Genome editing in human medicine
Methods of genome editing
The term genome editing is used to describe modern molecular biological methods that allow for targeted changes to be made to the genome of an organism. Due to their precision, modern methods differ from previous genetic engineering methods in two important ways. Firstly, the mutations caused by genome editing can rarely be distinguished from those that occur naturally. Secondly, modern methods usually do not introduce external genes or external sequences of genes; instead, the existing DNA is usually changed at a few precisely defined points.
Most modern methods consist of three similar steps. (1) A specific site of the genome, a gene sequence, must be identified and targeted by "probes" matching the target sequence. (2) The DNA double-strand is then cut at a precisely defined point. Newer methods such as prime editing and base editing do not require the complete break of the double strand. (3) Cellular mechanisms repair the breaks in the DNA, and the type of repair determines the effects of genome editing. In this way, individual genes can be disabled by the repairs (referred to as "knocking out" a gene), and sections can be inserted (insertion of a repair template) or removed (deletion) and thus altogether cause the formation of new properties.
The most important methods are the so-called designer nucleases CRISPR/Cas (clustered regularly interspaced short palindromic repeats), ZFN (zinc-finger nucleases) and TALEN (transcription activator-like effector nucleases). The most widely used is the CRISPR/Cas9 system. In the CRISPR/Cas system, the integrated RNA (referred to as the "guide RNA") is used to recognise the specific DNA sequence to be edited. In general, the RNA reads information on the structure of proteins from the genome of a cell. In addition to the integrated RNA, the CRISPR/Cas system uses the Cas protein (often Cas9) coupled to the RNA, which can be used to cut the genome. In general, the CRISPR/Cas9 system mimics a defence mechanism of bacteria directed at the unwanted invasion of the bacterium by a virus. As part of the bacterium's immune response, the genetic material of the virus is cut, rendering it harmless to the bacterium in the best-case scenario. The rapid, simple, and inexpensive production of these precise “gene scissors” quickly led to their use in complex research projects.
General areas of application
Since genome editing can be performed on all organisms, the scope of possible applications is wide. Important application fields include genome editing in plant and animal breeding and human medicine. The present “In focus” investigates the latter.
Introductory insights into the application of genome editing in plant breeding are provided in the “In focus” on Genetically Modified Foods.
Application areas in human medicine and research goals
Given the variety of potential areas of application and research goals, even in the field of human medicine, it is helpful to differentiate between the starting points of genome editing: either a modification of the genetic material of somatic cells is performed, which is limited to the individual patient (somatic gene therapy), or the genetic material of germ cells (sperm or oocytes and their precursors) is interfered with to change the genetic material of the offspring (germline therapy). Somatic gene therapy and germline therapy thus differ in the type of cells that are genetically edited.
Clinical application of genome editing for somatic therapy
The genome editing of somatic cells can support diverse processes in clinical practice. In addition to the treatment of genetic diseases, it can also be used, for example, in the treatment of diseases that were acquired only later in life, such as infectious diseases or certain forms of cancer. Beyond the treatment of diseases, genome editing can also support the prevention of diseases. In addition, genome editing methods could also be used for enhancement purposes, i.e., to improve certain human capabilities or characteristics that are not associated with a disease.
Clinical application of genome editing for germline modification
The ability to perform genome editing on human germ cells has only existed since the discovery of editing tools, particularly the CRISPR/Cas9 system. Genome editing at the germline level on human embryos has already been performed as part of several studies. Previously, the genome editing of germ cells was only possible in other organisms such as mice or rats.
Germline intervention (also referred to as germline therapy) aims to genetically modify germ cells, i.e., sperm, oocytes, or precursors of both cell types. While genome editing within somatic gene therapy can initially target only a selection of somatic cells, the modification of unicellular embryos, for example, allows the genetic modification to be completely passed on from this cell to all cells that divide from it. Since germ cells undergo cellular differentiation, genetic modification consequently permeates all or almost all cells of the human subject.
Germline interventions usually aim to prevent the transmission of serious genetic diseases and disorders to a person’s offspring. In addition, the modification of the genetic information of germ cells could also be used to alter other dispositions, capabilities or characteristics.
Genome editing and basic research in human medicine
Important insights into molecular biological processes from basic research may further the clinical application of genome editing. The possibility of disabling individual genes with editing tools generates questions on the positive and negative effects of the respective genes and their interaction in basic research. For example, some hope that genome editing research will reveal the causes of disorders during early embryonic development. At the same time, these findings, in the longer term, may speak to interactions at the molecular biological level; for example, they may allow for the tailored development and use of active substances.
Genome editing methods can also produce cell models, cell types, or even organoids that can generate insights into disease progression and the mechanisms of action of drugs in a more targeted manner. This includes the creation of genetically edited mammals for experimental purposes, which may be tailored to the needs of researchers and aid in the development of therapeutic options for serious diseases.
Although genome editing research on human cells often seeks to fulfil high-level therapeutic goals, it is accompanied by several central ethical issues.
The ethical problems and questions raised by genome editing in human medicine may be addressed at three stages. Before a clinical trial of genome editing in humans can take place, researchers must ensure that its implementation is overall ethically permissible and sufficiently safe. The extent to which interventions are considered safe is determined by the quantifiable risks and scope of the interventions. If, following the first stage of ethical evaluation, no reasons can be identified that generally speak against the application of genome editing in humans, a case-by-case weighing of risks with the potential therapeutic benefit follows that focuses on clinical aspects. For the ethical evaluation of human genome editing, it is essential to clarify the extent to which the therapeutic benefits outweigh the risks. Finally, in anticipation of possible clinical applications, further ethical implications must be considered, for example, concerning fair access to novel medical therapies or the impact of human genome editing on the social fabric of societies.
Before application: Genome editing of human cells and risk considerations
As with other novel procedures, the first requirement for genome editing in human medicine is that an application in humans must be deemed sufficiently safe. This requirement is largely based on the central biomedical principle of beneficence, often met by weighing the risks against the therapeutic benefits.
Risk considerations and the efficiency of editing procedures
To safely use individual genome editing methods in human medicine in the future, associated risks and side effects would have to be known and controllable, at least in certain respects. This necessitates an understanding of the mechanisms of action of genome editing, which can be determined by basic research on the process.
So-called off-target effects and on-target effects represent a significant challenge here. If the use of genome editing results in the modification of a DNA sequence other than the one that was intended to be modified, this constitutes an off-target editing effect. Undesirable off-target effects on somatic cells that have been observed include the formation of tumour cells. Off-target effects may thus pose challenges not seen in previous, conventional gene therapies. There is an increased likelihood of off-target effects during the editing of germ cells. This is because the process is associated with cell divisions, and cells divide particularly frequently in embryos, foetuses, and infants.
An unintended edit occurring in the targeted DNA sequence leads to an unwanted effect within the target region (referred to as an unintended on-target effect). This usually results from a faulty repair of the double-strand break, which can lead, for example, to the undesired insertion or deactivation of sequences. As a result, the therapeutically intended effect of editing fails to occur at all or to the extent desired, rendering the therapeutic intervention ineffective or only partially effective. Therefore, the depth of the intervention into the DNA (as a complete break or partial cut) as well as the success of the subsequent repair of the cut by cellular mechanisms are of decisive importance. Newer methods of genome editing which do not involve double-strand breaks in the DNA – so-called prime editing or base editing – are a promising alternative.
A further challenge associated with on-target effects is the occurrence of so-called mosaicism, in which the editing of some cells is successful but fails in others, leading to a poor result overall. This is particularly important in somatic treatments, for example, when the cells of several organs affected by disease need to be edited. In the context of germ cells, the unintended effects of cell editing are exacerbated by the fact that only partial control is possible following genome editing. This is because preimplantation genetic diagnosis (PGD) only allows for the examination of the cell taken from an embryo or foetus. Statements about successful editing can thus only be made about the specific cell taken from the embryo or foetus. The possibility to control editing is of great importance to a possible mosaic formation in embryos, since, later, undesired side effects could occur. Therefore, another important step in research on mosaicism is the further development of tools to detect these effects. Genome editing of artificial egg or sperm cells, among other methods, is being explored as a possible therapeutic solution.
From an ethical point of view, such knowledge gaps, i.e., uncertainties about undesired on- and off-target effects, are important because, given the desired therapeutic applications, the magnitude and scope of risks should first be weighed if these procedures are to be applied in the context of clinical studies in humans.
Specific risk considerations for germline editing
Unlike the use of genome editing methods for somatic gene therapy, the ethical discussion on germline therapy is focused not on conditions of clinical testing and application but rather on the overlying question of the extent to which its exploration can be justified. The ethical aspects of germ-line intervention were already being considered by the end of the 20th century. However, with the breakthrough of the CRISPR-Cas9 system, the technical feasibility of such an intervention changed, coinciding with the change in assessment of possibilities of technological assistance in human reproductive medicine.
The use of genome editing to alter the germline is associated with further risks for the offspring of individuals whose genomes have been edited. Since, in contrast to somatic gene therapy, the genetic alterations of germ cells affect all future offspring of the individuals whose genes were edited at the embryonic stage, adverse reactions resulting from the genetic alterations may occur in later offspring. This is because recombination of parental DNA occurs in each new generation, which could promote previously unknown genetic interactions. This profound impact on multiple people generations is compounded by the fact that editing is potentially irreversible, and thus cannot be interfered with, or can only be interfered with to a very limited extent, in the event of the occurrence of possible undesirable side effects.
From the perspective of research ethics, a difficult issue arises from the fact that the safety of the clinical application of germline therapy can only be assessed after it has been tested on human subjects. A central concern would be to determine the extent to which the editing of the germ cells manifests in all body cells over the course of the development of the embryo as well as in later stages of human development. A comprehensive safety assessment would also have to consider possible interactions between different genetic sequences and between genetic sequences and environmental factors. According to current research, the success of any genome editing can only be determined by examining the respective subjects of genome editing over the course of their development from the embryo to birth and beyond, including effects on the descendants. At the same time, given the depth and scope of the possible consequences, a degree of certainty on possible risks is needed before such clinical trials can be initiated to be able to justify testing in the context of a clinical trial.
According to the current state of research, the various ethical considerations outlined above regarding the safety of genome editing procedures have led many institutions and researchers to speak out against the use of germline intervention, including its current application in clinical trials, and to call for an international moratorium to limit its use.
Research on genome editing of germ cells and the use of embryos
Insights into the ways in which targeted, precise, and sustainable genome editing procedures can alter germ cells are only partially applicable to experiments in animals to human medicine. Comprehensive insights can result only from testing on human embryos. Experiments of this kind include the destruction of embryos for research purposes, the ethical evaluation of which is controversial.
The German Embryo Protection Act, for example, only permits modifications to embryos with the goal of ensuring embryo health during pregnancy. If modifications and thus also research on embryos that to not pursue this goal are illegal, many applications of genome editing on embryos could not be justified. Consequently, in Germany, further clinical research and application of germline therapy are prohibited by law. However, this strict prohibition could be opposed by the opinion that research on embryos may be permissible if it pursues high-level therapeutic goals. This means that modifying embryos in the context of research for genome editing could sometimes be justified as ethically permissible. Such a position is expressed, for example, in the 2017 statement on genome editing by the U.S. umbrella organisation for the science academies, the National Academies of Sciences, Engineering, and Medicine, which maintains the possible approval of genome editing of human embryos under strict conditions if conducted in pursuit of high-level therapeutic goals.
Clinical trials: the potential therapeutic benefit to human medicine
The potential benefit of genome editing of somatic cells
Gene therapy interventions in somatic cells have been performed with viral vectors for many years (for further information, see the “In Focus” on Somatic Gene Therapy). Although the use of genome editing methods is also newer in this area of application, there is prior knowledge of the effects on and interactions of alterations with the genetic information of human somatic cells due to the other gene therapy methods already in use. As a result, genome editing procedures are being used more frequently in this area of medicine. Consequently, ethical considerations in this context have been focused on clinical studies and their safety requirements. An assessment of the potential benefit of genome editing in the context of somatic therapy is then largely based on an evaluation of the therapeutic goals pursued as well as the availability of therapeutic alternatives. In the following, we present several therapeutic starting points that could justify the potential benefit of genome editing and a rationale for the admissibility of clinical studies.
Genome editing of somatic cells and the improvement of conventional gene therapies
A key goal of gene therapy research is to improve conventional gene therapies with the help of the CRISPR/Cas9 system. Newer, targeted genome editing methods may help meet this goal by reducing or completely preventing the occurrence of so-called insertional mutagenesis, which in some cases causes undesirable side effects due to unintended mutations in previous gene therapies.
Among the diseases that have been researched and partially treated – initially with the help of conventional gene therapies and, in recent years, genome editing methods – are genetically predisposed blindness, spinal muscular atrophy, β thalassemia, and certain forms of cancer such as leukaemia.
Another possibility for improvement is to reduce immune responses that can occur because of established therapies, such as those used to treat cancer, and thus weaken the effectiveness of the therapy.
Furthermore, genome editing procedures are expected to create improved therapeutic possibilities for unborn humans in utero. This form of genome editing is considered somatic gene therapy rather than germline therapy since it is performed on cells that have already differentiated beyond the germ cell stage. This therapeutic approach has potential especially where genetic diseases negatively alter several areas prenatally, such as in metabolic diseases like cystic fibrosis. Conventional somatic gene therapy, which can only be applied to people who have already been born, shows only limited therapeutic success in clinical settings because the disease has already manifested at the time of application. However, the success of genome editing therapies is also limited in some cases, largely because of the low efficiency of the transport of the editing tools to the affected tissue types and sites.
When weighing the therapeutic risks and benefits of somatic gene therapy utilising genome editing, it is, therefore, necessary to consider the extent to which established and less risky therapeutic alternatives exist, the efficiency of these alternatives, whether genome editing promises a cure instead of a treatment, and whether these aspects can justify the exposure to increased risks of genome editing.
Genome editing of somatic cells and the correction of cellular dysfunction
Finally, the use of genome editing in somatic gene therapy for humans may compensate for disease-related cell malfunctions. For example, research is being conducted on the extent to which genome editing may enable the activation or re-activation of genes in specific cells which could then replace or support the function of other cells. Among other benefits, this could provide a therapeutic solution to sickle cell disease since the disease is connected to the malfunction of specific blood cells.
Genome editing may have especially large potential in clinical settings where gene therapies have not yet been applied. For example, Leber's congenital amaurosis type 10 has previously been considered untreatable because too many sections of the genome would have to be changed at once if treated by conventional therapies. Genome editing also promises therapeutic possibilities for diseases in which the function of a gene does not need to be supported but rather the malfunction of a gene needs to be prevented, such as Huntington's disease, which could be treated by deactivating the malfunctioning gene.
The decision on the admissibility of clinical trials for these areas would have to take into account that there are no therapeutic alternatives. Thus, the potential risks for test subjects in a clinical trial would have to be weighed against the potential benefits of treating a previously untreatable disease. However, this balancing would also have to consider the fact that, given the novelty of the editing procedures, there is only partial knowledge of possible side effects – the test subjects in clinical trials could be unexpectedly confronted with undesirable, serious side effects. Thus, given the small number of trials of human genome editing procedures to date, these types of studies often fall into the realm of curative trials rather than clinical trials where the latter type usually aim to generate broader knowledge in the field of investigation and involve a larger number of participating subjects. Given the therapeutic lack of alternatives and the great potential of genome editing to treat or even cure previously untreatable diseases or those with limited treatment options, the incentive is usually very high to accept great risks.
Genome editing of somatic cells beyond the medical treatment of diseases
The expanded potential of genome editing methods entails further approaches in human medicine beyond the treatment of diseases that have already manifested. For example, research is being conducted into the ways in which targeted changes to the genome of humans can reduce susceptibility to viral diseases. Research also covers the potential of targeted genetic modifications to improve the immune response to diseases, such as viral diseases.
Furthermore, the modification of cells in the human body can be used not only for exclusively therapeutic purposes, i.e., those that treat diseases, but also for enhancement purposes. An ethical question related to this is whether the weighing of risks and potential benefits of the novel technologies of genome editing is different if the aim of use is not to alleviate or cure serious diseases but to improve characteristics or abilities that are not directly related to a disease.
The potential therapeutic benefit of germline alterations
The central therapeutic focus of germline alterations is preventing the transmission of serious genetic diseases. Research related to germline alterations focuses on monogenic diseases and involves the modification of the genetic sequences that cause diseases using genome editing techniques.
The established methods of preimplantation diagnostics (PGD) and germline therapy pursue the same goals of preventing the transmission of severe, monogenic diseases to offspring. However, in some cases, germline therapy offers therapeutic options not currently possible with PGD. In contrast to PGD, germline therapy can also create an embryo for couples for whom no (or too few) embryos can be obtained over the course of in vitro fertilisation (IVF) that do not bear a genetic alteration related to a specific disease. This may be the case, for example, if both parents carry a variant in their genome that should not be passed on or if medical reasons, such as the low availability of oocytes, prevent the creation of several embryos as part of a reproductive treatment.
Relatedly, previous gene therapy interventions for persons with severe genetic diseases are often only partially effective and must be repeated. Assuming successful research, the genome editing of germ cells in unborn persons or embryos who would likely develop these diseases could represent a more effective and less invasive therapy.
A similar therapeutic goal of germline therapy is the attempt to prevent the transmission of monogenic predispositions to serious diseases: for example, preventing the transmission of a genetic sequence that is highly likely to lead to serious breast cancer later in life.
Finally, another therapeutic goal of germline modification is the generation of genetic resistance to infectious diseases. In this context, the attempt of the Chinese researcher He Jiankui, who genetically edited two embryos to promote resistance to the HI virus (and one manifestation of the disease AIDS), received public support as well as criticism. The embryos subjected to genome editing were carried to term, and female twins were born in 2018.
Overall consideration of risks and therapeutic potential
Should genome editing take place in human clinical trials? An important step in answering this question is to weigh the risks and potential benefits of an intervention. Given the increased risks in the case of a germline intervention, a lack of knowledge about the probability of occurrence of possible damage, and the probability of occurrence of the potential benefit, a risk–benefit assessment may suggest greater risk. This interim consideration is also reflected in international legal regulations. In the European Union, for example, Article 90 of Regulation (EU) 536/2014 of the European Parliament and of the Council prohibits the modification of genetic information in germ cells in the context of clinical trials. Also, following the Oviedo Convention, modifications to the human genome that can be transmitted to offspring are prohibited within the European Union. However, these conventions, as well as other international conventions such as the UNESCO Universal Declaration on Bioethics and Human Rights (2005), are often not legally binding for all states, and their interpretation of germline intervention is not always clear. Consequently, at the international level, the pending agreement and adoption of joint international regulations on germline intervention aim to implement mechanisms of monitoring and control that prevent ethically contentious clinical trials in humans.
In contrast, the genome editing of somatic cells is considered and undertaken as ethically justified in selected clinical trials and some areas of application. This is again reflected in the legal regulation. For a detailed description of the general legal regulations on somatic gene therapy at the international and German levels, which also includes regulations on genome editing, see the “In Focus” on Somatic Gene Therapy.
Ethical principles: evaluation of genome editing beyond cost–benefit considerations
Beyond this ethical perspective more focused on weighing the opportunities and consequences of research and application of genome editing procedures in human medicine, complementary overarching ethical principles, such as those of non-maleficence, beneficence, autonomy and justice, can also be used to assess risks and benefits. The way in which a possible application of genome editing in human medicine is evaluated in individual cases therefore also depends on interpretations of principles such as beneficence and their scope. These principles complement the weighing of risks and benefits by setting ethical limits to certain considerations – for example, the deliberate discrimination of individuals in favour of the well-being of others – or by giving additional weight to certain opportunities or risks. For example, the prospect of a therapeutic cure for hitherto untreatable diseases could be given particularly strong weight in the sense of beneficence when compared to possible undesirable side effects. In its statement of 2019 on evaluating interventions in the human germline, the German Ethics Council suggested that, in addition to risk–benefit considerations, human dignity, protection of life and integrity, freedom, non-maleficence and beneficence, naturalness, justice, solidarity, and responsibility should also be taken into account as additional points of ethical orientation.
Wider implications: ethical aspects of widespread clinical application
The question of equity in the use and funding of genome editing procedures
In anticipation of a possible approval of genome editing procedures for human medical applications, the ethical question of those who should be able to use them also arises. This entails the substantive justification of claims to use as well as downstream questions of social justice.
As a basis for fair regulation of access to these procedures, the extent to which possible claims to the use of these procedures can be justified must be determined. General criteria in the context of human medicine are, for example, urgency, the severity of the disease, a lack of alternatives, and the prospect of success of the therapy. Regarding germline therapy, interpretations of reproductive autonomy are sometimes used to justify a possible claim of parents intending to use this treatment. In particular, individuals who wish to have a biologically related child but would pass on a genetic predisposition to a serious disease without medical intervention may wish to claim a right to use this treatment. Proponents of such a claim usually derive it from the concept of reproductive autonomy, which maintains that the desire for a genetically related child free from hereditary diseases is part of the parents' pursuit of personal fulfilment and well-being. Against such a justification of a claim to germline therapy, however, reference could be made to the widely researched and significantly less cost-intensive method of PGD. In this context, PGD represents an alternative, at least in cases where a monogenic cause of the disease is present. In contrast to genome editing, however, PGD requires the creation and, if necessary, destruction of several embryos, which is also subject to controversy.
Furthermore, for fair regulation of access to these procedures, the extent to which a possible claim to the use of genome editing can be met by society must be examined. This may consider how the financing of mostly very cost-intensive genome editing procedures fits into the social planning of healthcare. Questions about financing tend to take a back seat compared to other concerns about research on germline therapy (e.g., the potential irreversibility of the interventions or possible undesirable side effects for offspring). As in the case of other, novel treatment procedures, the distribution of costs would have to be based primarily on the relevance of the criteria of urgency, the severity of the disease, a lack of alternatives, and the prospect of success of the therapy.
Even if one assumes that the criteria of urgency, the severity of the disease, individual need due to a lack of alternatives, and the likelihood of success of the therapy are fulfilled – especially in the context of the somatic use of genome editing methods, for example for the treatment of sickle cell disease (a method explored in many promising studies) – these criteria must be weighed against the costs of such treatment. Fundamental ethical considerations include the distribution of scarce financial resources for healthcare to those in need. If one grants reimbursement of the high costs of treatment with editing procedures to individual persons who are eligible according to the criteria mentioned above, the costs of treatment for other persons with less serious illnesses may not be covered. However, depending on the treatment costs for the unreimbursed group, there is a risk of underuse, as some individuals will decide against the treatment given cost-sharing requirements.
Other fundamental considerations are related to the definition of costs, i.e., the range of possible costs included in a trade-off. Very high costs for the treatment of individual persons with genome editing procedures would also have to be compared in a holistic approach with the costs of refraining from such treatment. In addition to the costs of the alternative, possibly less successful, treatment methods, travel and care costs – including costs for the training and labour market which may arise if a person is unable to pursue regular work in the long term due to an alternative and less effective treatment – should be taken into account.
In addition, societies vary in their willingness to assume the costs of treatment based on the principle of solidarity. Societies differ, for example, in their beliefs on how the age of a patient should be factored into decisions on the allocation of scarce financial resources in the healthcare system. Decisions on the reimbursement of treatment costs will also vary between societies.
The complex need to both finance the sometimes extreme costs of treatment and provide medical treatment to sick persons is met with different financing models. These range from partial cost-sharing to reimbursement procedures based on individual therapy results. Such models are complicated by the varied possibilities for financing between different countries with different levels of economic development. Beyond the question of the fair distribution of healthcare resources within a society, there are thus also ethical questions about the global distribution of healthcare resources.
Autonomy and personal rights of persons whose genome has been edited
In the previous presentation of the risks of genome editing in the modification of the human germline, reference was already made to the occurrence of possible undesirable side effects for the offspring of persons whose genome was edited in the embryonic stage. Furthermore, it was emphasised that genome editing may be irreversible and that the safety of the procedure can only be assessed after human experiments have been carried out. Apart from these ethical considerations, which are related more to concrete risks, supplementary aspects related to the protected interests of autonomy and personality can be included in a comprehensive ethical evaluation.
Regarding the central ethical protection of autonomy, questions arise regarding the extent to which genome editing on embryos represents a promotion or restriction of autonomy. For example, editing aimed at preventing a serious hereditary disease could promote the autonomy of the human subject by giving them a wider range of options to make a positive contribution to their own health. On the other hand, it could be considered a restriction of autonomy in that the human subject as an embryo could be inadmissibly instrumentalised by the intervention. Instrumentalisation could arise because they could not actively consent to the risks associated with genome editing.
The preservation of the personal rights of individuals grown from a genetically edited embryo may also come into question: while the treated individuals may not wish to disclose the genome editing performed on them, at the same time there is a great interest, at least for researchers, in being able to accompany the development of these individuals through longitudinal studies in order to gain knowledge about the efficacy and continuity of the therapy.
Societal implications
Finally, from an ethical perspective, overarching questions arise regarding the possible consequences of the application of germline therapy not only for individual societies but also for humanity. A broad application of germline therapy to prevent the inheritance of selected diseases could, for example, result in discrimination against those who, despite the existence of the treatment, continue to have diseases or impairments. Or, in contrast, those whose genome has been genetically edited at the embryonic stage may also experience discrimination.
In the case of germline therapy applied across several generations, a broader question has been raised of how this intervention should be evaluated from an ethical perspective when considering its potential effects on the entire human gene pool. This may encompass considerations of the naturalness of the human genome, the genetic resilience of the human species, and mutual respect.
The danger of a slippery slope?
Critical voices, particularly those who have scrutinised genome editing in germline therapy, point to the danger that even narrowly defined, clearly regulated research on and applications of germline therapy could, in the longer term, result in cases no longer morally justifiable following their initial ethical evaluation. This so-called slippery slope argument has been raised in several other bioethical contexts. The extent to which such an argument is valid depends, among other things, on whether the initial action – in this case, the narrowly defined possible approval of germline therapy – directly leads to later action deemed ethically impermissible. It must also be possible to precisely describe this morally reprehensible act, as a general reference to the development of eugenic tendencies within a society, for example, is not sufficient.