pp. 270-275 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.

Bioethics in Human Genome Research

Norio Fujiki
Professor, Department of Internal Medicine and Medical Genetics, Fukui Medical School, Fukui, JAPAN


Foreword

Since 1960, I have made every effort to solve the suffering and anxiety of patients with birth defects, through genetic counseling services(1), in order to apply the knowledge of human genetics learned under guidance of my respectful tutor Professor Emeritus T. Komai for human welfare. I have tried to develop my clinical medical practice, with medical and ethical considerations taught by another of my respected tutors Professor Emeritus M. Masuda, who passed away from lung cancer 6 years ago.

Not only myself but also many physicians have been taught from caring for severely handicapped infants the fact that even physically or mentally handicapped people have human dignity which is still to be respected, although we have discussed with surgeons difficult decisions such as withholding a heart operation for an infant with Down's syndrome.

I. Bioethics in Medical Genetics

Through the clinical applications of human genetic knowledge, early diagnosis, neonatal mass screening, prenatal diagnosis followed with selective abortion, genetic counseling, as well as carrier detection for genetic diseases, together with such preventative measures as the prohibition of inbreeding in eugenic law and promotion of family planning, have been mostly effective. This is shown by the WHO thalassemia eradication campaign in Europe (2).

Therefore, we have recognized the importance of the dignity of human life through wider discussion, not only from the specific professional areas of clinical and basic medicine, but also from other areas of biology, sociology, law, psychology, economics, ethics and philosophy. Hence, we held the First International Bioethics Seminar in Fukui in 1987, welcoming Prof. J. Bernard, former President of French National Academy of Sciences, and the Second International Bioethics Seminar in Fukui in 1992 (3), as well as the International Association of Human Biologists - Japan Society of Human Genetics Joint Symposium on Medical Genetics and Society in Fukui (5) in 1990, and published their proceedings, respectively, as Human Dignity and Medicine, Human Genome Research and Society, and Medical Genetics and Society. This time we have just finished the Third International Bioethics Seminar in Fukui in 1993, concentrating attention on intractable neurological disorders, human genome research and society. By developing bioethics in medical genetics, we have drawn attention to the ethical, legal and social issues of DNA diagnosis in the areas of medical genetics.

Concerned with the ELSI issues of DNA diagnosis, we should emphasize the need to think separately about early diagnosis, prenatal diagnosis, presymptomatic diagnosis and carrier detection for high risk persons with a given hereditary disease, and neonatal mass screening, genetic testing in the workplace and general population screening for occupational diseases and common diseases.

1) Diagnosis of Genetic Diseases

As emphasized before in the Guidebook on Genetic Counseling (1), we should discuss genetic discrimination, whether any anomaly should be ruled out or permitted with coexistence, and diagnosis, under our basic concepts of non-directive counseling, informed consent, self-decision making and confidentiality, in genetic counseling. Before DNA diagnosis, even in the indicative cases, people should give informed consent fully after discussion of prospective and retrospective behaviours for reproductive outcomes and following selective abortion. Especially we should make careful discussions about genetic heterogeneity. For example, recently, Fukumaki's study (6) of DNA diagnosis on thalassemia variants in Asian continents has shown 26 variants at various allelic, genomic and other levels, which appear to be derived from an original 4 variants through recombination, and distributed among these continents.

2) Presymptomatic Diagnosis

Huntington's disease is a dominant late onset disease (30 - 40 years of age, after finishing reproduction) and brings progressive involuntary moment and early severe dementia. Only this year the gene was identified. Now we can make definite diagnosis, and avoid extensive study in large families that was needed for linkage analysis. Also we have other candidate genes in chromosome #19 for late onset cases and another gene in chromosome #14 for early onset cases. This indicates a complicated mechanism for such heterogeneity of genetic diseases. Familial Alzheimer disease also has the same problem and a mutated gene for beta-amyloid precursor on chromosome #21 has been found, which leads to excessive production of beta-amyloid and deposits in nerve cell, resulting in early degeneration and dementia at an earlier stage, compared with physiological processes of nerve cell degeneration. The recently identified allele ApoE4 should help diagnosis, but we are still not sure (7). Among such common diseases as cancer, hyperlipidemia, diabetes and hypertension, there is genetic susceptibility related with different gene anomalies, interacting with the environmental risk factors, some of which can be prevented by the improvement of diet and exercise.

3) Carrier Detection

The autosomal recessive diseases result in one quarter of children by consanguineous mating of carrier couples, for example in the cystic fibrosis gene in the pancreas, a mutation ÆF508, has been located on 7q in 68% of all cases and not all other candidate genes have been recognized yet. One in 25 persons are carriers in Europe, and there is one patient per at least 2500 (8). Therefore, we may want to recommend avoiding the marriage of carrier couples in such high risk population, and carefully explain the significance of being a carrier. We have recognized some misunderstandings of carrier status through our international opinion survey, described before.

Therefore for sickle cell anemia in black populations and cystic fibrosis in white populations, we should explain fully the purpose of this screening and do follow up. For the genetic counseling high risk individual clients, we should fully explain the significance and meaning of being a carrier, the 25% risk of a child patient in carrier marriages, such as consanguineous unions. However, we could predict the birth of patients through prenatal diagnosis. Such information is needed to educate the general public, in order to avoid prejudice as carriers of severe hereditary diseases.

4) Prenatal Diagnosis

As there is higher risk of the birth of Down's infant for older women, we generally only screen those over 35 years of age, except if there is a previous history of translocated Down's syndrome. However, we have performed serum screening for AFP and estriol decrease, or gonadotropin increase, in maternal peripheral blood. We have further extended these methods for many genetic diseases, such as direct DNA diagnosis for inborn errors of metabolism and X-linked diseases after their recent development of DNA technology. Recent progress of chromosome, enzyme and DNA diagnosis using chorionic villi sampling means more efficiency and earlier prenatal diagnosis.

Such genetic counseling services for clients with necessary information and continuous support, is insufficient at the present in Japan. We should carefully discuss these services, and the fact that in the case of a positive result on diagnosis we do not always have any possibility for treatment for a chromosomal anomaly, nor in utero treatment for metabolic anomaly. We have to carefully consider the selective abortion of abnormal fetuses, a type of feticide after prenatal diagnosis and genetic counseling. On the contrary, we need to also carefully consider the opinion that prenatal diagnosis and following selective abortion should be not permissible which removes self-decision making from the pregnant women. Therefore to remove the woman's anxiety about abnormal child-birth, we have emphasized informed parental decision making, as the duty of clinical geneticists, only they should be responsible for the decision whether pregnancy should be continued or terminated. Of course we also have our own individual faith and philosophy as clinical geneticists regarding birth defects. In all cases we should consider the necessary guidance and followup support, as much as possible for the pregnant woman's wishes and also for family care, which are the two most important aspects of preventative and supportive medical care.

5) Neonatal mass screening

Normal development of fetuses diagnosed and treated earlier and well-balanced economic cost-benefit analysis for the case for institutionalized mental retarded people without mass screening, and prevention of mental retardation by neonatal mass screening has been done for 6 years. Eight different diseases such as PKU, or MSUD, or Hypothyroidism have been detected by neonatal mass screening and avoided from secondary symptoms, such as severe infection. These are shown in the excellent results of WHO preventive measures, such as programmes for thalassemia and cystic fibrosis in white populations, and sickle cell anemia and G6PD deficiency in black populations, which have high prevalence rates in some regional populations. However, we genetic counselors, should tell others through home doctors about the natural history and outcome of these genetic diseases, and also it is absolutely necessary for followup and further assistance for medical and psychological treatment.

6) Genetic Testing in the Workplaces

Haldane observed that not all workers exposed to particular occupational hazards become symptomatic and the differences in response to toxic exposures was at least partly genetically determined, so that we could reduce the number of people who become ill. The early proponents of workplace genetic screening did not foresee the political economic and ethical complexities revealed later (9).

The first publicized case of such screening was the screening for sickle cell traits among black workers, which was purely on a voluntary basis, and was used in hiring or job placement decisions. Genetic susceptibility was believed to put the individual at greater risk of occupational diseases associated with hazards in that place. Debate about the ethics of workplace genetic testing has focused on how such tests might be used, as diagnosis, research, information and exclusion. Unfortunately this testing for sickle cell trait in black population in U.S.A., was leaked to third parties for genetic discrimination and finally was legally stopped.

7) Genetic Testing for Common Diseases

Another way to use genetic testing is for early diagnosis for common diseases, such as hypertension, diabetes, or coronary sclerosis, in order to reduce the medical costs to individuals and society, which might be desirable for the employers. For example, genes responsible for hyperlipidemia such as familiar hypercholesterolemia and LDL receptor gene anomalies, have great variety including the number and function of receptors, total cholesterol concentration, as well as atherosclerotic changes, which might be closely related with the ApoE4 allele. The genes responsible for diabetes also have great heterogeneity. As pointed out above, such common diseases, as coronary sclerosis, brain stroke, diabetes and cancer, even psychiatric diseases have various combinations of genetic heterogeneity and associated environmental risk factors.

Therefore, in order to predict genetic susceptibility, genetic testing in the general population will be increased. From a public health policy point of view, we have previously promoted mass predictive screening for gastric cancer and uterine cancer. However, genetic testing has led to some genetic discrimination for the persons screened and their siblings. Therefore, we should ensure informed consent and careful bioethical considerations for the followup.

Another problem for insurance businesses is sharing these risks to all people. We have higher insurance fees for the elderly or infants and also for pilots, who have a higher risk of death compared to general populations. Such genetic testing for predicting genetic susceptibility might be of interest to an insurance company, which has already realized. Therefore, we have carefully discussed the utility of such genetic information, which should not be used by a third party for genetic discrimination from the standpoint of ethics.

As said above, we have severe social problems for sickle cell anemia screening in black populations. However, on the other hand, we have succeeded with carrier screening for Tay-Sachs disease in Jewish populations in Boston. They carefully discussed the significance before the screening test and also treatment and prevention after the screening, which was emphasized in the Reports of the President's Commission in the USA (10), Reports on Testing for Occupational Diseases by the OTA (9), as well as our Guidebook on Genetic Counseling (1), edited by the Study Group on Birth Defects sponsored by the Ministry of Health & Welfare of Japan. The four basic principles, informed consent, self-decision-making, confidentiality, and equal welfare must be established before and after such testing. In other words, we need enough information on the significance, and must ensure self-decision-making for such tests and should not provide this genetic information to a third party without the informed consent of the persons or their guardians. We have to give equal and good medical services for care and prevention for the patients who are unfortunately found to be suffering from an abnormality. We have been disappointed that in Japan we have found the great misunderstandings of heredity and prejudices against the handicapped, so that we must emphasize correct education to the public on genetics.

II. Bioethics in Gene therapy

Many human diseases are caused by abnormal alleles. The idea that the most effective ways to correct such genetic deficiencies is the replacement, correction or supplementation of malfunctioning genes, has been discussed for almost two decades, but has only recently become technologically plausible. The President Commission (11) reported this problem to U.S. Congress in 1980, and now many research proposals on human gene therapy in the NH. have passed the review meetings through the Recombinant DNA Advisory Committee.

Is gene therapy ethically different from conventional medical care? How do we get informed consent for treatment of high risk patients, who might have high risk descendants? The principle of informed consent which might be justified for the risk of medical care, is not simply applicable for the descendants of the patient who received germline gene therapy. There may be unbelievably great hazards in the case of transmittance of risk to following generations than in the case of the patient in question, if any genetic changes have occurred by the gene therapy. We emphasize the big ethical differences between somatic cell and germ line gene therapy. As somatic cell changes end by the death of the individual who received gene therapy, we have ethically agreed to follow the same careful considerations as with other conventional medical cares. At present, human germ line gene therapy, including not only germ cell but also preimplantation gene therapy, has excluded, as stated in Inuyama Declaration of CO.M.S. Tokyo Conference in 1990 (12). Of course we should continue the discussion about non-human experiments of germ line gene therapy and debate the ethical considerations for the application to human beings.

The first experiment for gene therapy was done by Cline in 1980, using mouse experiments which transferred exogenous genes for normal human globin synthesis with great successes. However it was without sufficient ethical consideration and the necessary proposals to the NH. Subcommittee on Gene Therapy. It was rejected by the NH. The gene therapy for thalassemia in humans needs careful informed consent, and we should not attempt germ line gene therapy now. There may be conventional treatment for the severe intractable diseases, like the use of antibiotics, hormones, enzyme replacement, and bone marrow transplantation.

As of August 1993, we had over 52 clinical trials of gene therapy approved. For example, two alternative gene therapies are for ADA deficiency patients, whose peripheral T lymphocytes have been cultured with solutions containing anti-CD antibody and IL-2, then infected with non-duplicating retroviruses with neomycin resistance and human ADA genes, and these cells infused to the ADA deficient patients. Another is for melanoma patients, whose tumour infiltrating lymphocytes (TIL) have had neomycin resistant genes introduced and those cells infused back to the patients, whose exogenous gene has been effective for long survival after transfer experiments. These have been approved by NH. Gene therapy into hepatocytes for LDL receptor deficient patients and into cancer cells for activation of cancer immunity introducing tumour necrosis factor (TNF) antigen or IL 2 genes into cancer cell has also been conducted.

In Japan, we have discussed in a Working Group sponsored by the Ministry of Health & Welfare, and established guidelines for research on gene therapy. They include justifications for procedures based on examining the protocols, quality control, selection of the patients and subjects, as well as financial assistance of medical care, adverse effects and following accidents, and technology assessment.

Besides gene therapy, human genome research has developed the applications of the purification of gene products. Cloned human genes can be introduced into microorganisms or mammalian cells. This has also raised ethical, legal and social issues, for example, scarce amounts of human pituitary hormone extracted from human autopsied hypophysis tissue in the brain, has been used for the treatment of pituitary dwarfism, due to deficiency of human growth hormone. However, after the discovery of recombinant human growth hormone, plentiful amounts could be made, and can be given to people of short stature. This can be applied among normal variation if desired, and sometimes to apply for physiological, behavioural even anti-geriatric effects. These considerations should be carefully discussed from the standpoints of bioethics, of course we would all agree with the indications to use human growth hormone for a real deficiency. Therefore, such tremendous development of excellent scientific knowledges should be limited to the treatment for the severe and unpleasant diseases, not used to strengthen or weaken cosmetic traits, such as intellectual characters.

III. Summary

As described in the forward, I, as one medical geneticist or genetic counselor, have faced difficulties and suffered from the conflicts, and have responded, to such ELSI issues raised by Human Genome Research, for the resolution of various fields of scientific and medical applications. A summary of issues is in Figure 1.


Figure 1: Prevention of genetic diseases 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, sterilization and abortion
7) Family planning - family size reduction, reduction of aged pregnancy
8) Genetic counseling -public and professional education

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

Public policy:
13) Natural selection and relaxed selection - genetic hygiene
14) Avoidance of nuclear weapons and pollution - monitoring mutagens
15) genetic registry - record linkage and polymorphisms
16) Guidance and education of genetic knowledge


Concerning genetic testing, it is absolutely necessary to make informed consent, before and after genetic counseling, for the purposes, aims, and follow-up studies. Confidentiality, the moral justification, and collection of genetic information and self-decision-making should all be respected. Who should know, who should use genetic information of somebody? In order not to be able to link these information to genetic discrimination, we should work hard for the self-assessment and education of our medical and paramedical staff and also make every effort to remove misunderstandings and prejudices of general public.

As described before, we have succeeded with carrier detection and presymptomatic diagnosis in Huntington disease, and the predictive diagnosis in cancer and coronary sclerosis. However, we should discuss more whether we could tell the diagnosis of diseases such as Huntington's disease. Also without effective treatment and predisposition of cancer and coronary sclerosis, these can also cause genetic discrimination. We have clarified the significance of polygenic susceptibility, such as P53, ApoE4 genes, and environmental agents, such as diet and exercise, and also emphasized the importance of the global ecosystem, as Gadjusek did in the last seminar (4).

Not only medical geneticists in both basic and clinical medicine but also social, philosophical, ethical, economic, anthropological, and psychological scientists, should join together, in order to make well-balanced and justified discussions. This I have already made three times in Fukui, and I joined with an NIH-DOE Conference 1989 (Bethesda), CIOMS Conference 1990 (Tokyo, Inuyama), HUGO Ethics Workshop, 1992 (Amsterdam). This year I have attended the UNESCO International Bioethics Committee meeting in Paris, the Third International Bioethics Seminar in Fukui, as well as the WHO Working Group Discussion in Geneva.

We should not open Pandora's Box, unless we can close it. It might cause the destruction of whole world, through the misuse, misunderstanding and temptation of biotechnology. Also we should consider our problems in both professional and non-professional fields.

Genetics is the science itself of individuality and all human beings have different combinations of DNA sequences and human genomes. Therefore, we should respect human dignity, because of these biodiversity which also effects biological evolution.

Finally, 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 enrol bioethical and genetic considerations into medical and postgraduate curriculum, as well as into public education.


References

1. Sakamoto, S. & Fujiki, N., et al. (Eds.), Guidebook on Genetic Counseling, (Tokyo: Ministry of Health and Welfare, 1982).
2. Schull, W.J. & Fujiki, N. et al. (Eds.) Ethical Issues on Diagnosis, Treatment and Rehabilitation of Hereditary Disease (WHO/HDP/WG, 1989).
3. Bernard, J., Kajikawa, K., & Fujiki, N. (Eds.), Human Dignity and Medicine, Human Genome Research and Society (Amsterdam: Excerpta Medica, 1988)
4. 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) .
5. Fujiki, N., Bulyzhenkov, V, & Banzowski, Z., (Eds.), Medical Genetics and Society (Amsterdam: Kugler, 1989).
6. Fujiki, N. (Ed.) Introduction of Medical Genetics (Kimpodo, 1987); Fujimaki - Japan J. Internal Medicine.
7. Jenkins, J.B. & Conneally, P.M. (1989) The paradigm of Huntington's disease. Amer. J. Human Genetics 45: 169-75; Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72: 971-83.
8. Wilford, B.S., Post, N. (1990) The cystic fibrosis gene: Medical and social implications for heterozygoyte detection. JAMA 263: 2777-83; Kerem, E. et al. (1990) The relation between genotype and phenotype in cystic fibrosis - analysis of the most common mutation (DeltaF508). New Engl. J. Medicine 323: 1517-22.
9. U.S. Congress, Office of Technology Assessment, Genetic Monitoring and Screening in the Workplace, OTA-BA-455 (Washington, DC: U.S. Government Printing Office, 1990).
10. President's Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Screening and Counseling for Genetic Conditions (Washington, DC: U.S. Government Printing Office, 1983).
11. President's Commission for the Study of Ethical Problems in Medicine, and Biomedical and Behavioural Research (1982) Splicing Life: a report on the social and ethical issues of genetic engineering with human beings (Washington, D.C.: U.S. Government Printing Office, 1982).
12. Bankowski, Z. & Capron, A., (Eds.) Genetics, Ethics and Human Values. Human Genome Mapping, Genetic Screening and Gene Therapy (Geneva: CO.M.S., 1991).


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