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Association of British Science Writers
Wellcome Wolfson Building
165 Queen's Gate
London
SW7 5HD
Tel: 0870 770 3361
absw"at"absw.org.uk
These pages were designed, well, cobbled
together, by Michael Kenward on behalf of the ABSW.
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The future of genetic screening*
Pre-natal testing
Current techniques for screening and diagnosis
New developments
Predictive testing
The psychological implications of genetic screening
Issues that need resolving
Legislation and regulation
The view of the Select
Committee
Insurance
The new Commission
Summary
Genetic screening is one of the fastest moving fields in medical science - and arguably one of the most contentious. But how fast is the science really progressing, and are we equipped to cope with the results?
Pre-natal testing is becoming ever more sensitive. Recent advances in screening and diagnostic techniques mean that about 70% of lethal fetal abnormalities can be detected by good scanning as early as 12 weeks gestation. As well as allowing abortions early on in pregnancy for fatal abnormalities, there is the very real prospect of therapy in the womb to alleviate or prevent the problems that would occur once the child is born.
Diseases caused by a single gene are relatively rare and so the real impact of genetic screening on public health is likely to come about as more work is done on the genetics of common diseases. Although the environment plays a part in most common diseases, the list of diseases with a genetic component is long. Recent advances mean that, for the first time, there is the prospect of unravelling the biochemical mechanisms underlying these disorders. This will allow diseases to be better defined, enabling drug companies to adopt a rational approach to drug design and allowing better targeting of the drugs.
For some diseases, a genetic test will be highly predictive, while for others, the strength of the environmental contribution is such that a test result will serve to tell an individual how much at risk they are compared with the population at large, in the same way that cholesterol acts as a predictor for heart disease.
* Summary of a media briefing held on 29 January 1997
Research into the psychological implications of genetic screening is still at an early stage but it is already clear that this is a highly charged area. Rather than simply clearing up uncertainty and pointing the way towards possible therapy, evidence shows that test results can throw up feelings of helplessness and blame, feelings that are heightened because of the family implications. Perhaps the biggest problem is one of false reassurance, where prospective parents misinterpret a "low risk" test result as meaning "no risk". This makes the way information is presented to prospective parents prior to and following genetic testing crucial, and yet the signs are that practice varies up and down the country.
The Human Genetics Advisory Commission set up by the Government in response to the House of Commons Science and Technology Select Committee enquiry, "Human genetics: the science and its consequences", has been charged with keeping scientific progress under review and reporting on issues with wider social, ethical or economic implications. Issues raised during the enquiry where the Select Committee had strong views included the disclosure of test results in relation to life and health insurance. The confidentiality of tests in both an employment and family context was also fraught with difficulties. The issue of whether patenting a piece of DNA should be allowed also drew a strong response.
Finally, one question raised was that of whether the way we, as writers, portray the issues surrounding genetic screening is affecting the final outcome. Are genetic factors being focused upon at the expense of environmental and societal contributions? Experience in the US would seem to suggest that this is so.
Pre-natal testing
Fetal life is the most rapid time of development. By the time we are born, it is too late to prevent most things. Peter Soothill, Professor of Maternal and Fetal Medicine in the University of Bristol, stressed that the objective in pre-natal testing was not the creation of designer babies, rather the prevention or amelioration of genetic disorders before the baby is born.
Ultrasound and minimally invasive techniques allow genetic conditions to be detected, diagnosed and more recently, treated. A genetic disease can be diagnosed pre-natally if there is a known DNA mutation, a marker for the mutation, a faulty protein, or any anatomical changes in tissue form.
It is vital that the confusion which exists between screening and diagnostic tests - in the minds of doctors as well as prospective parents - is cleared up. Pre-natal screening tells parents whether the fetus is at a high or low risk of a disorder, not whether the baby is affected - that is the aim of a diagnostic test. To accurately diagnose whether a fetus has a genetic disorder, a small amount of fetal cells needs to be examined. This process, however carefully done, carries a small risk for the fetus, and hence the effort being put into screening research.
Genetic diseases occur when there is a problem with an individual's DNA. The cause can sometimes be traced back to a gene or genes, or to a chromosome abnormality. For example, in Down's syndrome the baby has trisomy 21 - three copies of chromosome 21. Or, as with spina bifida, the cause could be a mixture of genetic and environmental factors, known as a multifactorial condition.
Current techniques for screening and diagnosis
A family's health history already holds a major place in pregnancy care as a form of screening. Relevant details include whether there have been previous fetal abnormalities and how related either of the parents are to a family member with a genetic disorder. Doctors can go on to identify high risk groups for tests to see whether the prospective parents are carriers of certain diseases. For example, some racial groups are at risk of major blood disorders, such as thalassaemia or sickle cell disease. Down's syndrome can be screened for in older women with a Down's blood test.
Ultrasound is probably the most valuable screening method, but the timing of the scans is crucial. Women used to be offered one scan at 16 weeks. Now the timing is around 20 weeks, although some more enlightened health authorities are also offering a scan at 12 weeks (see image). At 12 weeks much can be seen already and this timing has the advantage that, if there are serious problems, they can be detected early in pregnancy. At 16 to 18 weeks, the fetus's position in the womb makes access poor and scanning difficult. At 20 weeks the fetus can again be seen easily, making it possible to pick out potentially fatal genetic disorders involving vital organs like the heart. The consequences of early structural abnormalities range in severity from hypertension later in life through to death immediately after birth. Obstetricians' preferences these days would therefore be for two scans at 12 and 20 weeks.
As early as 12 weeks, an ultrasound scan can portray the huge hernia to be seen bulging out of this otherwise normal fetus, a symptom of Beckwith Wiedermann syndrome.
If screening suggests a risk, diagnostic tests can check out DNA, chromosomes, protein or blood cells to confirm whether or not a fetus does have a genetic disorder. Using ultrasound scanning to guide them, obstetricians pass a needle to exactly the right spot: the umbilical cord for fetal blood, the placenta for a chorionic villus biopsy, amniotic fluid for amniocentesis or they can even perform mini skin or liver biopsies.
New developments
The key with all techniques requiring fetal material is to obtain the cells in the least invasive manner possible. A cervical washing may be one way - fetal cells "leak out" of the cervix - and Professor Soothill is working to develop a pregnancy "smear" test. The cells collected could then be screened for fetal abnormalities using fluorescent in situ hybridisation (FISH). In the mother's blood, only about 1 in 100,000 cells are fetal cells; with cervical washings, it is more like 1 in 100.
Developments in scanning are proving important, particularly because the outward signs of genetic syndromes change during pregnancy. Signs of many abnormalities present at 12 weeks disappear by 20 weeks.
Research by Professor Kypros Nicolaides at King's College, London, with 66,000 women has shown the power of a new ultrasound technique, nuchal translucency - nuchal being the Latin word for neck - in screening for Down's syndrome. For the 1 in 20 women picked up by this technique, 80-85% of the fetuses with Down's syndrome can be detected. The black area in the image signifies water behind the back of this 12 week fetus' neck. This is a sign of chromosomal abnormality or sometimes a genetic syndrome, but it can disappear in the next few weeks (see image).
Fetus at 12 weeks with water at the back of the neck, indicating a chromosomal abnormality
Nuchal translucency can pick up genetic syndromes where the fetus has a webbed neck, as in Turner's syndrome, the condition where a female child is born missing one of her X sex chromosomes. And if the chromosomes are normal, there is a growing list of genetic syndromes which this test is better at detecting.
The Human Genome Mapping Project will have major implications because - theoretically at least - every gene identified through the Project can be tested for. FISH is a technique which helps by "lighting up" the chromosome or part of a chromosome being looked for. It is proving useful in looking for mini deletions in genes. Other developments include studies looking at the effectiveness of screening carriers in relatively low risk groups, for example, looking for a mutation associated with cystic fibrosis in the general population.
Why bother with pre-natal tests?
Diagnosis before rather than after a baby is born gives a chance for therapy to make a real difference. For example, if a female fetus has a condition called congenital adrenal hyperplasia Ð an excess of the masculinising steroid testosterone because of a genetic deficiency in one of the enzymes that makes the steroid cortisol Ð it can make females develop abnormal Ð more male Ð genitalia. If this can be diagnosed, the mother can be given steroids which cross the placenta and greatly reduce the degree of masculinisation. Sometimes the secondary consequences of a genetic disorder can be prevented through surgery. The first few cases of in utero bone marrow transplants have taken place and gene therapy is on its way.
Research has shown that 70% of spina bifida cases can be prevented by mothers taking folic acid before and during pregnancy, showing how an environmental manipulation can overcome a genetic predisposition. If this is possible with spina bifida, Professor Soothill asks why not with cases of cleft lip palate or babies with heart defects once more is understood about the mechanism leading to the disorder.
Predictive testing
Genetics research will have the most significant impact on our health since the microbiology revolution at the end of the 19th Century, says John Bell, Nuffield Professor of Medicine in the University of Oxford. The international Human Genome Mapping Project seeks to identify the 100,000 or so genes that encode the proteins that make up our bodies. A large number of these genes vary in form throughout the population. By understanding more about the nature of the genes and their variation, scientists hope to understand more about our susceptibility to disease at both an individual and a population level.
The list of common diseases with a genetic component is long, ranging from infectious and neurological diseases to cancer and heart disease. Many have a major environmental component too, but it is the basic genetic and biochemical events responsible for our susceptibility which the Genome Project will uncover.
Until the advent of genetics, the only diseases where we had any chance of understanding the mechanism were the infectious ones. All other diseases were defined phenotypically - that is, according to a description of the symptoms. For example, in the early 1900s, if you looked a bit yellow you were diagnosed as having jaundice. The severity of the symptoms varied tremendously, from those whose jaundice came and went, to those who died soon after. Now we call the disease hepatitis, we know of five clinical subtypes, each with their own distinct natural history and prognosis, and selective drugs have been developed. The drugs which work against hepatitis C don't necessarily work on A or B. As with malaria, when the infectious agent is identified, then its natural history can be followed, and therapies developed to target discrete steps in the infection cycle.
As scientists find out more about the underlying mechanisms, so they are realising that each disease has more than one form. Genetics is showing us, for example, that diabetes - previously loosely categorized by a high blood sugar condition - may be subdivided into 10 to 20 subtypes.
Genetic tests look set to become an important part of everyday clinical practice. Professor Bell believes that the pharmaceutical companies will be the main engine in this context. Until now, much drug discovery has been rather haphazard. Genetics allows a rational approach to be taken, whereby first the mechanism is revealed, then the biochemical pathway and finally drugs can be developed to tackle specific parts of that pathway.
Pharmaceutical companies will also want to ensure that drugs put on trial are targeted at the subgroup of affected individuals with the subtype of the disease the drug has been tailored to tackle. So, before doctors can enter anyone in a trial, they will need to diagnose the disease subtype with a genetic test. This practice will be reinforced by health care providers, who will not want to pay for people to be on drugs for the wrong disease subtype, as well as regulators seeking to reduce the risk of exposure to unwanted side effects.
Does the test predict the disease?
Across the spectrum of common diseases, a general pattern seems to be emerging. For each disease there will be a subset of people for whom the disease-causing genes are highly predictive - if they have the genes, they are highly likely to get the disease, and environmental factors play very little part. This is known as high penetrance, and means that a genetic test could tell individuals whether they are at high risk before symptoms develop.
Even if the proportion with the highly predictive form of the disease is small, this can still mean a large number of people. With colon cancer, for example, the 5% of people with the highly predictive form make up a larger group than all those with rare childhood single gene disorders put together. And the latest gene to be associated with colon cancer, HNPCC, occurs in its mutated form in 1 in 500 people, accounting for 5Ð10% of everybody who gets colon cancer. If screening was introduced, these people could be identified and monitored. And since colon cancer is completely treatable, providing the tumours are picked up early enough, these people would have normal life expectancy. Professor Bell believes that examples like these show the need for predictive screening in asymptomatic populations.
In the other subgroup of people, the genes interact heavily with environmental factors and, at an individual level, a test for these genes would not be a strong predictor of whether the person is at risk of getting that disease. These genes act as population risk factors - they can tell how much individuals are at risk of getting the disease compared with another group of individuals. This form of test will prove important in terms of identifying whole groups at risk of certain disorders where interventions can be developed en bloc.
On an epidemiological level, we assume that risk factors like high blood pressure and cholesterol levels are distributed throughout the population in a normal distribution. We assume that those at the top end of the curve are those most at risk of heart attacks, and these are the people we treat. But there are people in the middle part of the curve that die of heart attacks and who would also benefit from their cholesterol being reduced to sub-normal levels. With genetic population risk factors, Professor Bell emphasised that we are not talking about screening everyone. The real issue is whether genetics could help us to identify the people in the middle of the curve who would benefit from being helped or encouraged to reduce their risk factors either by environmental change or drug therapy.
The psychological implications of genetic screening
In introducing her talk, Professor Theresa Marteau, Director of the Psychology and Genetics Research Group in the United Medical and Dental Schools of Guy's and St Thomas' Hospitals, stressed that much of the discussion in this field is still at a speculative stage. There has not been much research into the psychological and social implications of genetic testing, partly because many of the tests, particularly the predictive ones, have yet to reach the clinic.
As well as improved health prospects, results from genetic tests can help individuals by reducing their sense of uncertainty about whether or not they are affected by a certain disease. This finding holds whether the test results are positive or negative, and is particularly true for people with a known family history, such as breast cancer and Huntington's disease (see figure).
Whether positive or negative, a genetic test result can lower distress levels by reducing the uncertainty experienced by those with a family history, as shown by the study here of a group of people, each with a 50% risk of getting Huntington's disease.
© 1992 Massachusetts Medical Society
With pre-natal testing, prospective parents have the opportunity of aborting a fetus that will be born seriously disabled. Another advantage in underlining the genetic cause of a condition with a positive test result is that it can stop a person from feeling as if somehow they are to blame for the disorder (see cartoon). In terms of health there have not been any studies about whether people feel less to blame if their test result is positive, but this scenario has already been used, albeit unsuccessfully, by the legal profession in at least one murder trial in the US.
Drawing by D. Reilly; © 1991 The New Yorker Magazine, Inc.
Not everyone undergoing a genetic test feels more certain afterwards, however. This is particularly so for those for whom the test cannot give a definitive answer. Studies over the last decade show high levels of distress in pregnant women after being told that their unborn child is at high or increased risk of a disorder.
Population tests which indicate diseases that may not have appeared before in a family raise other sorts of uncertainty. Giving genetic information to people is not the same as giving other risk factor information because of the family implications. Interviews conducted by Professor Marteau's group with individuals who had been tested three years before to see if they were cystic fibrosis carriers showed that positive test results sometimes instilled a climate of unease within the family.
Professor Marteau believes that the biggest problem in genetic tests is that of false reassurance. This relates to the difficulty in explaining the difference between screening and diagnostic tests, particularly in pre-natal testing. Research done by Professor Marteau's group in a pilot study prior to a large, ongoing national study showed that parents whose babies did have Down's syndrome following a low risk result following pre-natal screening for the condition felt angry and betrayed, and tended to blame the medical establishment. Parents who blamed health professionals felt under more stress coping with the child than those not blaming the health system, and the mothers tended to be more depressed.
Another problem associated with genetic testing relates to the commonly-held perception that there is nothing that can be done about genetic risks. The idea behind genetic testing for common diseases is that the information should be used as one of a number of risk factors. But genetic results are not simply like high cholesterol readings, where everyone knows what steps can be taken to reduce cholesterol levels. Raising the concept of a disorder being hereditary also makes people alarmed not just for themselves but for their family.
Issues that need resolving
Good information prior to genetic tests is believed to help people decide if they want the test, as well as helping to prepare them for the result. At the moment, practice in ante-natal clinics varies up and down the country with some people receiving too little information and others being given inaccurate information. Helping people to understand risk information is vital. Laboratory work shows, for example, the way risk information is presented, whether as an absolute or a comparative figure, has a bearing on people's understanding. Professor Marteau believes that the provision of good quality information should fall under the remit of the Government's Advisory Group on Genetic Testing - yet at the moment the committee has no regulatory power.
Another question is whether there should be a time limit for pre-natal testing. What conditions are serious enough to warrant a late termination and how late should terminations be allowed? With pre-implantation diagnosis, prospective parents can look at an embryo's genes before it is implanted. The Human Fertilisation and Embryology Authority is currently deciding whether there should be any limit on which genes should be looked at.
Does pre-natal testing make society less tolerant of disability? Professor Marteau called for research that charts public attitudes over time to explore the issue, incorporating the views of parents with children with disabilities.
Finally, Professor Marteau questioned whether the way we, as writers, are portraying the issues may affect the final outcome. It has been argued that, by continually focusing on the genetic factors, we might be neglecting important environmental influences and, as a result, society's policies may reflect this neglect. Experience in the US over recent years would suggest this: stories in the media on criminality have tended to focus on biological, in particular genetic determinants, at the expense of environmental factors.
Legislation and regulation
As a molecular biologist, Professor David Porteous' areas of research are aimed on the one hand at using gene therapy to correct the fault in the single gene disorder, cystic fibrosis, and on the other, at identifying possible genetic susceptibility factors in psychiatric illness. From 1994 to 1996 he also acted as an adviser to the House of Commons Select Committee on Science and Technology during its enquiry, "Human genetics: the science and its consequences". In July 1995, following the government's limited response to the Select Committee's first report, the Committee took the unprecedented step of reopening its enquiry. The Select Committee's second report, delivered in June 1996, was met with a swift response. A new body was to be established - the Human Genetics Advisory Commission - charged with overseeing the field and taking a broad, overarching view of related problems and issues.
The view of the Select Committee
Professor Porteous, Head of Molecular Genetics at the MRC Human Genetics Unit in Edinburgh, said that the Select Committee stood "in awe" of the part research into human genetics could play in improving human health - but it had a number of major concerns.
One of these was commercial screening. With information on genes freely available in the scientific literature, any company can set itself up as a supplier of genetic tests. The Committee recommended that a body be set up to regulate companies offering genetic screening, and legislation should be enacted if necessary.
In terms of medical confidentiality, if an individual did not want to share test results, his or her right to privacy should be respected. Situations where this could become a problem include employment and insurance. In the case of employers, do they have a right to know about a disorder that an employee has where conditions at work might inadvertently raise the risk of some disorder? This is already becoming a problem in the US where health insurance is often tied to the job. The Committee recommended that an employer should not be allowed to undertake genetic screening unless there was good evidence of a clear connection between the working environment and the risk of some genetic disorder. There are, for example, some people who are far more susceptible to a variety of environmental contaminants or pollutants. But where should the line be drawn? And how should society ensure that tests aren't used by employers as a means of evading their duties to reduce risks in the working environment? Equally, what about an individual who refuses to take a test, but happens to be in a high risk group and goes down with a rare but fatal cancer. How should the employer be protected against inappropriate litigation?
In the family context, knowledge of the genetic status of one person has implications for other family members. If an individual's results were made public without permission, others could infer something about the health status of other family members. The Committee was clear: the misuse of genetic information, here defined as anything that could lead to stigmatisation or discrimination, should be considered both a civil and criminal offence.
Insurance
These days insurance pervades many sectors of our lives - life insurance is linked with home-ownership, health insurance can be job-related. Could genetic testing be used to prevent individuals at genetic risk from obtaining reasonable levels of insurance? This is already happening with some of the late-onset disorders like Huntington's disease. The Association of British Insurers gave evidence on two occasions and were charged with coming back with a self-regulatory proposal that was acceptable to Parliament. If not acceptable, necessary legislation should be put in place. The Committee felt that the risks and opportunities offered by genetic research confirmed the value of a society-wide health insurance scheme such as the National Health Service.
Patenting is another tricky topic. Pharmaceutical companies will want to guard their investments by protecting their intellectual property. But how can a piece of DNA which is common to us all be patented? The Select Committee's view was that patenting was important, but that exclusions and exemptions, for example, on moral grounds, should be considered more often. Witnesses agreed that genetic fragments should not be patentable on their own. Patenting of a gene was acceptable providing it related to a novel utility but there was concern about whether the novelty and utility criteria were being applied too loosely. A process should be developed whereby it was possible to patent a separate utility subsequently developed without having to refer back to the base patent.
The Committee also charged the scientific community and the media with improving people's awareness and understanding of the issues. There was a case, the Committee felt, for genetics to form a stronger part of the National Curriculum. During discussion, the need for professional training and updating in genetics was raised, and Professor Porteous confirmed that the Select Committee had stressed the need for human genetics to play a larger part in the medical curriculum.
The Select Committee felt that whatever direction society takes will be up to public and Parliamentary debate, and the ethical, legal and social implications should be considered as well as the scientific issues.
The new Commission
The Commission will have a role for evaluating current provision of genetic services, promoting best practice guidelines, and assessing whether local services meet the standards set.
A number of existing bodies report to the Human Genetics Advisory Commission, including the Advisory Committee on Genetic Testing, the Gene Therapy Advisory Committee, the Medicines Control Agency, and the Local Research Ethics Committees. It will also be in contact with other bodies such as the Health and Safety Executive and the Nuffield Council on Bioethics. Its remit can be divided into three main areas: to keep under review the scientific progress; to produce reports on issues, which must be made at least annually and made public; and to advise on ways to build public confidence.
Many people hoped the Commission would be an interim step and that, in due course, the Commission would evolve into a statutory body along the lines of the Human Fertilisation and Embryology Authority.
Professor Porteous concluded that the future of genetic screening becomes a question of how society looks at those who are less fortunate in their chance inheritance and to what degree it decides that research results can be used to their benefit and consequently to the benefit of society as a whole.
Susanna Harris
ABSW
September 1997
Contacts
Professor Peter Soothill,
Professor of Maternal and Fetal Medicine, University of Bristol
Tel: 0117-928 5277 Fax: 0117-928 5683
Professor John Bell,
Nuffield Professor of Medicine, University of Oxford
Tel: 01865 221340 Fax: 01865 220993
Professor Theresa Marteau,
Director - Psychology and Genetics Research Group, UMDS
Tel: 0171-955 4955 Fax: 0171-955 2654
Professor David Porteous,
Head - Molecular Genetics, MRC Human Genetics Unit
Tel: 0131-467 8403 Fax: 0131-343 2620
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