and immune factors at PPL Therapeutics. While research on animal cloning and transgenic species may yield benefits which include therapeutic applications. We must at all times remain alert to their possible negative outcomes, such as cross species transmission of communicable diseases to man (Appendix 4).

After the Dolly's cloning experiments, immediate reports from U.S.NBAC (22), E.U.Group of Advisors, UNESCO (23), WHO (24), CIOMS, Science Council of Japan (25) has successively presented that human cloning is ethically unacceptable, although animal cloning is acceptable, if welfare is considered and safeguards are clarified. Many other governments and scientific societies have recommended the above mentioned statements, and have proposed a moratorium for 3-5 years, on research related to human cloning experiments. It is indispensable to study in depth the ethical consequences for the whole of humankind, before considering the case by case review of such investigations. A 3 year moratorium could allow animal embryo research investigators to determine the scientific conditions required to adopt the safety of these techniques to the human embryo, and also ethical, legal and social issues in the general public to better understand the consequences of such wonderful advancement of science, technology and humanity (Appendix 5).

The UNESCO IBC has upheld the right of every one to enjoy the benefit of specific progress and its application, and the need to respect the freedom as being indispensable for scientific research, and also stressed that there is universal consensus on the need to prohibit extreme forms of experimentation, against human dignity. These may include human cloning, interspecies fertilization, chimeras, and at present, germ-line gene therapy. This should serve as a starting point for the public debates required at the international level to establish the necessary norms and safeguards.

Conclusion

Our UNESCO IBC and MURS Japan, as well as the WHO Assisted Satellite Symposium, and the UNESCO Asian Bioethics Conference in Kobe and Fukui, emphasized the responsibility of scientists for the further international debates on the Declaration for the Protection of Human Genome and Rights ; exchanging ideas on ethical, legal and social issues, or providing genetic and scientific knowledge and biotechnologies, and to educate policy-makers and the general public for the universality and freedom of fundamental human rights.

In conclusion, we should not open Pandora's Box, which might cause the destruction of the whole world and human species, through the misuse, misunderstanding and temptation of biotechnology. We should consider Human Genome Projects in both professional and non-professional fields. Therefore, we should make every effect to educate, not only medical and biological professions but also the general public, as a part of scientists' responsibility. Now ending my talk with Spinoza's "Ethica", "The souls of men are not conquered by arms, but by love and generousity."

References

1. Bernard, J. Fujiki, N. & Kajikawa,K. (Ed) : Human Dignity and Medicine. Excerpta Medica (ICS# 778), Amsterdam. 1988.

2. Fujiki, N. , Boulyjenkov, V. & Bankowski, Z (Ed) : Medical Genetics and Society. Kugler Publ., Amsterdam. 1991.

3. Fujiki, N., & Macer, D.(Ed) : Human Genome Research and Society. Eubios Ethics Institute 1992.

4. Fujiki, N., & Macer, D.(Ed) : Intractable Neurological Disorders, Human Genome Research and Society. Eubios Ethics Institute 1994.

5. Okamoto, M., Fujiki, N., & Macer, D.(Ed) : Protection of Human Genome and Scientific Responsibility. Eubios Ethics Institute 1996.

6. Bernard, J. (Translated by Fujiki,N. & Nakazawa, N.) De la Biologie a l'Ethique. Masson, Paris. 1994. (Igaku Shoin, Tokyo 1995)

7. Fujiki,N. et al. : Clinical application of human genetics knowledge -Genetic counselling- Jap. J. Const. Med. 49 : 120. 1985. (J)

8. Fujiki,N. : Medical geneticist's Responsibility. Proc. 3rd I.B.C UNESCO, Paris. 1995.

9. Sakamoto, S., Fujiki,N. et al.: Guidebook on Genetic Counselling, Ministry of Health & Welfare. Tokyo. 1983.

10. Matsuda, I., Fujiki,N. et al. (Ed) Genetic Counselling, Prenatal Diagnosis and Gene Diagnosis. EJIAB 6 (1996), 137-8.

11. Fujiki,N. et al Genetic counselling Update. J. Clin. Rehabil. 4: 856, 948, 1060, 1171. (1995). (J)

12. Mc Kusick, V. A.(Ed): Mendelian Inheritance in Man. Johns Hopkins Univ. Press. (11th Ed) Baltimore. 1995.

13. Fujiki, N., et al. : Social problem in genetic counselling services. Proc. 21th Proc. Jap. Med. Assembly. 2 : 861-864, 1983.

14. Berg, K., Fujiki,N. et al.: Control of Hereditary Disease WHO (TRS# 865) Geneva, 1996.

15. Wertz D. & Fletcher J. C. (Ed): Ethics and Human Genetics. A Crosscultural Perspectives. Springer Verlag. N. Y., 1989.

16. Shirai, Y.,Fujiki,N.: Doctor's attitudes of prenatal diagnosis and selective abortion. Rep. Study Group in Ministry of Health & Welfare. 1 : 80. 1982.(J)

17. Mano, K., Fujiki,N. et al.: International Opinion survey for bioethics and medical genetics. Coll. Anthropol. 17(2) 191. 1983.

18. Fujiki,N. :Bioethics on DNA diagnosis. Ped. Med. 25: 1801. 1993

19. Takaku, F.: Guidelines on clinical research on gene therapy of Ministry of Health & Welfare. IN. Gene Related Problems. (Kato, I. & Takaku, F. : (Ed) ) Nihon-Hyoronsha. 227. 1995.(J)

20. Krauthammer, C. : Special Report on cloning. Times. 28. March 10. 1997.

21. Yamada, M. et al. : Shocking Report on cloning Experiment. Chemistry. 52(8) 12, 1997.

22. Shapiro, H.R. : Ethical and Policy Issues of Human Cloning. Science. 277 (1997), 195-7. (Report of U.S.NBAC)

23. Lenoir, N. : Universal Declaration in the Human Genome and Human Rights. (UNESCO, IBC) Bio 97/conf.-201/6 Paris. 1997.

24.Nakajima, H. : Cloning in Human Reproduction. 5th World Health Assembly WHA 50 : 37. Geneva.1997

25. Hashimoto, R. : Development Plan for Research on Life Science. Cabinet Council of Science and Technology, Japan. 1997.

Appendix 1: Preventative Measures for Hereditary Diseases

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

Appendix 2: 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

Appendix 3: Assisted Reproductive Technology

Includes in vitro fertilization (IVF), embryo transfer (ET), as well as transgenic and cloning experiments. IVF and ET are used as treatment for infertile couples. There is also fundamental human research, such as fetal tissue transplants for treatment for Parkinson’s disease.

IVF and ET are used in economic animal production (e.g. gender and selective breeding). Animal cloning experiments have possibility for improvements in agricultural products, offering the opportunity to advance biomedical research in diagnosis and treatment of human disease, clarify the etiology of disease and interactions between gene and environmental factors.

However, human cloning experiments, such as replication of the human individual is unacceptable, in order to preserve the dignity of the human being and protect the human genome and rights, as stated in the UNESCO Declaration.

Appendix 4: Significance of Cloning Experiments

It revealed the mechanism of reverse differentiation by initialization and nuclear transfer. It offers new procedures for molecular genetics and embryology; study of gene function for differentiation, aging and cancer; tissue culture for transplantation purposes. may help the prevention of disease, treatment and diagnosis using transgenic animals. The alternative is to use embryo splitting and ET.

Have to consider safeguards that it does not have long term effects on aging and reproduction and genetic diversity. There is a need for justification and legal regulation. A public debate on ELSI issues is needed, and we need to consider individual human rights for reproduction and the concept of the family. There is differing legal regulation in different countries.

Appendix 5: Interim Report of the Working Group on Cloning Experiments

Some of the conclusions were:

Such research for production of cloned animal has already been practiced on the early embryo in economically important animals and it also has great feasibility in scientific and applied fields. We should promote in vitro and animal experiments, including study of the variability in somatic cells and instability of coding regions.

However concerning, the production of a cloned human individual we did not yet have any study in the world, and we need accumulation of basic knowledge on safeguards and ELSI debates. We should carefully discuss environmental interactions with human personality and human dignity.

At present we have much misunderstanding and prejudices connected with psychosocial conflicts for direct application of animal cloning techniques to humans. We should have much public debate on the future directions of this research. Therefore we propose a three to five year moratorium in order to safeguard persons and the develop public understanding.

Immediately after the report of Dolly, the US NBAC, EU, IUBS, CIOMS, WHO, UNESCO, Cabinet Council on Science and Technology in Japan, have reported that cloning is ethically unacceptable at present, although animal cloning is acceptable if safeguards are present and animal welfare is clarified.


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