REVIEW published: 03 September 2019 doi: 10.3389/fgene.2019.00767 Ethical Challenges of Germline Genetic Enhancement Ignacio Macpherson 1,2*, María Victoria Roqué 1,2 and Ignacio Segarra 2,3 1Department of Humanities, International University of Catalonia, Barcelona, Spain, 2 Pharmacokinetics, Patient Care and Translational Bioethics Research Group, Catholic University of Murcia (UCAM), Murcia, Spain, 3 Department of Pharmacy, Faculty of Health Sciences, Catholic University of Murcia (UCAM), Murcia, Spain The new reproductive technologies have opened the door to different processes of germline genetic enhancement by which the characteristics of an individual according to the interests of the agents involved could be selected during its gestation. Although the initiative is apparently oriented towards developing individuals that would excel in society, critical voices raise the concerns about that this approach would generate and need for a reflection on the ethical, social and legal implications of these techniques and their implementation in society. We reviewed the literature about these issues throughout their historical records to date, focusing on the moral arguments and non-clinical aspects that affect the legal and social environment. We have observed various trends of thought with divergent positions (proactive, preventive, and regulatory) as well as a large number of articles that try to reconcile the different approaches. This review illustrates Edited by: a series of concepts from the ethics and philosophy fields which are frequently used Go Yoshizawa, OsloMet – Oslo Metropolitan in studies that evaluate the ethical implications of germline genetic enhancement, such University, Norway as dignity, benefit, autonomy, and identity. In addition, amongst the many unresolved Reviewed by: controversies surrounding genetic enhancement, we identify procreative beneficence, Stuart A. Newman, New York Medical College, genetic disassociation, gender selection, the value of disability, embryo chimerization, United States and the psychosocial inequality of potentially enhanced individuals as crucial. We also Marsha Michie, develop possible scenarios for future debate. We consider especially important the Case Western Reserve University, United States definition and specification of three aspects which are essential for the deployment of new *Correspondence: reproductive technologies: the moral status of the embryo undergoing enhancement, the Ignacio Macpherson legal status of the enhanced individual, and the responsibility of the agents executing the imacpherson@gmail.com enhancement. Finally, we propose the precautionary principle as a means to navigate Specialty section: ethical uncertainties. This article was submitted to Keywords: genetic enhancement, human identity, genetic interventions, reprogenetic, human procreation, ELSI in Science and Genetics, precautionary principle, ELSI a section of the journal Frontiers in Genetics Received: 06 November 2018 Accepted: 19 July 2019 INTRODUCTION Published: 03 September 2019 The interest for the physical, moral, or cognitive well-being of all human individuals and its Citation: transmission to following generations has existed in the minds of the wise and rulers for thousands Macpherson I, Roqué MV and Segarra I (2019) Ethical Challenges of years. Accomplishing this objective demands to specify the means to reach it, something especially of Germline Genetic Enhancement. difficult when it comes to transmitting the biological features of parents to children, that is, the Front. Genet. 10:767. genetic inheritance. Throughout history, civilizations have implemented various means to achieve doi: 10.3389/fgene.2019.00767 the correct transmission of biological inheritance, generally through negative laws that forbid the Frontiers in Genetics | www.frontiersin.org 1 September 2019 | Volume 10 | Article 767 Macpherson et al. Ethical Challenges Genetic Enhancement pairing of consanguineous individuals as well as incest (Bittles, approach was called “enhancement” and included the acquisition 2003). In these cases, the laws were not intended to “enhance” of physiological, genetic, cognitive, and moral capabilities the inherited characteristics rather to avoid the emergence of (Faust, 2008; Gordon-Solmon, 2015; DeGrazia, 2016). From diseases or inbred disabilities (Güvercin and Arda, 2008), and the mid-1990s to the present, various initiatives have appeared the “worsening” of the offspring. However, in Plato’s Republic trying to apply genetic enhancement to the individual for non- we may find the formulation of one of the first political theories therapeutic purposes by means of manipulating, eliminating, trying to enhance the individuals of a society with proactive or incorporating specific genes in adult subjects or in the means. Amongst Plato’s proposals we may find the selection of germline (Blackburn, 2004). What makes this new phase in quite couples, the controlled inbreeding and crossing, the classification distinctive is the implication that the intervened individual will of newborns and their upbringing, or abandonment according survive, will transmit his/her genes and will become a subject of to their physiological characteristics (Güvercin and Arda, 2008). rights. The appearance of Dolly, a cloned sheep in 1997, would The genetic enhancement proposal appeared again strongly at start this new period including social alarm before the unknown the end of the 19th century and for the first time its postulates and reactions calling for legislative caution. In 1997, both were put together by Galton and triggered a series of measures in American and European legislation proposed a ban on human Western society that sought to improve the genetic inheritance, cloning (Newman, 2003; Hildt, 2016) which only had territorial not only of the physiological characteristics of the population but influence. Despite these bans, there have been proposals for also their intellectual and moral capacities. The means to achieve new therapies that take advantage of newer genetic technologies such improvement included marriage restrictions, selective and which are loaded with controversy, such as human cloning sterilizations and control of immigration (Galton, 1904). Later, involving nuclear transfer (Robertson, 1998), mitochondrial after the Second World War, these approaches were stigmatized replacement (Rubenstein et al., 1995; Richter and Bacchetta, after the Nuremberg trials and became banned, although not in 1998), modification of the genomic map (Agar, 1995; MacKay practice in several countries (Tännsjö, 1998; Yap, 2007). et al., 1997), and genetic edition CRISP/Cas9 (Ishii, 2017a; Ishii, Thus, during the 80s of the last century, a second approach 2017b). Although the regulatory warnings seemed unanimous, took place with a series of measures focused on preventing the the legislations were progressively adapted to the evolution of spread of the disability–and disabled subjects–in society (Hens the different research evaluation committees. Therefore, there is et al., 2013; Thompson, 2017). These measures included prenatal a greater development of ethical objections and restrictions to diagnosis, favored by the approval of abortion laws. Shortly research on severe medical conditions in some associations such after, techniques for preimplantation genetic diagnosis and as ESHG and ESHRE which remain more inclined to encourage screening, thanks to the development of assisted reproduction social debate and to establish a moratorium (De Wert et al., 2018). techniques, were largely implemented. All this prompted a new However, other associations such as ASHG and NASM tend to legislation that was progressively adapted to new demands of raise the social and political problems involved in conducting society (Fagot-Largeault, 1987). Simultaneously, dissenting this research (Lyon, 2017). voices appeared that criticized the commodification of human This new paradigm (“enhancement”) raises a recurrent life, its conditioning and its designing (Hirschman, 1991). question in the general health care field: what is the Contrary, other authors emerged criticizing the alarmism and threshold between therapy and enhancement to intervene? encouraging the development of suitable legislation to avoid Undoubtedly, the will to cure, intrinsic to the medical abuses (Resnik, 1994). Consequently, the role of independent, profession, is at its best in the effort to develop therapies third party institutions become essential to evaluate the ethical targeting the cause of the problem, be it at the functional dimension of the new techniques (Pergament and Bonnicksen, origin or at the structural level. In this context, gene therapy 1994) and fostered new regulations based on empirical data is a medical intervention which is considered proportionate and not on moral abstractions (Bonnicksen, 1994). In this line, in its intention and in its means — to recover lost health for example, the AMA Council on Ethical and Judicial Affairs according to what it is to a human individual. On the contrary, put forward the criteria for accepting prenatal diagnosis and genetic enhancement would try to modify non-pathological preimplantation genetic diagnosis, provided it was directed human traits and optimize capabilities in the individuals to therapeutic ends (AMA, 1994; Agar, 1995; Nicholson (NHGRI, 2018). Without a doubt there exists an intrinsic et al., 1995). Even so, the preventive selection of embryos, the desire for the human zenith, constructed on a theoretical manufacture of experimental embryos and the accumulation of conception of what a perfect human being ought to be. And cryopreserved embryos, led to new debates. As the therapeutic it is precisely this vision that is currently being challenged purpose became more diffuse or gave way to enhancement and questioned: the very concept of human identity, paired interventions, the debates shifted towards aspects such as the with succeeding questions: is that identity immutable? Are identity, benefit and dignity of the new creatures (Agar, 1995; there arguments for not modifying it? And how far can it be Davis, 1995; Vines, 1995; Glannon, 1998). modified? (Bostrom and Sandberg, 2009; Greenbaum, 2013; A new phase was initiated in the 90s when novel cloning Macpherson and Segarra, 2017), and what are the long-term technology was developed and proposed for the acquisition psychological and social consequences on individuals and or improvement of capabilities which are above the “normal” populations (GüellPelayo, 2014; Cabrera, 2017; Ishii, 2017b)? parameters for a human being (Richter and Bacchetta, 1998; In fact, all these issues frame the ethical challenges of “genetic Scully and Rehmann-Sutter, 2001; Greely, 2004). This new enhancement” and, specifically, the genetic enhancement Frontiers in Genetics | www.frontiersin.org 2 September 2019 | Volume 10 | Article 767 Macpherson et al. Ethical Challenges Genetic Enhancement applied to the individual’s germline, aimed to improve the argues that genetic enhancement in germline is to use the capabilities of the human subject. human being which may end up ‘making use’ of his being. These interventions are becoming an incipient new field From Habermas’s perspective, the preservation of the of bioethics where the ELSI perspective is essential at its core “non-chosen” or inherited nature, would protect us from (Henderson et al., 2012; Greenbaum, 2013; Macpherson and ourselves (Neil, 2008), a protection that could be radically Segarra, 2017; Ishii, 2017a; Ishii, 2017b; De Melo-Martín, 2018; degraded if market laws were deployed in the reproductive Tamir, 2018). This perspective permeates and affects all legislation industry (Fox, 2008). These laws would eventually of the clinical and pharmacology fields, subject to strict ethical determine the criteria for any action facing enhancement, controls, and associated to the precautionary principle (Gonzalvo- including genetic doping (Gaffney and Parisotto, 2007; Cirac et al., 2013). This principle is applied in other fields too, such McKanna and Toriello, 2010), gene patents (Rodriguez, as protection of the environment (Rippe and Willemsen, 2018). In 2016; Du, 2018; Greenbaum, 2011), or competition this context, a key question arises: is this sensitivity regarding the between enhanced beings (Jensen, 2011). An additional environment also present for genetic enhancement interventions critical approach may be added, fueled by the instability in the individual’s germline? To answer this question, we carried and insecurity of reprogenetic techniques leading to out a literature review on the moral dimension of the problem unpredictable consequences, in which case, use would be and its non-clinical argumentation, that is, the argumentation irresponsible (Fox, 2010; GüellPelayo, 2014; Hildt, 2016; generated in the process to assess the ethical dimensions to reject Newman, 2017; Fox, 2018). This would be particularly or support genetic enhancement carried out in the germline relevant regarding the modification of the germline by (Sparrow, 2014b; De Wert et al., 2018). genetic editing techniques (Niklas et al., 2015; Reagan, 2015; Sykora, 2015; Qiu, 2016). In summary, these studies may suggest that a balanced equation of risks and benefits TRENDS would not suffice to determine the ethical assessment and There is an on-going debate on germline genetic enhancement morality of a technique. Rather, deeper understanding within the public media and amongst specialists (Henderson of key concepts identity, nature and dignity is necessary et al., 2012) which manifests certain distrust towards solutions (Chan, 2015; De Melo-Martín, 2018; Jensen, 2018). coming from the field of philosophy (Hayry, 2003; Coggon, 2011; b) Proactive trend. This trend rejects any intellectual barrier to Selgelid, 2014). This leads scientific debates to commonly end up research and claims to investigate freely, expanding knowledge, on discussions around the political and ideological spheres with and eliminating alarmism (Harris, 2015). Therefore, they trends which oscillate between the so-called bioconservatives propose to overcome the precautionary principle and dismiss versus bioliberals factions (Roache and Savulescu, 2016). Both of the arguments of the slippery slope in order to avoid slowing them fluctuate between the anxiety before a new unpredictable down the development of science (Pattinson, 2000; Bailey, technology and the demystification of their dangers (Cartier- 2001; Bernal, 2005). Thus, these authors propose cloning Lacave et al., 2016). Even so, there is no shortage of attempts of germline DNA without any barriers (Robertson, 1998); to reconcile both tendencies and seek a third way (Roduit the non-therapeutic purposes of preimplantation genetic et al., 2013; Shapshay, 2012; Qiu, 2016) that is able to integrate diagnosis to select the individual’s features (Roberts, 2002; elements of both. For this reason, we have synthesized the Sperling, 2011); the desire for greater intelligence by means of reflections extracted from the various studies and grouped them the selection of alleles (Kirk, 2003); or the selection of children into three main trends: preventive, proactive, and regulatory. It is according to their human potential (Gordon-Solmon, 2015), worth noting that these tendencies show certain intertwining of even if these initiatives were theoretical and utopian. It is their authors’ arguments and opinions but keeping their different common in these studies to denounce the impediments of starting points. moral restrictions (Smith et al., 2012; Murphy, 2014) and the cautions against cloning and genetic editing (Bernal, 2005; a) Preventive trend. This trend groups diverse currents of Fenton, 2006; Resnik and Vorhaus, 2006; Powell et al., 2012) thought whose common element is the attempt to preserve although there is also moderate unwillingness to create hybrids the human nature from the initiatives of germinal line between species (Robert and Baylis, 2003; Savulescu, 2003). modification. The studies in this group contain reflections In general, any opposition from philosophical, religious or from the Christian tradition (Polkinghorne, 2004; political origin to scientific progress is questioned (Roberts, Massmann, 2018) and deontological philosophy (Jensen, 2002; Brooke, 2004; Smolin, 2004) and a more empirical, less 2011; Kim, 2017). They caution about the risk of modifying speculative analysis is pursued (Chyrowicz, 2001; Blackburn, the essential element of human corporality, the DNA. The 2004; Selgelid, 2014). These studies transmit the perception most representative author is Habermas (2003), who tries that there are social needs which are imperative to meet to analyze the reasons why we do not accept inherited urgently and any attempt to hinder (obstaculizar) this process nature and therefore would want to modify it genetically. may be considered an attack, not only to progress, but also to It is an approach already evoked by other philosophers social and global welfare. such as Kirkegard, Heidegger, or Jonas (Malmqvist, 2007; c) Regulatory trend. Another group of studies shows great Christiansen, 2009), but Habermas goes a step further and sensitivity for the consequences, positive and negative, Frontiers in Genetics | www.frontiersin.org 3 September 2019 | Volume 10 | Article 767 Macpherson et al. Ethical Challenges Genetic Enhancement that may accompany genetic enhancement and try to solve it the concepts “therapy” and “enhancement” which could also by proposing the need for clear legislation as a result of a public, be interpreted as antagonists between the actions to “recover open, and reflective debate (Marden and Nelkin, 2000). This capacities” and means to “add capabilities” (Du, 2018; trend tries to be an in-between solution between the positions Thompson, 2017). Based on this divergence, a first reflection of the two previous trends (Evitt et al., 2015; Thompson looks into the value of the arguments promoting genetic 2017). The regulatory trend anchors its main argument on the enhancement in germline (Neil, 2008) if the questions of what utilitarian pragmatism approach. Thus, it proposes decisions and why to enhance are not solved beforehand (Henrich, based on the function they may generate on the individual and 2011). A second reflection comes out from the supposed in society. At the same time, this tendency considers essential benefit or harm caused through modification of the DNA, to rely on strong laws to avoid abuses, keeping open to debate the genes or the human identity (Ebbesen and Jensen, 2006; certain interventions, marked by individual or social need: e.g. Fenton, 2010). Some authors consider that modifications of cloning for sterile couples (Strong, 1998), the elimination of human nature are advantageous (Powell et al., 2012), while defective embryos (Verlinsky, 2005), the selection of embryos others consider it detrimental to human beings, due to the with antisocial genes (Tabery, 2009), the gamete planning potential corruption of the human genome (Sykora, 2015). In (Delaney, 2011) or the experimentation with embryos any case, the term benefit seems to be the most used amongst without procreative purposes (De Miguel Beriain, 2019). At the authors and the foundation to carry out improvement and the same time, supporters of this regulatory approach also enhancement interventions. show concern for the social implications (Marden and Nelkin, b) Autonomy. The subject’s autonomy is a condition present 2000), especially injustice and inequality that could generate sine qua non in any human initiative and makes possible (Shapiro, 2005; Sparrow, 2015). There is, therefore, a great the subject’s informed consent. Thus, can reprogenetics sensitivity to understand the consequences (Mehlman, 2003, cause detriment to individual autonomy? The answer seems Mehlman, 2005; Delaney, 2011; Anomaly, 2018) and a special very controversial (Mameli, 2007; Murphy, 2014; Schenker, interest to ensure coherent, global and coordinated legislation 1997) due to deficient criteria with a comprehensive (Mackenzie, 2005; Ishii, 2014; Kaebnick, 2017; Kanaris, 2017; ethical assessment (Selgelid, 2014). However, since the Lyon, 2017; Ishii, 2017a; Ishii, 2017b; Liao, 2019). implementation of embryo selection techniques by means of prenatal diagnosis and preimplantation genetic diagnosis, there is a perception that these interventions may alter the CONCEPTS autonomy of manipulated individuals (Malmqvist, 2007; As indicated above, studies on genetic enhancement on the Henrich, 2011). This is especially evident when genetic germline employ concepts which are used beyond the scientific– enhancement is pursued: First, there are two wills which experimental dimensions of the problem and reach an ethical– merge, the will of those responsible for the enhancement logical dimension, more typical of philosophical approaches (e.g. parents, guardians or institutions) and the will of the (Shapiro, 2005). This review has allowed us to highlight four enhanced individual (Tamir, 2018) which may not always significant concepts that are embedded in all debates and coincide. Furthermore, a second dilemma is posed: the discussions addressing genetic enhancement: benefit, autonomy, autonomy of parents who want to have a child may be deeply identity, and dignity. Moreover, its significance differs in the conditioned by the balance between their personal interests various trends (Table 1) and a short-term consensus on its and the altruism of their action (Gordon-Solmon, 2015; importance and relevance is not foreseen. DeGrazia, 2016; Jensen, 2018). c) Identity. In its classical conception, human identity is considered a) Benefit. This is the focus of the discussion which configures the what characterizes the human individual. It is a concept basis of the enhancement and is determined by the good that that integrates the biological basis and the rational features is pursued. For this reason, it is frequently addressed in most of the human being. Often it is assimilated to the concept studies. The concept has been linked to the difference between of Aristotelian nature, as described by Habermas (2003). TABLE 1 | Summary of trends from the description of the main concepts. Trend Concepts Benefit Autonomy Identity Dignity Preventive The human good is the Limited by the dignity of the individual Determined by its nature, beyond its Based on its ontological perfection of its being natural conditions nature Proactive The human good is the Limited exclusively by the biological Determined by their will, based on Based on the development individual’s well-being (a laws technological advances of its capabilities good life) Regulatory The human good is the Limited by the laws that regulate Determined by social consensus after Based on consensual consensual social well-being society an open and regulated debate legislation Frontiers in Genetics | www.frontiersin.org 4 September 2019 | Volume 10 | Article 767 Macpherson et al. Ethical Challenges Genetic Enhancement However, a new definition and conceptualization of the future identity, dignity, and good lifetime) of individuals which meaning of identity seeks to include new technologies of are especially vulnerable and without autonomy, such as embryos genetic transformation (Shapiro, 2005) and other aspects or a newborn (Liao, 2019). such as autonomy, interpersonal relationships and longevity (Glannon and Harris, 2002). Nowadays, the lack of clear meaning and definition of the term identity is causing Procreative Beneficence Faced with the technology available and the possibility of confusion in the debate on mitochondrial replacement and predictably beneficial enhancements, a question comes out nuclear transfer techniques, as well as the proper identity of unstoppably: should not the selection of genes be mandatory? embryoids and chimaeras (Scott, 2017; De Miguel Beriain, Shouldn’t governments be allowed to promote or prevent certain 2019). In addition, the dilemmas of social identity of genes upon citizens in a similar way as it is done with vaccination children generated in vitro including confused filiation which programs (Kanaris, 2017; So et al., 2017)? Anticipating these consequences have not yet been studied in depth (Rose and issues, Savulescu developed what would be called “the Principle Novas, 2005; Lock and Nguyen, 2010) are added to the above of Procreative Beneficence” by which parents would be morally problems. It is generally assumed that the concept of identity obliged to discard an embryo with potential criminal genes and will be decisive to guide reflections on the moral status of the at the same time choose the embryos that have the most favorable embryo (DeGrazia, 2012; Francis, 2015). genes for himself and for society (Savulescu, 2001; Savulescu d) Dignity. It is the most discussed concept in the debate et al., 2006). This issue was already an old controversy, which on germline genetic enhancement and it is strongly was raised even before the emergence of prenatal diagnostic contextualized and linked to the concept of identity techniques and preimplantation genetic diagnosis: the obligation (Savulescu, 2003). In spite of being used repeatedly, it is not of the principle of beneficence against the foreseeable diseases well defined in the debate and it remains unclear (Henrich, present in the embryo, e.g. Huntington disease, Asperger 2011). Originally, this concept was mostly discussed in the syndrome, Down syndrome, cancer, cystic fibrosis, and spina debate on cloning (Caulfield, 2003), chimerization (Robert bifida amongst others (Harris, 2006; Walsh, 2010; Bosslet, 2011), and Baylis, 2003; De Melo-Martín, 2008), and cryopreserved removing the procreative autonomy of the parents (Faust, 2008; embryos (Glannon and Harris, 2002; Ehrich et al., 2010). DeGrazia, 2016). This state-driven intervention approach to Hence there have been repeated attempts to develop new eliminate the supposed “antisocial” embryos has been strongly conceptualizations rooted on neurological basis, consensual criticized (Tabery, 2009; Bosslet, 2011) due to the fact that it basis or rational basis (Bostrom and Sandberg, 2009; would require a substantial drift in the defense of human rights: it Jotterand, 2010; Chan, 2015). Undoubtedly, Habermas would not differentiate between a desire for moral enhancement is the author who develops most deeply this term, dignity and a mandatory action to implement it (Saunders, 2015). The (p.29) (Habermas, 2003) in the field of genetics, especially root of this disruption may be found in the moral imperative– due to its relationship with the concept of human nature. the moral good as obligation–and its mandatory application This concept would confer an infinite value to the fact of leading to morally designed individuals (Holland, 2016). In the being human which would grow to be the foundation for an same line, psychological pressure on parents would be especially unconditional respect towards individuals and their human significant (Bonte et al., 2014) to encourage them to choose rights (Habermas, 2003; Christiansen, 2009). the “best” embryo amongst several, that would be the most “valuable,” “intelligent” or “excellent,” a quantification attitude that would seem incoherent, or at least surprising, for parents CURRENT CONTROVERSIES with unconditional affection for any of their children (Tonkens, Next, we deal with the main aspects that have caused greater 2011; Jensen, 2018). Therefore, some authors have taken another controversy in scientific, technological, legal, or philosophical approach and are inclined to transform the obligation into forums about the existence of a human genetic identity and the suggestion, option or advice (Jacobs, 2015; Carter, 2015; Francis, free initiative to modify that identity (Mehlman, 2003). This 2015; Sparrow, 2015; Kanaris, 2017; Liao, 2019). framework does not include other types of human improvement that science puts forward–physiological, cognitive or moral improvement through external elements such as drugs, surgery, The Value of the Disability or somatic genes–even if the focus remains similar: the happiness The principle of procreative beneficence raises a new question: and well-being of individuals (Bostrom and Sandberg, 2009; who is entitled to decide what an advantage is (Karpin, 2007; Savulescu et al., 2011). The fundamental difference of these Macpherson and Segarra, 2017)? It is not clear whether some tendencies with genetic enhancement in germline lies in a enhancements are desirable per se or whether a disability is concept previously mentioned: the autonomy of the individual. deprived of any value (Nunes, 2006; Francis, 2015). According The recipients of the genetic enhancement have not chosen to be to the expressivist objection current, the elimination of disabilities better, something that is required for any other pharmacological, would be a loss of human identity for those who suffer them neuronal, or surgical improvement, which usually includes free, (Alper et al., 2002; Malek, 2010; Collins et al. 2016; Shakespeare informed consent. Therefore, we focus on specific areas in which et al., 2017). Within the same context, then, we consider how genetic improvement affects the fundamental rights (including negative interventions should be assessed: the selection of Frontiers in Genetics | www.frontiersin.org 5 September 2019 | Volume 10 | Article 767 Macpherson et al. Ethical Challenges Genetic Enhancement features that we may consider detrimental for the future child, individual (Streiffer, 2005; Kaebnick, 2017). Moreover, this e.g. deafness or Asperger, may also present some kind of benefit uncertainty acquires special relevance when the human– (Karpin, 2007; Walsh, 2010; Graber, 2017). Would there be animal interaction may affect the brain structure and an obligation to avoid them? At this point, some authors have functionality as well as the gametes (Dolgin, 2016; Levine and raised the concept of the “asymmetry of the damage,” by which Grabel, 2017). The current trends range from the elimination the benefit of living with a disability would not compensate the of any restriction due to lack of ethical reasons, to the damage of having it (Glannon and Harris, 2002; Sparrow, 2012; concern for individual and societal consequences (Palacios- Francis, 2015). Furthermore, the anti-equality shadow appears González, 2015; Hyun, 2016; Rodriguez, 2016). We believe simultaneously, either by genetic enhancement or by embryonic that the solution can only be developed departing from a clear selection technologies, since their application effectively would conceptualization of their moral status, a term still not agreed impose social segregation between the enhanced individuals and upon for embryos and much less for chimeras (Giacomini the non-enhanced subjects, who would identify themselves with et al., 2007; De Melo-Martín, 2008; Eberl and Ballard, 2009; the disabled (Cavaliere, 2018). It is here where the legal regulatory Chan, 2015; Munsie et al., 2017; Hübner, 2018). bodies need to deepen the knowledge and the consequences of their implementation since mandatory actions to eradicate disability could lead to the extermination of full groups (Kanaris, Genetic Untying The problem of genetic untying or the absence of any genetic 2017; Thompson, 2017; Ishii, 2017a). linkage between the embryo and the parents surged with the requirement of anonymity of the donors of the gametes Gender Selection for in vitro fertilization and surrogate motherhood. Further Undoubtedly, sex selection for non-therapeutic reasons has speculation to this debate has been added when taking into already generated a multitude of controversies (Arnold et al., account the dissociating effects of new technologies, such 2002; Sperling, 2011; Winckler, 2002). Currently, a new debate as the IVR technique (in vitro iterated reproduction) where is taking place regarding the advantage or disadvantage of the gametes are generated directly from the embryos and sexual dimorphism (Sparrow, 2010a) focused on the supposed mitochondrial replacement technologies that involves genetic “normality” of the existence of two sexes and whether one should material from three gametes (Bredenoord et al., 2011). In this prevail over the other (Kahane and Savulescu, 2010; Slatman technique, the intervention is not carried out directly on the et al., 2010; Sparrow, 2010b; Sparrow, 2012). If that normality embryo but on its precursors, e.g. its gametes (Delaney, 2011). In were to be questioned, would it be justifiable to eliminate sexual all these cases, the result is an embryo genetically disconnected dimorphism and select the best female or male genes to design from its progenitors either because the gametes used are an asexual being (Kahane and Savulescu, 2010)? This proposal generated in vitro (Palacios-González et al., 2014), or they are could even go as far as to suggest the mandatory choice of the derived from multiple gametes, or they have been generated female subject by the tutors or the reproductive leaders upon by iterated reproduction (Sparrow, 2014a). The end result is a consideration and assumption that the most aggressive genes “genetic orphan,” an individual without living parents, since the would come from the male individual, an extremely controversial most immediate ancestor would be deceased embryos (Sparrow, trait (Slatman et al., 2010; Sparrow, 2012; Casal, 2013). According 2014b); a situation which cannot be assimilated to the natural to other authors, this debate is insubstantial in nature because generation of monozygotic twins (Douglas, 2014). The concern sexual dimorphism has a neutral effect on human development caused by mitochondrial donations and transfer techniques is (Kahane and Savulescu, 2010) and the normality of each of the flagrant generating new legislative doubts about the conditions sexes is accepted (Sparrow, 2012). In spite of everything, the for its application (Ishii, 2014; Harris, 2015), especially regarding appearance of ectogenetic technologies will possibly repeat the anonymity (Brandt, 2016). Thus, there is discussion on the controversies generated when the embryo selection techniques emergency of a new idea within the human procreation context: were and currently are applied to sex selection (Kendal, 2017). the abolition of procreative filiation and the possibility of raising design individuals without kinship (Palacios-González et al., 2014; Roache, 2016). Creation of Chimeras, Hybrids, and Embryoids Their creation has always raised rejection. The recent change of Psychosocial Inequality social mindset has been preceded by their potential usefulness The alteration of the social balance has always been a great in research, primarily related to therapeutics (Brickman and concern for the agents involved in enhancement efforts (Davis, Serup, 2017). This approach was fueled when IVF surplus human 1997; Davis, 2009). This has been even more explicit if it could embryos began to be used to produce stem cells, thus justifying affect the future of the child (Sparrow, 2016; Krutzinna, 2017). the elimination of any restriction on embryonic experimentation The lack of restrictions makes it possible to foresee the social drift (Robert and Baylis, 2003; Savulescu, 2003; Ehrich et al., 2010; that these technologies may cause (Mehlman, 2005; Ishii, 2017b) Volarevic et al., 2018; De Miguel Beriain, 2019). In spite of although some authors consider this caution for inequality everything, the doubt and aversion have persisted due to the disproportionate (Fenton, 2010) and limit their scope to assess uncertainty of the moral status of the hybrid human–animal of damage that might be predicted after implementation of Frontiers in Genetics | www.frontiersin.org 6 September 2019 | Volume 10 | Article 767 Macpherson et al. Ethical Challenges Genetic Enhancement enhancement interventions (Persson, 2012). Even so, the fear of non-contradiction, something cannot be both true and of a social disadvantage in unenhanced children is recurrent not true in the same way and at the same time, pushes the and considered immoral and unjustified due to its potential debate towards a binary solution. The possibility that there for discrimination (Jensen, 2011), the possible unknown may even be allowed the slightest manipulation of embryo consequences in complex thinking and reasoning (Rosoff, beings, predictably human, without a defined identity status 2011) and other long term secondary effects (Glick, 2011). In and without any biological linkage with anyone, could lead this sense, the alarm over the application of techniques that we to a profuse and disturbing legislation to coax their adult do not understand completely or do not know how to control development, whether they be clones, chimeras, enhanced (GüellPelayo, 2014), ranges from conditioning and alteration chimeras, or enhanced embryos (Mason, 2017; Scott, 2017; of the child’s future (Bredenoord et al., 2014) to a series of De Melo-Martin, 2018). In this context, the framework of enhancements that eventually may lead to social fragmentation reflection goes beyond the purely scientific or technological and disintegration (Sparrow, 2015). For the moment, the debate sphere and invades the anthropological arena. Thus, the has crystallized in the production of legislation that continues philosophical framework in it anthropological dimension to be diffuse or even contradictory (De Souza, 2015; Kim, would be the one qualified to define the ontology of beings 2017; Tamir, 2018). whose status is, apparently, diffuse, as well as their moral, social and legal identity (Eberl and Ballard, 2009; Qiu, 2016). We consider it essential to determine the ontological status FUTURE DEVELOPMENTS of these beings because its clarification will serve as a starting point to determine the administration of their destiny, Germline genetic enhancement presents important challenges either as non-human, their use, their property, or as human that should be progressively clarified, mainly to prevent being, their respect and their rights (Polkinghorne, 2004; reproductive technology from being hijacked by its own Streiffer, 2005). advances. We must bear in mind that the ultimate reason for b) The rights of the modified individual. The question of genetic these initiatives is a concept of elementary ethics: the common enhancement on the germline would not imply special good and the happiness of individuals. In essence, this is the obstacles if it were not because it breaks into the most engine that activates actions that promote, limit or regulate intimate sphere of human beings in two dimensions: first, the genetic technologies progress. We understand that a thorough decisions that are made and implemented will be irreversible argumentation within the ELSI framework, including the and second, the genetic characteristics are likely not to have reprogenetic arena (NHGRI, 2018), would be a way to ensure been chosen by the individual itself but imposed on him/ a proper application and implementation of any genetic her, not by nature but by a particular will. This situation was, enhancement initiative, whether theoretical or practical. In view precisely, the scenario that was aimed to avoid: the imposition of the studies reviewed, this working framework would have by “nature” on the individual of certain characteristics that an impact on three fundamental questions where the ethical he or she had not chosen but rather had to accept resignedly. implications of the new technologies are rooted: Would we be falling again into an injustice? What should be done if the modified individual does not accept his modified a) The moral status of the embryo. The issue was initially status? It could be argued that it is a scenario similar to an raised when the technologies that affected the integrity of individual conceived in a natural way, (e.g. through sexual the embryo were implemented pushing the debate about intercourse) who would not accept his/her condition or a its nature and identity (Fox, 2010; DeGrazia, 2012). The specific feature (e.g. height, intelligence or even an inherited discussion and social debate about the embryo’s moral status pathology, etc). However, there is an essential difference became especially relevant when it came to specific issues between both scenarios. The natural inheritance cannot be such as the fate of hundreds of thousands of cryopreserved imputed to anyone, a key element for legislative purposes embryos, their use for experimentation, the consensual since the individual is not responsible for it. However, arbitrary limitation 14 days for research and the patented modified inheritance is the result of the deliberate action of embryos (Ehrich et al., 2010; Cavaliere, 2017; Chan, 2017; other individuals (e.g. parents or guardians) who decide how Appleby and Bredenoord, 2018). In fact, the fragility of the child should be. Therefore, they are fully responsible for this status is what allows the manipulation of embryos the action carried out in the child with legal responsibility through genetic editing, provided that they are subsequently (Sundby et al., 2018). In fact, there is general consensus about eliminated and not used in the germline. (De Miguel Beriain, the non-implementation on children interventions with 2019). More recently, research the creation of transformed serious risks which may be not properly balanced with the clones, hybrids, chimeras, and embryoid bodies has added benefit received from it (Delaney, 2011; Powell and Buchanan, a greater uncertainty to a question that remains unclear. It is 2011). It is worth noting that therapies applied to children, not known exactly what the entity of embryoids, organoids, who cannot agree to an informed consent (e.g. vaccination, or synthetic embryos may be (Chan, 2017; Kaebnick, 2017; corrective surgeries, etc) are only ethically justified when Munsie et al., 2017). Society is looking for answers to the benefit is the survival or the integrity of the newborn formulate the most elementary question: what is it? or who is or child. In addition, those therapies should always respect it? The reflection on the most basic definition of the principle their identity and should not lead to the modification or Frontiers in Genetics | www.frontiersin.org 7 September 2019 | Volume 10 | Article 767 Macpherson et al. Ethical Challenges Genetic Enhancement selective destruction of other individuals (Millum, 2014; the enhancement pursues to satisfy the desire of some individuals Hendrix et al., 2016). who decide the type of enhancement without clarifying who will assume the consequences (Thompson, 2017; Ishii, 2017a; But the existence of enhanced genes in the newborn inflicts Anomaly, 2018). Although some entities (NHGRI, ASHG, and characteristics that make that individual unique to himself and ESHG) have expanded their scope of studies and include risk others (Shapiro, 2005). Here a set of questions come out: did he assessment, we agree with the authors who consider that these have the right not to be enhanced? Did he have the right to reject measures are insufficient (Mehlman, 2009). Given that germline imposed selection or imposed genes, positive or negative, not by genetic enhancement application occurs at the beginning of the laws of nature but by the will of his managers? Does he have the living stages of the human being (embryos, newborns, or the right to a biological filiationties (Malmqvist, 2007; Karpin, 2007; even children), it is especially important to assess the long-term De Melo-Martín, 2018)? If these rights existed, they would generate psychological and social consequences, with the conviction that a dilemma of difficult solution: the need for an informed consent there are red lines that should not be crossed (Mehlman, 2005; to undergo the enhancement procedure and at the same time the Mehlman, 2009; Greenbaum, 2013). right of refusal to be modified (Rodriguez, 2016). Furthermore, it would be unclear how to resolve its true biological identity–the cause and reason for its origin–and its right to biological filiation, CONCLUSION a question that has already led to the modification of legislation about the anonymity of the donor of the gametes. In brief, will the It is probable that the desire for specific human enhancement will enhanced individual have the right to know his detailed origin? Or become a reality and, consequently, some agents will implement the purpose of the enhancement carried out in him (Reagan, 2015; the germline’s genetic enhancement in society. For this reason, we Sykora, 2015)? The analysis of the right to be a genetically enhanced consider essential to create effective expert panels and committees individual is still in its infancy because it has yet materialized. In fact, with society’s feedback (Kaebnick, 2017) that could elaborate global some authors speculate that this right would depend on external normative documents, rooted and established on universal ethical factors to the individual (Tamir, 2018), an approach that may cause principles (Ishii, 2014; Lyon, 2017; De Wert et al., 2018). additional restlessness. Consequently, we consider it essential to The information about the creation of enhanced twins in exercise extreme caution in all interventions (Holm, 2019), in order China (Regalado, 2018) reinforces our conviction about the to generate a truly human technology (Nordberg et al., 2018). need to put forward the underlying reasons that support future legislation aimed at prohibiting or allowing enhancements. c) The ethical, social and legal responsibility of the enhancement Otherwise, if the different reasons are circumstantial without a agents. The technologies of germline genetic enhancement deep foundation, the laws will be ineffective. carried out on individuals raise additional questions regarding We propose the precautionary principle as a means to navigate the ownership of the action: Who is accountable for the changes, ethics’ uncertainties and as the point of departure to assess moral positive or negative, executed in individuals (Rodriguez, 2016; enhancement. Certainly, an abusive application of the precautionary Du, 2018)? There are a variety of agents that could be expected principle would lead to its ineffectiveness. Conversely, that to be accountable: the parents, the tutors, the researchers, the precautionary attitude may improve the objectives and the means corporations, or even the State (Sparrow, 2016), that is, any regardless whether it is directed to protect the autonomy of adults, agent interested in the realization of the enhancement (Millum, the global human welfare or the dignity of the individual. We think 2014; Kanaris, 2017). This accountability seems similar to the that these concepts may structure and configure any advance in responsibility that is acquired when a therapeutic process is germline genetic enhancement technologies. applied, however the motive and objective of the intervention produces a key difference between one and the other. 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Attitudes of stakeholders in psychiatry towards the inclusion original publication in this journal is cited, in accordance with accepted academic of children in genomic research. Hum. Genomics 12 (1), 12. doi: 10.1186/ practice. No use, distribution or reproduction is permitted which does not comply s40246-018-0144-8 with these terms. Frontiers in Genetics | www.frontiersin.org 12 September 2019 | Volume 10 | Article 767