6
Human Genes and Genomes

We are all mutants but some of us are more mutant than others.

From Mutants, Armand Marie Leroi (2004)

We hold these truths to be self‐evident: that all men are created equal.

From Declaration of Independence, Thomas Jefferson (4 July 1776)

The 100,000 Genomes Project will create a legacy for generations to come.

Genomics England (2015)

6.1 Some History

Contrary to what one might read in the media, research on human genetics did not start in 1990 (when the Human Genome Project (HGP) was initiated). Interest in human inheritance goes back a very long way and there were some remarkable insights into inheritance patterns centuries before there was any knowledge of genes. Plato, Hippocrates and Aristotle certainly made observations of the inheritance within families of particular characteristics. A few hundred years later, in 200 CE, the Jewish rabbi, Judah the Patriarch, deduced that a condition involving uncontrolled bleeding (leading to the death of baby boys after circumcision) was a familial trait. Of course, the condition he had observed was what we now know as X‐linked haemophilia. This latter example introduces us to one of the main interests in human genetics, namely, an interest in the inheritance of disease. There are over 10, 000 single‐gene disorders (i.e. caused by mutations in single genes), most of which are rare. Amongst the best known of these are sickle‐cell anaemia, cystic fibrosis, achondroplasia (skeletal dwarfism), Huntington’s disease and X‐linked haemophilia. There are also many conditions where there are interactions between genetic and environmental factors and other conditions where a particular mutation may lead to a predisposition to disease.

Before the availability of genetic modification and associated techniques (including the direct detection of DNA sequences), study of any disease‐associated gene was a frustrating business. For the most of these genes, studies of their inheritance depended on who had chosen to have children with whom. A couple concerned about whether they were at risk of having a child with a genetic disease could be given only a statistical probability, often not very accurate or specific, based on the pattern of inheritance of the condition in their families and knowledge of the population frequency of the particular mutation. There were just a few conditions where the estimates of genetic risk could be backed up by biochemical analysis of blood samples from the child after birth, for example in phenylketonuria. The ability to isolate individual genes therefore received a very warm welcome that was echoed right across the world of molecular biology, whether particular labs were working on microorganisms, plants, animals or human genetics.

6.2 Molecular Genetics and the Human Genome Project

So, for a period of some 10–12 years after the development of gene isolation and DNA sequencing techniques, into the late 1980s, these techniques were applied in individual labs to the particular genes under investigation. This type of research, where sequencing is associated with a particular focussed project, is still very much part of molecular biology; indeed one of us has direct experience of this. However, the past 25 years or so have also seen the initiation and completion of coordinated projects (often international) to sequence the genomes of particular organisms. The HGP typifies this approach. Prior to the HGP, there was extensive activity in human genetic research in many labs all over the world. Of course, some of these labs collaborated with each other but in the main the research was not coordinated. Research focus was on genes of interest to particular biomedical scientists and some significant progress was made during this time, including the isolation of the cystic fibrosis gene and of several other genes involved in single‐gene disorders.

Then, in 1988 a consortium of scientists in the United States persuaded Congress to fund a programme to sequence the entire human genome with the motivation of understanding not only heritable diseases but also those diseases based on molecular malfunctions in an individual, such as cancer. Interestingly, 5% of the funding was set aside for a study of ethical and social implications of the project. In the main, the project was welcomed both inside and outside the biomedical community but there were some critics. A significant minority of scientists believed that this focus would ‘skew’ the balance of research so strongly towards genes that other areas of science would be starved of resources. This aspect of resource allocation was also raised both by clinicians and bioethicists, some of whom suggested that such large allocation to the project would divert attention from more important and widespread factors in disease, including poverty, malnutrition and poor living conditions. Further there were some who believed that the potential for abuse of the knowledge was so great that such research should not be done. However, the climate in the United States was right for the establishment of a large prestigious project that would ‘lead the world’. The project very much appealed to the American people, many of whom felt at the time that the United States had ‘lost the space race’ and thus needed to lead in something else. Is it very interesting that sociopolitical factors have such an impact on science progress. In the event, the United States did not in fact go it alone because the project incorporated human gene analysis already in progress and stimulated further work (and funding for that work) in other countries, including the United Kingdom, Germany, France, Japan and Canada. Overall therefore about two‐thirds of the project has been carried out in the United States, despite the impression still given in some American textbooks that the project has been entirely American (again giving food for thought on social factors in science).

The HGP was originally set to run from 1990 to 2005. Many scientists, including one of us, thought the timescale to be overambitious. However, such was the rapidity of the technical development that the sequencing was finished two years early.1 Scientifically, the data are fascinating as these examples will illustrate.

The ‘completion’ of the project was of course not the end of the matter; rather it was, after to use a well‐worn phrase, the end of the beginning. Vast areas of ‘unknowns’ were opened up by the data obtained during the project, recalling a quotation from the science philosopher Karl Popper: ‘Our knowledge can only be finite, while our ignorance must necessarily be infinite’. For a start, the small number of genes will continue to stimulate research on how genes are regulated in subtle and complex ways that go far beyond a simple understanding of transcription factors and enhancers. Further, the decreasing cost of sequencing and of other forms of genome analysis has led to genome‐wide associative studies in which associations between particular alleles and particular conditions may be detected.

The field of epigenetics has also opened up. For decades this has been a quiet backwater of genetic research. In the early years of this century, there has been extensive progress in understanding the ‘epigenome’, those modifications of DNA and of chromatin, some of which are heritable at least through one or two generations and which are involved in gene regulation. Thus, a pair of identical twins, with identical genomes, may express some of their genes differently because of differences in their epigenomes, some of which may have been acquired in utero. Epigenetics is likely to remain a very important area of research over the next few years, for example, in increasing our understanding of the factors that lead to the onset of some cancers.

However, going back to the HGP itself, we need to recall that the original ‘pitch’ to obtain the support of Congress was that there would be significant medical benefits. Has this happened? Yes, to some extent it has in that some of the findings from the project have already been incorporated into clinical (mainly diagnostic) practice. We will discuss the use of human genetic data in Section 6.4 but at this point we need to take another brief look at history.

6.3 Some Thoughts on Eugenics

Over 2000 years ago, Plato suggested that human society might be improved by selective breeding and was thus the first to set down ideas of eugenics. The term eugenics may be approximately translated as ‘well‐born’ or ‘good breeding’ and it is linked in many people’s mind with human genetics. How then did this situation arise?5

The application of eugenics to human society was certainly something that Charles Darwin thought about but it was his cousin Francis Galton who, in 1883, formally presented eugenic theory to British society. Galton’s idea was that Darwin’s evolutionary theory could be applied to humankind – that the quality of the human species could be improved if those with ‘better’ qualities produced more offspring than those with ‘inferior’ qualities. Those regarded as having inferior qualities included the ‘criminal classes’, the ‘morally incompetent’ and the ‘feeble‐minded’ (the latter category described those whom we would today classify as having various grades of learning difficulties). These ideas were enthusiastically taken up by the Victorians and remained in vogue for several decades. However, support for eugenic ideas declined in the United Kingdom from the mid‐1940s (largely as a result of the Second World War) but nevertheless there was still a small but clearly identifiable eugenic movement, albeit with little or no influence in wider society, up until the early 1960s.

Although eugenics in the 19th century was given to world by a British scientist, it was in other countries that the concept was taken most seriously. For example, in the United States, a ‘perfectionist’ colony was set up at Oneida in New York State in 1847 (well before Galton’s ideas were published) in which from, 1869 onwards, ‘Sexual relations were strictly regulated, and the propagation of children was a matter of community control. Those who were to produce children were carefully chosen and paired’.6 Couples were selected for features which would lead to the production of ‘perfect’ children. Fifty‐eight children were produced in this ‘stirpiculture’ programme. The colony eventually closed in 1880.

Eugenic policies were incorporated into law in many American states during the 1920s and 1930s, leading to the compulsory sterilisation of the ‘morally feeble’ and of ‘imbeciles’. Often, especially in the southern states, there was a strong racial element, with particular ‘races’ being regarded as inferior to others. Overall it is estimated that in the 20 years leading up to the Second World War, at least 40,000 people were sterilised in the United States for eugenic reasons. The practice declined during the 1940s and was ceased totally in the early 1950s.

Eugenic policies were also adopted in Canada and in several European countries, most notably in Germany, and it is the latter example that most people think of when eugenics is mentioned. Indeed, eugenic policies were taken to almost unbelievable extremes during the time of the Nazis, whose programme included sterilisation (probably involving at least 400,000 people), experiments on humans, compulsory euthanasia and some enforced breeding experiments, as well as the extermination of millions of Jewish people in the name of racial purity. However, other countries also introduced compulsory sterilisation on eugenic grounds; in Canada and Switzerland, eugenic sterilisations continued until the 1960s and in Sweden until the 1970s.

6.4 Use of Human Genetic Information

6.4.1 Introduction

The HGP and the ongoing research arising from it have provided new information about the involvement of genes in human disease and will continue to do so as the implications of the basic sequence information are worked out. The question thus arises as to how we will use the increasingly detailed and sophisticated knowledge and understanding of human gene structure and function. We will look at this specifically in relation to applications in medicine under the following headings:

  • Genetic diagnosis
  • Genetic screening
  • Genetic discrimination
  • Community‐wide genome sequencing projects
  • Direct‐to‐consumer genome analysis
  • The burden of genetic knowledge
  • A promise as yet unfulfilled

More direct use of genes in gene therapy is discussed in Section 6.5.

6.4.2 Genetic Diagnosis

One of the most obvious outcomes of our increased knowledge of human genetics is the increased availability of direct tests for the mutated genes that cause heritable conditions. In the mid‐1980s only a very few direct diagnostic tests for ‘disease genes’ were available. By 2004 the number had grown to about 300 and now, at the time of writing this chapter in late 2017, the total had grown to several thousand. However, because many of these tests relate to rare conditions, while many others simply provide a measure of risk or likelihood, most clinical genetics centres will have only a fraction of them routinely available.

Because these diagnostic tests rely on DNA, they may be applied at any stage of life (i.e. there is no need to wait for symptoms to develop), as follows:

  • Postnatal – After birth, in a baby, child or adult
  • Prenatal – before birth but after the embryo has implanted into the wall of the uterus
  • Pre‐implantation – before the embryo has implanted into the wall of the uterus

6.4.2.1 Postnatal Diagnosis

The first point that must be made is that, although the new generation of gene tests makes use of DNA sequences, nevertheless, the implications of a positive test are not always clear. This is first because different people may express genes to different extents, particularly when the mutation concerned causes a strong disposition to disease rather than a total certainty. Secondly, there may be complex interactions between the gene and other factors such as environment, lifestyle and diet. Thirdly, some genes are certainly multifunctional so the effects of a mutation may be hard to predict. Fourthly, the development of DNA tests is proceeding faster than the development of treatments, so even with a specific test result, the person concerned may in practical terms be no better off. It is thus imperative that clinicians are very clear in the information they give about genetic testing.

But this does not mean that genetic testing is worthless. In the United Kingdom, for example, it has been the practice for several years to test all newborn babies for phenylketonuria, congenital hypothyroidism, sickle‐cell disease, cystic fibrosis and MCADD (a deficiency in medium‐chain acyl‐CoA dehydrogenase, an enzyme involved in the metabolic breakdown of fats). More recently, four more conditions have been added to the list, namely, homocystinuria, maple syrup urine disease, glutaric aciduria type 1 and isovaleric acidaemia.7 These recent additions are all described as rare. Early detection of any of these conditions allows the establishment of treatment and management programmes that will eliminate or at least alleviate the deleterious effects of these conditions. In some regions, the tests on newborns also include thalassaemia, especially in ethnic groups where this condition is more common. In the United States, genetic testing of newborns involves routinely 29 diseases, with tests for a further 25 being optionally available. These tests on newborn babies are carried out at a stage when symptoms have barely had time to develop but genetic tests administered after symptoms have already become apparent can also be useful, confirming or refuting the initial diagnosis.

Diagnosis of particular conditions may lead to immediate help and perhaps even treatment for the condition (as mentioned above). It may also spur the parents on to locate appropriate support groups and/or to obtain support through welfare and educational authorities. Similarly, testing of an adult who has presented with particular symptoms may enable them to manage or even to obtain some treatment for their symptoms, to make appropriate lifestyle changes and so on. However, both for children and adults, a genetic test may reveal an especially distressing condition, perhaps of late onset, for which the prognosis is poor. In such cases, the knowledge itself may be difficult to bear. We discuss this more fully in Section 6.4.7.

6.4.2.2 Prenatal Diagnosis

Prenatal diagnostic tests for Down’s syndrome and other chromosomal abnormalities have been available for over 45 years and some genetic tests for about 30 years. As indicated earlier, several thousand gene tests are now available but in general, genetic tests are only carried out where the family history indicates that the foetus may be at risk of having a particular genetic disease, for example, because the disease has appeared in previous generations or because both parents have discovered that they are carriers.8 The tests are applied as early as possible in pregnancy (in practice at about 12 weeks); in some cases, ultrasound imaging may also be used in establishing a diagnosis. For chromosomal disorders such as Down’s syndrome, a new test, based on analysis of foetal cells circulating the mother’s bloodstream, can be applied at ten weeks.

If a test is positive, termination of the pregnancy (abortion) is usually offered. In the United Kingdom, under the terms of the Abortion Act of 1967, the medical criteria for offering termination include ‘a substantial risk that if the child were born it would suffer from physical or mental abnormalities as to be seriously handicapped’ (see Chapter 4).

We have already discussed abortion in Chapter 4 but here we need to deal with it in the context of prenatal testing. Some prospective parents will have no hesitation in going for the abortion; others will feel more comfortable about a termination at 12 weeks (or even earlier; see above) rather than at 16 or 17 weeks into the pregnancy (as happened with earlier generations of prenatal testing) and will also therefore go ahead with it. However, some will express concern that any termination, whether at 12 or at 17 weeks, destroys the life of a potential human being. For them, the decision is difficult to make and the potential severity of the condition may be a factor in their decision. Even so, there are some who, because of their total opposition to abortion, perhaps on religious grounds, will bring a foetus, even with a very severe genetic condition, to full term.

As hinted at briefly above, there is a tendency that the more severe the genetic disease that has been detected by prenatal diagnosis, the more comfortable the prospective parents feel about termination, on the grounds that severe suffering is thereby prevented. Making a right judgement about a foetus who will be born to a life of severe disability and suffering, with the possibility of early death, is very difficult because different ethical principles, each valid and indeed praiseworthy on its own, come into conflict. The child may elicit from its parents and carers remarkable qualities of unselfishness and devotion. On the other hand, the child itself may suffer badly and caring for him or her may place huge stresses on individuals and on the parents’ relationship that are unbearable. Perhaps sometimes it is legitimate to at least ask whether it would be better had the child not been born.9

So, although the prevention of suffering is a worthy ideal under all ethical systems, it may raise problems. For example, does the current practice of offering abortions in respect of particular genetic conditions start a slide down a slippery slope, as some have suggested?

Whether or not one accepts the slippery slope argument in ethical discussion, it can be seen that prospective parents may seek, or may be pressured into having, a wider range of genetic tests with the possibility that abortions will be offered in respect of conditions that, hitherto, had not prevented the living of fulfilled and happy life. Some will be comfortable with these developments but others will be very concerned.

6.4.2.3 Pre‐implantation Genetic Diagnosis

The ability to carry out genetic tests on very early embryos (and indeed, to carry out genetic modification on early embryos, should it ever be legalised) arises from a ‘marriage’ between two powerful areas of biological science. The first is embryology, in particular the knowledge and skills that have arisen in decades that have followed the birth of the first ‘test‐tube baby’ (Chapters 3 and 4). The second is human genetics, the subject of this chapter. Thus, techniques that enable the amplification of small amounts of DNA mean that it is possible to do diagnostic tests on the DNA of a single cell. This has been the basis of developing genetic tests with very early embryos created by in vitro fertilisation (IVF), a procedure known as pre‐implantation genetic diagnosis (PGD). A single cell is removed at the eight‐cell stage (see Figure 4.1) and the test is applied to the (amplified) DNA from that cell. Thus, if a couple is at known risk of having a child with a genetic disease, they may opt to have children by IVF (which in itself is a demanding and sometimes traumatic procedure). Several embryos are produced. They are tested in the laboratory for the genetic disease at the eight‐cell stage. Embryos free from the disease are implanted into the mother’s uterus. Those with the disease are discarded. Thus, no pregnancies are established with the embryos that have the genetic condition and so the couple avoids the tricky decision about termination of pregnancy. Nevertheless, we note in passing that this establishes the precedent of ‘accepting’ or rejecting embryos on the basis of their genotypes.

Whether or not PGD is regarded as ethical will depend on the view taken about the status of the early human embryo. Many people hold the view that although the early embryo has the potential to become a human person, it is very far from actually being one: they do not ascribe human personhood to the early embryo (see Chapter 4). According to this view, the significant event at the start of life is the implantation of the embryo into the lining of the womb to establish a pregnancy. Only when this has happened can the embryo grow into a person. In the main, those holding such views regard PGD as an entirely acceptable way of preventing genetic disease from developing. However, those who believe that the very earliest embryo is a human person argue that discarding embryos that carry deleterious genes is ethically equivalent to aborting an affected foetus.

PGD has been available in the United Kingdom and the United States since about 1989. In the United Kingdom, the Human Fertilisation and Embryology Authority (HFEA) (see Chapters 3 and 4) has to approve any proposal to add a ‘new’ gene to the list of those that are permitted to be tested by PGD.10 Thus, of the DNA sequences known to be correlated with the development of diseases (at least 3000 of which currently have some clinical application), about 430 have been approved by the HFEA.

Despite the availability of PGD and of prenatal genetic testing, many at‐risk couples, both in the United Kingdom and the United States, still give birth to children suffering from conditions such as cystic fibrosis and sickle‐cell disease. In the United Kingdom, the number of children born each year after IVF‐PGD is only a few hundred and it is likely that both the trauma of IVF and its cost (there is only limited National Health Service (NHS) funding for IVF) inhibit the uptake of PGD. However, these tests are also available for use during pregnancy but there is evidence that many at‐risk couples do not opt for prenatal testing or, having received a positive diagnosis from a prenatal test, do not opt for a termination of pregnancy.

6.4.2.4 Saviour Siblings: A Very Special Case

In 2000 a new bioethical story hit the headlines. It was claimed that in the United States a ‘designer baby’ had been born specifically to save the life of a pre‐existing sibling. In fact the truth was less dramatic than this; the baby had not been designed except in the sense that PGD had been used to ensure that he could donate stem cells to his sister. The full story was nearly a very tragic one.11 In 1994, Molly, a first child for Jack and Lisa Nash, had been born with Fanconi anaemia. This is a recessive condition and neither Jack nor Lisa had previously known that they were heterozygous symptom‐free carriers for this mutation.12

Details of disease are not needed here, except to say that an affected child will generally die in childhood or in their teenage years. However, because this is a bone marrow stem cell disorder, a sufferer’s life may be saved by a stem cell donation from a disease‐free compatible donor. With no compatible donors available, the situation looked bleak but eventually the Nashes were offered the chance to use PGD to select an embryo with the appropriate characteristics. We are thus not thinking just about an embryo free from the Fanconi mutation; it also had to be an immunological match for Molly.

We need to emphasise that although this story had a happy ending for the family, it was not an easy process. Lisa underwent five cycles of IVF before finally giving birth to a baby, Adam. Molly was nearly seven years old by this time; she was very ill and likely to die within a few months. The transplant of stem cells obtained from Adam’s umbilical cord (not his bone marrow) saved her life.

When the news broke it created a storm of protest. Those who in any case opposed IVF and/or PGD thought that this was a further unethical step. However, a further objection was also raised, namely, that a child had been born with a specific function in mind, namely, to save his sister. He was, it was said, a commodity and indeed had been specifically selected (or designed, in the words of some reporters) to be that commodity. For devotees of Kantian ethics (discussed in Chapter 2), this certainly seems to run counter to the imperative that we do not use other human beings to fulfil our own desires. However, under other ethical systems, given the proviso that IVF and PGD are acceptable (which, for some, as we have noted, they may not be), this course of action may be regarded as a good one.

Jack and Lisa Nash are very clear that they always intended to have more than one child, but were initially diverted from that intention by caring for Molly. However, the opportunity to undertake IVF and PGD gave them a chance both to fulfil their wish to have another child and to save Molly’s life. They have always maintained that Adam and Molly are equally loved as would be a brother and sister in any functional family. We are certainly not in a position to doubt them but nevertheless, there are some unanswered and perhaps unanswerable questions here. What if Molly had needed further stem cell infusions and Adam had indeed needed to donate bone marrow? (Jodi Picoult addressed this type of question in her novel, My Sister’s Keeper). How does Adam feel about saving his sister’s life? Does he feel as if he is a commodity? How would he and his parents have felt if Molly had died?

Since the birth of Adam Nash, the use of PGD to select a saviour sibling has been accepted as an ethical procedure and entered medical practice in both the United Kingdom and the United States. In the United Kingdom, the use of PGD is regulated by the HFEA and in respect of selection for saviour siblings, each case must be presented to the HFEA for consideration.13 Only if there are no feasible alternatives will the authority give permission. Sadly, the first British couple to be given such permission, Raj and Shahana Hashmi, gave up their attempt in 2004 after six cycles of IVF had failed.14 In the meantime, in 2003, there had been a successful saviour sibling conception and birth for a British couple, Jayson and Michelle Whitaker, who had gone to the United States for this procedure. The first successful saviour sibling birth in the United Kingdom, to Katie and Andy Matthews, was in 2010. This was a case directly parallel to that of the Nashes in the United States: Megan, suffering from Fanconi anaemia, was saved by stem cells from her baby brother Max.

6.4.2.5 Where Next?

While it is doubtless true that prenatal and pre‐implantation genetic tests are carried out with the motivation of lessening human suffering, the availability of these tests raises some further issues. Thus, it has been suggested that it should be illegal (or at least regarded as immoral) for parents to knowingly bring into the world a child with a serious and non‐treatable genetic condition. For example, several years ago, the IVF pioneer Robert Edwards stated that ‘…it will be the sin of the parents to have a child who carries the heavy burden of genetic disease’. More recently, the Oxford philosopher Julian Savulescu has developed the concept of procreative beneficence in which we have a duty to use all possible means of selecting the ‘best’ children.15

Certainly in the United States, some insurance companies have taken an attitude that when a child is born with a serious genetic condition that was known about in pregnancy, the child’s healthcare costs will not be covered (see Section 6.4.4). What is the next step here? Should all couples at genetic risk be compelled to undergo IVF and PGD or to have prenatal testing (with the implications of abortion of affected foetuses)? Such a move would run counter to all our ideas about individual human freedom and autonomy (including an individual’s rights to refuse medical intervention) and would ride roughshod over the ethical objections that some people have to these procedures.

A further question concerns the range of conditions for which tests are offered. Even with the relatively limited range of tests used in the United Kingdom in prenatal and pre‐implantation testing, some of the conditions for which tests may be offered are (as noted above in the discussion of prenatal testing) manageable, even if not treatable. With the number of tests available worldwide increasing by the month, we may ask about their potential application. For example, should tests be offered that give an indication of the possibility of mental illness and if they are offered, how should one respond to the results? This is undoubtedly a complex issue, but a recent study at the University of Exeter did not show widespread support for such tests, should they ever become available.

Finally we may ask about non‐medical traits, for example, related to appearance or to sporting ability. To take an example in which one of us, as a long‐distance runner, is especially interested, there are 23 genetic variations that are known to contribute to the ability to run long distances. It would not be worthwhile to test embryos for all 23, since only about 1 in 20 million people is likely to possess the full set. Nevertheless, one very basic difference between long‐distance runners and sprinters is the predominance of ‘slow‐twitch’ muscle fibres in the former and of ‘fast‐twitch’ muscle fibres in the latter. It is a character that could be tested for, but would we want to? In the United Kingdom, this trait is not on the list of conditions licensed by the HFEA but who knows whether societal attitudes will change in the future.

6.4.3 Genetic Screening

The term genetic screening refers to the practice of testing a large cohort of the population to see whether individuals have mutations that are likely to lead to specific diseases. We should also note that the word screening has strong implications of prevention (i.e. screening out). For example, in the United States in the 1980s, soon after the isolation and characterisation of the mutation that causes fragile X syndrome,16 it was suggested that every foetus should be tested for this condition (followed by abortion of any foetuses with the mutation). Affected boys show varying degrees of learning difficulty and are often poorly coordinated physically. At the time, it cost $200 to administer the test, whereas, according to the company that wished to market the test, it would cost $2 million to provide lifetime care for a badly affected individual. However, the test itself does not indicate the likely severity of the condition. The arguments were purely economic and those who opposed the proposal, which included anti‐abortion groups and a group representing some of the parents of boys with fragile X, did so on the grounds that the screening programme measured the value of lives, albeit lives affected by fragile X syndrome, in purely monetary terms.

Thus far in the United Kingdom, there is no universally implemented programme of screening aimed at preventing the birth of affected babies (even though all pregnant women are offered prenatal tests for conditions such as Down’s, they are totally at liberty to refuse the test – and many do). The programme of genetic testing of newborns is certainly not aimed at terminating the lives of those newborns although, since the tests are universally applied, we may regard this as a screening programme. This leads us to consider a proposal that was discussed in the United Kingdom in the early years of this century, namely, that, under the direction of the relevant authorities within the NHS, a genetic profile should be obtained for all newborn babies. What this proposal, known colloquially as the barcode baby programme, entails is that DNA samples from newborns would be screened so as to obtain a genetic profile (which might be confined to health‐related information but could actually involve the whole genome). This genetic information would be part of the lifelong electronic record kept for each person by the NHS. It is suggested that the information will help an individual to manage their health and lifestyle, will provide information on susceptibilities and will help clinicians to plan specific interventions and to come up with individually tailored treatments (see also Section 6.4.5).

In fact, the proposal was rejected on the grounds of cost but other objections were also raised. Critics were quick to point out that we lacked the knowledge to predict the health implications of many individual genetic changes, let alone the effects of other factors such as environment and lifestyle on these possible outcomes (and that is still true in 2017). Even of those 3000‐plus tests that were mentioned earlier, many do not provide a certain prediction of disease. On this basis, critics maintain that the idea is certainly premature and may indeed prove to be less useful than envisaged, even in the longer term, because of the uncertainties surrounding interactions between external factors and disease susceptibilities. Our increased understanding of epigenetics certainly reinforces this criticism.

Two other issues have been raised by opponents of universal genetic testing or screening. First, there is the question of genetically testing babies without their consent (they are obviously much too young to give it). Supporters of genetic screening however point out that in law, parents may give consent for any treatment on behalf of a child who is too young to give it and that society in general accepts this. Thus babies are already tested soon after birth for several genetic conditions, as described above. Secondly, it is suggested that the data will affect attitudes to people – that some people will be regarded as having less worth than others. In other words there is a danger of genetic discrimination, even as far as the creation of a genetic underclass, based on a DNA profile obtained soon after birth.17 The thought‐provoking science fiction film Gattaca (1998) envisaged a society in which IVF was the norm. All in vitro embryos were genetically ‘barcoded’ and parents selected only their ‘best’ embryos for implantation. Babies born by more conventional means (e.g. in the film, as a result of unprotected sexual intercourse in the back of a car) were also genetically tested and for both groups, detailed predictions about likelihoods of contracting illnesses and about lifespan were made on the basis of the ‘barcode’. Those born without the intervention of in vitro technology clearly had not been advantaged by pre‐implantation genetic selection and were treated as less worthy beings, the ‘Invalids’, as opposed to the genetically selected ‘Valids’. Will real life eventually imitate art?

We end this section with two real examples of genetic screening. The first concerns Tay–Sachs disease, which is common amongst Ashkenazi Jews.18 These are Jews originally from Eastern Europe but many of their descendants live in the United States. Tay–Sachs is a neurodegenerative disease causing, amongst other things, progressive loss of movement and an early death. The genetic condition is recessive: it takes two copies of the mutated gene to cause the disease. So, if two carriers each with a single mutated copy have children together, each child has a 1 in 4 risk of having Tay–Sachs disease. Wishing to avoid termination of pregnancy as a means of dealing with this, Rabbi Joseph Ekstein of New York set up a system for testing all young people for carrier status with respect to Tay–Sachs disease. The results are coded but not revealed to the young people who are tested. The test results are available when two young people begin to think of marrying each other and if they are both carriers, they are advised not to marry. This is very hard for young people who are in love (or, in very traditional Jewish families, who have been brought together by the ‘matchmaker’). Nevertheless, the programme is known within the community as Dor Yeshorim, a Hebrew phrase meaning ‘the generation of the righteous’ because it has reduced very dramatically the incidence of Tay–Sachs disease amongst Ashkenazi Jews in the United States and more recently in Israel itself, without the use of termination of pregnancy.

In Cyprus a similar approach has been taken in respect of thalassaemia,19 a disease in which the body fails to make haemoglobin, the oxygen‐carrying protein of the blood. This is often a painful and crippling condition and sufferers require very frequent blood transfusions; even so they often die by the age of 20. In 1981, the Orthodox Church set up a programme in which it was insisted that all couples planning a church wedding should be tested for thalassaemia. If they are both carriers, they are strongly advised not to marry. This again avoids difficult questions about termination of pregnancy but is equally tough on the two young people concerned. Interestingly, the church’s approach to thalassaemia was in some ways a response to the programme set up in the 1979 by the Cyprus government. There is a government‐funded testing programme for thalassaemia, very often applied to foetuses, accompanied by the ready availability of abortion (with which the Orthodox Church is unhappy). As with the Tay–Sachs programme, these measures in Cyprus have led to a significant fall in the number of babies born with the disease.

In both these examples, a particular population is at risk and measures are taken to avoid conception of an affected foetus or the birth of an affected baby. But as noted already, the accepted courses of action may be difficult for the people involved. Are these examples where, instead of terminating pregnancies or even relationships, IVF and PGD would now be appropriate? Perhaps once more, the answer to this question will depend on views about the early human embryo.

6.4.4 The Possibility of Genetic Discrimination

There is no doubt that the application of new genetic and genomic data to the understanding, at the molecular level, of human disease is beginning to be useful in real healthcare situations, mainly but not exclusively in the areas of genetic testing and diagnosis. The number of available genetic tests, many of which are absolutely or strongly predictable of the likelihood of suffering from a genetic disease, including late‐onset conditions such as Huntington’s disease, is rapidly growing. However, the downside of this is that the increasing availability of genetic tests increases the possibility of discrimination on genetic grounds, as we have already noted in our discussion of ‘barcode babies’.

One area in which discrimination has been shown to occur is the provision of insurance, both life insurance and health insurance. This is particularly important in countries where there is no state provision for healthcare. In several cases in the United States, health insurance has been refused for a child born with a genetic disease because the insurance company will not cover ‘pre‐existing conditions’ (and there may also be, in such cases, an unspoken assumption that a positive prenatal diagnosis of a genetic disorder should lead to termination of pregnancy20). Further, in relation to pre‐existing conditions, some insurance companies have successfully argued that the later onset of symptoms not present at birth but which arise from an inherited mutated gene, is also a pre‐existing condition – pre‐existing because the mutated gene was already present. It is perhaps paradoxical that many in the United States who adopt a strongly ‘pro‐life’ position and who thus oppose abortion (Chapter 4) are also supportive of a system in which babies and children cannot get medical insurance cover.

Such cases seem straightforward cases of discrimination against people who are in some way disadvantaged by their genetic make‐up but the insurance companies suggest that this is not so. Life insurance companies may argue, for example, that denying life insurance cover to (or greatly increasing the premiums of) people carrying a gene that is strongly predictive of a serious disease in later life is perfectly ‘fair’. The companies also state that it is not fair for the financial burden of insuring the lives of such people to be borne partly by those who are free of such conditions. But against this it may be retorted that until the availability of the genetic test, the financial burden had indeed been spread amongst all the company’s clients and so why should this not continue. Indeed, in general this is how insurance works: the many support the few. The debate thus continues.

In employment too, the situation is complex. Certain illnesses or physical impairments make it impossible for some people to do particular jobs; this is accepted even in countries where there is legislation to support the rights of disabled people. There would thus be no pressure to employ someone who already had the symptoms of a genetic condition which made them unsuitable for the work in question. It is however much more difficult to decide the right course of action when a genetic test is strongly predictive of a serious late‐onset condition. Furthermore, the situation is, month on month, becoming even more complex because we are achieving increased understanding that people vary considerably in their susceptibility to bacterial and viral infections and are also differently reactive to factors such environmental carcinogens. Some of this variation is undoubtedly genetic in origin and it is very probable that tests for some of these susceptibilities will become available. What would the reaction be then to an employer checking on the vulnerability of a prospective employee to the common cold or to influenza, in an attempt to reduce absences caused by illness? Another scenario is that employers might favour people who are less likely to succumb to the effects of environmental toxins such as carcinogens while paying less attention to chemical safety in the workplace.

6.4.5 Community‐Wide Genome Sequencing

The costs of DNA sequencing have come down very dramatically since the start of the HGP and will continue to do so as the new DNA sequencing methods are increasingly employed. As recently as 2007, the cost of sequencing a genome was $10 million but in 2015 that figure had dropped to $1000 (£650) (Figure 6.1). With this reduction in costs combined with the very much increased speed of sequencing, it has been possible to set up community‐wide genome sequencing programmes that would have been prohibitively expensive and frustratingly slow even just a few years ago. Examples of such projects include the Personal Genome Project Network, initiated in Harvard University Medical School, United States, and now also incorporating projects in the United Kingdom, Canada and Austria. These projects use volunteers who agree to have their genomes sequenced while also providing health information. Also in the United Kingdom, the 100,000 Genomes Project, set up by Genomics England (part of the Department of Health) in 2012, sequences the genomes of patients with rare genetic conditions or who suffer from certain cancers, plus the genomes of members of their families. Within a few years the project aims to have sequenced the genomes of 70,000 people plus 30,000 cancer samples (to ascertain which genetic changes are associated with particular cancers). Sequencing that number of genomes within such a short time seems incredible when we consider the rate of progress in the early phases of the HGP itself.

Graph illustrating the changes in cost of sequencing an individual human genome, displaying a descending line representing Moore’s law and descending diamonds.

Figure 6.1 Changes in the cost of sequencing an individual human genome. The dramatic fall from 2007 onwards coincides with the increasing use of second‐generation sequencing methods and departs significantly from predictions made by application of Moore’s law.

Source: Figure reproduced by courtesy of the National Human Genome Research Institute, USA.

The aim of the UK’s 100,000 Genome Project is to provide information that will aid in the diagnosis and treatment of disease. In the long term, but outside the current remit of the project, it may be decided to sequence the genome of every newborn baby in order to provide healthcare better tailored to individual needs (but see Sections 6.4.3 and 6.4.4). Both this longer‐term possibility and the current programme will thus, it is suggested, lead the way to personalised genetic medicine, something that, as one of us has mentioned before,21 has been ‘just round the corner’ for rather too long (see also Section 6.4.7). Indeed, there have recently been examples in which treatments have been tailored in a patient‐specific way because of gene‐sequence information.22 Perhaps the corner has been turned.

By contrast, the Personal Genome Project is specifically research oriented, looking at the range of genetic variation and examining correlations between particular sequence changes and specific health‐related conditions. Such information may well in the long run also lead to better diagnosis and treatment but the primary aim is research. Both these types of project raise a number of issues but here we want to focus on just three. Firstly, there is the nature of the information provided by the sequencing programming. This may include specific ‘unwelcome’ genetic information or highlight an increased risk of the suffering from a specific condition. As cancer geneticist Shirley Hodgson has written,23 ‘the amount of information that will be available to an individual…is enormous…it is clearly unrealistic that data should be automatically available in uninterpreted form – some interpretation is needed. General practitioners or other healthcare professionals who are not genetic specialists might not understand either’. Nevertheless, we, the authors of this book, have been impressed, in talking to scientists, healthcare professionals and counsellors, by the care taken to ensure that information derived from genome sequencing is conveyed accurately to a participant in a sensitive and informative way.24 This contrasts with what happens when a customer receives their data from a commercial sequencing company, even if via a ‘personalised web page’ (see next section).

Then there is confidentiality. Patients expect their health information to be confidential between them and those involved in providing their healthcare. Thus, the DNA samples are anonymised until such time as is necessary to make the connection between a DNA sequence and a person in order to give that person their diagnosis and hopefully to develop a treatment regimen. With whom else to share the data is then the prerogative of that person (although advice may be given if it is thought advisable for family members to know).

However, for both diagnosis/treatment‐oriented projects and for research‐oriented projects, data do end up in the public domain in order to be useful for further research and for the development of treatments. The question then is, can confidentiality and anonymity be maintained? In the 100,000 Genomes Project it is stated that patient data will be available anonymously to pharmaceutical companies to develop new drugs. However, some civil liberties groups, increasingly concerned about the accessing of individual data by ‘the authorities’, have suggested that the procedures to safeguard genomic data are not adequate. Further, the specifically research‐oriented Personal Genome Project states on its website: ‘Privacy, confidentiality and anonymity are impossible to guarantee in a context like this research study where public sharing of genetic data is an explicit goal. Therefore, our project collaborates with participants who are fully aware of the implications and privacy concerns of making their data public. Volunteering is not for everyone, but the participants who join make a valuable and lasting contribution to science’.

Thirdly, there are technological challenges. The first of these is the challenge of ‘big data’. This is related to bioinformatics and use of computing to compare the data from large numbers of genomes and to perform genome‐wide associative studies in order to ascertain which variants are clinically important and which are not. The second is the challenge of application, the need to use the information to develop more effective drugs and other treatments, with the possibility of treatment regimens tailored for individual patient needs (as mentioned above and in Section 6.4.8). Further, the timeline from acquisition of data to effective treatment needs to be shortened. As Mark Caulfield, chief scientist at Genomics England, has put it,25 ‘It takes an average of 17 years for discoveries to translate from the bench into having a health‐care impact. We are seeking to do this in three years’.

6.4.6 Direct‐to‐Consumer Genome Analysis

The dramatic fall in costs and the dramatic increase in speeds of genome sequencing (mentioned above) have led to several companies offering a direct‐to‐consumer sequencing service. For the time being, most companies just offer an analysis of ‘informative’ parts of the genome although full sequences are likely to become more widely available as costs continue to fall. For some customers it may be a simple DNA fingerprint to establish paternity (paternity testing based on DNA has been available commercially for over 20 years), while for others, the analysis may be confined to the X or Y chromosomes in attempts to elucidate ancestry. However, increasing numbers of customers want more and indeed are offered more by the companies that provide these services. We take as an example, one American company named 23andMe. Their DNA sequencing service is confined to the parts of the genome that are expressed, namely, the exons. In mid‐2012 the price of this service was $299 but in mid‐2017 the cost had dropped to $199.

In 2012, the company stated that customers will be able to learn about their ancestry and thus understand more of their past. The company also tests for about 70 of the more common inherited conditions, including detection of carrier status in recessive traits and reports on risks related to a number of other conditions and traits. Knowledge of carrier status for recessive traits will, it is said, help customers in making reproductive choices, while knowledge of genetic health risks will encourage vigilance in looking for symptoms. Indeed, the company claimed that ‘knowing your health risks will help you and your doctor figure out health areas to keep an eye on’ and that personalised healthcare plans can be discussed with a customer’s doctor. What the doctors think of this we are not told but one can imagine their reaction to being besieged by the ‘worried well’ armed with their genetic analyses!

Doubtless it is true that some customers are motivated by specific family reasons, while others simply want to have their genomes analysed out of general interest. Nevertheless, we might have questions about the value of providing customers with genetic risks where there is no indication of what other factors may be involved. For example, what exactly does an 8% risk of getting type 2 diabetes actually mean?

There are other ethical issues too. This particular company, 23andMe, asks customers to complete a questionnaire about a range of their own traits and to give permission for the data to be kept in the company’s database. This of course gives the company the ability to carry out genome‐wide associative studies (mentioned in Sections 6.2 and 6.4.5). The customer is therefore participating in the company’s research so that they are ‘part of new genetic discoveries that can benefit us all’ and further, the customer is paying for that privilege!

However, in late 2013, the company was ordered by the US Food and Drug Administration (FDA) to stop marketing its DNA tests. This happened after several unsuccessful attempts to get 23andMe to comply with FDA requirements. The FDA was especially concerned about ‘the potential health consequences that could result from false positive or false negative assessments for high‐risk indications’. For example, false positives for ovarian or breast cancer may well ‘lead a patient to undergo prophylactic surgery, chemoprevention, intensive screening, or other morbidity‐inducing actions’, while a false negative may ‘result in a failure to recognize an actual risk that may exist’. Thus, ‘Serious concerns are raised if test results are not adequately understood by patients…’. The FDA is also concerned that patients may attempt to self‐manage, without a doctor’s input, any conditions they may actually have, especially if ‘…test results are not adequately understood by patients or if incorrect test results are reported’. It is already known that patients who attempt to self‐manage any serious condition are at high risk of negative consequences. Doctors have frequently raised these concerns leading, prior to the FDA directive, to the banning of direct‐to‐consumer genetic tests in two states, New York and Maryland. However, the company continued to market its tests, giving results without health‐related components until October 2015 when it complied with FDA requirements for the way it presented the health implications of its tests. The statements made on the company’s website have been scaled down whilst proudly stating that [23andMe is] ‘The first and only genetic service available directly to you that includes reports that meet FDA standards for being clinically and scientifically valid’.

23andMe has recently widened its commercial activity to Canada (from October 2014) and to the United Kingdom (from December 2014). In both countries, the results are presented with both ancestry‐related and health‐related implications, despite the fact that in the United States, FDA approval had not at that stage been obtained (see previous paragraph). As of mid‐2017, the cost in the United Kingdom was £149; the results will enable the consumer to:

  • ‘View reports on over 100 health conditions and traits
  • Find out about inherited risk factors and how you might respond to certain medications
  • Discover your lineage and discover DNA relatives’

As mentioned above, there continue to be concerns about the way the data are presented to the consumer, in comparison, for example, with what happens in the community‐wide projects in the United Kingdom and elsewhere (see Section 6.4.5). In order to ‘soften’ the possible impact of the results (see next section) and to warn about possible wider implications, the company makes the following statement under the heading ‘What your DNA says about you?’

Bear in mind that many conditions and traits are influenced by multiple factors. Our reports are intended for informational purposes only and do not diagnose disease or illness. There is also a warning that information about inherited traits has implications for other members of the family who ‘may or may not want to know this information’. For some, the possession of genetic knowledge may not be a blessing, as we now discuss.

6.4.7 The Burden of Genetic Knowledge

In the previous section, we mentioned the ‘worried well’ ‘armed’ with their genome analyses and looking out for the slightest symptoms of a condition for which they carry some risk. However, for some people, the situation is more serious than this. In our teaching we often ask classes of students whether they would like to know if they carried a gene that either caused or gave a strong predisposition to genetic disease occurring later in life. There is always a majority who say ‘Yes’. On the other hand, when we have talked to young people who actually were at risk, a different picture emerged, namely, that there was more uncertainty about wanting to know. For some, the knowledge that one is certain to suffer a serious and distressing condition is a burden too heavy to bear and thus ignorance is bliss. Indeed, in the later part of the 20th century, there was more general evidence that people did not want to know, especially for those serious late‐onset degenerative conditions such as Huntington’s disease or familial Alzheimer’s disease for which there is no cure. This had led to a situation in which the number of people requesting tests for these conditions was much lower than would be predicted from the number of those likely to be at risk. However, there is now evidence that the situation is slowly changing, perhaps as a result of the more widespread awareness of genetic tests and medical genetics in general. Further, more people are aware of the implications of late‐onset conditions for any children they may have and finally, for some, there will be the relief of finding that one does not carry the ‘disease gene’. The situation is thus complex but certainly emphasises the importance of genetic counselling both in the phase of deciding whether to take the test and, if the test is taken, when the results are available.

6.4.8 A Promise Unfulfilled?

One of the points made when funding was being sought for the HGP was that our understanding of human disease would be greatly increased. This did not apply only to directly heritable diseases but also to a range of non‐heritable cancers and even to infections by pathogens. Indeed, as the project progressed, the claims became even broader that through genetics, medicine would become personalised as we understood an individual’s susceptibility to infection and their reaction to particular drugs. Thus, when the first draft of a human genome sequence was announced in 2000, Bill Clinton, then president of the United States, suggested that because of this new genetic knowledge, many people could look forward to living to the age of 100 or more. This was in effect a clear support for the view that we were ‘witnessing a revolution in medical genetics’ and that the new genetics would lead to significant improvements in Western medicine and hence increased lifespans.

So, what is the real situation? Firstly, it is true that we have a greater understanding of a range of heritable diseases. This has led to more accurate diagnosis, to better treatment of symptoms and, for a very small number of diseases, development of gene‐based therapies. At the same time we are beginning to understand those gene‐based differences between individuals that lead to differences in the effectiveness of drug treatments, albeit that this only applies to a very small number of drugs and certainly is only very slowly being adopted into general medical practice. So, despite the optimistic claims, the revolution has not yet occurred. Nevertheless, claims that gene‐based personalised medicine is ‘just around the corner’ continue to be made. One might comment that it is proving to be a very long corner. Indeed, it is true to say that in 2017, on both sides of the Atlantic, a person’s street address and postal code are more indicative of their general health and lifespan than their genomes. These effects of social conditions on health are even more apparent in international comparisons of, for example, lifespan, as we discuss in Chapter 8. However, as we discussed in Section 6.4.5, things are changing: we have started to turn the corner.

6.5 Genetic Modification of Humans: Fact or Fiction?

6.5.1 Introduction

Based on the techniques used for genetic modification of other mammals and on over 35 years’ experience in working with human embryos in vitro, it would be entirely feasible to attempt genetic modification of humans. That is not to say that the outcome of an individual genetic modification experiment could be predicted with any degree of accuracy. The variation in the level of expression of the foreign gene and its expression in subsequent generations would be subject to the same uncertainties that apply to other mammals. So, what is the current situation and what are the ethical issues that arise? We will discuss these questions under four headings:

  • Somatic cell gene therapy
  • Germ‐line gene therapy
  • Genetic enhancement
  • Genome editing

A fifth topic, mitochondrial replacement during IVF, mentioned briefly later, was discussed more fully in Chapters 3 and 4.

6.5.2 Somatic Cell Gene Therapy

Supposing a patient has an illness that leads to permanent kidney malfunction, then the only effective cure is a transplant into the patient of a healthy kidney. It is in this light that we consider gene therapy. The rationale is simple enough. If a patient has a disease caused by a malfunctioning gene, then a ‘gene transplant’ may be a good way of curing the disease. But we immediately run into three problems. In dealing with the first, we will assume that, as indeed is commonly the case, the condition has been diagnosed in a child. There is no way in which the functioning gene can be transplanted into all the cells of the child’s body so the gene is targeted to the particular cells that suffer from the effects of the gene malfunction. For cystic fibrosis, for example, the cells targeted are those that line the lungs, while for immunodeficiency diseases, the bone marrow is the appropriate target. These cell targets are part of the already formed body (soma) of the patient – hence the term somatic cell gene therapy. A key feature of this is that the gene correction is limited to one generation only: the correctly functioning gene is not heritable. The second problem is that of actually delivering the gene. This is generally achieved by using a modified virus that will carry the gene into the target cell. Finally, there is problem of whether or not the gene actually works.

The motivation to bring benefit to seriously ill children has driven the development of gene therapy for a handful of diseases, including cystic fibrosis and severe combined immunodeficiency disease (SCID). With cystic fibrosis there has been until recently very little success; gene function is at best only partially restored, and thus symptom relief is poor. Further, since the cells of the lung lining are constantly renewed, repeated treatments are necessary. However, recent developments have led to better results in clinical trials, albeit that repeated treatments remain necessary, and it is predicted that gene therapy for CF will be routinely available by 2020.

Repeated treatment is not necessary with SCID because the target cells are the self‐renewing stem cells of the bone marrow (see Chapter 5); if the correctly functioning gene is inserted into the stem cell DNA, then it will be perpetuated throughout life. And indeed, there have been some spectacular successes in gene therapy for SCID: children who previously had been unable to fight off any infection were able to start to lead normal lives. However, several of these children have subsequently developed side effects in the form of a leukaemia‐like illness. It seems likely that the insertion of the functioning gene into a patient’s chromosomes had activated an oncogene (a gene that, when it is switched on at the wrong time, causes cancer). This is another classic example of weighing potential harm against potential benefit although, in these cases, the final outcomes were happy ones: the children were treated successfully for the leukaemia.

Further, in 2015, gene therapy was developed for another rare bone marrow condition, Wiskott–Aldrich syndrome (WAS), which reduces a child’s ability to fight infection. Symptoms may include recurrent skin infections, eczema, bleeding and autoimmune disease. Life expectancy is shortened significantly and patients may need to spend long periods in hospital. As of mid‐2015, six children had been successfully treated in London or Paris. In one of the reports of this success,27 it was stated that ‘The…six children’s immune systems showed a remarkable recovery and most of their symptoms were resolved. Over a period of two years, patients went from spending an average of 25 days in hospital before the gene therapy to zero days in hospital afterwards’. One of the patients was Daniel Wheeler, a 15‐year‐old boy from the English city of Bristol who said that gene therapy had transformed his health: ‘I’m fine. I bruise a lot less easily, I’m not on anywhere near as many medicines and I’m getting more of an education’.

Attention has now also been focussed on inherited bone marrow diseases that are more common than SCID and WAS. Trials using gene therapy to cure thalassaemia (inability to produce functional haemoglobin) have been successful and the technique is likely to be adopted more widely. Sickle‐cell disease is also likely to be a target for gene therapy in the future and if trials meet with success, this would have immense potential for the many people who suffer from this condition.

One of the keys to successful gene therapy is the safe delivery of a functioning gene to the cells affected by a particular mutation. The retina and the cornea are both considered to be appropriate targets for gene therapy to cure certain forms of blindness and while this chapter was being written, a very effective virus‐based vector was developed for delivering genes to the retina. Other possible applications involve conditions in which genes have become active in the wrong place (e.g. as in cancer) or in which genes have ceased to properly function (as in certain degenerative diseases). In both, there have been some early successes, albeit not on a large scale. Genes active in the wrong place have been switched off and in respect of degenerative diseases, there have been limited but nevertheless encouraging trial on Parkinson’s disease.

There has also been progress in gene therapy in order to create immune responses to different types of cancer. Essentially, either genetic modification or gene editing is used to alter one or more genes of the immune system so that the body neutralises the cancer cells but not normal cells. Small‐scale trials have been carried out with a number of different types of cancer with varying degrees of success but certainly indicating the possibility of wider applications in the future.

Overall, somatic cell gene therapy seems to us to be a good and positive use of our increased understanding of genes and of gene malfunction. We think it probable that many of readers will agree. However, the technique raises another possibility, namely, that it may also be used for genetic enhancement, to improve or enhance a trait or ability in a normally functioning individual. In such a scenario, it is again not a foreign gene that is introduced but a further copy (or more) of one of the subjects functional genes. It has often been discussed, for example, in relation to improving athletic performance where the term ‘gene doping’ is used (as discussed in Chapter 7).

In general, public opinion is very supportive of genetic research in relation to medical therapy but opposes the use of genetic techniques to bring about enhancement. Indeed, this is the position that we hold but we also acknowledge, with several other commentators, that firstly we run into the problem of drawing the line between therapy and enhancement (see Section 6.5.4) and secondly there is a danger that medicine may become over‐geneticised.

6.5.3 Germ‐Line Gene Therapy

Surveys of public opinion show that in general there is strong opposition to the idea of genetically modifying humans in a way that allows the new gene to be inherited from generation to generation. However, many people, including some professional ethicists, make an exception if the genetic modification is directed at correcting a genetic illness. The reasoning here is that eliminating a genetic condition in a heritable way, that is, in the germ line, would bring benefit to subsequent generations as well as to the initial recipient of the correctly functioning gene. But what is the reality?

It is entirely feasible to insert a new gene into a human egg immediately prior to or immediately after IVF and then to establish a pregnancy by placing the genetically modified (GM) embryo in a woman’s womb. However, as we have mentioned before, success rates both in terms of the number of live births and in the activity of the inserted gene are likely to be lower than in ‘normal’ IVF. Nevertheless, as techniques for genetic modification of mammals improve, the possibility of success with human germ‐line modification will increase, leading to pressure to use it as a therapeutic procedure.

However, even if this type of germ‐line therapy is adopted as an acceptable technique, it is unlikely to have wide application. The probable scenario is that a couple with an absolute certainty of having a baby with a genetic condition, for example, if both prospective parents are homozygous for a recessive harmful mutation (i.e., they both have two copies of the faulty gene) will request germ‐line therapy when they are planning to start a family. The couple would opt for IVF and the correctly functioning gene would be inserted into several embryos that, prior to placing any in the womb, would be tested for the presence of the new gene. We note that one of the possible uses of genome editing (Section 6.5.5) is exactly this: the ‘faulty’ genes would be cut out and replaced with the wild‐type version. Such situations are very rare; in most cases where couples are at risk of passing on a genetic condition, not all the offspring will be affected. In this latter instance a couple may opt for IVF coupled with PGD. Germ‐line gene therapy would not be necessary.

Further, even though germ‐line gene therapy would be needed only very rarely, some hold the view that genetic modification of a future human being should never be allowed. Indeed, in the United Kingdom, under the terms of the HFE Act, genetic modification of very early embryos is permitted in experiments aimed at understanding developmental processes; such embryos are destroyed 14 days after fertilisation. However, attempting to establish a pregnancy with a GM embryo is currently forbidden, even if the modification has been directed at eliminating a genetic disease. The one exception to this is the replacement of faulty mitochondria in so‐called three‐way IVF (see below and also Chapter 3).

Two main lines of argument have been raised by those who oppose germ‐line therapy. Firstly, it is not yet clear, in GM of large mammals, whether or not it poses any risks for succeeding generations, even if it has been shown to be safe for the immediate recipient. Secondly, it has been suggested that germ‐line therapy – and indeed any form of direct genetic intervention – goes too far in altering our biological nature; ‘playing God’ is a term that has been used in this context (although it is not entirely clear what is meant, it is often used to imply an intrinsic objection to germ‐line genetic modification). Further, there is concern, even amongst some who do not oppose germ‐line therapy itself, that it may open the way for other forms of genetic intervention such as genetic enhancement. This is of course a version of the slippery slope argument. Is it in any way justified?

However, one clear exception to the rules has already been made. The ‘three‐way’ IVF procedure mentioned in Chapter 4 effectively adds mitochondria and hence mitochondrial DNA from a third party into an embryo in which, had the transfer of mitochondria not happened, the mitochondria would be malfunctional. This may certainly be classed as germ‐line gene therapy (the ‘new’ mitochondrial DNA is inherited) and it is interesting that the HFEA put the topic out to public consultation before giving its approval.

Finally, genome editing, as mentioned briefly above, raises a different type of possibility for germ‐line gene therapy (Section 6.5.5) but the ethical issues are the same as we have dealt with here.

6.5.4 Genetic Enhancement and Designer Babies28

The concerns of those who adopt the slippery slope argument are focussed first on the idea that the technical developments needed for germ‐line therapy make it equally possible to apply them for non‐therapeutic purposes such as genetic enhancement – using GM technology to improve in some way a human embryo. Secondly, it is argued that the general acceptance of germ‐line therapy will make it socially and emotionally easier to accept non‐therapeutic use of human GM. And thirdly, they point out that the technique of PGD already allows the selection of or the rejection of particular genotypes, which although used for a number of therapeutic reasons could equally enable prospective parents to select for or against particular features according to their own wishes. This may be regarded as another form of genetic enhancement. In addition to these arguments, people who hold a very ‘high’ ethical view of the early embryo, attributing to it the full status of human personhood, will object to any manipulation of embryos. We have discussed different aspects of this ethical position more fully in Chapters 3, 4 and 5. Here we return to the other arguments that deal with genetic enhancement.

First, we must eliminate the more far‐fetched possibilities that often feature in science fiction and even, sadly, in documentary programmes on TV. We are not talking about designing football (soccer) players to perform well in the English Premier League, nor about baseball pitchers whose performance will ensure that their team wins the World Series. Neither are we talking about ensuring that a child will turn out to be a great clarinet player or rock guitarist. While it is certainly true that many of the physical features that enable someone to be, for example, an Olympic rowing champion, are obviously genetic in origin, it is also clear that qualities such as sporting ability and musical and artistic talent are very complex, influenced by many genetic and non‐genetic characters. So, while we may envisage one day ‘designing’ (by genetic selection of an embryo) a person with an abundance of ‘fast‐twitch’ muscle fibres and a high tolerance of lactic acid, we cannot ensure that he will turn out like Usain Bolt. So what can we manipulate? We can manipulate, both by pre‐implantation selection and by direct genetic modification, characters for which direct involvement of a gene (or small number of genes) has been identified. And in that sense then ‘designer babies’ are a real possibility.

For some, the answer to the question in the box is ‘No’. For example, the British philosopher John Harris, based at Manchester University, has written:

If it is not wrong to hope for a bouncing, brown‐eyed, curly‐haired and bonny baby, can it be wrong to ensure that one has just such a baby? If it would not be wrong of God or Nature to grant such a wish, can it be wrong to grant it to oneself.29

Although on the surface this sounds very plausible, there is no evidence that this view is held by the majority of prospective parents. Indeed, couples who choose to have children generally accept and love them as they come, whether boy or girl, blue‐eyed or brown‐eyed, blonde or brunette. Harris goes on to say that if it becomes possible in the future to provide the child with characteristics that give it a distinct advantage in life (that is to say, a greater advantage than might be effected by hair or eye colour), then that too will be acceptable.30 Oxford philosopher Julian Savulescu goes further31: parents have a moral obligation to create children with the best chance of the best life and that may include use of genetic techniques. So, according to these philosophers, genetic selection and/or enhancement are no different from paying for private education or for intensive sport or musical training. Their view is that all these activities represent the parents’ wishes to give their child the best in life; there is thus no ethical difference between genetic enhancement of the embryo and paying for one‐to‐one tuition on the trumpet.

We leave aside for the moment the topic of societal inequalities raised by these views in order to examine more fundamental issues. Those who oppose the use of GM techniques in genetic enhancement (and currently, this is majority of those whose opinion has been sought32) have a range of reasons for doing so. At one end of the spectrum, there are those who hold that any form of GM is intrinsically wrong (a view that is discussed in Chapter 9). Then there are those who hold that the human embryos are not to be experimented on or to be selected or rejected for any reason, because each one is a human person. But mostly, objections to human genetic enhancement are based on the view that to choose specific genetic features of a child (without of course any possibility of the child – embryo – giving consent) turns that child in a very obvious way into an object of its parents’ wishes. Some have gone as far as to say that this is a local form of eugenics; this may be rather strong but many writers agree that it amounts to ‘commodification’ of the child. Thus, Professor Celia Deane‐Drummond of the University of Notre Dame, Indiana, United States, has written:33 ‘…we should be more concerned with broader cultural trends that elevate liberalism to such an extent that children become rights that can be purchased according to parental desires and wishes’. In specifically ethical terms these attitudes do not conform to the virtue ethics approach of dealing with others as we would have them deal with us, nor with Kant’s (deontological) categorical imperative that no human should treat another as means to an end. For the present at least, these views prevail and a clear ethical line has been drawn between germ‐line gene therapy and genetic enhancement.

However, there is a further complexity in this discussion, illustrated by a question that was alluded to in Section 6.5.2, namely,

  • Is it always possible to distinguish between therapy and enhancement?

The fact that we ask the question implies the answer – ‘No’. There are several forms of medical intervention that certainly appear to be no more than enhancement but for some may be therapeutic. Various aspects of cosmetic surgery fall into this category. Breast reduction may be undertaken to make a woman look better but it may also relieve painful side effects of having disproportionately large breasts. On the other hand, enlargement of small breasts, currently a popular form of cosmetic surgery in the United States and the United Kingdom,34 is claimed to make women more confident in themselves and is therefore held to be psychologically or emotionally therapeutic. Other examples include leg‐lengthening surgery (there was a case in the United Kingdom of this procedure being paid for by the NHS so that a young woman would be tall enough to follow her chosen career) and the administration of growth hormone to children of short stature, even if their lack of height is not caused by hormone deficiency. In all these cases, the boundary between therapy and enhancement is very blurred and there will doubtless be instances in genetic modification where the distinction is equally difficult to make.

We must also ask whether it is likely to happen. In the United Kingdom the answer is at present very clear: genetic modification of embryos that will be used to establish a pregnancy is not permitted, except for mitochondrial donation.35 However, it is probable that pressure will mount to allow germ‐line gene therapy in the very limited range of cases that were described earlier. On the other hand it seems very unlikely that the doors will be opened to germ‐line genetic enhancement or to pre‐implantation genetic selection for non‐medical reasons, the views of writers such as John Harris notwithstanding.

The situation in the United States is somewhat different. General public opinion on genetic enhancement is probably overall more conservative than in the United Kingdom but nevertheless, there are those who are enthusiastic about the possible uses of genetic technologies. Further, there is not a national authority such as the HFEA to regulate these activities. And so several American commentators have indicated that it is just a question of time and money before genetic enhancement is attempted in the United States. For example, Gregory Stock of UCLA36 has written37:

If we could make our baby brighter, or healthier, or more attractive, or…otherwise gifted, or simply keep him or her from being overweight, why wouldn’t we? [Further] … neither governments, nor religious groups will be able to stop the coming trend of choosing an embryo’s genes, and that there is little point in even trying.

Stock takes his argument further, suggesting that the affluent will be able to afford to buy their children genetic advantages denied to the wider population. Again there are echoes of Harris who believes that buying genetic enhancement is no different from buying educational advantage or extramural music lessons. The driving force thus becomes economic and already in the United States, there are clinics offering, for a large fee, sex selection via PGD.38 Genetic selection for traits such as eye colour is also offered but there is no indication as to whether this is often requested (noting that selection for blue eyes would not be possible in some genetic backgrounds). All this raises much wider issues, such as the inequalities in society and the way that resources are allocated, issues that will exercise many of our readers but which lie outside the scope of the present discussion.

6.5.5 Genome Editing

In Chapter 9 we discuss some of the recently developed methods for genome editing including the removal of specific genes and replacing them with other genes. The latter may be modified versions of the genes that were removed or may be the correct version of a mutant gene that had been edited out. It is the latter feature that has caught the attention of medical geneticists. Thus in China in the summer of 2015, gene editing techniques were used in experiments aimed at correcting a harmful genetic mutation in early human embryos. We need to add here that the Chinese scientists used embryos that were already known to be non‐viable; this de‐fused some of the ethical objections raised by ‘pro‐life’ groups.

Genome editing to correct a disease‐causing mutation is of course another version of germ‐line gene therapy and raises all the same questions and issues that we covered in the previous section. Nevertheless, it does raise the possibility of some very precise genetic manipulation and thus, although some scientists are keen to further develop the technique, others have called for at least a temporary halt on using it, albeit experimentally, on human embryos.

In the event these early experiments did not work. The ‘faulty’ genes were removed successfully but the researchers found it much more difficult to replace them with the properly functioning versions (although similar experiments carried out later on mice showed some degree of success). At present, for anyone knowing that they may pass on a faulty gene to their offspring, embryo selection via PGD (as described in Section 6.4.2) is the method of choice to avoid starting a pregnancy with an embryo carrying the gene in question.

However, in late 2015, news came out of a completely different (and still very experimental) use of genome editing. It was employed as part of a gene therapy procedure to cure childhood acute lymphoblastic leukaemia.39 The patient was a baby girl, Layla Richards, whose leukaemia had not been cured by aggressive chemotherapy, nor by a bone marrow transplant. The treatment, carried out at Great Ormond Street Hospital, London, involved donation of T‐cells (one of the types of cell in the immune system), which were genetically modified so that they would attack leukaemia cells. Genome editing was then used to remove genes, firstly so that the donated cells would be invisible to the cytotoxic drugs that Layla was receiving and secondly so that the donated cells would not react unfavourably with Layla’s normal cells. After about two weeks, the treatment began to work and at two‐month post‐treatment Layla was completely clear of leukaemia. She then had a second bone marrow transplant and went home one month later.

Layla’s case is particularly poignant because the treatment had never been used on a human before, although it had been shown to be successful in mice. Without this treatment Layla would have died and indeed, her parents, Ashleigh and Lisa Richards, had been told that she was dying. However, it was their persistence that led the clinical team to ask for ethical permission to use this untried treatment. As Lisa said, ‘We didn’t want to accept palliative care and give up on our daughter, so we asked the doctors to try anything…even if it hadn’t been tried before’. The ethics committee was thus faced with a classical risk–benefit analysis. The risks were that it would not work and that it might possibly extend Layla’s suffering. The possible benefits were a remission from leukaemia and hopefully even a long‐term cure. In this case the committee found it easy to give permission, ensuring at the same time that the medical team kept Layla’s parents fully informed of possible outcomes.

Cancer specialists say that this type of therapy could be suitable for five to ten children with acute lymphoblastic leukaemia in the United Kingdom each year and many more children across the world. Further, it is hoped that the therapy can be modified to treat other forms of cancer.

6.6 A Gene for This and a Gene for That

Over the past 25 years, progress in genetics and genomics has been very rapid and the pace of that progress shows no sign of decreasing. For anyone who wants to understand more about how living organisms work, this is very welcome. Indeed, as several authors have said, DNA and ‘the gene’ have become modern ‘icons’. Nevertheless, there are also drawbacks. In medicine, for example, some areas are becoming ‘over‐geneticised’ with the danger that other factors that have a profound effect on health, including socio‐economic and environmental factors, are not given enough weight. There is also the sense, reported by some prospective parents, that a genetic ‘verdict’ arising, for example, from a prenatal test is regarded as final. The genes have spoken; there is nothing else to be said. The child to be born is defined in terms of a genetic condition. The parents on the other hand may not want their child to be defined in terms of a ‘faulty’ gene and are very happy to bring up and care for a child, who, amongst its many other characteristics, happens to have a particular genetic ‘condition’.

The emphasis on genetics is actually indicative of a wider trend to attribute too much to genes. The idea that the sequence of bases in our genomes ‘tells us who we are’ has been expressed by, amongst others, James Watson (the co‐discoverer of the structure of DNA). Customers who use direct‐to‐consumer genome analysis often make similar comments. And then there the over‐simplistic statements, often made on radio and TV or in newspapers, about a gene for this and a gene for that, where ‘this’ and ‘that’ may be complex traits or behaviours that are certainly not attributable to individual genes. Nevertheless, it is an easy ‘story’ to tell and the media often prefer easier stories, even if they are not right. But there is another reason and that is the view, propounded by some scientists, that our individual personhood can ascribed completely to our genetic make‐up. This is a view known as genetic determinism or genetic essentialism.

This view has been strongly criticised by a former Director of the HGP, Francis Collins. He is very strong supporter of genetic medicine and yet was concerned about the ‘tendency to genetic reductionism/determinism’, the ‘belief that it is all in our genes’. Some of our readers may be aware that Collins has a strong Christian faith and thus may be expected to criticise genetic determinism. That may be true, but the determinist/essentialist view is also strongly criticised by high‐profile biologists such as Denis Noble, Steve Jones and Steven Rose and by the eminent philosopher John Dupré, none of whom have a religious faith. Indeed, Jones has stated that it is ‘nonsense’ to think that our genes tell us who we are. The fact is that many, many investigations have led to the conclusion that there is very limited evidence for one‐to‐one links between genes and particular behaviour patterns. It is clear that, as far as these things can be quantified, features such as personality traits, behavioural tendencies and intelligence have about a 40–50% heritability but that level of heritability is made of small contributions from a large number of genes. Further, with a small number of specific exceptions, we do not know what most of those genes actually do. Finally, our biological development is not totally determined by genes. Neither are the changes in brain ‘wiring’ that occur as we learn new things and have different experiences through life. Identical genomes do not make identical people, as we know from study of identical twins. Indeed, as we have already noted, there may be actual physical differences between identical twins that arise from epigenetic changes (see Sections 6.2 and 6.4.2). Modern genetics and genomics and their appropriate application to medicine are a genuine source of wonder but we can never define a person by the sequence of bases in their genome.

Key References and Suggestions for Further Reading

  1. Ainsworth C (2015) Q & A: Mark Caulfield. Nature 527, S5. doi:10.1038/527S5a.
  2. Ball P (2017) Designer babies – an ethical horror waiting to happen? The Observer, 8 January 2017. https://www.theguardian.com/science/2017/jan/08/designer‐babies‐ethical‐horror‐waiting‐to‐happen (accessed 8 September 2017).
  3. Bashford A, Levine P (2012) The Oxford Handbook of the History of Eugenics. Oxford University Press, Oxford.
  4. Belkin L (2001) The made‐to‐order savior. The New York Times, 1 July 2001. http://www.nytimes.com/2001/07/01/magazine/the‐made‐to‐order‐savior.html (accessed 8 September 2017).
  5. Bryant J (2013) Beyond Human? Lion, Oxford.
  6. Dinger ME, Pang KC, Mercer DR, Mattick JS (2008) Differentiating protein‐coding and noncoding RNA: challenges and ambiguities. PLOS Computational Biology 4, e1000176. 10.1371/journal.pcbi.1000176 (accessed 8 September 2017).
  7. Ezkurdia I, Juan D, Rodriguez JM, et al. (2014) Multiple evidence strands suggest that there may be as few as 19,000 human protein‐coding genes. Human Molecular Genetics 23, 5866–5878.
  8. George A (2004) The Rabbi’s dilemma: interview with Josef Ekstein. New Scientist 181, 44–47.
  9. Harris, J (1998) Genes, Clones and Immortality. Oxford University Press, Oxford.
  10. Harris J (2009) A world without men – that’s not the real issue here. The Independent, 7 July 2009. http://www.independent.co.uk/voices/commentators/john‐harris‐a‐world‐without‐men‐thats‐not‐the‐real‐ethical‐issue‐here‐1736211.html (accessed 8 September 2017).
  11. Hodgson SV (2015) Sequencing genomes: we need to think ahead. The Biologist 62, 9.
  12. Human Fertilisation and Embryology Authority (2017) Pre‐implantation Tissue Typing (PIT). https://www.hfea.gov.uk/treatments/embryo‐testing‐and‐treatments‐for‐disease/pre‐implantation‐tissue‐typing‐ptt/ (accessed 14 September 2017).
  13. Human Fertilisation and Embryology Authority (2017) Approved PGD and PTT conditions. https://www.hfea.gov.uk/treatments/embryo‐testing‐and‐treatments‐for‐disease/approved‐pgd‐and‐ptt‐conditions (accessed 14 September 2017).
  14. Public Health England (2015) https://www.gov.uk/government/news/newborn‐babies‐screened‐for‐more‐rare‐conditions (accessed 8 September 2017).
  15. Sample I (2015) Baby girl is first in the world to be treated with ‘designer immune cells’. The Guardian, 5 November 2015. http://www.theguardian.com/science/2015/nov/05/baby‐girl‐is‐first‐in‐the‐world‐to‐be‐treated‐with‐designer‐immune‐cells (accessed 8 September 2017).
  16. Savulescu J, Kahane G (2009) The moral obligation to create children with the best chance of the best life. Bioethics 23, 274–290.
  17. Stock, G. (2002) Re‐designing Humans: Choosing Our Children’s Genes. Profile Books, London.
  18. Torrents D, Suyama M, Zdobnov E, Bork P (2003) A genome‐wide survey of human pseudogenes. Genome Research 13, 2559–2567.
  19. Turnpenny P, Bryant J (2002) Human genetics and genetic enhancement. In Bioethics for Scientists, eds Bryant J, la Velle LB, Searle J. John Wiley & Sons, Ltd, Chichester, pp 241–264.
  20. Willmott C (2016) Biological Determinism, Free Will and Moral Responsibility: Insights from Genetics and Neuroscience. Springer, Berlin.

Notes