3. Ethics in genetic research and practice

3.2 Gene therapy
This book sets out general international ethics principles regarding genetic research and gene therapy. Where applicable, specific reference is made to the South African situation.

Genetic manipulation is an awesome power within our grasp, and responsibility rides on the back of that power. Discussing the ethics of gene therapy is like the toss of a coin - the outcome depends solely on which face is presented to the world. This theme recurs in the commentary that follows, and it requires more than just fleeting attention. It is mindful of the potential for both advancement and harm that the ethics of this procedure are explored.

Essentially, the practice of gene therapy relates to two groups of cells - somatic cells and germ-line cells. A germ-line cell is a cell which, during the first few weeks after conception, is put aside in the embryonic sex organs to provide, possibly decades later, ova or sperm. A somatic cell is any body cell except a germ-line cell.¹⁵

"The genes carried by each of these two kinds of cell have distinct roles, and the distinction is very important. Genes which are carried by germ-line cells may be transmitted to offspring and successive generations. Genes which are carried by somatic cells have their role in the corporate life of those cells within the tissues and organs of the individual whom they endow. So far as is known, an alteration to the genes of somatic cells will affect only that individual, but an alteration to the genes of germ-line cells might affect offspring and successive generations."¹⁵

Concerns with regard to somatic cell gene therapy are much the same as those regarding any novel form of medical practice or treatment. Somatic cell gene therapy impacts only on the individual subject of the gene therapy, and ethical concerns are centred around the risk to the participant or patient and the concomitant obligations of the investigator.

3.2.1 Innovative practice or research?
The ethics of gene therapy are largely dependent on its status either as medical practice or as research. While practice is undertaken with the primary intention of benefiting an individual patient, research is undertaken with the prime purpose of testing a hypothesis and permitting conclusions to be drawn, in the hope of contributing to general knowledge¹⁵ (see also 2, Book 1). At present, gene therapy has not yet been assimilated into mainstream medical practice. It is still perceived to be different, both in its nature and possible consequences, from any treatment used hitherto in medical practice.15 Thus, gene therapy should be considered to be in the research stages and subject, therefore, to those ethical considerations that currently govern genetic and medical research:

"... accordingly, any proposal to conduct gene therapy should be subject to approval following authoritative ethical review, which includes critical scrutiny of its medical and scientific merit, the legal implications, and wider public concerns. It should also be subject to conditions laid down for the conduct and oversight of therapy and evaluation and reporting of the outcome."¹⁵

National guidelines for the conduct of human gene therapy are essential. These, with an expert national body to consider and approve proposals for such therapy, would ensure public confidence in the introduction of novel and sophisticated gene therapy practices.¹⁶ A regulatory system would go far in allaying public fears that gene therapy might be misused, or that it might be extended to enhancement uses beyond what is strictly medical therapy.¹⁷ This is discussed further in the topic 'Supervision of gene therapy' under 3.2.4 and 'Regulation of cloning research' under 3.4.5.

3.2.2 Somatic cell gene therapy
Somatic cell gene therapy takes multiple forms. In its simplest form, it entails supplementing or replacing dysfunctional or faulty genes with ones that are able to function correctly.¹⁸ Ideally, somatic cell gene therapy provides the correct genetic information in those cells which require it for their normal function.¹⁵ This form of therapy corrects or alleviates the genetic defect present in the individual alone, without impacting on the genetic information transmitted to any issue.¹⁵ It is argued that, in principle, somatic cell gene therapy is similar to current routine therapies such as organ transplantation, and therefore raises no new ethical issues.^16,18 However, there is a greater danger present in gene therapy:

"The correcting gene might be inserted into the wrong cell type, or be expressed inappropriately, either in the wrong amount or at the wrong time during development. The therapy might then do more harm than good. The gene might [also] be inserted in such a way as to cause a new mutation, by disrupting some other gene or its means of control. This might initiate a new genetic disease, or perhaps an uncontrollable multiplication of cells which could lead to cancer."¹⁵

These factors bear on the effectiveness, safety and risk of somatic cell gene therapy. Safety should be the paramount factor when considering whether to conduct somatic cell gene therapy on a particular individual as a form of medical practice. One commentator remarking on the future of the practice of somatic cell gene therapy stated that:

"Judgements on the ethics of gene therapy in man will initially apply to individual cases and will require assessment of factors such as safety, efficacy, alternative treatments and prognosis - in other words, the balance of risk and benefit for the patient. In the near future, treatment by gene therapy might be justified in cases of invariably fatal or life threatening diseases for which no alternative treatment is available...If damage caused by a genetic disorder in a particular patient is irreversible, then there may be no case for intervention through gene therapy."¹⁶

Different considerations apply in somatic cell gene therapy research. The Report of the Committee on the Ethics of Gene Therapy¹⁵ has set out the following conditions as prerequisites to gene therapy research:

1. There must be sufficient scientific and medical knowledge, together with knowledge of those proposing to undertake the research, to make sound judgements on:
   1. the scientific merit of the research;
   2. its probable efficacy and safety;
   3. the competence of those who wish to undertake the research;
   4. the requirements for effective monitoring.
2. The clinical course of the disorder must be known sufficiently well for the investigators and those entrusted with counselling to:
   1. give accurate information and advice;
   2. assess the outcomes of therapy.

3.2.2.1 Public policy and the practice of somatic cell gene therapy
Where are the boundaries for the practice of somatic cell gene therapy? It is arguable that current gene therapy should be directed to alleviating disease in individuals.¹⁵ However, gene therapy could have a wider application than the correction of single gene disorders.¹⁵

"For example, it is being investigated as a possible new approach to the management of a wide spectrum of diseases, ranging from infections such as AIDS to cancer, and it is being studied as a means of strengthening the body's immune response to viral infections. Various approaches are being used which require the insertion of genes into particular cell populations in an attempt to counter some of the basic changes in cells which lead to them becoming cancerous. Gene therapy is also being explored for the management of chronic diseases such as diabetes."

There are other non-disease-related uses to which genetic manipulation could be put.¹⁹,a The current limits placed on the use of gene modification, however, curtail its use for the enhancement or change of human traits not associated with disease. Somatic cell gene therapy will be a new kind of treatment, but it does not represent a major departure from established medical practice; nor does it, in our view, pose new ethical challenges.

It will, of course, raise familiar issues, which attend any new medical procedure. However, there are public concerns about a medical intervention that may be perceived, understandably, as different from any used hitherto. In addition, because of the special qualities of an individual's genetic make-up and the complex nature of genetic disorders, the issues will assume greater prominence. They are:

1. questions of safety, which are heightened by the possibility of inadvertent and unpredictable consequences of gene therapy to the patient, and the possible long-term consequences;
2. the need for long-term surveillance and follow-up;
3. the matter of consent, especially in view of 3.2.2 (a) above;
4. the probability that children will be among the first candidates for therapy;
5. confidentiality, and disclosure of genetic information important to kindred.

It is essential to ensure that these issues are properly considered, and to demonstrate satisfactorily that this has been done.

It is therefore recommended that, initially, somatic cell gene therapy should be governed by the exacting requirements which already apply to other research involving human participants in South Africa.

While the safety and effectiveness of somatic cell gene therapy remain uncertain, this new treatment, as with any other treatment, should be limited to patients in whom the potential for benefit is greatest in relation to possible inadvertent harm. We therefore recommend that the first candidates for gene therapy should be patients:

1. in whom the disorder is life threatening or causes serious handicap;
2. for whom treatment is at present unavailable or is unsatisfactory but forwhom treatment may be beneficial.

Gene therapy should be directed to alleviating disease in individual patients, although wider applications may soon call for attention. In the present state of knowledge, any attempt by gene modification to change human traits not associated with disease would be unacceptable.

3.2.3 Germ-line gene therapy
"The insertion of genes into fertilised eggs or very early embryos is fundamentally different because these genes would be passed on to the offspring in subsequent generations. Germ-line therapy should not be contemplated."^16,18

See Section 39A of the Human Tissue Act, No. 65 of 1983, which seems to prohibit the genetic manipulation of gametes and zygotes outside the human body in South Africa if there is any intention of implanting the zygote. (It is not clear if experimentation on the zygote or the pre-embryo would be permitted so long as implantation would not follow.)

This line of thinking is, fundamentally, the point of departure for most commentators on the ethics of gene therapy.¹⁶,b It is also a simplistic response to a complex ethical issue. The predominant feature of germ-line therapy which posits the greatest ethical dilemmas is also its greatest advantage:

"Gene modification at an early stage of embryonic development, before differentiation of the germ line, might be a way of correcting gene defects in both the germ line and somatic cells."¹⁵

It is fundamental to separate the various ethical issues surrounding germ-line gene therapy. There are at least three aspects to the ethical concerns raised. First, that relating to the research of germ-line gene therapy; second, that of the safety of the procedure and its impact on the patient; third, the public policy issues relating to the practice of germ-line gene therapy. The first two questions pose no new ethical concerns.18, c It is the public policy questions regarding the use and misuse of germ-line therapy, both in medical practice and outside of the practice of medicine, with which these guidelines are most concerned.

3.2.3.1 Public policy and the practice of germ-line gene therapy
There are no simple solutions to the dilemmas presented by the practice of germ-line gene therapy. On one hand, germ-line gene therapy may lead to the eradication of genetic disorders in the human genome; on the other, the line between the elimination of genetic disorders and the genetic enhancement of normal human traits becomes blurred.

"At present, no human germ-line manipulation is possible, and none, so far as we know, is contemplated in any part of the world...The question for the future is, whether the possible benefits might outweigh the disadvantages sufficiently to justify removing the current prohibition on research."¹⁸

It is with germ-line therapy that the question of boundaries is most starkly confronted. Once sufficient knowledge has been attained to evaluate the risks to future generations, the question of limitation becomes central. It is in this context that ethics becomes paramount.

Eugenics is widely defined. It accepts within its confines both the enhancement of certain human traits and the reduction of the incidence of certain severe hereditary diseases.14 It is seen to be either a private issue or a matter for State intervention. This book assumes a definition of eugenics that incorporates only the enhancement of attractive traits, either through social programmes or private operations. A universal response to eugenics in this sense is one of opposition.

"This is an approach to which people around the world object, because it denies human freedom, devalues some human beings, and falsely elevates the reproductive status of others...mandatory approaches, including refusal of marriage licences, forced contraception, forced sterilisation, forced prenatal diagnosis, forced abortion and forced childbearing are all affronts to human dignity...In undertaking genetic programmes such as carrier screening or biochemical screening in pregnancy, the primary goal must be the welfare of the individuals/couples, not the welfare of the State, future generations or the gene pool."¹⁴

Eugenics, better termed 'genetic enhancement', has dogged our history. Nazi Germany is only one example of the pursuit of eugenic goals. There are many current examples, and two are cited below.

"The government of Singapore instituted a policy of providing financial incentives to 'smart' people to have more babies. The California-based Repository for Germinal Choice, known more colloquially as the Nobel Prize sperm bank, has assigned itself the mission of seeking out and storing gametes from men selected for their scientific, athletic or entrepreneurial acumen. Their sperm is made available to women of high intelligence for the express purpose of creating genetically superior children who can improve the long term happiness and stability of human society."²⁰

Criticism of genetic enhancement is neither invalid nor inappropriated. There are many ethical dangers in pursuing genetic enhancement, including increased social inequality and a lowered tolerance for human diversity.¹⁴ One perceived consequence of the development of genetic knowledge is the use of genetic information in social policy development.²¹ This theme is developed by Jerome Bickenbach who surmises that:

"In times of perceived restraint on social resources, policy makers will be driven to seek ways of predicting future costs. Genetic information is optimal for these purposes. If a health care policy analyst could have at her disposal accurate information about the prevalence of a variety of mental and physical conditions in the population, then precise cost and resource projections could be made. If a specialist in income security policy could predict with accuracy the number of people who will need income supports in the next fifty years, she would be able to integrate this policy into the general supply-side labour policy, with considerable savings."²¹

Enhancement creates inequality in the competition for social goods such as wealth, status or power in a meritocracy²² and violates the goals of medicine.^14,e In this context genetic enhancement is seen to be a misallocation of scarce resources that would be better placed in serving medical practices. However, it begs the question to state that gene therapy should be limited to medical practices. What are the boundaries of a medical practice? One method of differentiating between genetic enhancement and medical practice lies in the definition of disease, and yet, how does one assess the significance between difference and abnormality?

Understanding that the potential for 'the most profound form of stigmatising' exists in the labelling of genetic disorders,²¹ it is suggested that the response to the question is not a novel one:

"The question of disease as currently assessed in the realm of clinical genetics is not entirely a hypothetical one. After all, counsellors and clinicians have been treating patients for genetic diseases for decades. It is instructive to look and see how they currently define disease and health."²⁰

Initially scientists took a restrictive view of what constituted a genetic disease. This was expressed in the view that "the simplest, most straightforward definition of a genetic disease (type 1) was a single locus defect, with a 100% heritability."²³ This definition evolved over the years to encompass "polygenic traits with less than 100% heritability... (type two)"²³ so that any traits which included a genetic component, fell within the ambit of the definition. The definition evolved further to encompass "complex behavioural traits where the evidence for heritability was less clear (type three)."^23,f It has been even further amplified by the inclusion within the ambit of 'genetic disease' of any trait which can be altered by gene therapy.^23,g The expanded definition no longer assumes the heritability of the trait. This is easily explained from a scientific basis,^23,h but from an ethical perspective it may not be advisable to adopt such a broad definition of genetic disease. This definition does not distinguish between medical and non-medical gene therapy.

The purpose of defining disease in the ethical context is to draw a distinction between acceptable and unacceptable gene therapy practices, those practices designed to prevent, correct or alleviate disease being acceptable while all other forms of gene therapy are not acceptable. However, it is not sufficient to delineate health as the basis for distinction. Health, like disease, is not readily ascertainable without reference to an individual opinion. Certain 'disorders' such as idiopathic haemochromatosis, which results in increased iron absorption, are an advantage to communities under starvation conditions, but are a disorder in any other circumstance.²⁴ The distinction between 'health' and 'defect' is particularly dangerous when applied to mental or intellectual capacities and behavioural traits - the ideal of a norm 'healthy', against which 'defect' is judged, cannot find a valid place in an eclectic society where diversity of opinion is protected by the most powerful law of the land. There must be other factors that can be used as indicators of what constitutes acceptable gene therapy.

Serious consequences follow the labelling of a condition as a genetic disease. For this reason, labelling genetic variations as abnormal or disease should be done with caution. One commentator states that:

"For now, clinical genetics ought to restrict itself to the identification and assessment of only those genetic states which are known to be dysfunctional as well as different. It should discourage efforts to allow 'fishing expeditions' to become part of prenatal, carrier or workplace screening. And, it should assert clearly that the central goal of human clinical genetics is the prevention or amelioration of disease, not the improvement of the genome."²⁰

It is recommended that further investigation of the distinction between medical and non-medical therapy be undertaken before gene therapy is considered. It is indisputable that prior to being introduced into medical practice, gene therapy must be ethically acceptable.¹⁵ To find a position which commands acceptance, requires wide consultation. In the interim, germ-line gene therapy should not be contemplated on human subjects. However, we have concluded that the development of safe and effective means of gene modification, for the purpose of alleviating disease in individual patients, is a proper goal for medical science.

"The way to handle legitimate concerns about the dangers and potential abuse of new knowledge generated by the genome is to forthrightly examine what are and are not appropriate goals for those who provide services and interventions in health care. There is nothing sacrosanct about the human genome. It is only our inability to openly and clearly define what constitutes disease in the domain of genetics that makes us feel that intervention with the germ line is playing with moral fire."²⁰

Thus, it is recommended that the necessary research on the distinction between medical and non-medical therapy should continue. It is clear that there is at present insufficient knowledge to evaluate the risks to future generations of gene modification of the germ line. It is therefore recommended that gene modification of the human germ line should not yet be attempted until such time that it is clearly sanctioned by South African law.

3.2.4 Supervision of gene therapy

3.2.4.1 Expert supervisory body
Continuing supervision of gene therapy is necessary. No existing body is constituted for this task. Therefore it is recommended that a new, expert supervisory body be established. An example of such a body is the British Human Fertilization and Embryo Authority.

The supervisory body should be of sufficient standing to command the confidence of existing Research Ethics Committees and of the public, the professions and Parliament. It should have a responsibility for:

1. advising on the content of proposals, including the details of protocols, for therapeutic research in somatic cell gene modification;
2. advising on the design and conduct of the research;
3. advising on the facilities and service arrangements necessary for the proper conduct of the research;
4. advising on the arrangements necessary for the long-term surveillance and follow- up of treated patients;
5. receiving proposals from clinicians who wish to conduct gene therapy in individual patients, and making an assessment of:
   1. the clinical status of the patient;
   2. the scientific quality of the proposal, with particular regard to the technical competence and scientific requirements for achieving therapy effectively and safely;
   3. whether the clinical course of the particular disorder is known sufficiently well
      • for sound information, counselling and advice to be given to the patient (or those acting on behalf of the patient)
      • for the outcomes of therapy to be assessable;
   4. the potential benefits and risks for the patient of what is proposed;
   5. the ethical acceptability of the proposal; and
   6. the informed consent documents (see 5.3, Book 1).

In the light of this assessment the expert supervisory body should make a recommendation on whether the proposal should be approved, and if so on what, if any, conditions. The supervisory body should also have a responsibility for:

6. acting in co-ordination with existing Research Ethics Committees;
7. acting as a repository of up-to-date information on research in gene therapy internationally;
8. setting up and maintaining a confidential register of patients who have been the subjects of gene therapy;
9. oversight and monitoring of the research; and
10. providing advice to Health Ministers, on scientific and medical developments which bear on the safety and efficacy of human gene modification.

It is recommended that any proposal for gene therapy be approved by this body as well as by a properly constituted Research Ethics Committee.

At first, and probably for several years, gene therapy will be applicable to a small number of uncommon disorders and be confined to a few patients. As with other new, specialised medical interventions, it is recommended that it be confined to a small number of centres while experience is gained.