Darryl R. J. Macer, Ph.D. Eubios Ethics Institute 1990
Every individual has a unique DNA sequence. There is also much variation between different alleles of each particular gene. Some variations in gene sequences are neutral, and others have positive or negative influence. Genetic screening is the testing of this variation, the same as we may screen people according to their weight. The purpose is to determine whether an individual has the certain test characteristic or not. In terms of molecular genetics the screening may be either of a protein or of a DNA sequence. The screening of a DNA sequence is the most powerful and the type of test that will be increasingly used, though protein testing has often been easier. Usually genetic screening involves the detection of a harmful gene sequence. It is possible to screen for a desired sequence also, as in the detection of the Y-chromosome if sex selection is the goal.
The basic principle relied on is the binding of a probe to the DNA molecule of the patient. Complementary DNA nucleotide sequences bind to each other. The probe used is usually single-stranded DNA , which binds to the test sample. It is applicable to any DNA sequence. DNA probes have many uses for genetic analysis, in all living organisms, but this chapter will focus on human genetic screening. DNA probes have many benefits for parts of medicine that I do not discuss, such as use in epidemiology (Gibbs & Caskey 1989).
DNA probes that are independent of family history are preferred as probes. This means that no prior screening of the parents is necessary. This avoids the need for obtaining consent from other family members for the taking of DNA samples. Prior to this the situation was that DNA samples were taken from parents and other family members. They were usually taken after the birth of the first affected child. These samples can then be analyzed by a technique called restriction fragment polymorphism (RFLP). In this technique the DNA sample is cut up with a mixture (or a particular) of restriction endonucleases, which cut the DNA at specific sequences, and then the mixture is size separated, and examined. The pattern of size distribution is quite individual, and the disease causing or linked fragment can be found, and examined in any children or fetus. The results are not always clear, for instance in sickle cell anaemia prenatal diagnosis was only possible in 60% of cases. There are clearly advantages in using family-independent DNA probes. They can be used for all pregnancies without a history of genetic disease. Many genetic diseases arise spontaneously in each generation so would not be predicted. The parents who are carriers of recessive harmful alleles do not need to be screened and marked as carriers, which can have harmful psychological and social problems.
Most progress has been in disorders due to a defect in a single gene. The mutations consist either of single bases changes, affecting a single amino acid in the critical regions of proteins or else gross abnormalities such as deletions, insertions, or rearrangements of genes (Antonarakis 1989). The number of disorders that are screenable is measured in the hundreds, and is rapidly increasing (OTA 1986). Examples of some single gene diseases for which gene-specific probes are available, though not necessarily for all mutations that cause the disease, are given in Table 13-1. The screening can be performed prenatally or postnatally, and most of the autosomal dominant disorders have a late onset so that clinical signs do not occur until later in life. The problems of Huntington's chorea are discussed later, as they are representative of the dilemmas faced.
Disorders and Frequency/1000livebirths
Polycystic kidney disease 0.8
Huntington's chorea 0.5
Myotonic dystrophy 0.2
Polyposis coli 0.1
Cystic fibrosis 0.5
Sickle cell anemia Race specific (see Table 2-1)
Thalassemias Race specific (see Table 2-1)
Duschenne muscular dystrophy 0.3
Haemophilia (A & B) 0.1
For common genetic diseases, screening for predominant mutations may still be a worthwhile goal. Cystic fibrosis affects about 1 in 1600 births among Caucasians. Approximately 70% of the mutations correspond to a specific deletion of 3 basepairs at amino acid position 508. A simple therapy, but it is not necessary to use germ-line therapy as embryo screening should be adequate. However, we will still have people suffering from genetic disease, who should be treated. There will be a place for somatic cell gene therapy, together with other therapies. There may be one for germ-line therapy when it comes to future generations, but that requires much more discussion.
There are also differences in expressivity, one person may express the disease to a different extent, or at a different age, to another. Sometimes this is due to multiple gene activity, or the presence of some environmental factors as is the case with Wilms Tumour, or Retinoblastoma, or Glucose-6-phosphate Dehydrogenase deficiency. The progress and severity of genetic diseases does vary (Holtzman 1988).
There is much commercial interest in screening, as the market is very large. Companies are working on many diseases, and packages that can screen a hundred or more disorders should eventuate in the near future. There is a very large commercial market, though it is much less than the huge pharmaceutical industry. It is best for the patient if only one sample is taken, and as many tests as possible are performed. There is a shortage of trained personal for genetic counseling, and will be for some time, as the new clinics are established. It needs to be done only in clinics with good support for counseling.
The DNA probes and genetic information is perceived to be 100% reliable by many people. Public attitudes need to be educated against this type of blind faith in genetic techniques, that we saw 70 years ago. That is a lesson of the eugenics programs of history. Many tests can be made, access will need to be made fair. The uncertainty of prognosis needs special stressing in multifactorial disorders, and psychiatric diseases.
Another problem is that many genetic diseases occur spontaneously, and are not inherited from the parents. This is true for about a third of the cases of hemophilia and a half of muscular dystrophy. It is also true for the chromosomal aberrations (Chadwick 1987). In retinoblastoma, many cases are new germline mutations, arising in egg or sperm, or the early embryo. It has been found that new mutations for this disease occur more frequently in the paternal chromosome. This could be because new mutations at this gene locus arise more frequently during spermatogenesis than during oogenesis, or that imprinting in the early embryo affects chromosomal susceptibility to mutation (Zhu et al. 1989). As we discover more, we may be able to lower mutation rates.
There are various applications of genetic screening. The screening of adults to predict their susceptability to disease may be important in certain industrial environments. It can also be used by medical insurance companies. There is also screening with an eye towards reproduction. The screening of people prior to their marriages being allowed occurs in some states of the USA and in Denmark. It may also be used for fetal screening, with the view to selective abortion of genetically diseased fetuses.
The first major type of genetic screening used by medicine was screening of newborn children for PKU deficiency. In the 1960's it was made compulsory in the USA. It is the most widespread screening worldwide. If a newborn is found to have PKU deficiency, they can be put on a special diet, and will not suffer from severe mental retardation that would otherwise result. As well as a very major healing motive, it also works out economically cheaper to treat patients before serious damage is done to them by the genetic disease, than to the costs of keeping the sufferers in institutions.
In several states of the USA there is screening for a haemoglobin disorder, sickle cell disease, and it is compulsory in seven states. Hemoglobinpathogies are a major health problem in the USA, an one treatable part of this condition is the increased susceptability to severe bacterial infection during the first few years of life (NIH 1987). If the children are placed into care programs than they have much better health, which is a key justification for widespread screening. Some of the other disorders currently screened for in newborns are hypothyroidism, galactosemia, homocystinuria, and maple syrup urine diseases. There is little debate on whether newborn screening for serious avoidable genetic disease should be voluntary, or compulsory, as we discuss later. It is generally performed presuming consent. New techniques for the amplification of DNA from dried blood spots using the polymerase chain reaction (PCR) can be of use in examining the molecular basis of the positive results. Such tests are possible from dried blood samples, and have been performed for sickle cell disease (Jinks et al. 1989), phenylketonuria (Lyonnet et al. 1988) and cystic fibrosis (Ballabio et al. 1990).
The American Academy of Pediatrics (AAP 1989) has circulated sets of fact sheets which provide information to pediatricians. There is a growing number of tests available, at different costs. Some of these characteristics are presented in Table 13-2. In some of the diseases complete health restoration is possible. The frequency can vary between races in some cases. The costs of testing are given when several are jointly offered, as is common practise in developed countries. The advent of DNA testing will make a broader range of tests available.
Disease; Extent of Health Restoration; Frequency per live births; Testing Method; Cost US$;
Biotinidase; Complete; 1:70,000; Enzyme assay ; 0.50;
Branched Chain Ketoaciduria (Maple Syrup Disease); May be Complete; 1:250,000; Bacterial Growth Inhibition; 0.50;
Congenital Adrenal Hyperplasia; Complete; 1:13,000 Eskimos 1:680; Enzyme immunoassay; 1.50;
Congenital Hypothyroidism; Yes; 1:4,000; Radioimmunoassay; 1.50;
Cystic Fibrosis; Yes; 1:2,000; Immunoreactive trypsin; 1.00;
Duschenne Muscular Dystrophy; No; 1:4,000 male; Enzyme assay; 10;
Galactosemia; Complete; 1:60,000; Microbiology or Enzymatic; 0.50;
Homocystinuria; Yes; 1:50,000+; Bacterial Inhibition; 0.50
Sickle Cell Diseases and thalassemia; Yes; 1:400 in US Blacks; Protein electrophoresis; 1.50;
There is screening for genetic susceptability to suffer from environmentally induced disease, like elevated blood cholesterol, which can advise us to alter our behaviour to lower our risk. This is an extension of preventive medicine. The programs for the detection and treatment of individuals with elevated serum cholesterol levels have been advocated in most developed countries (Pearson et al. 1990). In 1968 the World Health Organisation (WHO 1968) recommended criteria for a condition worthy of a screening program, which are as follows:
1. The condition sought should be an important health problem.
2. The natural history of the condition, including the progression from latent to apparent disease, should be adequately understood.
3. There should be a recognizable latent or early symptomatic stage.
4. There should be an accepted treatment for patients with recognized diseases.
5. There should be an agreed policy on whom to treat as patients.
6. Case finding should be a continuous process and not a once-and-for-all project.
7. A suitable screening test should be available.
8. The test should be acceptable to the population.
9. Facilities for diagnosis and treatment should be available.
10. The cost of case finding (including diagnosis and treatment of patients diagnosed) should be economically balanced in relation to possible expenditure on medical care as a whole.
There are several diseases which could be screened consistently with these principles in developed countries. Other worthwhile mass screening programs include smoking habit, cervical cancer, breast cancer (mammography) and alcohol consumption. There are other possibilities such as hyperlipidaemia, obesity and faecal occult blood (Fowler & Mant 1990). There are still major problems with such programs. Although individual screening is very useful, mass screening is desirable for some. The method of doing this must be voluntary, but if it is left to people to come to a clinic for screening only certain types present themselves. There must be widespread education to inform people of the possibilities. To be effective the programs should allow wide access to the population, and good quality assurance both in the screening and any subsequent treatment. Good public registers are needed. Good ethical and scientific training of the health care professionals are required, as for all screening programs. There is usually a lack of personal to perform adequate follow-up of patients, which becomes even more critical in emotionally upsetting results.
It has been found that many common cancers, including colon, lung and breast cancer, develop by the stepwise accumulation of mutations affecting many genes. The changes include the loss of several "suppressor" genes, which normally inhibit cell growth. Analysis of the gene changes may aid the prediction of how cancer in different patients will develop, and can also be used to warn people that are close to developing cancer. If they already have 7 of the 8 gene changes required to develop cancer, then they should avoid agents that cause gene mutations (such as cigarette smoke). There are some genes that make people susceptible to certain types of cancer, requiring the presence of a mutating agent to develop. It is the accumulation of changes, not the specific order they occur in, that is important for cancer development (Marx 1989b). A particular diet or life style can be suggested to lower risks. There is a link between emphesyma, a lung disease, and a deficiency in a protein called alpha anti-trypsin. When people are screened and found positive, they know that if they smoke, they have high chances of lung disease. Some people may attack this as limiting freedom, however most people would prefer to have the additional knowledge, and another choice if they take heed of it.
The information obtained by population screening can be stored in a registry for later recall before marriage. Premarital testing can be used to exchange genetic information before marriage if people are concerned about possible genetic diseases in future children. If two carriers of the recessive gene for cystic fibrosis are married, then they will have a one in four chance of a child who will suffer from the disease. If they do not want to use selective abortion yet do not want to risk such a child, then premarital screening could be used. It has been used successfully with Tay-Sach's disease as I describe later. Some theologians, such as Paul Ramsey (1970) or Bernard Haring (1975) are in favour of such testing to protect the ignorant and avoid "complicity in tragic birth". Ramsey would approve the use of the United States' marriage-licensing laws to prevent the transmission of very bad genes. While it may be true that no one has an unqualified right to have children, it may not be right to approve of such law enforcement to prevent marriages. In Denmark, marriage licenses are refused to persons carrying certain genetic defects until one has been sterilised (Nelson & Rohricht 1984). This is a dangerous step towards eugenics, and should be resisted. As discussed in the last chapter, it is important to maintain voluntary use of new techniques, if people are educated most will try to avoid their children having a genetic disease, compulsion by law may turn people away from seeking aid and make them suspicious of the technology in general.
Prenatal screening has been used for several decades. It has become associated with normal prenatal care in most industrialised countries. There are some important nongenetic screening programmes. For example, if a woman is not immune to rubella, she should be immunised before becoming pregnant. There are other infective hazards to the fetus, such as tToxoplasmosis;, cytomegalovirus and herpes virus, which are also important for potential mothers to be immune to (Bull 1990). About 80% of pregnant women in France have evidence of past infection with toxoplasmosis, and if they are infected during pregnancy there is a 40% chance that the fetus will be infected. DNA screening services can be provided at low cost (US$3 or less) for some single gene disorders (Beech et al. 1989), and the costs will come down with the greater number of gene probes that are available in easy to be used packages. There have been extensive studies and use of DNA testing during the last few years in some countries, such as the U.K. (Harris et al. 1989, Rona et al. 1989).
Recombinant DNA techniques were first used for prenatal selection of sickle cell disease in 1982. For a growing number of genetic diseases, methods have been developed to detect the genetic defect early in fetal life. These methods rely on removing a sample from the fetal material and analysing it. There are different stages at which fetuses can be screened for genetic disease or abnormalities. As far as the ethics and the distress and the health risk to the mother are concerned, the earlier the better. Types of screening are illustrated in Table 13-3.
Type; Time; Risk; Application
Embryo biopsy; 2 days; ?; Embryo Transfer
CVS; 6-10 weeks; 1-2%; Wide
Amniocentesis; 12-16 wks; 1%; Wide
Fetoscopy; 14+ wks; 3-5%; Wide
Mat. Blood Sampling; 2+ weeks; 0; Total
Ultrasound; 8+ weeks; 0?; Total
It is now possible using very sensitive genetic probes to take a sample of the chorionic villi (membranes around the fetus) at 6-9 weeks and analyse the fetal DNA directly to determine whether it has a specific genetic defect, with the technique of chorionic villi sampling (CVS) (Rhoads et al. 1989). Like amniocentesis there is a 1-2% risk of miscarriage after the sampling due to the procedure. Further developments will bring wider applicability and increased sensitivity allowing earlier detection. We are still unable economically, ethically, or socially, to screen every fetus for so many diseases, with these techniques. They are currently used for screening fetuses from parents of high risk, however, if in the future cheap multiple screening techniques become available it may be possible they will have widespread use.
Fetoscopy involves examination of the fetus by percutaneous transabdominal uterine endoscopy, and anatomical malformations can be directly visualised. In common language this means that the fetus can be viewed through a hollow tube which is inserted into the amniotic sac. It may also be used for the removal of a sample of tissue from the fetus. The recently developed technique for the sampling of fetal blood is called percutaneous umbilical blood sampling. During this technique, an ultrasonographically guided needle is inserted into the umbilical blood vessel to withdraw a sample. The procedure can be performed on an outpatient basis, and does not require maternal sedation, and is safer than fetoscopy. It is still experimental (Hansen & Slavek 1989). Embryonic tissue biopsy is more dangerous, and unknown. With the improvements in genetic screening, it should be unnecessary if genetic diagnosis is desired.
Different methods may be combined, for instance the first screening may be maternal blood sampling, and if certain proteins are detected, CVS or aminocentesis may be used to detect spina bifida, or Down's syndrome. Ultrasound is routinely used, and has the advantage of being noninvasive. In West Germany, all pregnant women have been offered two ultrasound examinations since 1980, one week before 20 weeks gestation and a second at 31-35 weeks gestation. In the U.K., more than 80% of pregnant women undergo an ultrasound, but in the USA only 30-45% are scanned. In developing countries there are insufficient resources to allow routine screening. The optimal time for general screening using ultrasound is currently thought to be at 18 to 20 weeks gestation (Crespigny et al. 1989).
Maternal blood sampling at 14-16 weeks for a protein alpha-fetoprotein is routinely offered in the United Kingdom, and in some states of the USA such as California. A high level of the protein may indicate neural tube defect, and a low level may indicate Down's syndrome. The analysis of maternal blood for the level of alpha-fetoprotein, human chorionic gonadotropin and estriol, can lead to the detection of 60-70% of trisomy-21 (Down's syndrome) pregnancies. This is economically viable for mass screening, but further requirements are desirable, cost-effectiveness is one part of the ethical equation. If the indications are positive for the possibility of a fetal disease, then fetal sampling can be performed, as maternal blood screening is only an easy preliminary screening. A positive result only selects patients for the fetal screening. In California, all women have to sign a consent or refusal from for this voluntary testing, and can withdraw at any point from the program. Neural tube defects affect about 1 in 500 newborns, so are very common.
Because of the limited resources for genetic counseling services, not all woman, even in developed countries, can obtain services (Emery 1990). The indications that may be used for invasive testing, such as CVS or amniocentesis, include:
* Maternal age greater than 35 years (higher risk of chromosomal disorders).
* Abnormal levels of a protein marker, from maternal blood sampling.
* Parent carries a genetic translocation, or genetic disease
* Previously affected child or close relative
* Screening in high incident population.
During 1988 a minor revolution in genetic techniques occured, with the capacity to analyse DNA from a single cell using the DNA Polymerase chain reaction (PCR) (Li et al. 1988). In this technique, the single original copy of DNA is multiplied thousands of times by the technique, allowing DNA probing of the sample, within 4-6 hours. The technique is of very broad use in genetic analysis (Mullis 1990). This can be used for preimplantation screening, and is also applicable to CVS. If used after CVS very small samples will be required, allowing screening to be performed at earlier stages in pregnancy. The small sample required will also decrease the chance of miscarriages, and the need for multiple sampling. The only caution, is the need to avoid any contamination of the sample, as a small amount of contaminating DNA can lead to a false result.
The PCR has been used to detect the presence of a Y-chromosomal specific marker in maternal blood samples. In the pilot study it was found to work well, in samples from pregnant women who had gestational ages between 9 to 41 weeks (Lo et al. 1989). This technology has the advantage of ease and is relatively non-invasive. It promises much for further development, and has been further applied (Lo et al. 1990). There is a large number of false positives found in these tests, which is of concern. The consequences of a false positive may mean that an unaffected fetus is aborted. To be sure of the result a larger sample is currently required, because of the effects of contaminating samples (Editorial 1990b).
Preimplantation screening has only begun to be used in 1989, and is still being developed. The first study involved embryos that were not implanted after screening (Handyside et al. 1989), and did not provide any evidence of harm to embryos by the procedure. Another study used DNA from oocytes and the DNA polymerase chain reaction as a model for screening for the gene defect for cystic fibrosis, and found the technique could provide an answer within a few hours (Coutelle et al. 1989). There have been satisfactory tests using mouse embryos, screening for beta-thalassemia (Holding & Monk 1989). One ethical objection, once it is confirmed that it is safe, is that of interference with "nature", by the discarding of diseased embryos, as it is at such an early stage. However, we have established that prevention of disease is an ethical criteria for interference with nature. It is certainly less traumatic than abortion after prenatal diagnosis, at the earliest at 6-8 weeks after conception. However, it might never be widely provided, as it is limited to infertility clinics, and to parents that know that they carry a disease. It might be more ethically acceptable to using abortion, but because it is unlikely to be widely provided, the question of selective abortion must be addressed.
There have been several pregnancies established from embryos that were genetically screened before implantation. The first births were of female babies, selected by the absence of the Y-chromosome, for sex-linked genetic disease (not present in the female). Prior to this clinical use, metabolic studies on biopsed embryos showed that they were normal. The team included Hardy and Handyside (who completed a preliminary genetic study refered to earlier), and the gynaecologist Robert Winston at Hammersmith Hospital, as well as scientists from the University of York (Handyside 1990, Handyside et al. 1990). The actual costs of screening have been estimated at about US$2,500 for each successful pregnancy, which is comparatively low. Given the economic factors that often influence health care decisions, such as the high cost of health care for people suffering from severe diseases, this type of screening may be encouraged by governments. However, it should be stressed that it is still at an experimental stage, and few laboratories have the skills in embryo manipulation.
A possible ethical problem is that this procedure is based on the expectation that more embryos will be made than will be implanted. However, there is not too much difference to normal IVF in which more embryos are fertilised than may be implanted, and any embryo that shows abnormal growth is not implanted. A deeper concern is that this program is genetic selection. Many people support the alleviation of infertility, but a different idea is involved in genetic selection for disease, though it is also often well supported. In all cases that selective abortion is considered ethical, preimplantation diagnosis should also be acceptable, and given the early stages of embryo growth involved, it may be more acceptable. However, the practical problems such as the low success rate of embryo transfer to produce pregnancies, and the higher degree of intrusion for the mother in IVF and embryo transfer compared to selective abortion, mean that this technology is not widely used.
Considering the discussion presented in chapter 5 on the status of the human embryo, it is ethically preferable to have an early abortion, if any at all. In different countries the proportion of early abortions varies. The percentage of total abortions performed before twelve weeks in Denmark and France is 97%, in the USA 92%, and in the U.K. 84% (Gunning 1990). Among the late abortions, a higher proportion will be because of genetic abnormality of the fetus because the screening tests were only able to be performed later in pregnancy. With the use of new technology it is hoped that the number of late abortions will decrease. We should note that in the U.K. about 1% of the abortions are performed for reasons of fetal handicap, certainly a minority of the total.
Genetic counselors are placed in an increasingly powerful position, but are also increasingly necessary. There needs to be much psychological counseling and information provided to people who are considering prenatal screening. Many parents come after the birth of the first affected child, or in diseases such as Huntington's chorea, where there is possibility of the child being affected.
In a major international survey of genetic counseling (Wertz & Fletcher 1988), it was found that nondirective approaches are preferred by over 90% of the counselors. The role of the counselor is to provide information to allow the parents to make up their mind, rather then imposing any of their own ethical standards on the parents. This widespread acceptance of nondirective counseling means that they act as "decision-facilitators", providing information and leaving decisions up to the patient's autonomy. There is much importance on psychological aspects also, in avoiding anxiety. There are still substantial cultural differences in the responses of counselors in different countries (Wertz & Fletcher 1989a). There is a more directive approach seen in East Germany or Hungary, or India, where they see it more important to give more advice and guidance (Czeizel 1988) .This has been discussed in the previous chapter. Motulsky (1989) has suggested that the nondirective counseling has been a feature of genetic counseling because it was primarily scientists who developed the services, who unlike physicians, are not in the habit of giving directive advice. This may be one factor, but it is now accepted that nondirective counseling is required to respect the autonomy of the different people who use the services. Many patients, in any country, do expect guidance when making up their minds on difficult questions. It is very important that the easily available testing packages, are accompanied by good counseling.
From the results of Wertz and Fletcher (1989a) the principle concerns of geneticists can be seen. These concerns in order of priority were:
1) Fairness of access to genetic services
2) Abortion choices, and legal restrictions
3) Confidentiality problems
4) Protecting privacy from institutional third parties
5) Disclosure dilemmas
6) Indications for prenatal diagnosis
7) Voluntary or mandatory screening
8) Counseling incapacitated persons
These problems are also discussed in this book. The survey is important as it shows the order of priority seen from practising geneticists. From these factors, a code of ethics was drafted and proposed (Fletcher & Wertz 1990).
The human side of genetic counseling is clearly seen in the study of the proportion of women who would use selective abortion when the chances of the diagnosis being correct are increased. There is a 50% increase in the number who would abort the fetus if the probability of the fetus having a serious neural tube defect increased from 95% to 100% (Faden et al. 1987). This view of certainty versus high chance, a 19 in 20 chance, is interesting. The perception of what is a serious risk varies between patient and counselor, a patient may regard a one in four risk as low, when in fact it is quite high. It is something to do with the type of optimism that we have for things to turn out alright. Other factors found among women who favour selective abortion are those with higher education, those who wanted less children, those who had a previous abortion, and those who attended religious services less often. Women who were in the screening program had a similar attitude to those who were not. Between 60-90% were in favour of selective abortion, depending on the seriousness of the disease.
Public attitudes do change with time, and with counseling. Education increases our understanding of what the benefits may be, and may reduce anxiety about intrusive screening methods. Cultural and religious attitudes are important, and are affected by each societies view of science and the value placed on fetal life. In an American survey of 2,000 abortion patients, the reasons why women considered abortion were investigated. Only 13% listed as one of the reasons that they were worried that the fetus had a possible health problem, a small proportion (Torres & Forrest 1988).
As with all these medical issues, there is a major ethical problem in the delivery of services. There is unfairness in access to genetic services, and insufficient services to meet needs. This is especially acute for individuals, families and pregnant women who are not referred to genetic services by physicians, who suffer from poverty, and lack of education, or who live far from a genetic centre. The information provided must be of high quality and reliability. There are important psychological skills that are needed, especially after a couple have made their decision (Harper 1988). Whatever the decision is, the couple must be helped to cope with it. There may be feelings of shock, denial, anxiety, anger, guilt, possible depression, relief, reassurance, and various combinations of these.
Because of the explosion of information and possibilities that will be upon us soon, there are calls for a code of ethics of medical genetics to be debated and established (Fletcher & Wertz 1990). There does need to be some international discussion, and the power to sanction those who are unethical. They think that medical geneticists should become more professional in the sense of setting a written ethical code which members must follow. Until now, the arguments are oral or else in the literature. Other reasons for a written code include that the geneticists would be more publicly accountable and their views may be more considered in public policy. A code also enables the moral commitments of this generation to be transmitted to the next generation. What seems the critical question is whether such a code would aid the situation, which it probably would. During the process of deciding on the code it would also make them more aware of the ethical issues, on a broader scale than their daily practise experience. Some may argue that such a code might not be able to change with new technology, however I agree with Wertz and Fletcher that the same basic ethical problems exist. The theme of this book is that genetic engineering is principally a catalyst for us to think about other issues of bioethics.
A fundamental question, that will need to be addressed in each country, is what genetic diseases can be screened for. In developing countries they may concentrate only on the most prevalent diseases. For example in much of Africa, sickle cell disease is compelling, with 25% of the population of Nigeria carrying the recessive allele for this disease. In Middle Eastern countries, consanguineous marriages are still very common, and this may be the most urgent concern. In developed countries many diseases may be screened for. However, in all countries, there are problems to do with the seriousness of a disease that warrants an abortion. This section also gives some examples of specific diseases that can now be screened for.
The results of genetic screening may pose a dilemma to the parents if the fetus is known to have a genetic defect which will cause disease after birth. They must consider whether induced abortion is a satisfactory "treatment". Views on whether death before birth is preferable to disability after birth vary greatly and they depend on the status given to the human embryo. There are several key questions. Can a barrier on the slippery slope between severe disease and hair colour be drawn? Should a rigid boundary limit be imposed if it can? In which diseases do we consider no life at all to be desirable to a life of much suffering? It depends on our capacity to treat the disease, for example, can we give them eyeglasses, or a hearing aid, or is it a disease with no treatment.
The problem with fetal screening is that we might not be able to eliminate the disease without eliminating the subject of the disease. We need to answer the question of the status of the embryo? If we take a gradualist view, then we would aim to do screening before the time that we consider abortion unethical. To be morally consistent if the embryo is considered to be of absolute protectable status at a certain time, then if at any period after those dates the living embryo is aborted the death of an embryo is unethical. There are factors of the parents to be considered, but they should not be given priority once the embryo has protectable human status. When detection methods are available for screening at the earlier age then the approach of screening and selective abortion can be ethically used. The exception to this developmental limit might be if the fetus was certain to be destined to die when born.
The issue of embryo status was discussed earlier in chapter 5. An ethical time limit for selective abortion would generally be between the formation of the primitive streak and individualisation at 14 days and the time of brain life. If a fetus has a serious genetic impairment, with a consequence of serious mental deficiency, some people might say that the fetus does not, and will not in the future, have a"life" as "normal" humans have a life. Its potentiality is different. Still many believe potential spiritual relationships are present in all human fetuses. There is an increasing recognition that fetuses should be regarded as the second patient. This will increase as fetal surgery increases. The fetus makes claims for a right to nutrition, protection, and therapy (Blank 1984). The quality of man, the soul, his essence, his unique individuality, with its associated dignity or reverence means that man has a sanctity. However, we should not contend, as some arguments against abortion do, that existence is a good in itself as all other goods depend upon it. Some types of existence are not, and especially if there is no person, then there is no spiritual existence. Abortion is one of the key moral problems in this area, and in some countries it has become a major political issue also.
We must also consider the idea of replacement, by a healthy child, or affects on the family, to ignore these may be to have a negligent view. In a society where we may only have 1-3 children, there is much concern to have healthy children. This is more than in the past where even a century ago, half the children would die, including the weak ones. This type of medical decision is different to the one in a normal doctor-patient relationship, as it concerns the family as a unit.
Some respond by saying that selective abortion is playing God too much, however, they could respond as seeing this is part of a co-creativity with God, and part of our moral responsibility. Some of these diseases may be caused by our industrial pollution, and medical intervention to keep handicapped people alive. These are also human interventions. With some diseases the nutrients that the women has during pregnancy have been linked to birth deformities, such as neural tube defects like spina bifida, this is a more environmental influence. We need further investigation of the causes of disease. However, some argue that we are too ignorant to make these choices, or that the natural order has a certain rightness. If we use genetic screening it is argued it may be dehumanising, and making children consumer commodities, or damaging to our attitudes to others. However, while there is no reasonable therapy for the sufferers of some disease, there will be strong arguments to allow selective abortion.
About 0.5% of genetic diseases at birth are chromosome abnormalities. There are many different possible chromosomal abnormalities, though most are lethal before birth. The most well known and common survivable chromosomal abnormality is trisomy 21, or Down's syndrome. As discussed, it is the justification given for the chromosomal screening of fetuses of older mothers. Some other abnormalities have a apparently minor affect on individuals, such as an extra Y-chromosome in XYY males.
Some parents of children who have a genetic disease such as Huntington's chorea which acts in later life, may wish their children to be sterilised so that they will not pass on the harmful gene to the next generation. Huntington's chorea is an example of a dominant mutation which causes a dehabilitating disease in the 30's or 40's. Some genetic diseases such as Huntington's or Parkinson's disease only affect the patients after 30-50 years, in fact it is likely that children born now would not have to face the effects of such diseases by the time they are that old, because a therapy will be developed. However, if they are living under the threat of disease it could be very distressing, but the age limit is still better than the life expectancy in some third world countries. Certain families may have wide differences in the age of onset, Huntington's chorea in some families begins in childhood, or after 60 years of age. The symptoms are progressive, and include movement disorder, intellectual decline and psychiatric distress such as depression. There are other common autosomal dominant genetic disorders, for example Marfan syndrome, neurofibromatosis, hypercholesterolemia. Others also have gene probes available, such as familial amyloidotic polyneuropathy, but are rare, and the severity varies. There are also X-linked dominant genetic disorders.
Genetic screening for Huntington's chorea has been introduced in the last few years, and has raised many of the ethical issues of genetic screening. A genetic marker was found, that could predict 96% chance of developing the disease (Conneally et al. 1984, Wexler 1990). This testing is being performed at about 20 centres in the USA, several in the U.K., and others are beginning in developed countries. Before the test the people know they have a 50% risk, after they will know with high certainty, but with a little doubt. The results of testing of people that have an affected parent will be approximately half positive and half negative. Half the people will know for sure that they are not at risk from the disease and will feel much relief, and the others will know that they carry the harmful gene and until there is effective treatment for the disease, face an early death. There needs to be psychological screening before the genetic screening, so that people with suicidal tendencies are not involved. Some people may prefer to remain in uncertainty, but it is not so easy if their relations have screening. In the unusual case of identical twins, the results will be identical. So if one twin has a result the other can know their verdict. The main problems relate to presymptomatic prediction (Morris et al. 1989).
In most Huntington's chorea screening services, very careful selection of the test subjects is performed. The applicants for testing may come for counseling several times before the decision to test and the information is given. The results are always given in face-to-face meetings, not over the telephone. Post test counseling must also be sort, and a companion is often required to accompany the person awaiting the result.. Those people who are emotionally unstable are not tested (Wexler 1990). It is essential that such information be accurate, so tests are usually performed twice for confirmation. Because the gene for the disease is not yet isolated, linkage analysis must be used. This requires some samples from family members, making the subject of the services more than just an individual. In this way genetic counseling can involve the family as a unit as well as the individual. Family members who are not themselves afflicted, will still be affected by the presence of the suffering patient in their family. It has been suggested that access to the tests should be conditional on agreement to release their DNA sample for use in other family members who also want the test performed. This is a reasonable request, but should not be used to prevent people using genetic services who do not want others to use their samples.
Because of the nature of presymptomatic testing, it has highlighted more of the ethical problems that arise in genetic screening than some "simpler" cases. Autonomy of the patient requires that the patient can make an informed decision about the procedure. The information must be presented, and the counselor must also examine whether other people are putting pressure on the patient to have the test performed. Beneficience involves the protection of the patient from harm, which in this case may mean those who are emotionally unable to face the results of such a test. Confidentiality is clearly required, and may be difficult in family genetic linkage studies. The principle of justice can be applied so that while there are shortage of resources the most needy are served first (Huggins et al. 1990).
There is the important question of whether we should test children for "adult" genetic diseases. International guidelines have specifically excluded presymptomatic testing of children for this disorder, but there are still many requests from patients, clinicians and adoption agencies to perform tests (Harper & Clarke 1990). The situation may change if the onset of the disease is during childhood, and of course if therapy is available, or lifestyle changes would affect the disease course. In the example of Becker muscular dystrophy, minor symptoms may start in childhood. However, if a child is fatigued it might not be due to this disease, but rather they are just tired. In this case DNA testing of the at risk child could relieve many years of anxiety from their life, they could make normal life plans whereas without the test they might have become pessimistic and depressed, living only with shortterm goals. These benefits need to be balanced against the opposite case, when a child is found positive for the disease and may react very negatively. Medical research with children has many dilemmas (Nicholson 1986).
The testing for Huntington's chorea can also be performed in a nondisclosing prenatal test, so that the risk status of the at-risk parent is not altered, only the risk of the fetus. The DNA from the fetus is tested for the presence of grandparental DNA. The chance of error in the test is about 2%, the rate of recombination between the marker and the unknown gene (Wexler 1990).
There are many new problems regarding the use of such genetic information, as to who owns the information, and if donors of genetic material can control the use of the information in testing of other relations. It can be argued that the test will improve the quality of life of the people who are negative. It is still in the future when the people who are positive can be treated satisfactorily, but it should come after the gene is studied. Prenatal screening can be used as well as predictive screening for adults. Generally, predictive tests are not considered ethical for children, before they can give their consent and can be considered able to deal with the knowledge. There are also arguments that if the children do know, they can make appropriate career choices if they so wish to.
Some genetic screening tests have been tried on large scale, such as those implemented by the 1972 US National Sickle Cell Anemia Control Act. This provided for research, screening, counseling and education concerning this disease. About one in twelve American Negros carries the allele for sickle cell anemia. There were problems in implementing such a program, as it was seen by some as racist and aimed at slowing down the Negro birth rate. Fortunately the disease can now be treated, so that there are two medical options, one is abortion, the other clinical treatment. Sickle cell diseases (anemia, sickle cell-haemoglobin C and sickle cell-B-thalassemia) affect about 1 in 400 American black newborns. Together with the other haemoglobin disorders they are one of the most common genetic disorders. This situation has recently improved, so that early screening can significantly reduce the rates of morbidity and mortality for the affected individuals, as they are put under better clinical care. They can be given vaccines such as pnemococcal vaccine to reduce the chance of their dying from infection, a common side-effect of these disorders. It is recommended by medical associations to have universal screening of all newborns for hemoglobin disorders, at present using protein analysis, and in the near future using DNA analysis. If a fetus or newborn is found, then the mother will be approached first, to consider whether the family should have screening. Education on screening programs is given in schools, and in the mass media, and will need to expand to give a clearer understanding of the purpose of screening.
Also in USA there have been major screening efforts for other groups at risk, such as Mediterreans for thalassemia, and Ashkenazic Jews for Tay-Sach's disease. Tay-Sach's disease is a rare genetic disease which affects the brain, causing a painful death by 3-4 years age. One in thirty Ashkenazi Jews carry the allele, a ten times higher level than in the general population. When both parents are carriers, the risk of their children being afflicted is one in four. Since it as prevalent in the Jewish community, there have been various screening programs used with the cooperation of the Community. The preference is to screen people before marriage, as the Jewish view is that it is better to prevent marriage than to use prenatal screening and abortion. Premarital testing is more widely accepted than selective abortion. This is slowly being accepted (Merz 1987), and the results can be kept secret to avoid labelling of people and families. Screening has had a major result, as the annual number of new cases in the USA has decreased from 50 to about 10 or 12 annually, though it is not so feasible currently in the United Kingdom due to the low number of Jews, the births are found at a lower level in the general population. There have been major psychological problems with these screening programs, as carriers often are treated, and feel as if they are outcasts. Their have also been real benefits of reducing parental anxiety, and of the adults if they are screened and found not to have the disease. Many can get real peace of mind after years of concern.
One of the most successful prenatal screening programmes of a high risk population has been the diagnosis of beta-thalassemia in Sardinia, Italy. The 15 year program has been based on carrier and prenatal screening. The incidence of homozygous state is 1 in 250 live births in Sardinia, with a carrier rate of 1 in 8, meaning that about 1 couple in 60 are both carriers, at risk of having a homozygous child. Thalassemia major leads to death by the age of ten. The carrier screening program has detected 30,500 carriers and 1,544 at risk couples, by mid-1990 (Cao 1990). Another 812 couples are known to be at risk because of an affected child, together 87% of the at risk couples in Sardinia know their status. About 90% of possible cases are now prevented by the use of prenatal diagnosis and selective abortion. The population of Sardinia are mainly Catholic, but less than 1% of the couples who were found to have an affected fetus decided not to have an abortion. The reasons for the residual cases of thalassemia were analysed, and it was found that 67% were because of parents ignorance of thalassemia, 13% were for mispaternity, and 20% were for reasons of rejecting abortion. This is very effective screening, and shows the usefulness of an effective carrier screening, prenatal screening, and counseling service in controlling an untreatable genetic disorder. The screening test used CVS followed by DNA amplification and hybridisation, to provide an answer within 24 hours.
Another successful screening program for thalassemia was performed in Cyprus. It was performed with the cooperation of the local church, so that all couples who were getting married were asked to provide certificates showing the alleles that they had. If they were both carriers of thalassemia than they would know that they could use prenatal diagnosis. This represents a good cooperation between geneticists and the church, who were effective agents for the procedure, to reduce the suffering that would otherwise be caused. A similar interaction is being seen with Muslim communities in Britain or the USSR, now that first trimester prenatal screening is available.
In mid-1989 the gene responsible for cystic fibrosis was cloned (Riordan et al. 1989). This allows widespread screening for the known mutation. About 70% of mutations correspond to a specific deletion of three base pairs at amino acid position 508 of the protein (Kerem et al. 1989, Lemna et al. 1990). A simple PCR-based test that allows direct visualization of the result on a stained gel has been described (Ballabio et al. 1990). The American Society of Human Genetics recommended that general screening of the population should wait until other major mutations are identified, and also until there is a better idea of the education and counseling that could be given to cystic fibrosis carriers. There are already commercially operated tests available in the USA, at a cost of about US$ 170 per person (mass screening would be much cheaper). While there is pressure to use new information immediately, there is a general need for a full range of prescreening and followup services to be available for the population to be screened, before a systematic program is introduced. It is also being contemplated in other developed countries, due to it being the most common genetic disorder (affecting about 1 in 1600 live births of Caucasians). The proportional of mutations that correspond to the major mutation is lower in Ashkenazic and Latin families than in Caucasians.
A year after the cystic fibrosis gene and the principle mutation was found the other mutations have proved difficult to find. Another 40 mutations have been described, but these are only found in either one or up to 30 individual cases, so as a total they only account for a few percent of the total. Those mutations often appear only in family groups. Although they contribute to our understanding of the disease, which is still poorly understood, the added complexity delays hopes of a widespread screening service. Individual families may have particular mutations, and services can be offered to them, but there is pressure to commence general population screening. The major mutation is present in 75% of carriers, which means that 50% of the cystic fibrosis suffering babies (they have the two recessive alleles) could be prenatally detected by a full genetic counseling service. This is still a very high number, but there are reservations about using the screening until it can detect 90% or more of the cases. Among people in Denmark, this mutation comprises 90% of the mutations, but among Ashkenazic Jews and Arabs only 30% of the mutations. However, it may take several years to characterise these other mutations, and should those people at risk wait? As long as there is good counseling and education, the major mutation test should be used as soon as possible to aid the considerable number of couples who will conceive affected fetuses. For example, if one member of a couple is found to carry the major mutation, their spouse could undergo a more detailed genetic testing with the range of probes to other cystic fibrosis gene mutations, as it is not worthwhile to screen the general public for mutations of very low occurrence. Genetic services for those couples who know they are at risk are available in developed countries, so the gene discovery has already been useful in a clinical way, beyond the ability to understand more of the disease and develop better therapies.
An important question is whether it is ethical to use abortion for treatable conditions. An example of this is PKU, which when detected as a newborn, can be treated by dietary measures, with little ill effects, though there is suggestions that there is a higher probability of women with PKU giving birth to retarded children. The people still require special care. A survey has found that most families that have a PKU child would not use prenatal screening on the next fetus, but attitudes may change. If screening is provided it should be funded by medical schemes or insurance so that all could have access. It depends on the age at which it is done. Another complication is that severity of different diseases varies. Some can be treated, such as the continual removal of cancerous tumours caused by neurofibromatosis. On the other side of the line might be short-sightedness that can be corrected with eyeglasses, as that poses very few problems in most societies. Similarly, we may be able to screen for the presence of a normal growth hormone gene, but since adequate therapy is available, it would be unethical to perform prenatal diagnosis for this type of dwarfism. Other diseases, such as albinism, are undesirable, but many people, including Noah (Taylor 1987) suffered from it, and lived otherwise normal lives. The outlooks for an albino are different depending on whether the patient lives in a temperate or tropical climate. If therapy can be begun during fetal life, genetic screening to detect fetuses to be treated is certainly justified.
People tend to be more worried about genetic screening tests for people with mental diseases. An interesting, and sad, story of this type of screening was the case of men who have an extra Y chromosome, called the XYY syndrome. They were imprisoned for long periods if they had this (Beckwith & King 1974), as they were falsely thought to be violent. This screening lead to unfair labelling of people, such as the very weak connection with criminality thought to be associated with the XYY condition. This idea of geneticophobia has been a reason for social discrimination. Many still advocate continued genetic study to see the influence of genes on behaviour, it has important purposes but should be free of any harmful labelling.
There have been different conditions used in the past for judging the sufferers of psychiatric diseases and they have been abused for political purposes. The problem is that they are often very multifactorial, having a large environmental input. The screening can label some people as unstable, and if the appropriate counseling is not given, then the screening has a negative effect. There are genetic links to several psychiatric disorders, and one would expect many more to be found, as very little research has been done. Psychiatric disorders only receive 6% of the medical research budget in Britain, typical of international medical research priorities. There are genes which appear to lower the environmental threshold to maniac depression, and schizophrenia, and these are being searched for. The actual genes should be sequenced in the coming years, though there may be several. There are several types of cases that come for screening for psychiatric disorders. In some cases people who want to adopt a child come if the child's parents have a psychiatric disorder to see what the chances of the child developing the disorder are. There are also relatives of patient's coming to ask how likely it is that they will develop the disorder, as well as parental screening.
Another dilemma is posed by the finding that there is a strong association between an allele of the gene for dopamine D2 receptor and alcoholism. This discovery must be stressed to be putative, but it illustrates the type of dilemma that our great expansion in genetic knowledge will provide us with. There has been two decades of research which has shown that part of the vulnerability to becoming alcoholic after exposure to alcohol is inherited (Gordis et al. 1990). This has been found by studies of twins, and adopted children, and animal research. In the recent genetic study, 70 brain samples from dead alcoholics and nonalcoholics were used. One allele of the dopamine D2 receptor gene was found in 77% of the alcoholics, but was absent in 72% of the nonalcoholics (Blum et al. 1990). The 70% figure is very high, and was surprising. There is current research being conducted to closely investigate this finding, and other tissue samples can be used since the genotype is the same throughout the body. We must be careful to classify alcoholics in a meaningful way for this sort of study. Understanding how genes and environment interact to lead to alcoholism is a broader challenge. There may be several genes involved, unlike single cell disorders, and several different types of alcoholism may involve different genes. Alcoholism is a common serious disease and may not always be caused by genetic factors. However, many people may be at high risk for it, so we must consider whether we should screen for such alleles if there is some therapy available, or to know who to offer alcoholism prevention schemes to?
There continue to be more diseases that genetic links are found in, such as coronary heart disease (Price et al. 1989), and diseases that markers are found for. Recently a DNA test for type 1 Diabetes was described, where a single substitution in an amino acid of a type of human leukocyte antigen protein is found to increase the chances of developing this type of diabetes by 100-fold (Tcucco et al. 1989). For many diseases there will be many different DNA probes available. Screening for some diseases where the genes are very large will require multiple probes, such as for muscular dystrophy. However, while the gene extends for over two million base pairs, it is possible to test nine mutation hotspot regions simultaneously, to identify deletions and duplications in about 80% of cases (Caskey & McKusick 1990). This illustrates the power of modern technology and how the number of diseases amenable to DNA diagnosis will rapidly expand. In July 1990, the gene for another genetic disease, neurofibromatosis was isolated (Wallace et al. 1990). Neurofibromatosis type 1 is an autosomal dominant disorder affecting 1 in 3500 individuals of most races. It is currently incurable, and varies in severity. The normal gene restrains cell growth in the brain. New mutations have been found to be frequent like Duschenne muscular dystrophy. The gene mutates about one hundred times more frequently than some other genes responsible for genetic diseases. It appears to also cover a large region of the genome, the message is 11 kilobases long, but for the first 4 kilobases found, the exons are distributed over 110 kilobases of genomic DNA, so it likely it is also a very large gene (Cawthon et al. 1990). The gene has been found to contain other genes within it, a new phenomenon. With these types of frequently mutating genes we can envisage an enormous array of results from each sample, even more if it is screened for a variety of diseases.
The types of criteria that are important for parents to consider when reaching a decision include the severity of the disorder and its effect on future life (including life expectancy); the physical, emotional and economic impact on the family; availability of medical management and special facilities to care for the child to be; the reliability of diagnosis and prognosis; effect on society, and the value placed on the human embryo. These decisions will become complex, as the variety of different genetic diseases of varying severities are detectable.
Prenatal Diagnosis Without Abortion
For people who consider abortion always to be unethical, there are still good reasons to use prenatal diagnosis. The procedure may be of significant benefit to both mother and child. Most results will show that the fetus is normal, and so the principle benefit of the test will be to alleviate worry regarding the fetus. This worry can be a significant psychological burden to some mothers and families. The decision regarding abortion should not be considered until after the test results (Clark & DeVore 1989).
If there is found to be an abnormal level of maternal serum AFP, it is usually not due to a neural tube defect, but because of other causes and it can alert the physician to other pregnancy complications. The detection of abnormalities by other tests can significantly alter the care of affected fetuses, and allow them to be born in hospitals where appropriate neonatal care immediately available can positively influence longterm survival and health.
In some circumstances it is better to know that the fetus has a serious genetic abnormality so that should the fetus require very intensive care and put the mother at some risk, then the parents who reject abortion may still consider it best to let the fetus die, to be content with letting nature take its course. If a fetus has a serious abnormality it may still be better to be aware of this before the child is born. The parents can chose to raise the child, and advance knowledge allows them to prepare educationally, emotionally, physically and financially for the caring of the child. There is very little risk attached to prenatal screening and in view of the advantages to the parents and child to be, it should be widely used where available. While we would never see selective abortion as compulsory or as official government policy in a democratic country, when the benefits of prenatal screening are even greater there will be a case for making it standard policy, though because it involves the mother's body, her consent should usually be required.
There can be more direct fetal interventions. The earliest type was the use of blood transfusions to the fetus to treat Rhesus factor incompatibility, which has been done since the 1960's. Medication can be passed to the fetus indirectly in the mother's bloodstream (for example, biotin). Blood transfusions to the mother to save the life of the fetus have been court-ordered in the USA in some cases where the mother was a Jehovah's witness and rejects the principle of blood transfusion. In the U.K. the law protects the pregnant woman's autonomy. In this case, the courts have overruled the mother's wishes, considering the fetus. It is a difficult area of conflict between mother's autonomy and duties owed to the fetus, and will continue to pose ethical problems. More invasive techniques, such as when direct fetal surgery is possible, using ultrasound and fetoscopy are becoming possible. The surgery can also be performed outside of the mothers' body than the fetus replaced.
Even if the decisions remain voluntary, society can influence the decisions that we make. It could say that it would not provide health care for some "avoidable" diseases, as that is inconsistent with public fairness to health resources, as it may be. Society can publicise the genetic screening much more, or offer incentives. There is a fundamental question of how far to develop alternative therapies, which are often expensive, versus genetic screening. However, some of the conditions that arise in accidents are similar so if the technology overlaps that could be used. There is equal ethical claim to treatment from children whose parents do not use genetic screening, but limits might be placed. When we think of some individual cases where several million dollars have been spent, and the large number of lives that this money could save in the third world especially, we must question priorities. People may talk of protecting a single parent's autonomy while forgetting that 40,000 people die everyday because of malnutrition, and more from preventable diseases that developing countries cannot prevent or treat. There may be less research spent on some serious screenable diseases because they are seen as preventable, but in most cases the same research that discovers the genes that allow screening, also opens the door for research into therapy. Research into rare genetic diseases provides much important basic biological knowledge which can be applied to other problems, so will continue to be seen as important in biomedical research.
However, it would seem to be unethical for the state to refuse to contribute to the care of children who suffer from genetic disease because their parents refused to use genetic screening, as it is unjust to blame the children for their parents actions. It is unlikely that democratic societies would impose selective abortion. In cases of therapy after prenatal screening it is possible, but abortion itself remains controversial. There are economic reasons to favour it, but it still should remain voluntary. There will be more problems when the time arrives when insurance companies include as a criteria for consideration, prenatal screening. If free choice is lost there will be a large cost in human dignity, the main lesson of the enforced eugenic programs as in the United States or Nazi Germany.
The United Nations World Population plan of action declares that "All couples and individuals have a basic right to decide freely and responsibly the number and spacing of their children,". There are several ideas in this statement, and we can find cases where all aspects of it have, and may still be, prevented. Many are conditional and are prevented in some societies. A question must be, which aspects of reproductive freedom can be limited without violating the basic idea of autonomy.
The right to rear children is conditional on the ability of the parents to look after the child, and not to abuse them. The number of children is limited by very strong policy in some countries, such as Mainland China, because of overpopulation. Different societies have used different criteria to control access to infertility treatments. A current problem is the regulation of AID using "germinal choice", which in many places is not controlled. People can have free choice regarding surrogacy, IVF or AID in some countries such as the USA, but not in others such as West Germany where there is control. Should the law control? The right to have genetic offspring has been made conditional in some time periods with compulsory sterilisation, because of fears of transmission of disease or presumed inability to bear a child, or presumed psychological harm. There is the idea of the right to marry anyone, but has been prevented in some countries, by premarital testing, or making a class of unmarriable individuals, and is subject to family restrictions.
Reproductive freedom is based on the need for bodily-self-determination, or integrity. It is not based on any "right to procreate" itself, but the freedom to determine when, whether and under what conditions we can bear children. A second claim for reproductive freedom for women is because it is predominantly women who must bear the major consequences of pregnancy and raising the child. The interests of the child are a valid part of the argument, even though the person may not yet exist.
The major thrust of the eugenics movement today is in fetal screening and selective abortion (Hubbard 1984). The language has moved to fetal "rights" to health and well-being. The selection criteria has moved from the emphasis on behaviour, to emphasis on health being the major concern. This argument is based on the traditional theme that we should not burden society and successive generations with genetic diseases, as discussed last chapter. Joseph Fletcher (1988) discussed various types of child abuse, including those who preconceptively or prenatally abuse children by "knowingly passing on or risking passing on genetic disease". We have seen the emergence of court cases such as wrongful life, where the fetus is meant to have a "right to health" (Robertson 1983). Some lawyers argue for a position that, while a patient can refuse any medical procedure or treatment, a pregnant woman loses this right if she decides to carry the fetus to term. She is no longer judged to be competent, and some court cases have imposed tort liability on women who fail to use prenatal diagnosis. This is seen by many as a dangerous step back along the road to eugenics. The courts have so far refused to appear to condone abortion, saying it is a question for philosophers whether no life at all is better than a disabled life. Some argue that since the fetus is attached to the mother the choices about treatment should only be made with her informed consent (Fletcher 1979). The US government body set up to examine the question of whether screening (President's Commission 1983), stressed the autonomy of individuals meant that only under the special circumstances of people being unable to protect themselves, could screening be compulsory. The other arguments, such as social utility (economics), allocation of resources evenly, and improving society's "genetic health" are not sufficient to make genetic screening be enforced.
Can Society Limit Genetic Freedom?
We can define genetic freedom as the freedom to bring about the conception of a child with any characters, be they good or bad, or desired or undesired. A fundamental principle of bioethics is autonomy, the freedom of individuals to make decisions regarding their own lives. It is based on the idea that human life is of high value. It is not unconditional freedom, as part of the concept of autonomy must be a recognition of other people's autonomy, or values. Freedom is limited by recognition of other's autonomy to pursue to an equal degree of freedom. There are limits in the way that we should affect other people. The idea of limiting genetic freedom also involves how we treat other people, but people who may not yet exist. There are a few examples of how we already accept limits on behaviour of individuals because of the affect on future people. Pregnant women may be prohibited from certain areas of risk in factories. Foods and drugs are carefully screened to avoid any agents which may cause birth defects.
People are given freedom in their lives, but only as long as they do not prevent others from pursuing an equal degree of freedom, the idea of equality stems from autonomy. In society we should try to maximise the consciousness and participation of individuals, but the social framework of conditions and constraints is not one of individual making. The types of limits that are imposed on people for the benefit of others, called society, includes limits on the noise they can make, the places they can visit, the speed they can move at, and where they can build a house. Inside their house can be protected against others, the idea of privacy, but there are still limits, such as the number of people they can marry, and how they can treat members of their family.
Joseph Fletcher (1988) has argued that reproduction that is planned and controlled is more human than playing "genetic roulette". Humans are distinguished from animals because they have the ability to chose traits. He goes as far as claiming that coital reproduction is less human than laboratory reproduction, as it is more rationally developed. He advocates a shift from accidental or random reproduction to rationally willed reproduction.
Genetic freedom has two sides, on one hand can society say that genetic screening must be used and the disease-causing genes subject to control. If there is some therapy available it may be enforced on children, until they are able to decide themselves, or should it be up to the family. Compulsory gGenetic screening is only justified to protect those who can not give their consent, such as for newborn screening for PKU, when there is therapy available. People are given freedom in their lifes, but only as long as they do not prevent others from pursuing an equal degree should have a right to reproductive freedom but does this include genetic freedom? It is the children (who are yet to exist but who can still be considered as individuals) whose genetic freedom should be protected from influence that limits choices, within the framework of a healthy life.
Genetic counseling aimed at the immediate family can be very successful, but on the wider societal level for eugenic goals it may not be. It can have some affect, for instance in 1988 the proportion of Down's syndrome babies born in the United Kingdom was a quarter less than that before screening, due to the widespread use of fetal screening and selective abortion of afflicted fetuses. This screening has no eugenic outcome in the gene pool, as the sufferers of the disease are sterile and can not reproduce, however, it has had an affect on many potential families. It has been routine to use amniocentesis screening of pregnant women over 35 years old, as they have a greater chance of chromosome trisomies such as Down's syndrome (trisomy 21, three copies of the chromosome number 21 are present). The risk increases with age. If used on the total population than because of the risks of miscarriage after CVS or amniocentesis, than more fetuses would be lost then detected. The figures in the United States would be approximately 2,000 fetuses miscarried, and 1,000 fetuses detected with Down's syndrome. However, if incorporating screening for multiple disorders from the single sample, then the result would be better. The risk of miscarriage is 1% loss, is negligible compared to the 70-80% loss from conception, as far as numbers go. It depends on the fetal age. There are new methods for maternal blood testing (Wald et al. 1988), as a preliminary screening test which should increase the number of fetuses that can be examined, and will make it possible to offer the technique to younger women.
Compelled medical treatment of pregnant women is generally not ethical. Society may gain more by allowing each pregnant woman to live as seems good to her rather than by compelling certain screening or fetal therapy (Nelson & Milliken 1988). Voluntary measures are better to protect the body, this is different to decisions made directly because of desired characteristics in the fetus. There has been much controversy surrounding enforced caesareans in USA, which are not possible in Britain, and there have been women who have run away from hospitals due to this, placing themselves and the child at greater danger. Many of these cases end up giving birth in the natural way, with good results, which calls into question the necessity of the court order. In a April 1990 Washington D.C. Appeal Court decision, the court upheld by 7 votes to 1, that a pregnant woman may not be forced to undergo a caesarean section to save her fetus (Brahams 1990). This may help prevent the practise in the USA of overriding the mother's interests. In the USA there is a very high number of caesarians performed (Evans 1988).
The greater use of prenatal genetic screening will highlight this problem. There are two types of case, one is when there is some therapy for the affliction that should be begun before birth. Then there are some grounds for enforcing some types of treatment, such as blood transfusions. There have been women put in prison to prevent them taking drugs during pregnancy. There is much legal debate in the USA. The other is when there is no therapy, and the prefered course by the family medical insurance company is for selective abortion. This is a key issue, and one which will be discussed later, but currently courts are unwilling to condone abortion and it will not occur in societies that recognise the autonomy of mothers or some right to life of a fetus. If there is no therapy then society cannot ethically enforce abortion, but it can control the application of medical resources in a national health service.
We must accept that human beings are conceived in a very risky way, with a greater chance of genetic disease than any other species. We also all need to accept that we all die, and will suffer. The question whether a human life involving genetic suffering is one which is not worth living will remain an unanswerable decision, and so must be left up to individual cases. We can seek therapy, and there is an obligation to seek therapy, but there is no obligation to kill other creatures if they suffer, only sometimes, to let them die. We need to let autonomy dominate in order to avoid any future societal abuse, this has also been called in the US the "Right to privacy", a right to be left alone regarding decisions to bear a child. However, there are many external pressures that will push couples to use genetic screening and selective abortion. These include the willingness of society to care for the sick, which is often lacking. People may shun those who did not abort a child who suffers from genetic disease. The underlying values of society need to be changed to avoid problems, and while we should strive for this goal, we have to be pessimistic. The laws in some countries, such as Sweden and the USA, to protect handicapped people from employment discrimination are useful, but fully nationally funded health and education systems are the minimum ethical duties that societies must use to change the situation.
On the otherhand can society allow individuals to have free choice over the use of genetic manipulation when there is no medical reason for it? Such as nonmedical sex selection, which may have some cultural reason but a reason that is based on inequality, or something such as hair colour which is just a passing whim of the parents.
There are various possible techniques for sex selection (Bennett 1983, President's Commission 1983, Warren 1985), though this has been officially limited to use for parents who are carriers of a sex-linked genetic disease. This type of disease prevention is different to the general question, and includes diseases such as haemophilia and muscular dystrophy when carried by the woman, will affect only male offspring. Sex selection is a precedent for genetic screening for characters that have nothing to do with disease so it is interesting to ask what attitudes genetic counselors and the public have to it.
There are preconception methods, arising from the study of sperm formation and the factors that influence it. There are various manipulations of the movement of the sperm within the vaginal tract, such as the presence of antibodies in the vaginal tract, and the slightly different motilities of sperm containing the X or Y chromosomes, and artificial insemination with specially treated semen. Y-chromosome carrying sperm are 3% lighter than X-bearing sperm. Methods that have been used to separate sperm, including separation by mass, electric charge or staining are not very successful. There has been a method using differential binding to a protein solution, which can increase the chance of having a male to 75%. A company called Gametrics claims that after 600 births using their treated sperm, 75% were male (Ericsson 1988). There are also dietary methods that have been suggested. The methods do not seem to present any harm to the offspring as a result of the technique. There is much research in these techniques as they have many uses in agriculture, where a female calf can be worth ten times more than a male. The primary postconception method is fetal screening and selective abortion. It is possible to sex a single cell using embryo biopsy or preimplantation diagnosis, which may have more immediate use in agriculture. There have also been methods developed to identify male and female embryos by specific sex-linked antibodies. In the near future it will be possible to use maternal blood sampling for sex determination. While sex selection has less problems if done before conception, there are still major objections.
In many countries of the world, feminicide is practised. It is a dangerous precedent to allow sex selection to be part of reproductive choice. The current technology allows routine screening at 9-11 weeks by ultrasound, or the earlier use of the more invasive technique of CVS. Fetal chromosome analysis through maternal blood sampling may be available, as well as preconception methods. The attitudes of doctors to allowing sex selective abortions varies between different countries. In certain cases the physicians in countries such as the USA would comply with requests for prenatal sex selection. In a case where a couple with four healthy daughters wants a son, and will abort the fetus if it is female or if there is no diagnosis, many would comply with this request. In a 1985 survey, the percentage of genetic counselors that would comply in various countries were, USA 62%, Hungary 60%, Canada 47%, Sweden 38%, Israel 33%, Brazil 30%, Greece 29%, United Kingdom 24%. Most argued that they would do it out of respect for the patient's autonomy and rights of choice, only in Hungary did they add the threat of abortion as being significant (Wertz & Fletcher 1989a). The trend over time is to be more tolerant of sex selection, perhaps extending the other trends of control over pregnancy and birth of children.
Arguments against sex selection include the fact that being a particular sex is not a disease, if it was used it could lead to social inequality between the sexes, it is not a sufficient reason for abortion, and it is a waste of resources as there are many genuine cases to deal with. The two major arguments for sex selection are that it is individual liberty, and that it may reduce population growth in countries where people try to have a male and will continue to have children until they do. When having smaller families there is greater pressure for sex selection, but it should still be resisted. Warren (1985) examined the claims that sex selection would enhance the quality of life of child and family, however there is no evidence and probably more against it. It could lead to marital conflict if the parents have different ideas. In the end, sex selection is inherently sexist and it believes that different sexes are unequal. Even if prenatal diagnosis became common for all, it will still be objectionable as it undermines the major moral reason that justifies prenatal diagnosis and selective abortion - the prevention of serious genetic disease (Wertz & Fletcher 1989b).
Sex is one character that is not a disease, as are others such as height, eye and hair colour, and skin colour. Many parents include some of these characters when they think of their ideal child also. Sex selection would set a precedent for the near future, as the number of testable characters increases. It is important to take a stand now against this growing trend. It may be better to avoid making many reproductive laws, but it may still be necessary if genetic counseling and information can not control the abuse of selective abortion. A simple method is to withhold the information of fetal sex,which is already done in some clinics. It is a case where directive counseling is required, and possibly legal control.
Genetic Selection for Nondisease Should be Illegal
In the current situation we could use the argument that genetic screening should not be performed for nondisease conditions as there is a shortage of resources already (Fletcher 1988a). In some countries, money can buy anything, including many unnecessary medical resources, we can also say that this is wrong in a world, or even country, where many people do not get adequate medical resources. This is something that should be applicable to all of medicine, and both cases are wrong, despite what capitalism likes to say. We should direct scientific efforts towards treatment and prevention of serious diseases away from trivial pursuits. It will be useful if genetic counselors do refuse to offer their services for this reason, but it still begs the underlying question. If resources were available would it be ethical?
We can make the situation easier if we consider there is no risk involved in the process, no abortion required, but preconception control? There is still a dilemma to be faced. These three arguments will eventually not be significant, and they are not applicable for some existing methods.
One view is that there is no difference between altering genes, and the variability in the environment that parents can subject children to. However, we can argue that the danger in this is that this would limit something we could call the natural autonomy of the new individuals. This would introduce the concept of a "natural genetic autonomy", the freedom to let the genes come together naturally and to let that individual develop their genetic potential without unnecessary interference by parents or society. While we may give freedom to nurture children in various ways, there are imposed limits.
It has been argued by some that present nonexistence of future persons entails that obligations we have towards them are not based on rights. However, the present non-existence of future persons is not an impediment to the attribution of rights to them (Elliot 1989).
Parental concern with chosing characters of children is incompatible with the attitude of unconditional acceptance that is found to be essential to good parenting. The more a child's genome is subject to manipulation, and is a result of the choices of others, the more we can consider children to be a social product, no longer unique persons. Society needs to promote good attitudes to children and the family.
The family is the natural and fundamental unit of society and is entitled to protection. It is a fundamental human right. In the USA there is a very strong "rights" movement, and the value orientation of most gives preeminence to the right to procreate (Blank 1984). The new technology may lead to a move away from this. There is increasing consideration given to fetal rights and the rights of the child. This is reflected in the recent decisions of the US Supreme Court, in the Webster case which limits access to abortion, and other related decisions. We may need to promote "family rights", to protect the interests of the family.
The basic justifications that are used to limit reproductive choice are paternalism, the public health, and economics. Paternalism is the protection of others against the effects of their own "wrong" decisions but that should not enforce behaviour in people able to make a balanced decision. We should be responsible in our own behaviour, but we can not enforce others to follow our own values. The exceptions will be those who are mentally incompetent. The public health and economic arguments are much less justifiable reasons, especially in the world where so much government money is spend on military spending. Society has little moral weight to enforce behaviour change on others, until they have eliminated many factors which damage health and misuse money. There can be no moral superiority to a society which spends on the military but refuses to spend on the sick or poor.
There is another argument that if we let society or parents chose characters in their children then it will have a harmful affect on social attitudes to people who fail to meet those characteristics. A problem with the increasing availability of genetic screening is that while it can help people have children free of known genetic defects, it makes life more difficult for many parents and their children who suffer from the disease, who did not use screening. It may increasingly be seen as not an act of fate but the parents' fault (Hubbard 1986). Modern society is moving towards viewing reproduction as a commodity, producing a luxury item, a newborn child free of defect. It may make people less tolerant of the variety of human beings. In the case of sex selection it represents prejudicial attitudes which are inappropriate in a world where we are trying to get rid of such prejudice.
Opponents of social control of genetic screening argue that if we promote selective abortion against sufferers of a particular genetic disease, our attitude to handicapped people will change. These ideas can be philosophically separated, but in some people's minds they are connected. The social affects of a technique are often far-reaching, and so we should be cautious regarding ideas which could lead to eugenic discrimination. We should remember the concept of charity, or agape, which they introduced to Western medicine in the third century from Christianity, and which has been with us since. We can never eradicate genetic disease, as there are always mutations occuring. The aim of research into genetics is not primarily to eradicate them but for therapy. Some countries have taken steps towards the compulsory genetic screening of individuals before they can marry. We can learn some lessons also from the screening processes that are being used on AIDS sufferers, the discrimination that they face, and the growing recognition of the protection from discrimination that they need. One USA state, Illinois, had a policy for mandatory pPremarital testing for HIV virus, and couples wishing to be married had to submit to this test, or else get married in a neighbouring state. The idea is that the spouse should know if the partner has HIV, and the public health motivation was to slow the spread of HIV. However, it is ethically unacceptable to enforce such screening. A more practical problem was found with this testing program, the cost. The cost was worked out to be US$320,000 per individual identified with HIV, which would possibly avoid a similar number of individuals becoming HIV positive. This is very cost inefficient. In New York city, such a program was rejected prior to use for this ineffective use of resources. Such mandatory screening programs are ineffective ways to combat disease, and we need to remember this example when considering genetic disease screening. An older example was mandatory premarital screening for syphilis. In 1958, a comparison of 9 states without a compulsory law, and 30 states with a compulsory law for premarital syphilis testing, showed that the decrease in syphilis was the same in both states. Actually 21 states still have such laws, they are difficult to remove from the statutes once there (Silverman 1990). Nevertheless, we do have some genetic responsibility to our offspring if the techniques are available. If we have the option of screening a fetus before it is a person, or ourselves before marriage and procreation, than we should value the technology, and use it wisely. It has the potential to be used to enrich lives if not abused, but it should be voluntary. Education about diseases and risks is the most important goal.
There is the argument of reducing genetic variability, but it is doubtful as to whether this sort of selection would really have much affect biologically. The major affect is on reduced social variability. If we want to maintain or should we say develop a society where people's autonomy is respected then we should not allow the acceptance of genetic restrictions on nondisease characteristics. This means that society could for the benefit of society, and protecting its members from developing narrow views whether they be sexist or intelligence seeking, restrict the freedom of individuals to use techniques to affect the children. We already limit the environmental freedom of parents, we also need to limit their genetic freedom to chose.
The President's Commission (1983) and others have recommended that public policy should discourage sex selection but that it should not be a legal prohibition. One of the major reasons given was that it would be impractical. However, a legal prohibition may be quite possible, by withholding information on the sex of the fetus during genetic counseling. Wertz and Fletcher (1989a) argue against a legal prohibition, unless attitudes in a particular country make it the only means to prevent it. There is a desire not to create many laws connected with reproductive decisions, which is fine, as long as it works in practise. A similar principle will be needed for other nondisease characters. At least national and international medical organisations should make strong stands that their members should follow.
Society has some role in reproductive control. This represents a tension between the individual and society, however it is consistent with justice, fairness, autonomy of future generations. There is a tension between human liberty and responsibility of individuals (Dunstan 1988). It is not based on a fear of changing the genes themselves, but can be argued in view of the protection of society's social behaviour. We should direct science and medicine towards the treatment and prevention of disease, and sex selection or AID for germinal choice are two current techniques which set a dangerous precedent for future tinkering, and move away from the goals of our society. We need to decide the goals of society and adjust technology to them. As a social morality grows out of the tension between personal and social interests, we need to take account of the broader social consequences of clinical decisions made primarily in the interests of individual patients. There are more important arguments based on the effects of individuals upon society. Physicians or genetic counselors are not merely technicians to aid the pursuit of their patient's desires, they need to be constrained within social policy, responsible ethically and clinically for the procedure's outcome.
We must apply caution in the use of genetic screening. As we saw in the last chapter, over enthusiasm with genetics led to widespread acceptance of eugenics. This euphoria was not even supported by much real science. The social influences that the future programs will have is very large. We may need to advance our social attitudes before introducing such systems.
There will be many medical advantages from the increased ability for genetic screening. Many individuals will be identified that carry genetic disease, and appropriate therapy given to them or their progeny. There will be a dramatic increase in the amount of patient genetic data that can be collected. The number of human genes that are sequenced is exponentially increasing, in 1982 only 22 were known, by 1984 there were 132, by 1989 we have over 5,000 human gene sequences. The total human genome sequence might be available within a decade. This raises many questions regarding the rights of individual privacy, regarding what information others can have access to. This will be a key issue for the future as so many diseases, or genes, will be able to be screened for. The type of information that can be screened for covers blood type, tissue type, to predisposition to diseases, or the certainty of knowing that a late acting disease will come. They may reveal important hints on a person's physical or intellectual potential.
The data can play an important role in the life of the individual, affecting the choice of spouse, psychological health, reproductive decisions such as whether to have children, and whether to use prenatal screening and selective abortion or therapy. There will have to be decisions regarding personal health risks which may be affected by diet, smoking, etc., and the type of work. There may also need to be decisions regarding insurance schemes, and retirement. The genetic information can be of great benefit to the individual person to know about their genetic constitution. However, there can be great risk involved if other people obtain it (Zimmerli 1990). While screening for susceptability to lung disease if exposed to asbestos might be an advantage if an alternative job in the company can be found, it has already been used to prevent people from working in some factories (Nelkin & Tancred 1989, Holtzman 1989).
There are two different technologies for genetic testing. Genetic screening can be used to identify people who are susceptible to certain illnesses. Genetic monitoring is different, it is aimed at understanding the significance of genetic mutations that occur in groups of people as a result of exposure to chemicals (Murray 1985). Gene monitoring is targeted at a group, to determine whether a carcinogen is present in the workplace.
Genetic screening targeted at individuals can be used as an effective exclusionary tool (Rowin 1988). It may become an excuse for companies not to hire susceptible workers, or women of child-bearing age, instead of cleaning up the factory. It is a major problem ethically to decide if insurance companies are entitled to genetically screen potential clients. Some employers screen for sensitivity to some pollutants present in the factory, such as genetic predisposition to cancer if there are carcinogens present. What is ironic is that genetic screening may exclude some workers, who will be more suited to other aspects of the work. Some workers will be hired whose genetic weaknesses have yet to be determined. This screening is regardless of the more important occupational suitability for each job (Weiss 1989). This also interferes with rights of people to chose (Harsanyi & Hutton 1982). On the otherhand, if a person suffers from hemophilia it would be wrong not to warn them of the risks of becoming a butcher (Motulsky 1989). Employers also offer insurance schemes, which in some countries are the best systems for health care available. The U.S. law states that companies can not discharge an employee for the purposes of reducing their benefit costs. In July 1990 a new law was passed to outlaw employers from discriminating on the basis of handicap. This is of major importance, and some lawyers believe it extends to genetic disease. Before this employers could refuse to hire on the basis of medical and genetic findings, unless they were in a state that had specific laws. In New Jersey there is a specific prohibition on discrimination based on an individual's atypical cellular or blood trait (Rowan 1989). If an employer is receiving Federal financial assistance, that employer may not make preemployment inquiry about whether the applicant is handicapped, unless all candidates are required to have such a medical examination. This means that a general genetic screening could be performed, unless new laws prevent it, as in the case of New Jersey. In Britain, the law does not protect against genetic discrimination, and if a person lies about the results of a genetic test they can be dismissed from their employment. International law is required, as well as a change in society.
There are diseases such as Huntington's chorea which will mean people have to retire early, and will require payment of insurance or pensions, so companies, and even governments, have required information from people. If they carry the gene they can not get the job, or maybe cannot be insured. They may not be able to get a morgage if they have increased risk to psychiatric diseases. There will have to be guidelines on the availability of such information. It is not the same as AIDS, which itself is not normally contagious, as these diseases have no public health risk. In the cases were a disease is noncommunicable, the only other people at risk are the progeny.
Closely related individuals may share the disorder, so if one is tested the others will get a hint. There are important ethical and legal questions concerning the relatives of test subjects. There are issues of confidentiality. Respect for confidentiality is one of the key principles in the development of genetic screening programs. Genetic diagnostic information must be held strictly confidential. The only exception is when another family member needs to know the information because of a direct medical risk that would be averted if the information is known. If a person is found to be positive, will relatives be warned of their risk? Is there a right to know, and a right not to know? If genetic registrars are established, should relatives be involved in deciding whether one member of the families' data can be recorded, as the information could be used to affect other family members as well as that individual?
It may be very difficult to protect individual that do not want to know from learning of "bad" news from their relative's test results. However it may be done, it is one thing to maintain privacy, and another to aways tell the truth. A similar dilemma often arises in the case of nonpaternity, the genetic father is not the husband of the woman. A very limited amount of paternalism, in the sense of considering the adverse consequences of revealing the information, may be justified. With presymptomatic screening, the problem is avoided if psychological screening is completed before any genetic information is obtained, but it is not aways possible. Huntington's chorea, colonic polyposis and polycystic kidney disease may not be expressed until middle or old age, the information can predict the future health of the person. There are many emotional problems, as with AIDS screening, for those people. In studies and counseling of patients that have had predictive testing for Huntington's chorea, among the people given a positive answer, about 20% of them did not accept the conclusion and believed that they would not get the disease. If the counseling is good, and patients are screened psychologically before testing, than there is little evidence to support the idea that they will commit suicide. However, if people are not considered able to take the bad news, than they should not be tested. Of course some people will be negative too, which may relieve much anxiety from their lives, allowing them to marry and have children which in some cases they would not of done before the testing.
If people are going to benefit from the information provided by genetic screening there must be no stigma attached to carry a potential disease causing allele. The people may be branded if they carry a disease. Our society tends to brand people into a positive or negative category if they suffer from some affliction. A sign of disability can be very detrimental to future life prospects. New technology will provide the information about disease susceptability, but they can not determine a moral choice. The type of decisions that depend on genetic data involve the most personal decisions concerning people's lives, such as the choice of spouse, reproduction decisions, personal health habits, financial and insurance, and retirement decisions (OTA 1984). Decisions regarding life choices should be left to the individuals concerned, with as much counseling aid as possible. The screening should be accessible to all, to be fair (President's Commission 1983). Rather than this new technology making us more mechanistic, the best approach will need to be much more community support and love for our neighbour than before. In a just society there are no justifications for genetic discrimination, only therapy.
There are many benefits to insurance companies and to the general public economically, from knowledge of people's genetic data. Insurance companies costs can be lowered, to make them more competitive, if using genetic testing. If it is not stopped at this early stage it will lead to much discrimination. In a few cases predictive genetic testing can allow individuals currently unable to get insurance because of family history of disease, to get insurance. If society wants to be just it will have to make a rule that there is no genetic discrimination. To select for smoking habits, or for dietary differences may be fairer, as people can chose to lower the risks associated with bad habits however, it is unfair to discriminate on the basis of what is something over which people have no control, their genes. There may be genetic susceptability to alcoholism, and it is possible even smoking has deeper roots than personal choices. These possibilities pose future ethical dilemmas about treatment, environmental, social therapy and genetic therapy may all be used. It would have to be a general rule so that all the insurance companies shared the cost. In the early 1970's some U.S. insurance companies charged blacks, who were carriers of sickle cell diseases, higher rates, even though they are at no risk from the disease. There is less discrimination for carriers currently, but still some. There is a list of diseases for which some insurance companies will not insure sufferers for, including sickle cell anemia, Huntington's chorea, insulin-dependent diabetes, muscular dystrophy, and many more (Holtzman 1988). However, these screening tests are not routinely requested, but many insurance companies use tests for HIV infection, and reject the positive applicants. In several states (Florida, Maryland, North Carolina) sickle cell disease allele carriers are protected by laws preventing insurance companies discriminating against them, though this is not for those who suffer from the disease. In a few U.S. states there are so-called high risk pools, which are available to help those people who are uninsurable. State-regulated insurance companies are required to pay into the pool, but it is better to have premiums shared among all, or a national health service (Holtzman 1989). It is certainly more ethical. Group medical insurance, which covers about 85% of US citizens, is offered to particular employment groups and usually does not consider health risks of the individual applicants, so that access to patient genetic data is not necessary. However, the agreement signed when entering some group schemes may allow unrestricted access to their health records, which could be used (OTA 1984).
The procedures that are used by insurance companies and employers are generally a questionnaire, and physical examination. The physical examination may include blood and urine analysis. The doctors may test for the presence of different drugs, both drugs such as nicotine and cocaine, and prescription drugs taken for different medical conditions. In the USA more than half those seeking employment must undergo a physical examination, and it is especially common in larger companies. Employers in the USA have a federal law which protects the handicapped from employment discrimination. It is also general practise not to screen for HIV infection by employers. As the costs of AIDS treatment rises, it is likely that more companies will screen for it, unless a law prevents them from this. It is unlikely that the employers will offer general genetic screening tests in the immediate future, only in specific industries. If an easy genetic test becomes available it may be tempting to use it, so laws to prevent discrimination should be enacted to prevent this. It is also important to ensure that any testing which is done, is accurate with very low probability of false positive tests.
In certain cases there may be a duty to know genetic information if a third party might be harmed. If children are born, then this could save them from a disease. For some diseases, certain types of employment should be avoided. For instance when people start to suffer from Huntington's chorea they can have losses of concentration for a few seconds or longer. If they are an air traffic controller, or pilot, or quality control worker in a factory, then this could have serious consequences for others. Should screening be compulsory for sensitive areas, possibly? However, there needs to be information protection. The issue is whether "pre-clinical diagnosis" should be used, as the worker may still have twenty years normal work with no clinical condition. There will also be potential spouses, which are also third parties that should know. However, numerous studies of the ethical principles to follow when genetic screening recommend that mandatory genetic screening programs are only justified when voluntary testing proves inadequate to prevent serious harm to the defenseless, such as children, that could be avoided were screening performed (President's Commission 1983).
An important parallel is being seen with compulsory drug testing of federal employees in the USA. Workers from groups such as fire fighters, police officers, school bus aides, and computer programmers have been subjected to mandatory drug testing. In the U.S. Constitution, the fourth amendment forbids unreasonable searches of individuals. It is agreed that a blood, urine or breath test constitutes a search. What has been disputed is whether it is reasonable to search people without any suspicion of guilt. The U.S. Supreme Court has supported mandatory searches in the case of railroad workers and Custom's service employees, for utilitarian reasons (Glantz 1989). However, there has been much criticism of these and similar decisions as they infringe individual liberties. The test results were not even available to those who were tested. If it becomes accepted practice, then it is likely to be extended to genetic tests, when it is seen to benefit the public good.
Recently, several private companies, such as bus tour operators, have used a computer based performance test as a measure of the capacity of the employees to concentrate. The test involves keeping a marker on a computer screen in one place as the computer tries to move it around. If the employees cannot do this they will be sent home that day, but no enquiry is made into whether they are emotionally upset, or under the influence of alcohol or drugs. In this way respecting their privacy. The test looks only at the symptoms that affect others. There are related issues to those found with Huntington's chorea, described above, in screening for causes presymtomatically.
Genetic patient data are different from other types of disease-related medical information. In contrast to communicable disease, the public at large is not at risk of contracting genetic disease, only potential children. With contagious diseases the issue of public health may override some of the protections normally given to individuals. Future individuals do have some interest in the data. Closely-related individuals may be directly affected by the knowledge, and vice versa; which may be a benefit, or an unwanted burden. Pre-clinical prediction provides a look at the future health of an individual. The awareness of a disease with no cure can be an unnecessary emotional burden to give to people.
Confidentiality is a long-standing principle of good medical ethics. It is considered essential to maintaining a good doctor-patient relationship. If the patient does not trust the doctor, than they may not reveal delicate health issues to the doctor. Only if a third party is in serious risk may a doctor consider breaching confidentiality. Another argument for the maintenance of confidentiality is from the rights of the patient. For example a sample of the patients' tissue may be collected and used for tests, but this should only be done with their consent. Consent to use tissue for one test does not mean consent for other tests, unless specifically stated, though in practise it consent for all tests is not sought.
Genetic research also involves necessary contributions from the public, in both the donation of samples and the provision of information. If we expect to benefit from medicine it is good for all to contribute if needed, as it may directly benefit us in the future, and we have all benefitted indirectly from medical research during our lives. The issue of who owns patients' data is a current question in the some countries. The U.K. Government has proposed the total computerisation of National Health Service general practice records. This will improve efficiency, but it will also create a vast store of potentially valuable data. The data is being anonymised and sold to private companies in return for computers given to the general practitioners to use. The data can be used in research, for public interest, or for private gain (Brahams 1990). The patients' data is effectively sold to private companies, though confidentiality is not breached as long as it is ensured to be anonymous. In New Zealand similar projects are underway. One example involves the results of about 4,000 patients who have, and are being treated for hypertension, to compare their drug treatments. One drug company wants to test their own drugs' performance in this system. It is legally uncertain whose data it actually is, though if anonymous, it can be argued that given the potential benefits from the information arising from studies of the data, it may be ethically acceptable.
It is one thing to provide data, but another to provide DNA samples. There are different DNA banks that have been created in many genetic clinics. There are guidelines which detail some of the precautions that should be made in these banks. The purpose of DNA banks is to provide for the future requirements of those families that gave the samples. Verbal consent is required from all people donating samples for research use (Yates et al. 1989). One criteria for the release of samples or information is that nonidentifying information could be released given prospects of general benefit, but identifying information should only be given with the consent of the donor (Zimmerli 1990).
There have been some publications that have deliberately changed family pedigrees to prevent relatives finding out information regarding there status, such as whether they have Huntington's disease alleles. While this is good to protect people's right to know, and right not to know, it must be very clearly noted in any paper that this is done. Otherwise, people may not be able to do future research, for some association with sex or age for instance, that may be useful in elucidating the disease. The original data should be stored in some repository so that researchers can apply for it. For example, a Venezelean Huntington's disease family pedigree collected by international researchers involves over 8,000 individuals, which is a very important resource for other genetic researchers, now and in the future in the study of other genes. There is a balance that can be maintained to ensure both privacy, and scientific integrity.
There is also the question of where actual samples of DNA should be held, and if these should be ever used without consent of the donors. It may be impossible if the donor has died, but the children, who share half the genes, must have some claim on the material also. It is a difficult issue, and represents the unique nature of genetic material. It is intergenerational in nature.
Another area where genetic information is increasingly used is in legal cases. The technology used is DNA fingerprinting. Most DNA fingerprinting involves comparing different restriction fragment length polymorphisms (RFLPs). Forensic science has begun to use these to study small samples of blood or semen from criminal cases to match up with suspects. The samples can be amplified by the Polymerase Chain reaction (PCR) so very small samples are needed. There has been recent controversy regarding the random probability of the matching, and the lack of scientific method used in some cases. The guidelines need to be clarified (Lander 1989). The probability of finding the same sample in the population is often exaggerated as the values are based on random mating, which is not what is found in most population and racial groups (Joyce 1990). People tend to marry within particular groups rather than in the general population.
There are still technical difficulties in analysis, such as correction for band-shifting which arises in 30% of DNA fingerprinting cases. The same bands may be detected in two samples, but the pattern may be displaced in one direction compared to the other because of other compounds in the sample. The contaminants may include bacteria, detergents, drugs and dirt, as well as DNA from other humans or animals. It is possible for sunlight or oxygen in the air to cause changes in DNA, which means we must be careful in the collection of very small starting samples. The DNA prints from the same individual may look identical, or patterns from the same individual may look dissimilar. The bands may be smudgy and smeared, which makes it difficult to tell where one band starts and another ends. By using standard markers it is possible to compare the samples. The scientific basis is well established, but the practice has been found poor in some cases (Norman 1989, Knight 1990).
Approximately half of each DNA fingerprint is inherited from each parent. Comparison of the parent's and child's DNA fingerprints can reveal the real genetic relationships. The evidence is accepted in many countries for criminal cases, and also in disputed paternity cases for immigration purposes. The technique can also be used to identify bodies that are otherwise unidentifiable. It can also be used for tissue transplantation matching.
The actual testing may be performed by commercial laboratories, under commission from government police departments. In Europe there is a standardised technique, using the same restriction endonuclease (HinfI) and two standard chemical probes for DNA identification. The probes used are Cellmark's MS43A and Promega's YNH24. Laboratories can use a variety of other probes for further clarification if required, after these two are used. The U.S. Congress may introduce legislation to stipulate standard technical procedures for commercial companies (Thompson & Ford 1990). Currently, the U.S. Fedral Bureau of Investigation's standard is HaeIII. There may still be room for improvement, so it may be best to postpone any legislation, but standardisation is desirable. The laboratories are subject to blind testing, any only those which maintain good results on these samples are officially used.
There are civil liberties problems, as mentioned earlier. It has been proposed that DNA fingerprints from all criminals be stored, as fingerprints are already. This would establish a database to be screened for police investigations. It will be feasible to do this later in this decade when the techniques have been standardised. It may aid forensic science sufficiently to be worth the cost in "liberty", as long as the database was used according to strict criteria to prevent abuse (Ballantyne et al. 1989).
If we consider individual human life to be of a high status, than we should protect individuals from discrimination. Some access to personal information will be required for medical emergencies, but otherwise third parties should not have any access. A just society must carry the cost of caring for the sick, as it has since the revolution in caring for the sick in the second and third centuries A.D. This will mean sharing out the cost of health insurance, and disability pensions, as in the past. This issue is very important, more than some of the other issues that grab our attention from new genetic technologies. The law must protect privacy of genetic information, as the alternative is widespread discrimination of many people.
The call is for any employer or insurer not to discriminate. Government action will be required. Genetic discrimination has joined, racial, sexual and religious discrimination. Knowledge obtained by genetic screening, at gene level or at the level of DNA fingerprinting, will be very powerful. We must be wise in our use of it. Like much offered by science, it has the power to enrich lives as well as to frustrate or destroy them.
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