pp. 255-266 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.

To know or not to know: that is the question

Hans Galjaard
Professor of Human Genetics and Chairman, Dept. Clinical Genetics, Erasmus University Rotterdam, The Netherlands

1. Introduction

Science has always been far away from the public and in most countries has had a low political priority. In this century there have, however, been periods of public debate about scientific advances and especially about the social consequences of their applications. A well-known example are the developments in nuclear physics and the threats of some of their applications such as mass destruction by nuclear bombs or radiation accidents associated with the civil use of nuclear energy. Other examples are the pros and cons of space research and the relationship between large scale chemical industry and pollution.

Biology and medicine have only recently raised public debate and political interest because of the revolutionary advances in gene technology and methods of artificial fertilization. More than a century ago Darwin's concept of evolution also caused emotional debates, but these were largely restricted to representatives of the church and the scientific community.

Today, most political leaders agree that economic growth is closely associated with the development of science and technology. This is one reason for the political interest in DNA technology which offers new perspectives in a wide area of agriculture, animal breeding and large scale production of specific proteins.

Another reason is public concern about possible harmful psychosocial effects of certain developments in predictive DNA testing of humans and a more deeply felt worry that with certain experimental approaches essential bounds are overstepped and that basic values are at stake. The latter is mainly related to the transfer of genes amongst different species, the combination of DNA technology and in vitro fertilization methods in man and most recently the cloning of human zygotes.

Unfortunately, many discussions about the ethical aspects of gene technology are characterized by insufficient knowledge, mixing up facts and fiction and political, social, cultural and religious dogmas which leave little scope for exchange of thoughts. In many debates participants seem to be more interested in expressing their own views than in learning about other people's opinions and experiences. Also, it is often forgotten that valuable applications in clinical genetics have offered new options to couples at risk of affected offspring and that the birth of an increasing number of otherwise severely handicapped people can be avoided.

Most of the important advances in basic genetic research have been made in North America and Western Europe and to a lesser extent in Japan and Australia. The application of gene technology in clinical genetics, aimed at early diagnosis of congenital/genetic disorders, carrier detection, genetic counseling of couples at risk of affected offspring and prenatal diagnosis is best developed in W. Europe and Canada and to a lesser extent in the USA and Australia. The implementation of genetics services varies considerably among the various wealthy, industrialized countries due to differences in political priority, demography and sociocultural and religious background. In Section 2 a short review will be given of the present status of clinical applications of gene technology in wealthy industrialized countries.

However, in the next century 95% of all children will be born in countries which are presently designated as developing countries, including China, India, Pakistan, Bangladesh, Indonesia, and continents like Africa and Latin America. Section 3 will deal with some major economic, medical, social and cultural obstacles in the future implementation of genetic technologies that are presently available in the western world.

When one reads about the worlds economic inequality, (female) illiteracy, low contraceptive use, high (illegal) abortion rate, teenage pregnancy and high infant mortality due to malnutrition and infectious disease, many ethical issues related to gene technology in the wealthy countries seem trivial.

Yet, scientists in these countries proceed rapidly with mapping the 50,000-100,000 human genes. Section 4 will deal with some of the consequences in terms of predicting individual predispositions of major diseases at adulthood and the perspectives of preventing disease symptoms. It will also discuss a number of ethical and psychosocial issues associated with the new era of "predictive medicine". The main principles of bioethics will be tested in a few instances of early DNA diagnosis that are already feasible in order to illustrate that the issues raised are no fiction but fact.

2. Gene technology and Clinical Genetics in Wealthy Countries

a) Technical approaches

During the past 25 years clinical genetics services have been built up in most industrialized countries. They consist of laboratory diagnosis of patients with congenital/genetic disorders, carrier detection, genetic counseling of couples at risk of affected offspring and prenatal diagnosis in pregnancies at risk with the option of abortion in case the fetus is found to be affected.

About 50% of all conceptions fail because of an abnormality of the genetic material in the germ cells or early stages of embryonic development and 40-60% of all spontaneous abortions are associated with a chromosomal aberration. Despite this natural selection 4-6% of all newborns have a congenital defect. This percentage is based on previous clinical criteria of diagnosis and will undoubtedly increase in the future when more refined (DNA) diagnostic methods will be used.

About 0.5% of the newborns have a microscopically visible chromosomal abnormality (1, 2); recent DNA technology enables the detection of deletions, duplications or translocations of much smaller chromosomal fragments, using fluorescent in situ hybridization (FISH) (3). This will lead to a better understanding of the etiology in patients with presently unexplained handicaps.

Improved gene technology has also provided more insight in the relationship between certain cancers and specific chromosomal aberrations both in germ cells and in particular somatic cells. Many dozens of (proto) oncogenes have been identified (4), which in some cases play a role during normal embryonic development. Other examples of progress in cancer genetics are the elucidation of DNA repair processes (5) and the identification of tumour suppressor genes which are involved in the molecular etiology of diseases like retinoblastoma, colorectal carcinoma, Wilms' tumour and neurofibromatosis.

During the past three decades the number of Mendelian conditions in man has tripled to more than 5700, most of which are severe genetic diseases based on a mutation in a single gene (6). In about 400 of these early laboratory diagnosis is possible by biochemical assays of the patients cells. In some instances biochemical analysis also enables the detection of carriers of a recessive mutation as in the case of hemoglobinopathies or Tay-Sachs disease.

During the seventies the indirect demonstration of a gene mutation using closely linked restriction fragment length polymorphisms became a new option of early laboratory diagnosis of monogenic disorders and of carrier detection and prenatal diagnosis (7). In an increasing number of cases the gene defect itself is being identified which usually leads to a more accurate diagnosis. In April 1993 810 disease genes had been mapped and for 122 Mendelian disorders of unknown molecular etiology (prenatal) DNA diagnosis had become possible. In nearly 40 of these the specific gene had been cloned. The latter also provides new perspectives to understand the molecular etiology and pathogenesis of a disease, in particular by producing and studying transgenic animals. Knowledge of the exact gene defect may also lead to new therapeutic strategies either by protein replacement or by gene therapy.

An exact diagnosis and carrier detection form the basis for genetic counseling (8). Most requests for genetic counseling come from parents who have given birth to a handicapped child and who fear recurrence and from couples in whose family one or more relatives have a congenital handicap, genetic disease or unexplained mental retardation. Consanguinity, advanced maternal age, a handicap or genetic disease of one of the counselees or exposure to a possible harmful environmental agent or teratogen are other reasons for concern.

The options of couples found to be at increased risk of affected offspring are: acceptance of the risk, refrain from pregnancy, adoption, fertilization with donor gametes or prenatal diagnosis with the possibility of selective abortion. Various follow-up studies have shown that about 50% of parents with a handicapped child and a high recurrence risk are deterred from a next pregnancy. However, when a prenatal test is available, 87% of couples in the same situation choose for a pregnancy (9). This implies that prenatal diagnosis is not only a method that may lead to abortion but it also motivates couples to reproduce who otherwise would not have dared a pregnancy because of fear for a handicapped child.

The methodology of prenatal diagnosis has improved over the years and most fetal disorders can now reliably be detected within the first trimester of pregnancy by chorionic villus sampling followed by cytogenetic, biochemical or DNA analysis (10). An alternative is amniocentesis at 16 weeks of pregnancy which also allows determination of an elevated alphafetoprotein (AFP) level associated with fetal open neural tube defects. There is general agreement about the main indications for prenatal diagnosis and Table 1 summarizes the results of more than 30,000 prenatal diagnoses performed in our own centre in Rotterdam.

At this moment many clinical genetics centres are busy developing new techniques to detect fetal chromosomal aberrations by using chromosome specific DNA probes which can also be applied in non dividing cells. Another method which may widen the scope of prenatal diagnosis is the analysis of fetal cells isolated from maternal blood. In some centres in the United Kingdom and the USA, maternal serum AFP measurements are used as a screening procedure to detect fetal trisomies, especially Down's syndrome (11). However, the low sensitivity (60-70%) and the 5% false positive values have led most Scandinavian and West European countries to renounce this approach.

Table 1: Total experience with prenatal diagnosis in Rotterdam (1993)

Indication: Number of pregnancies investigated; Number of fetal abnormalities (%);

Advanced maternal age: 15877 368 (2.3) 43 carriers
Previous child with chromosomal abnormality: 3209 45 (1.4) 5 carriers
Parental translocation: 530 49 (9.3) 231 carriers (44)
Risk X-linked disease: 489 35
Risk neural tube defect: 6989 94 (1.3) 2 carriers
Ultrasound abnormalities: 988 231 (23.4) chromosomal abnormalities
Risk inherited disease - metabolic: 1460; 289 (19.8)
Risk inherited disease - DNA: 172; 43 (25.0)
Other indications: 862 20 (2.4)
TOTAL: 30576 1455 (4.8)

A more promising method in prenatal management is ultrasonography. In addition to following fetal development this method enables the detection of an increasing number of structural and functional abnormalities of the fetus. In some instances this can be established in early stages of gestation, in other cases an accurate prenatal diagnosis is possible only later in development (for ethical and legal aspects see next section).

In most Western industrialized countries the number of requests for early diagnosis, carrier detection, genetic counseling and prenatal diagnosis has increased continuously. This is related to more confidence in the technology used, to better knowledge about gene technology among referring doctors and the general public and to incorporation of clinical genetics services into the health care system. Especially in the N.W. European and Canadian health care systems people at risk have equal access to clinical genetics services independent of their financial and social status.

Just to illustrate the type and number of activities in clinical genetics Table 2 summarize the combined activities of the 7 centres in the Netherlands. Altogether it can be estimated that the diagnostic investigations, genetic counseling and prenatal diagnoses result in the avoidance of the annual births of at least 600-1200 people who otherwise would have been born with a severe chronic handicap. Given the well developed medical and psychosocial care of the handicapped in most N.W. European countries this implies the avoidance of considerable costs, which are at least 15-25 times higher than those required for the clinical genetics centres. Although such economic considerations are important for policy makers the main aim of the clinical geneticist is to assist prospective parents in making an informed decision about offspring and to support those who have given birth to a handicapped child or who are at risk to do so.

The activities in most clinical genetics centres are directed towards the early diagnosis of an index patient in a family and subsequent counseling to prevent the birth of other affected people. In some instances, however, it is possible to perform carrier screening at a population level, thus identifying couples at increased genetic risk before the first pregnancy. This approach is technically feasible in populations with a high frequency of a specific gene mutation such as sickle cell anemia among American and African blacks, thalassemia among Mediterranean and Asian populations, gangliosidosis type Tay-Sachs among Ashkenazi Jews and cystic fibrosis among Caucasians. The heterozygote frequencies in these instances are of the order of 1:7 to 1:25-30. Carrier screening, followed by genetic counseling and fetal diagnosis in pregnancies at risk have resulted in a significant reduction of the incidence of some diseases mentioned above (Table 3). However, similar programmes have not been successful in other countries because of social, cultural and religious problems (see next section and Section 3).

Table 2: Overall activities of the Clinical Genetics Centres in the Netherlands (1991)*

Activity: No. persons tested; % abnormal detected;
Chemical analysis, metabolites (Blood, urine) 7859 6%
(Enzyme) protein assays 3022 15
Postnatal chromosome analyses (Tumour cytogenetics included) 10200 16
DNA diagnoses 3423 10% carriers
Genetic counseling in complex situations ca. 3000 -
Prenatal diagnoses in pregnancies 10949 4%

*Data kindly provided by the centres in Amsterdam, Leiden, Maastricht, Nijmegen, Utrecht and Rotterdam.

Table 3: Reduction in prevalence of genetic disease as a result of carrier screening programs*
beta-thalassemia: Cyprus: nearly 100% since 1984. Ferrara (Italy): nearly 100% since 1982. Sardinia: nearly 90% in 1988. Greece: 30-40%.
Sickle cell disease: Cuba: 30% in 1989 (programme started 1983).
Tay Sachs disease: USA: 75% whole population and 90% among Jewish population.
*Data from Angastiniotis, Loukopoulos, Cao, Granda, Heredero, Kaback and Modell

b) Social, legal and ethical aspects

With a few exceptions (see also Section 3) clinical genetics services are mainly developed in countries with a low infant mortality (<20 per 1000), a good infra-structure of health care and a high gross national product (GNP) per capita (>$10,000). In these countries congenital disorders are the main cause of infant mortality and of chronic physical and/or mental impairment. Also, in most wealthy countries there is sufficient basic research in genetics to stimulate the incorporation of new methods and approaches into clinical genetics services.

Wealth and a high level of research and technology are, however, no guarantee that clinical genetics services are available at a national scale. One example is the USA, where much of the gene technology has been developed but where clinical genetics services are very much privatized and commercialized and available only to citizens who can pay for these services. Despite the high average GNP the wealth is very unequally distributed and millions of Americans live in poverty. 15% Of all Americans are not insured for health care and 28% are underinsured these people have hardly access to genetics services. In addition legislation is very restrictive as far as abortion is concerned. Under the past Republican administrations it was not possible to have an abortion in federally funded clinics and it is in these clinics that the poor people (often blacks and Hispanics) have to find health care facilities. Under the Reagan and Bush administrations it was even forbidden to doctors working in federally funded clinics to mention the option of abortion or to refer pregnant women to other places. Fortunately President Clinton has changed this soon after his election. Also he has made a Health Plan aimed at improving equal access to health care, but such a plan should have been realized several decades ago.

Another example of social factors hindering the implementation of genetics services is the failure of carrier screening for sickle cell anemia among the American blacks. Although the incidence of this disease among blacks is 1 in 10 and although techniques for heterozygote testing and prenatal DNA diagnosis exist, only a very small minority of blacks use these services (12). The reasons are economic problems (see above), but also the fact that about 60% of all black children are illegitimate and 80% are born from very young mothers. In addition the education of black people forms a problem and at the start of some regional programmes, public information has not been sufficient to motivate the black community to participate. On the contrary, many blacks considered screening for sickle cell anemia as a discriminative activity. That black people under other circumstances are willing to use genetics services including carrier screening is shown by the good results of the Cuban genetics programme (see Section 3).

Another example of the influence of social and cultural factors on the implementation of genetic services can be found in Japan. This country has the lowest infant mortality in the world (5 per 1000 live births), a GNP per capita of >$25,000 and well developed research and technology. Yet, clinical genetics hardly exists as an academic discipline and no comprehensive services as mentioned in the previous section are available at a national scale. Prenatal diagnosis is not developed because the Japanese tradition does not allow termination of pregnancy on the basis of a judgement of the fetal status. Also it is not considered to be acceptable to interfere with pregnancy by chemical means which forms the basis for a low contraceptive use and consequently one of the world's highest abortion rates for socioeconomic reasons (14). To Western standards these facts are difficult to reconcile and form an illustration of the difficulty to discuss ethical aspects at a global level when there is such impressive social, cultural, traditional and religious heterogeneity (15) (see also Section 3).

In Japan congenital handicap and genetic disease are strongly associated with feelings of shame and guilt, much more so than in western societies (15). This seems at least partly based on differences in attitude towards failure in general and the way marriages have been arranged between families.

In European countries abortion because of a fetal abnormality is widely accepted and in most instances a limitation to 24 weeks gestation has been legally established. Last year in the United Kingdom a new abortion law was accepted which sets no time limit for interruption of pregnancy in case of an affected fetus, provided certain requirements are being fulfilled. Also in France legislation is quite liberal. In this country the government is of the opinion that for rapidly developing disciplines as clinical genetics one should be reserved with legislation. Instead, the French have stimulated public discussions on psychosocial, legal and ethical aspects of genetics and a national committee on bioethics translates the results of such discussions into recommendations for medical professionals or does proposals for legislation to the government.

In all European countries abortion has been legalized except in Ireland and Poland where the Roman Catholic Church still has great influence. Studies in The Netherlands and in France (16) have shown that in these countries the use of prenatal diagnosis and selective abortion is the same among Catholics and other groups of citizens indicating that the central dogma of the Church (prohibiting abortion) is not followed by individual couples who are at risk of an affected child. The uptake of prenatal diagnosis among women of advanced age (35-38 years) is of the order of 50-70% in most N.W. European countries and still higher among more motivated couples, who have personal experience with a handicap. About 10-20% of couples are against abortion for religious/moral reasons. Among immigrant populations, especially of Islamic background, the uptake rate is usually much lower (see also Section 3).

In summary there have been relatively few major ethical problems in establishing clinical genetics services in the wealthy industrialized countries. Abortion because of an affected fetus has been the most pronounced issue. Also the question whether legislation is required to limit prenatal diagnosis (and selective abortion) to severe disorders has been raised, especially in Scandinavia (17). In Sweden the professional organisation of medical genetics itself has decided that abortion should not be performed in case of sex chromosomal aberrations like Turner syndrome and 47,XYY. In most other countries such a limitation is rejected because it would limit the autonomy of the prospective parents. Also, various follow-up studies after genetic counseling indicate that "the same risk" or "the same disease" may be perceived very differently by different couples, depending on their previous experience with a handicap, their life situation, religious background and several other factors. The main issue here is whether one wants to give maximal freedom of choice to individuals or that one tends to central regulation because of the perceived need to defend certain moral values.

A more recent ethical problem has arisen with the introduction in the U.K. of large scale screening of pregnant women for the detection of fetal neural tube defects and chromosomal aberrations. Investigating maternal serum with the so-called triple test (AFP, oestriol and chorion gonadotrophin) around 16 weeks of gestation, 5% of all women with the lowest test values will be proposed to undergo further investigation (repeat serum test, ultrasound examination, amniocentesis). In the end about 60% of the fetuses with a chromosomal aberration will be detected, usually with Down's syndrome, but ca. 40% will be missed. The point of view of experts in the U.K. is that if one does not implement such a screening programme no abnormal fetuses will be detected at all among pregnant women younger than 35 years because they are not eligible for prenatal diagnosis by chorionic villus sampling or amniocentesis under the present rules (18). In most other European countries (Sweden, Denmark, Norway, the Netherlands, France) it has been considered unethical to introduce a screening procedure with such a low sensitivity and high percentage false positives. By introducing maternal serum screening a large number of young pregnant women would be involved who have a negligible risk (ca. 1:1000) of a child with Down's syndrome. Amongst many of them unnecessary anxiety will be initiated because of an abnormal test result (19, 20). Also many unnecessary abortions will be performed as a result of the larger number of amniocentesis based on abnormal maternal serum test results. Finally, screening procedures with a low specificity may in the long term undermine the public's confidence in prenatal diagnosis on an individual basis, which presently provides a near 100% correct answer.

Similar considerations as mentioned above apply to the introduction of carrier screening for cystic fibrosis. Although 1:25-30 Caucasians are a carrier, about 300 different mutations have as yet been described. The most common mutations may comprise 50-90% with a considerable variation among different ethnic groups. Even in the case that 90% of the CF mutations would be detected in individuals, only 80% of the couples at risk of an affected child would be found, More than 20% of the couples tested will still give birth to a child with cystic fibrosis and again this is likely to undermine the present public confidence in prenatal diagnosis.

Given the increasing public and political concern about new developments in gene technology (see Section 4) it seems wise that medical experts and public health authorities are more reserved with the introduction of new technologies which sometimes seem to do more harm than good. Often, professional enthusiasm, ambition and curiosity about the result of application of a new technology lead to a rashly introduction into the health care system. Reliable technology assessment is often no longer possible and follow-up studies about psychosocial effects may come too late and the same applies to recommendations of professional organisations and legislation. To avoid such problems there should be ample discussions both at the professional and public level before a new technology is being introduced at a large scale. Also it is important to organise such discussions at an international level (21).

3. Prospects of Clinical Genetics in Developing Countries

Since 95% of the future children will be born in what today are defined as developing countries it seems to me a major ethical issue whether there are perspectives for the majority of the world's population to have access to clinical genetics services i.e. possibilities to avoid the birth of handicapped children.

There are several major obstacles of economic, social, cultural and religious nature. First of all there is great economic inequality among the different countries in the world. According to the United Nations Human Development Report 1993 (22) the average GNP per capita in industrial countries in 1990 was $14,440 and in the developing countries $810. Even more impressive is the fact that 46 countries, including China, India, Pakistan and Bangladesh with more than half the world's population, have a GNP of less than $500. From the data in Table 4 about expenditure on education and health care it can be deduced that most developing countries have few economic means to built up a good health care infrastructure, let it be comprehensive clinical genetics services.

Malnutrition and infectious diseases result in the daily death of 40,000 (!) children (see Table 5). In many developing countries the infant mortality is 10-20 times higher than in wealthy countries (23). It is clear that clean water, sanitary facilities, adequate nutrition, vaccination programmes and good primary health care are first priorities. Also the problems of AIDS is impressive, especially in Africa. Even in South Africa, which belongs to the most wealthy parts, among black populations 10% of the pregnant women are HIV positive and at least 30% of their children are affected and die within their first years of life. This problem alone accounts for an infant mortality 4-10 times higher than the overall infant mortality in N.W. Europe or Japan.

Table 4: Expenditure on Education and health (US$ per capita)*

>2000: Canada, Sweden, Switzerland;
>1000: North America, Japan, Australia, N. & W. Europe;
100-500: U.S.S.R., Eastern Europe Spain, Greece, Israel;
50-100: Most Latin American countries, Caribbean
<20: Most African countries, China, India, Pakistan, Bangladesh, Indonesia

*Ruth Leger Sivard, World Military and Social Expenditures, World Priorities, Washington , 1989

Table 5: The state of the world's children (UNICEF Report, Oxford University Press, 1991)

Number of countries; Under 5yr mortality per 1000 liveborns;

>150: 33 Mainly Africa, Afghanistan, Bangladesh, Bolivia, Pakistan

75-150: 31 Africa, W. Asia, Middle East, Turkey, Indonesia, India, Latin America

25-75: 27 China, U.S.S.R., S.E. Asia, Middle East, Latin America

<25: 34 Europe, Japan, North America, Cuba, Australia, New Zealand, Hong Kong, Singapore, Israel, Kuwait

Figure 1: Family planning in different regions of the world (% of couples using contraception)

Figure 2: Abortion rates, per 1,000 woman aged 15-44, in selected countries (Source: The Alan Guttmacher Institute)

The criteria for the cost-effectiveness of clinical genetics, as described for developed countries in Section 2a, do not apply to most developing countries as their severely handicapped do not survive or if they do, are not taken care of in institutes providing costly medical and psychosocial care. Consequently, the establishment of expensive genetics services is not compensated for by avoiding high costs of care.

Another major obstacle in future implementation of genetics services and more importantly in the use of contraceptives is female illiteracy. The world's total of illiterate adults is about 900 million (!) 60% of whom are female. In 24 countries more than 75% of women cannot read and write, in 20 other countries this percentage is between 50-75% and in still another 20 countries between 25-50% (22, 23). As long as this situation exists there is no basis for family planning, carrier testing, genetic counseling and prenatal diagnosis.

Culture, tradition and economic factors play an important role why women in major parts of the world are not able to restrict their number of children. Most world religions are very reserved towards contraception and consider abortion unacceptable. Even when religion allows certain measures, like in the Islam where contraception may be used under certain conditions and abortion may be acceptable during the first 40 days after contraception, traditions within tribes and families are often more restrictive.

In most societies in Africa, Latin America and Asia the position of women is inferior to that of man. In some instances like in India, and previously in China, deeply rooted preference of male offspring has led to abuse of prenatal diagnosis. Pregnant women from higher social classes would ask for prenatal sex determination and interrupt their pregnancy if a female fetus were detected.

As a result of all these factors the contraceptive use is low in most of the African continent, and in large parts of Asia and Latin America (Fig. 1). The percentage of teenage pregnancy is as high as 18% in Africa and 8% in Latin America. In the latter continent no country has as yet legalized abortion and the same is true for many countries in Asia.

As long as women in developing countries have no option of restricting their progeny, refraining from pregnancy in case of a high genetic risk and of a legal abortion in case of an affected fetus, there is no prospect for implementation of clinical genetics services (24).

One of the sad consequences of legal prohibition of abortion is the enormously high number of illegal abortions which sometimes results in the death of young women by bleeding or in secondary infertility. Just a few numbers to illustrate the magnitude of the problem. In the world an estimated 40-60 million abortions are carried out annually, 50% of which are illegal. In India alone, 4-6 million abortions (90% illegal) are estimated to be performed and in the former USSR, where abortion is legalized and used as a means of contraceptive, at least 7 million abortions occur each year. In Latin America 30% of the beds for Obstetrics & Gynaecology are used for (young) women with complications after illegal abortion. As is shown in Fig. 2 countries with a high contraceptive use, a good education, an equal position of women and men and a good health care system, have the lowest abortion rates.

To me all discussions about the ethics of in vitro fertilization, pre-implantation diagnosis, prenatal diagnosis and transgenic animals seem trivial compared to the global problems of economic inequality, illiteracy and the many social, religious and traditional obstacles in achieving an equal position of women and men.

Although most developing countries do not seem to be ready for the establishment of clinical genetics services and the use of gene technology there are, however, also positive developments. Since 1960-1965 the average infant mortality in developing countries has decreased from 103 to 71 per 1000. The life span has increased and so has the participation in education and the percentage of adult literates. During the past thirty years the average fertility per woman has decreased from 5 children to 3, 4 (22-25). It is to be hoped that these trends continue and that family planning programmes will be better implemented parallel to a stronger economy and health care infrastructure. Only after this has been realized there will be prospects of clinical genetics services allowing couples to make informed decisions about their procreation.

Already there are a few examples of developing countries which have built up a network of clinical genetics services or which are in the process of doing so. In Cuba, the government has for several decades given high priority to education and health care. Despite a relatively low income Cuba has built up an advanced health care system with equal access to all citizens and with a network of primary care clinics in the most remote rural areas. Most remarkably the Cubans have also been able to implement regional services for cytogenetic analysis, genetic counseling and prenatal diagnosis. Since 1986 a nation-wide carrier screening programme for sickle cell anemia started because of the relatively high incidence of this mutation among the blacks and many mulattos. Thanks to large scale heterozygote detection amongst pregnant women and follow-up by testing husbands of carrier females, genetic counseling and prenatal DNA diagnosis a more than 30% reduction of the incidence of sickle cell anemia has already been realized (26).

In China, with a population of 1100 million, the government has started a one-child family programme in 1970 to ensure sufficient nutrition for all newborns. The birth rate decreased from 43/1000 in 1963 to 21/1000 in 1990. About 75% of all women at childbearing age use contraceptive methods and already in 1981 60% had a one-child certificate which gave couples socioeconomic advantages. Of course, this policy limits individual freedom and autonomy, on the other hand the infant mortality (29 per 1000) compares very favourably with that in neighbouring countries like India (90/1000), or Bangladesh (111/1000).

A side effect of the one-child family policy is that parents who are allowed to have one child are very keen to have a healthy child, especially since they usually are not allowed a second pregnancy if the first child has a congenital handicap. This individual pressure and the government's aim to reduce the number of handicapped people form the basis for a wide interest in the development of clinical genetics services. Already, many hospitals all over the country have cytogenetic laboratories and facilities for genetic counseling and prenatal care. At a few larger centres expertise in biochemical diagnosis and DNA analysis is available. The strong political infrastructure associated with an extremely good information system onto the rural areas, are of great help for the development of genetics services. On the other hand the limited resources (GNP of $370 per capita) are an obstacle which may well diminish in the future if the present economic growth continues.

The examples of Cuba and China show that even in developing countries a high political priority of health care and education may provide good prospects of implementing clinical genetics services. In this context it is noteworthy that family planning programmes and reduction of fertility and child mortality have mainly been accomplished in developing countries with a strong political system. It is, however, difficult to generalize because in many other developing countries with and without a democratic system, the poverty is still immense and the fertility and infant mortality high. Also, it is difficult to judge political systems, religions, traditions and social structures which on the one hand are treasured by people, but on the other hand form major obstacles in fulfilling basic human needs, including a good life expectancy, education, autonomy and informed decision about future progeny. Ethical issues at a global level.

4. Future Developments in Gene Technology

Due to the efforts of many research centres all over the world and with significant financial support of governments and non-governmental organisations the mapping of human genes proceed rapidly (Table 6).

Up to now the efforts have largely focused on the mapping and identification of disease genes in man (see Section 2a). It is to be expected that in the future decades all genes involved in monogenic disorders will be identified which will enable their (prenatal) diagnosis and hopefully treatment or prevention.

In addition genetic factors involved in multifactorial diseases will be identified and especially the interaction between various genes and the interaction between a specific genetic constitution and exposure to certain environmental factors will reveal much about the etiology and pathogenesis of various forms of cancer, certain cardiovascular diseases, diabetes, rheumatoid arthritis, various psychiatric disorders and congenital malformations.

Table 6: Progress in human gene mapping*

Year: 1973 1983 1987 1989 1993
Number of genes mapped: 219 742 1236 1743 2735
Cloned genes: 0 104 610 945 c.1500
Anonymous DNA segments: 0 215 2057 3417 12599
Total: 0 319 2667 4362 14100
(of which polymorphic): (0) (130) (1193) (1886) (4116)

*Data from Human Gene Mapping Conferences 7-11 and personal communication V.A. McKusick, via G.J. van Omnen, April 1993.

In the decades to come it will become possible to predict whether individuals have a high risk of developing a specific disorder, 10-20 years or even 40 years later. The search for a genetic predisposition by DNA analysis will most likely be carried out on the basis of the family history of the person to be investigated.

Gradually, clinical genetics will expand to predictions about increased risks of major diseases of adulthood. This will require many more genetic counselors than now are available (27).

The first question to be answered is whether information about certain genetic predispositions should always be provided at a counselee's request or that it should be limited to instances where something can be done to prevent or delay disease symptoms. It is clear that in many instances early knowledge about a genetic predisposition may be followed by adaptation of one's lifestyle to prevent harmful environmental factors or by repeated medical examination and timely intervention.

When no treatment is available, however, prediction of a health risk or the certainty that a person will become ill, might not have medical consequences. The possibility to perform DNA diagnosis of Duchenne muscular dystrophy or of Huntington chorea are examples. In the former case parents at risk might want to know whether their child is affected as early as possible in order to provide optimal care and to take measures to avoid the birth of future affected children. On the other hand it may be a heavy psychological burden for parents to see a perfectly healthy looking baby and know for sure that it will need a wheelchair after some years and that it will most likely die before adulthood.

In the case of Huntington chorea it is the possible patient him/herself who has to make the choice "to know or not to know". Disease symptoms usually appear in the third till fifth decade of life and eventually worsen to severe mental and physical deterioration. Since Huntington chorea inherits in a dominant fashion, offspring of an affected parent have 50% chance to inherit the mutant gene. On the other hand there is a 50% chance of not being affected and this hope motivates many individuals to lead a daily life as normal as possible during the first decades of adulthood.

The discovery of a closely linked DNA polymorphism in 1983 meant the possibility of a new approach, i.e. early DNA diagnosis, many years before the onset of disease symptoms. In 1993 the Huntington gene was identified which implies an even better way of DNA diagnosis. The main question is whether the introduction of this new technology has been beneficial or that it has done more harm.

An advantage of early knowledge about carriership is that the birth of affected offspring can be avoided by prenatal DNA diagnosis and selective abortion. If such a test would not be available couples at risk could only refrain from pregnancy or accept a high risk of an affected child. On the other hand early knowledge of being a carrier and the development of a highly incapacitating and fatal disease some decades later must mean a heavy psychological and social burden both for the patient and the family. Recent studies indicate that a small minority (<10%) of possible carriers ask for a DNA diagnosis and also it became clear that early diagnosis may be associated with unpredictable psychological reactions and very complex disturbances of relationships within the family (28). Reading the literature about this subject I wonder whether the introduction of this DNA technology has not done more harm than good and whether the practical use in health care should not have been preceded by a more intense discussion among experts from various disciplines followed by public debate.

It is to be hoped that the introduction of future technologies will occur more prudently, especially when they concern common diseases like carcinoma of the breast, large intestine or lung or chronic rheumatoid diseases. Irrespective of the possibility of treatment a number of problems have to be investigated and discussed:

* Can people cope with early knowledge about a high risk of a severe disease that will express many years later and will there be methods to ascertain an individual's capability in this respect?

* If repeated medical examination and eventually intervention or adaptation of ones lifestyle to a genetic predisposition may improve an individual's life expectancy, is the price of continuous focusing on ones own health from young adulthood on, not a high price?

* Does early DNA testing interfere with family relations and with the individual's attitude toward social and professional life?

* Will it be possible to prevent the use of predictive DNA testing by (life) insurance companies, banks, employers and other institutions that have an interest in assessing peoples risks?

Answers to these questions are difficult and may also be different for different people, even within the same society. In addition, socioeconomic, cultural and religious factors will play a role. Finally, countries which already have a high expenditure on health care have to prepare for difficult cost-benefit analyses before the era of predictive medicine really starts.

I have learned from my colleagues in bioethics that the four main principles are: beneficence, non-maleficence, autonomy and justice. Just to show how complicated, if not impossible it will be to achieve this goal in the practice of present and future application of gene technology the following example:

A 55 year old man suffers from a disease which is completely or partly determined by genetic factors. The disease is associated with severe mental and physical handicaps at increasing age. His 28 year old son knows about the genetic nature of the disease and also about a DNA test that may tell him whether he has the same genetic pattern as his father. The son decides not to use the test and tells his wife about his risk and the fact that he wants to use "his right not to know". After some years his wife becomes pregnant and tells her husband that she does not want their child to suffer from the same disease as the grandfather she wants a prenatal DNA test because she feels that "she has the right to know". The fetus is found to be affected and the couple decides to terminate their pregnancy. However, the only way that the fetus could have inherited its genetic predisposition is from his father. The latter will thus develop the same disease as his father. "His right not to know" has disappeared because of his wife's "right to know". What is beneficial for the one is maleficial for the other. The autonomy of one partner is in conflict with that of the other. To whom have we done justice? Hopefully the young generation of today will find answers to the complex problems of tomorrow.


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