Degree project, 30 ECTS 2020-01-15
Preimplantation genetic diagnosis and therapy
in humans
-
Opportunities and risks
Version 2
Author: Rickard Hedberg, MB
School of Medical Sciences Örebro University Örebro Sweden
Supervisor: Rolf Ahlzén, MD, PhD
Ethical Consultant, Region Värmland, General Practitioner, Assistant professor in medical humanities
Word count
Abstract: 249 Manuscript: 5882
Abstract
Introduction
Preimplantation Genetic Diagnosis (PGD) was developed in the 1990s and has been used since to diagnose and discard embryos with genetic conditions or chromosomal abnormalities. CRISPR-Cas9 was discovered in 2012 and has been used in research, but has not become clinical practice on humans yet. CRISPR-Cas9 could potentially be applied to treat and prevent genetic disorders.
Aim
The aim was to investigate the ethical dilemmas of each method through a set of research questions. The ethics of applying PGD according to Swedish guidelines and applying CRISPR-Cas9 on humans was investigated.
Methodology
This was not a systematic literature review. Instead, articles have been selected based on their explanation of each method and uniqueness or volume of ethical arguments surrounding each method, that is of relevance for the discussed issues.
Results
Arguments in favour of PGD addressed among other things the somatic and psychological health of future children and parents along with the economical benefits. Arguments against PGD addressed different dilemmas of discarding an embryo and thereby a future individual. Arguments against CRISPR-Cas9 addressed technical limitations, our limited knowledge of genetics and more. Arguments in favour addressed benefits in clinical medicine and research. Conclusions
PGD according to Swedish guidelines was found to be ethically acceptable, since its restrictive use that have not given room for ethically dubious applications. CRISPR-Cas9 was found not to be safe enough for human applications at this moment due to technical limitations. If these were to be solved, caution and restraint must be urged.
Key words: Preimplantation genetic diagnosis, CRISPR-Cas systems, gene editing,
1.1 Introduction
By the year 1869, the Swiss physiological chemist named Friedrich Miescher discovered a substance with high phosphorous content that exhibited a resistance to protein digestion while examining the protein components of white blood cells (WBCs). He called this substance “nuclein”, which came to be known as deoxyribonucleic acid (DNA)[1].
The function of DNA remained unknown until 1944 when Oswald T. Avery, Maclyn McCarty and Colin MacLeod made the discovery that DNA was coupled to inherited traits[2]. 9 years later, Crick and Watson discovered and presented the chemical structure of DNA[3]. Their research sparked further research into DNA, ultimately leading to discoveries such as preimplantation genetic diagnosis (PGD) and tools for gene editing, which was earlier only envisioned as futuristic fantasies in novels such as “Brave New World” by Aldous Huxley, published in 1932[4].
PGD is a technique that was developed in 1990, which enables the identification of chromosomal or genetic abnormalities in embryos produced via in vitro fertilization (IVF). After fertilization, an embryo biopsy is conducted in order to examine the embryo’s DNA regarding the presence or absence of specific genetic or chromosomal abnormalities[5]. The biopsy is carried out either on day 3 when the embryo consists of approximately 8 cells or during day 5-6 when the embryo consists of hundreds of cells[6]. Embryos in which the unwanted mutation(s) are detected become discarded[5].
According to Swedish guidelines, PGD may be used in cases where a couple has a large risk (usually 25-50 %) of having children with a severe genetic or chromosomal disease that entails a shortened lifespan or much suffering[7]. The present Swedish guidelines have been developed from and are regulated by “The law (2006:351) on genetic integrity”[6–8]. This law was revised in 2006 after a statement from the Swedish state’s council on medical ethics (SMER)[9]. The indications for PGD use may be categorized into two separate groups:
1. Hereditary chromosomal abnormalities (such as Robertsonian translocation and repeated trisomy’s)[10]
Gene editing dates to the 1970s, when transgenesis was first utilized in mice. Transgenesis was able to introduce a “transgene” into a cell. However, it was incapable of performing a targeted insertion into the genome. In the 1980s gene editing via transgenesis was improved by the usage of embryonic stem cells, which allowed for directed alterations in the genome to a higher degree. Nevertheless, the success rate was proved to be less than 10 %[12].
In the early 2000s much research was put into discovering new methods for gene editing. This led to the discoveries of zinc finger nucleases (ZFNs) in 2005 [13] and transcription activator-like effector nucleases (TALENS) in 2010 [14]. These methods were the first to be able to recognize specific sequences of DNA and cause double-stranded DNA breaks in these, subsequently leading to the activation of cellular repair processes in order to prevent apoptosis. However, these methods required considerable time and effort, which limited their usage [15]. In 2012, the bacterium Streptococcus pyogenes was found to possess a viral defence system that could function as a programmable gene editing system[16]. It contains two parts, the RNA molecule called “Clustered Regularly Interspaced Short Palindromic Repeat” (CRISPR) and the “CRISPR-associated protein 9” (CAS9). CRISPR guides genome targeting while CAS9 acts as an endonuclease in order to cause double-stranded breaks[16]. CRISPR was found to be able of being manipulated into a “single guide RNA” (sgRNA), which could be designed to target a specific genomic area. CRISPR-Cas9 was found to be capable of editing human, as well as other mammalian, genome with a higher efficiency and selectivity than ever before witnessed[17]. CRISPR-Cas9 is the method for preimplantation genetic therapy (PGT) that will be the focus of this paper.
2 Aims, methodology and ethics
2.1 Aim and research questions
The primary aim of this essay is to examine the ethical implications of PGD and PGT. The following research questions will be answered in order to achieve the primary aim:
• Which risks are associated with the use of PGD and PGT on human embryos? • In which ways can PGD and PGT be used on embryos to benefit their future health? • In which ways can PGD and PGT be used in favour of or against the principles of “do
2.2 Methodology
The study relies on a combined text-analytical and idea-analytical method with a hermeneutic approach. This implies searching for meaningful elements in texts and searching for relevant arguments in relation to the research questions. This does inevitably implicate a subjective element in selection and interpretation. The authors preunderstanding as well as the values and assumptions he carries with him into the study must be acknowledged and put aside as far as possible. The intention is to achieve as nuanced and broad analysis of the research questions as possible.
Search words
The database PubMed was used while searching for articles. The chosen search words were: (“Crispr cas9”) AND preimplantation genetic therapy, (“Crispr Cas9”) AND (“ethics”), (Preimplantation genetic diagnosis) AND ethics.
Selection of articles
This study is not a systematic literature review, instead, 25 articles which provided information surrounding the mechanisms and/or ethics of PGD and PGT through CRISPR-Cas9 were selected. Articles were selected based on: (1) their explanation of the mechanisms of either method, the presence of a (2) large volume or (3) unique ethical arguments that were relevant to the research questions.
The authors preunderstanding
The author did not hold any opinions regarding these techniques nor ideas of how these techniques should be applied at the beginning of this work.
Delimitation
At present, several forms of PGT exist, some of which are presented in the introduction. However, in this essay, focus will be put on a specific type of PGT called CRISPR-Cas9 since it has come to dominate in research because of its affordability and simplicity compared to earlier types of PGT and thereby its greater potential for widespread application on humans in the future. Commonly presented ethical arguments addressing PGD and PGT will be presented in the results section.
This essay will be limited to applications on humans, even though CRISPR-Cas9 could be used on other species.
PGD may be used in different ways, in this essay, PGD in accordance to Swedish guidelines will be discussed.
Only scientific literature was included, since popular science and mass media tend to focus on sensational aspects such as enhancement or curing severe genetic conditions, while overlooking less sensational aspects such as technical limitations.
2.3 Ethics
There was no personal sensitive information collected and analysed in this essay, which instead is based solely on texts on a general level. There were hence no ethical considerations involved.
3 Results
Several articles addressing the ethics of PGD and CRISPR-Cas9 were found and selected. Arguments from these articles will be presented in the results section and discussed in the discussion. Some of the presented arguments address overlapping areas from different angles.
3.1 Ethics surrounding PGD
Four sources[5,9,18,19] addressing the ethics of PGD were found. The arguments in favour of and opposition to PGD in accordance with Swedish guidelines will be presented here.
3.1.1 Some arguments in favour of the usage of PGD in accordance to Swedish guidelines are: • The unborn child will not be afflicted by a serious disease that would cause somatic as
well as psychological suffering for the child and its family.
• The cost of PGD is a known expense, whereas the costs of a potential severe chronic condition may be greater and present as recurring testing and treatment for the condition and lost income.
• There may not be any other treatment, or a treatment that is associated with severe side effects and low efficacy.
• Some would argue that it is morally acceptable as well as emotionally easier for the parents to discard a five or six day old embryo with a severe genetic condition compared to aborting a 12 week old foetus with the same condition after having been detected through prenatal testing.
3.1.2 Some arguments against the usage of PGD in accordance to Swedish guidelines are: • It is not always possible to predict if there will be an effective and affordable treatment
for the condition by the time of onset.
• Afflicted individuals may have healthy lives and a high quality of life for several decades before the onset of the disease.
• An autosomal dominant genetic disease may have variable patterns of expression and penetrance, thereby in some cases causing a milder form of the disease, perhaps even a subclinical form.
• Selecting to discard an embryo because of a condition, may devalue the lives of individuals with that condition by sending a message that a life with that condition is less worth living than a healthy life or that individuals with that condition should not be born. Furthermore, some would argue that simply discarding embryos is morally reprehensible.
3.2 Ethics surrounding CRISPR-Cas9
Risks associated with Cas9 may be divided into two groups: (1) Risks if CRISPR-Cas9 does not function as intended. This group consists of technical limitations that are yet to be solved. (2) Risks if CRISPR-Cas9 functions as intended, this group encompass many more areas.
3.2.1 Risks if CRISPR-Cas9 does not function as intended:
• Off-target effects: a mismatch of one to three base pairs (bp) between the target site and the sgRNA (CRISPR) may be tolerated, thereby allowing for targeting of unintended sites. I.e. in addition to altering the intended gene, one or several other genes may be targeted, thereby causing unknown and unintended mutations. These mutations may knock out the gene, increase or decrease its activity[20].
• Insufficient vectors: failing to deliver CRISPR-Cas9 to all cells may lead to mosaicism and thereby reduced or no effect of the gene edit. [21].
• Screening for off-target effects and mosaicism is difficult, giving an increased risk of a failed treatment being undetected until the patient or it’s descendants exhibit symptoms of disease[20,21].
• Host response to viral vectors: In order to overcome the risk of mosaicism, viral vectors have been tried, since they may enter cells efficiently and broadly. Viral vectors have historically been associated with a risk of eliciting a strong immune response causing adverse events such as severe illness or death. If CRISPR-Cas9 was to be used in somatic cells of immune competent patients, this risk is to be taken into account[21]. 3.2.2 Risks if CRISPR-Cas9 functions as intended
• Editing of genes with several and/or unknown functions: many genes have more than one function and the functions of many genes are yet to be discovered. Editing one gene may therefore result in unintended effects[22].
• Iatrogenic injuries: increased maternal risk of ovarian overstimulation syndrome will always accompany technologies that require prior IVF, such as PGD and CRISPR-Cas9[22].
• Non-therapeutic use: in history, technologies and techniques that initially was intended for therapeutic treatments, have come to be utilized in other, initially unintended, areas such as enhancement or cosmetics. E.g. plastic surgery was intended to treat victims of disfigurement due to war, however, today it is widely used for cosmetic applications. Although, some argue that this may not be problem[21].
• Flawed therapies: even if the therapy were to be developed to have no off-target effects, defective batches that by mistake are designed to target a similar, yet different site than was intended could be produced[22].
• Could lead to a society in which individuals are valued and treated differently exclusively based on their genetic traits[23].
• Could incite pressure from special interest groups, companies or patients to use the technology for inappropriate or premature applications[24].
3.2.3 Potential benefits from usage of CRISPR-Cas9 in research:
• Could be used for studying developmental, regulatory and signalling pathways[25]. • Could be used for studying the effects and interactions of different genes, alleles and
combinations of alleles[25].
3.2.4 Potential benefits from usage of CRISPR-Cas9 in clinical medicine:
• Prevention of genetic diseases. The most self-evident application mentioned in articles is against diseases with mendelian inheritance, since onset of these diseases are most easily predicted[21,25–27].
• There are highly rare cases in which a couple are unable of producing a healthy offspring with PGD, e.g. if one parent is homozygous for an autosomal dominant condition, the mother is homozygous for a X-linked dominant condition or both parents are homozygous for an autosomal recessive condition. In these cases, CRISPR-Cas9 would be the sole method for giving rise to a healthy offspring[21,26,25].
• Increased ability to target mitochondrial diseases: currently, inherited mitochondrial disease may only be avoided through mitochondrial replacement therapy (MRT), requiring a healthy egg cell donor, thereby limiting the availability of the technique. With CRISPR, pathogenic mutations in maternal mitochondrial DNA (mtDNA) could be repaired[26].
• Economical: in many cases the cost of germline editing is lower or at least more easily determined than that of testing for, monitoring progress of and treating a genetic disorder, as well as the costs that potential loss of income poses[28,29].
• Avoiding abortions: germline editing could allow couples with a known high risk of passing on genetic diseases to avoid the distress of testing and potentially terminating pregnancies in order to produce a healthy offspring[30], as well as the potential maternal health risks, however small, of abortion[22]. Furthermore, the ethical dilemma
of aborting a foetus or discarding an embryo on account of a genetic disease would be circumvented[31,32].
• Compared to PGD, fewer IVF cycles and the production of less embryos for testing and treatment would be needed to produce a healthy and viable embryo ready for implantation, thereby reducing the risk of ovarian hyperstimulation syndrome, as well as reducing the discarding of otherwise viable, yet not as healthy embryos[22].
• Polygenic diseases: compared to the case of monogenic diseases, using PGD to select embryos without polygenic diseases would require a larger number of embryos in order to find a low-risk embryo, thereby reducing the rate of success. Germline editing would be able to treat an affected embryo[22,27].
• Some mention the potential to eliminate heterozygous carriers of recessive diseases and thereby achieving eradication or reduced prevalence of recessive genetic diseases, this may however be unlikely since it would require extensive testing of the entire human population[33].
• Could be used on cells, tissues and organs instead of embryos, thereby curing genetic diseases that only affect a specific cell type, tissue or organ[21]. For example, targeting hematopoeitic stem cells in the case of hereditary spherocytosis, thereby avoiding spherocytosis of erythrocytes and subsequent hemolysis.
4 Discussion
In the discussion, PGD will first be examined and then CRISPR-Cas9, there will however be comparisons between the two techniques throughout the entire discussion. In both cases, safety and potential harm is first to be discussed, then comes the questions of limitations, benefits, enhancement and autonomy.
PGD is in many ways safer than CRISPR-Cas9 because it does not impose any genetic changes on the embryo. Instead, it is to be viewed merely as a diagnostic tool used to determine if an embryo will be affected by a genetic or chromosomal condition. Based on this information, an embryo without the condition is selected, while embryos with the condition are discarded. There have been concerns regarding if the biopsy, where one in eight or one of hundreds of cells, depending on when the biopsy is done, is removed from the embryo, may cause any future harm. No such harm has yet been found[18].
In most cases PGD is enough for a couple with a high risk of passing on a monogenic condition to select an embryo without that condition. However, there are rare cases in which it is difficult or impossible for a couple to produce a healthy offspring via PGD, e.g. if one parent is homozygous for a dominant condition or if both parents are homozygous for a recessive condition. In these cases, every offspring will be affected by the condition and germline editing via CRISPR-Cas9 could be the only way of having a child free from the condition. In some articles[21,34] it has been proposed that CRISPR-Cas9 could be applied only in cases where PGD is insufficient.
At first, PGD sparked fears of being a tool for creating designer babies, since it could be applied to select embryos based on other traits, such as gender, hair colour and eye colour. However, Swedish guidelines only allow PGD for severe conditions with a high risk of being passed on. Thereby, the risk of a society where PGD is used to select between traits that are not associated with disease is circumvented. Moreover, PGD would be difficult to apply for these aims, since it would require many more embryos in order to select based on complex polygenic traits or combinations of traits. This fact might on the other hand be viewed as a limitation of PGD
when treating polygenic conditions. Although, in Sweden this limitation is no issue since PGD is restricted to monogenic diseases.
PGD does however lead to the parents selecting between different embryos based on the presence of a condition, which raises the question of which moral status an embryo ought to be assigned. It may be questioned whether selecting and discarding embryos is necessary or ethical. If an embryo is assigned the same status as an individual that is born, the only consistent conclusion would be to not allow anything that involves discarding embryos, such as IVF and research on embryos. However, in this case, it would also be consistent to assign the same status to a foetus, which would lead to abortions being prohibited. Since many would find it difficult to argue for a ban on abortions, it would be inconsistent to assign more rights to an embryo outside of the uterus, than to a foetus within the uterus. One could therefore insist that selecting between and discarding embryos is at least as morally acceptable as an abortion and perhaps even more acceptable, depending on which moral status it is assigned.
When discussing benefits of PGD, there have been questions about who the ensuing selection benefits. Some[5] point out that PGD does not benefit the affected individual, since it means that it will not be implanted and born. The selected individual benefits in the sense that it is the only way it will come to be born. However, the health of the selected individual is not affected by PGD, since there is no scenario in which it would be born with the condition.
Therefore, one could claim that while PGD does not give a personal health benefit, since there is no scenario in which the affected embryos will be born healthy, nor the selected embryos will be born unhealthy. Instead, one could reason that PGD has an impersonal benefit, since it entails that of all those that are born, fewer will have a genetic or chromosomal condition. Thereby, the overall amount of suffering would be reduced. PGD and the ensuing selection could be viewed as part of preventive medicine.
For the parents, this selection would mean having a healthier child and avoiding the emotional and psychological stress of potentially having to see their child suffer from a severe condition. Although, one may ask whether it is ethically acceptable for a couple to choose between different potential children. It is already permitted for parents in Sweden to abort a foetus based on the presence of genetic conditions or chromosomal abnormalities, which is a right that many would find difficult to oppose. Selection after PGD merely makes the same process of
producing a healthy child more time efficient and emotionally easier for couples who run a large risk of passing on a condition, since it circumvents the risk of repeated abortions.
On the other hand, allowing parents to select embryos via PGD could be interpreted as if a genetically healthy life is more worth living than a life with a severe genetic condition is. Based on this interpretation, some[5,18] suggest that PGD may devalue the lives of those with severe genetic conditions by implying that they should not be born. However, before the PGD, several IVF cycles take place under which embryos are selected based on morphological appearance among other factors. This selection occurs in order to find embryos with a lower risk of implantation failure or miscarriage[5]. Selection via PGD could be viewed as only one more selection process among others at this stage.
Moreover, there are many other examples in society of selective reproduction aimed to reduce congenital diseases and/or defects, e.g. when women in areas that was affected by the Zika virus outbreak were recommended to not become pregnant for some time, or that fertile women who take teratogenic medicines are recommended to use a safe means of birth control as long as they are on that medication. The motives of this could be interpreted as a will to give one’s children the best conditions for a healthy life.
At present, the reproductive autonomy of couple’s has been increased through means of birth control, prenatal testing, as well as IVF and various fertility enhancing methods. PGD takes reproductive autonomy one step further by making it easier for parents to have healthy children. According to one source[5], the price of both IVF (adjusted for success rate of IVF) and PGD per healthy live birth was roughly one tenth of the lifetime health care cost of one individual being tested and treated for cystic fibrosis (CF). In addition, the loss of income due to having a condition may be added. Given that the risk for two heterozygous carriers of the defective allele of the CFTR gene for CF is 25 % of having a child with CF, the number needed to treat (NNT) in order to prevent one case of CF is 4. If adjusted for the NNT 4, the cost of IVF and PGD would amount to roughly 40 % of the cost of one case with CF. From an economical viewpoint, prevention via PGD would in many cases be preferable to treatment of a condition, even after adjusting for NNT. Health care resources could instead be allocated elsewhere, thereby benefiting other groups of patients.
However, there are techniques for prenatal testing that are cheaper, non-invasive and allows the discovery of chromosomal abnormalities and genetic conditions around gestational week 11-12. Moreover, most couples are unaware of whether they run a risk of passing on a condition and will use prenatal testing instead of PGD, thereby limiting its use in favour of more prenatal testing. In summary, PGD according to Swedish guidelines could entail a higher level of public health, reduced health care costs and reduced demand for health care, while circumventing the risk of being used for unnecessary or ethically dubious applications. The effects of PGD are small, since prenatal testing fills much of its role.
Before addressing any other ethical dilemmas regarding CRISPR-Cas9, the safety aspect must be discussed. If CRISPR-Cas9 can not be safely applied, many[22,25,26,30] agree that it can not be used in clinical settings.
Off-target effects may give rise to a new genetic disease or in rare cases be an enhancement of the individual. Because of the difficulty of screening for off-target effects, these might not be detected for several generations if the off-target effect gives rise to a recessive genetic condition, a genetic disposition for various disorders or a disease with anticipation, i.e. one that develops over generations with an even greater severity for each passing generation. During that time, a large number of individuals may have become carriers or even affected. Moreover, even if it were to give rise to a dominant disease, it is not certain that it would be discovered early, since dominant diseases may present at any point in life and with different degrees of intensity even within a family, ranging from subclinical to severe forms.
Some argue that off-target effects could be reversed through CRISPR-Cas9. However, if the technique is still prone to off-target effects, attempting to reverse these would be associated with the risk of causing further off-target effects, thereby exacerbating the situation.
Furthermore, if the treatment fails to give rise to the desired genetic change and instead causes a new harmful genetic mutation that is discovered many years after the individual is born, some fear that the individual could be subject to restrictions regarding how or even if he or she may procreate[22]. If such restrictions would arise, then we might be on a slippery slope towards implementing reproductive restrictions on individuals who carry alleles for genetic diseases without having received these through genome editing. If an affected individual unintentionally were to become pregnant or cause a pregnancy, the moral dilemma of such restrictions would be taken to its extreme.
If CRISPR-Cas9 would be improved to be safe, the question to which extent it should be applied arises. Some argue that one approach would be to only allow CRISPR-Cas9 for severe genetic conditions with a high risk of inheritance that are difficult or impossible to prevent via PGD[22,25,35]. This may be a prudent first step, since many conditions may be prevented without germline gene editing, thereby circumventing the risks thereof.
Allowing CRISPR-Cas9 for therapeutic applications would inevitably lead to the question whether some applications could be regarded as therapeutic or non-therapeutic. For example, if an individual would be born with a mutation that renders him or her completely blind, many would agree that using gene editing to prevent blindness would be a therapeutic application. Although, the question of how severely impaired vision it would require for this edit to be viewed as therapeutic rather than non-therapeutic would have to be settled. When it comes to restoring a function to normalcy, there may be a grey zone between therapy and non-therapy even when the gene edit occurs on the very same gene. This could be solved by setting cut-off limits, however, these limits could be viewed as arbitrary. It may be easy to state that improving human function above what is natural, is to be regarded as enhancement. However, whether restoring mildly or partially impaired function to normalcy is enhancement or therapy may be debatable, even if it may not to be regarded as a necessary therapy.
The argument against CRISPR-Cas9 because of potential non-therapeutic applications may not be regarded as a strong argument against gene editing[22,27]. Just like CRISPR-Cas9, PGD could also be used for non-therapeutic applications. Instead of restricting PGD for all applications due to this potential, it is only permitted for specific therapeutic applications. Equally strict restrictions could be applied on CRISPR-Cas9 in order to prevent non-therapeutic applications.
However, in what ways could genetic enhancement be positive or negative? For the genetically enhanced individual, it could imply advantages such as improved eyesight, higher intellect, reduced risk of cardiovascular disease, improved athletic performance, etc. When we exercise, eat healthy and undergo laser surgery for improved vision, we enhance ourselves. It may be hard to argue against enhancement through exercise and healthy eating. Some argue that genetic enhancement may be equally desirable[27], since it would increase our health and quality of life. Others would argue that it is morally corrupt, a modern approach to eugenics and would cause an exacerbation of inequality by creating a caste of genetically superior superhumans[22].
In one study, mice with twice as long lifespan were produced via germline editing[36]. Some argue for applying gene editing in order to decelerate the normal aging of humans and thereby extending our expected lifespan[27]. One could reason that an increased lifespan, combined
with increased health, would allow us to spend more years with our loved ones, as well as work longer and thereby add more value to ourselves and society. For example, instead of working between the ages of 25 to 70, a doctor could potentially work safely until the age of 120 or more, thereby accumulating greater experience, competence and ability to help patients as well as tutor younger colleagues than ever before seen.
Some argue[24] that CRISPR-Cas9 could have the potential of enhancing humans by introducing genetic traits previously not found in humans. Whether or not this is desirable is subject to debate. It could be dangerous since we can not know for certain if non-human genes will have the same effect in humans as in other species, nor how these genes would interact with genes already present among humans. The same applies for new alleles for already existing human genes. For these reasons, it would be safer to only introduce alleles that are already common and known to be safe in human populations.
“The end justifies the means”, was by the German writer and philosophy historian Johann Gottlieb Buhle ascribed to the Jesuits. In German “dass der Zweck das Mittel heilige”, more correctly means “that the purpose sanctifies the means.” The eugenics movement of 19th-20th century applied means which instead desecrated the purpose of human genetic enhancement, thereby making it unthinkable and morally repulsive given the historical context. With CRISPR Cas9, human genetic enhancement could occur without the use of such morally repulsive methods. One could consider if it truly is morally wrong if the method itself does no harm, the purpose is to do good and the consequences are good. Enhancement of human traits may be complicated since the understanding of the genetic background to traits such as intelligence or being athletic are unknown. Moreover, it is difficult to make a clear and measurable definition what being intelligent or athletic truly means, partly because these traits may be heterogenous combinations of a vast array of aptitudes and attributes.
Given these complexities, attempting human enhancement via gene editing would at the very least be premature and in the worst-case scenario, human enhancement could prove to be dangerous since it may have unintended and dangerous effects.
When discussing human enhancement and the line between therapeutic vs. non-therapeutic applications, the question of to which extent PGD and CRISPR-Cas9 should be used arises. Many[21,22] would agree that there is a lower threshold for accepting genome editing in
somatic cells than germline cells, since any mistake that occurs will only affect the treated individual and may not be passed on to his or her descendants. Perhaps a first step once the technical limitations of CRISPR-Cas9 are solved would be to allow it only on somatic cells in order to avoid the multigenerational risks of germline editing. There are concerns about allowing gene editing since it may lead to a slippery slope in which the boundaries for what is allowed are ever shifting. One could also imagine that as time passes, a more relaxed attitude towards gene editing will arise, thereby allowing for wider applications. Proponents of gene editing could argue that it would allow for the eradication of genetic conditions, as well as increase our quality of life by improving upon traits such as eyesight, intellect, physical strength and endurance, our looks and much more[22,27]. Opponents to gene editing could argue that it might lead to society in which an individual’s genetic makeup is viewed as ever more important [22].
In ethical discussions surrounding PGD and CRISPR-Cas9, autonomy and consent is by some used as an argument for caution, while others dismiss the notions of autonomy of embryos and consent of unborn future generations. Germline gene editing would inevitably occur without the consent of the yet unborn child and its potential future descendants. Any potential benefits as well as injuries caused would have been imposed upon them without their consent.
It may be true that we do not seek the consent of unborn future generations in decision making today. Although, it could be wise to consider the impact our present decisions will have on future generations and thereby act prudently in decision making. We must always keep in mind that it is the health of our future children and later descendants that we intend to improve and by doing so, we should act very cautiously in order to avoid the opposite outcome.
As previously argued, germline gene editing could be allowed only for cases in which PGD are insufficent, whereas gene editing on somatic cells could be used to a greater degree on adult individuals that consent to these changes. In that way, changes that may not be regarded as necessary can be imposed on some, without being capable of spreading to the rest of the population that may not be as willing to be affected by these changes nor being subject to the potential risks thereof. Thus, the autonomy of future generations would not be infringed through a hasty adoption of new genetic changes into the germline.
Somatic gene editing would circumvent the risk of multigenerational harm that germline gene editing is linked to. It would not have any direct effect on the prevalence of individuals born with detrimental mutations, since it would not remove nor insert any mutations into the germline. Given that gene editing is relatively new, our knowledge of genetics limited and our ability to screen for off-target effects is limited, it may be argued that somatic is to be preferred over germline gene editing at this point of time. Although, the risk of viral vectors eliciting a strong immune response that may be toxic will have to be circumvented first. Moreover, even if the risk of multigenerational harm is avoided, the risk of causing harm to the individual patient remains and must be considered carefully.
5 Conclusions
PGD according to Swedish guidelines may be viewed as ethically acceptable since its restrictive use does not give room for ethically dubious applications that may cause harm. PGD may increase reproductive autonomy for couples with a high risk of passing on a genetic condition, although, since most couples are unaware of this risk, prenatal testing will be more frequently used and thereby find more cases. Since prenatal testing in most cases fills the role of PGD and many do not know of PGD, it may not have any substantial effect on the attitudes of individuals or society regarding genetic health.
If CRISPR-Cas9, or any other future technique for gene editing, can not be improved and proven to be entirely free from the risks of off-target effects and mosaicism, it would be highly irresponsible to use it for human gene editing, especially in the germline given the potential multi-generational damage it could cause. Attempting to stop the spread of the damage that would be caused, could entail unethical treatment and restrictions on the rights and freedoms of afflicted individuals.
If gene editing were to become safe, it could bring the opportunity of repairing genetic mutations that otherwise would cause disease, however, it could potentially be used to alter the genome in many other ways as well.
Gene editing has the potential of increasing reproductive autonomy by allowing parents to have healthier children. However, the autonomy and the potential effects of the yet unborn should be considered carefully, in order to protect future generation from the dangers of premature applications.
It is difficult to tell to which extent CRISPR-Cas9 will be used on humans. It has the potential to affect individual and societal attitudes as little as PGD does or to become very prevalent and thereby bring about fundamental changes to society, for better or worse.
The importance of caution and restraint in all gene editing can not be stressed enough, especially in germline gene editing since it has the potential to change the course of human evolution by making us the coders of our genetic code.
Acknowledgements
The author wishes to thank Rolf Ahlzén for invaluable guidance, insights and reviewing throughout the entire project.
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Appendix 1. Popular scientific summary – “The power to prevent disease and create designer babies”
Since the 1990s, preimplantation genetic diagnosis has been used to detect genetically inherited diseases in embryos before they are put in the womb. Embryos without disease are selected to be born. Although it has prevented much disease and suffering, it is not without dilemmas, since it can be used to select embryos based on gender and future appearance. Some have feared that this will lead to a world of designer babies. This have however not happened.
These fears have arisen again when a new technique called CRISPR-Cas9 has been discovered. It is a gene scissor that allows scientists and doctors to cut out a gene and insert a new one. This could be an even more effective way of preventing diseases. However, it could also be used to design a baby by changing several genes according to one’s will.
What stops CRISPR-Cas9 from producing designer babies already now? It is not yet safe to use it, since it is not accurate enough to cut out exactly that gene which is intended, it can still miss the target and cut out a different gene, thereby causing a new disease. On top of this, our knowledge of how every gene works and which gene that affects different attributes is limited. If even CRISPR-Cas9 could make the changes, we would in many cases not know which gene to alter and in which way to alter it.
Appendix 2. Cover letter
Dear Editor of Science,
You will find enclosed a manuscript titled “Preimplantation genetic diagnosis and therapy – opportunities and risks”. Please consider it for publication in the journal Science.
We have investigated the ethical dilemmas and opportunities of preimplantation genetic diagnosis and therapy via gene editing. Our hope is that the manuscript will be of interest to the readers for the following reasons:
• It presents several important ethical dilemmas as well as potential benefits for healthcare.
• These topics are then discussed in order to examine the risks and opportunities from different points of view.
• PGT and CRISPR-CAS9 are discussed based on how these techniques can be applied in accordance with or in conflict with the principles of “do no harm”, “do good” and “autonomy”.
• PGD in accordance was found to be ethically acceptable according to these principles, since its restrictive use does not give room for ethically questionable applications. Moreover, the advent of non-invasive and efficient prenatal testing reduces the need and thereby use of PGD.
• CRISPR-Cas9 was found to have technical limitations that makes it too unsafe to be applied on humans yet. However, if it were safe, it would have an unprecedented potential to prevent disease and it would increase reproductive autonomy. However, the wellbeing of future generations must be held in mind and therefore, caution and restraint must be urged.
Sincerely,
Rickard Hedberg, MB Örebro University Örebro
Appendix 3. Ethical reflection
Since long, there have been fantasies about and aspirations to affect human genetics in order to reduce our vulnerability to disease and enhance human traits. Never has humanity been this close to achieving germline gene editing. Regardless of whether CRISPR-Cas9 or any future technique will be the technique that makes germline gene editing possible, it is important that the ethics is discussed, solved and made into law before the technology is ready for human applications. Otherwise, we may find ourselves in a situation where everything is allowed. If humanity were to find itself in a situation with functioning germline gene editing and no ethical or legal framework, it may be used for premature and inappropriate applications that may cause multigenerational harm on humanity.
In this essay, the ethics of PGD and CRISPR-Cas9 has been examined and the already existing and used technique of PGD has been compared to CRISPR-Cas9 to some degree. It has not been compared in order to determine which technique is best and should be used, rather the comparisons have filled the role of explaining how each technique may be a complement to the other and to scrutinize the ethical implications of respective technique.
This essay is not meant to provide an ethical or legal framework, it is merely an attempt to present common ethical dilemmas and discuss various aspects of these from different points of view.
