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• Published: 20 April 2022

Beyond safety: mapping the ethical debate on heritable genome editing interventions

• Mara Almeida   ORCID: orcid.org/0000-0002-0435-6296 1 &
• Robert Ranisch   ORCID: orcid.org/0000-0002-1676-1694 2 , 3  

Humanities and Social Sciences Communications volume  9 , Article number:  139 ( 2022 ) Cite this article

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• Medical humanities
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Genetic engineering has provided humans the ability to transform organisms by direct manipulation of genomes within a broad range of applications including agriculture (e.g., GM crops), and the pharmaceutical industry (e.g., insulin production). Developments within the last 10 years have produced new tools for genome editing (e.g., CRISPR/Cas9) that can achieve much greater precision than previous forms of genetic engineering. Moreover, these tools could offer the potential for interventions on humans and for both clinical and non-clinical purposes, resulting in a broad scope of applicability. However, their promising abilities and potential uses (including their applicability in humans for either somatic or heritable genome editing interventions) greatly increase their potential societal impacts and, as such, have brought an urgency to ethical and regulatory discussions about the application of such technology in our society. In this article, we explore different arguments (pragmatic, sociopolitical and categorical) that have been made in support of or in opposition to the new technologies of genome editing and their impact on the debate of the permissibility or otherwise of human heritable genome editing interventions in the future. For this purpose, reference is made to discussions on genetic engineering that have taken place in the field of bioethics since the 1980s. Our analysis shows that the dominance of categorical arguments has been reversed in favour of pragmatic arguments such as safety concerns. However, when it comes to involving the public in ethical discourse, we consider it crucial widening the debate beyond such pragmatic considerations. In this article, we explore some of the key categorical as well sociopolitical considerations raised by the potential uses of heritable genome editing interventions, as these considerations underline many of the societal concerns and values crucial for public engagement. We also highlight how pragmatic considerations, despite their increasing importance in the work of recent authoritative sources, are unlikely to be the result of progress on outstanding categorical issues, but rather reflect the limited progress on these aspects and/or pressures in regulating the use of the technology.

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Introduction

The ability to alter a sequence of genetic material was initially developed in microorganisms during the 1970s and 1980s (for an overview: Walters et al., 2021 ). Since then, technological advances have allowed researchers to alter DNA in different organisms by introducing a new gene or by modifying the sequence of bases in the genome. The manipulation of the genome of living organisms (typically plants) continues a course that science embraced more than 40 years ago, and may ultimately allow, if not deliberately curtailed by societal decisions, the possibility of manipulating and controlling genetic material of other living species, including humans.

Genetic engineering can be used in a diverse range of contexts, including research (e.g., to build model organisms), pharmacology (e.g., for insulin production) and agriculture (e.g., to improve crop resistance to environmental pressures such as diseases, or to increase yield). Beyond these applications, modern genetic engineering techniques such as genome editing technologies have the potential to be an innovative tool in clinical interventions but also outside the clinical realm. In the clinical context, genome editing techniques are expected to help in both disease prevention and in treatment (Porteus, 2019 ; Zhang, 2019 ). Nevertheless, genome editing technology raises several questions, including the implications of its use for human germline cells or embryos, since the technology’s use could facilitate heritable genome editing interventions (Lea and Niakan, 2019 ). This possible use has fuelled a heated debate and fierce opposition, as illustrated by the moratoriums proposed by researchers and international institutions on the use of the technology (Lander et al., 2019 ; Baltimore et al., 2015 ; Lanphier et al., 2015 ). Heritable human germline modifications are currently prohibited under various legislations (Baylis et al., 2020 ; Ledford, 2015 ; Isasi et al., 2016 ; König, 2017 ) and surveys show public concerns about such applications, especially without clear medical justification (e.g., Gaskell et al., 2017 ; Jedwab et al., 2020 ; Scheufele et al., 2017 ; Blendon et al., 2016 ).

To analyse some implications of allowing heritable genome editing interventions in humans, it is relevant to explore underlying values and associated ethical considerations. Building on previous work by other authors (e.g., Coller, 2019 ; de Wert et al., 2018 ; van Dijke et al., 2018 ; Mulvihill et al., 2017 ; Ishii, 2015 ), this article aims to provide context to the debates taking place and critically analyse some of the major pragmatic, categorical and sociopolitical considerations raised to date in relation to human heritable genome editing. Specifically, we explore some key categorical and sociopolitical considerations to underline some of the possible barriers to societal acceptance, key outstanding questions requiring consideration, and possible implications at the individual and collective level. In doing so, we hope to highlight the predominance of pragmatic arguments in the scientific debate regarding the permissible use of heritable genome editing interventions compared to categorical arguments relevant to broader societal debate.

Human genome editing: a brief history of CRISPR/Cas9

Human genome editing is an all-encompassing term for technologies that are aimed at making specific changes to the human genome. In humans, these technologies can be used in embryos or germline cells as well as somatic cells (Box 1 ). Concerning human embryos or germline cells, the intervention could introduce heritable changes to the human genome (Lea and Niakan, 2019 ; Vassena et al., 2016 ; Wolf et al., 2019 ). In contrast, an intervention in somatic cells is not intended to result in changes to the genome of subsequent generations. It is worth noting that intergenerational effects occur only when the modified cells are used to establish a pregnancy which is carried to term. Thus, a distinction has been made between germline genome editing (GGE), which may only affect in vitro embryos in research activity, and heritable genome editing (HGE), which is used in reproductive medicine (e.g., Baylis et al., 2020 ). HGE could be used to prevent the transmission of serious genetic disease; however, other applications could be imagined, e.g., creating genetic resistance or even augmenting human functions.

In the last decade, prominent technical advances in genome engineering methods have taken place, including the zinc-finger nucleases (ZFNs) and TAL effector nucleases (TALENs), making human genome modification a tangible possibility (Gaj et al., 2013 ; Li et al., 2020 ; Gupta and Musunuru, 2014 ). In 2012, a study showed that the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), combined with an enzyme called Cas9, could be used as a genome‐editing tool in human cell culture (Jinek et al., 2012 ). In 2013, the use of CRISPR/Cas9 in mammalian cells was described, demonstrating the application of this tool in the genome of living human cells (Cong et al., 2013 ). In 2014, CRISPR/Cas9 germline modifications were first used in non-human primates, resulting in the birth of gene-edited cynomolgus monkeys (Niu et al., 2014 ). This was followed in 2015 by the first-ever public reported case of genome modification in non-viable human embryos (tripronuclear zygotes) (Liang et al., 2015 ). This study has caused broad concerns in the scientific community (Bosley et al., 2015 ) with leading journals rejecting publication for ethical reasons. Five years after these initial experiments were conducted, more than 10 papers have been published reporting the use of genome editing tools on human preimplantation embryos (for an overview: Niemiec and Howard, 2020 ).

Compared to counterpart genome technologies (e.g., ZFNs and TALENs), CRISPR/Cas9 is considered by many a revolutionary tool due to its efficiency and reduced cost. More specifically, CRISPR/Cas9 seems to provide the possibility of a more targeted and effective intervention in the genome involving the insertion, deletion, or replacement of genetic material (Dance, 2015 ). The potential applicability of CRISPR/Cas9 technique is considered immense, since it can be used on all type of organisms, from bacteria to plants, non-human cells, and human cells (Barrangou and Horvath, 2017 ; Hsu et al., 2014 ; Doudna and Charpentier, 2014 ; Zhang, 2019 ).

Box 1 Difference associated with germline cells and somatic cells.

For the purposes of the analysis presented in this article, one of the main differences is the heritability of genes associated with either type of cell. Germline cells include spermatozoa, oocytes, and their progenitors (e.g., embryonic cells in early development), which can give rise to a new baby carrying a genetic heritage coming from the parents. Thus, germline are those cells in an organism which are involved in the transfer of genetic information from one generation to the next. Somatic cells, conversely, constitute many of the tissues that form the body of living organisms, and do not pass on genetic traits to their progeny.

Germline interventions: the international debate

As a reaction to the 2015 study with CRISPR/Cas9, several commentaries by scientists were published regarding the future use of the technology (e.g., Bosley et al., 2015 ; Lanphier et al., 2015 ; Baltimore et al., 2015 ). Many of them focused on germline applications, due to the possibility of permanent, heritable changes to the human genome and its implications for both individuals and future generations. These commentaries included position statements calling for great caution in the use of genome editing techniques for heritable interventions in humans and suggested a voluntary moratorium on clinical germline applications of CRISPR/Cas9, at least until a broad societal understanding and consensus on their use could be reached (Brokowski, 2018 ; Baltimore et al., 2015 ; Lander, 2015 ). Such calls for a temporary ban were often seen as reminiscent of the “Asilomar ban” on recombinant DNA technology in the mid-1970s (Guttinger, 2017 ). Other commentaries asked for research to be discouraged or halted all together (Lanphier et al., 2015 ). More firmly, the United States (US) National Institutes of Health (NIH) released a statement indicating that the NIH would not fund research using genome editing technologies on human embryos (Collins, 2015 ).

In December 2015, the first International Summit on Human Gene Editing took place, hosted by the US National Academy of Sciences, the US National Academy of Medicine, the UK Royal Society, and the Chinese Academy of Sciences (NASEM). The organizing committee issued a statement about appropriate uses of the technology that included the following: “It would be irresponsible to proceed with any clinical use of germline editing unless and until (i) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (ii) there is broad societal consensus about the appropriateness of the proposed application” (NASEM, 2015 ).

Following this meeting, initiatives from different national bodies were organized to promote debate on the ethical issues raised by the new genome editing technologies and to work towards a common framework governing the development and permissibility of their use in humans. This included an ethical review published in 2016 by the Nuffield Council on Bioethics, addressing conceptual and descriptive questions concerning genome editing, and considering key ethical questions arising from the use of the technology in both human health and other contexts (Nuffield Council on Bioethics, 2016 ). In 2017, a committee on human genome editing set up by the US National Academy of Sciences (NAS) and the National Academy of Medicine (NAM) carried out a so-called consensus study “Human Genome Editing: Science, Ethics, and Governance” (NASEM, 2017 ). This study put forward a series of recommendations on policies and procedures to govern human applications of genome editing. Specifically, the study concluded that HGE could be justified under specific conditions: “In some situations, heritable genome editing would provide the only or the most acceptable option for parents who desire to have genetically related children while minimizing the risk of serious disease or disability in a prospective child” (NASEM, 2017 ). The report stimulated much public debate and was met with support and opposition since it was seen as moving forward on the permissibility of germline editing in the clinical context (Ranisch and Ehni, 2020 ; Hyun and Osborn, 2017 ).

Following the report in 2016, the Nuffield Council on Bioethics published a second report in 2018. Similar to the NASEM 2017 report, this report emphasizes the value of procreative freedom and stresses that in some cases HGE might be the only option for couples to conceive genetically related, healthy offspring. In this document, the Nuffield Council on Bioethics maintains that there are no categorical reasons to prohibit HGE. However, it highlights three kinds of interests that should be recognized when discussing prospective HGE. They are related to individuals directly affected by HGE (parents or children), other parts of society, and future generations of humanity. In this context, two ethical principles are highlighted as important to guide future evaluations of the HGE use in specific interventions: “(...) to influence the characteristics of future generations could be ethically acceptable, provided if, and only if, two principles are satisfied: first, that such interventions are intended to secure, and are consistent with, the welfare of a person who may be born as a consequence, and second, that any such interventions would uphold principles of social justice and solidarity (…)” (Nuffield Council on Bioethics, 2018 ). This report was met with criticism for (implicitly) advocating genetic heritable interventions might be acceptable even beyond the boundaries of therapeutic uses. This is particularly controversial and goes well beyond the position previously reached by the NASEM report (which limited permissible uses of genome editing at preventing the transmission of genetic variants associated to diseases) (Drabiak, 2020 ). On the other hand, others have welcomed the report and, within it, the identification of explicit guiding ethical principles helpful in moving forward the debate on HGE (Gyngell et al., 2019 ).

As a follow-up to the 2015 conference, a second International Summit on Human Gene Editing was scheduled for November 2018 in Hong Kong (National Academies of Sciences, Engineering, and Medicine, 2019 ). The event, convened by the Hong Kong Academy of Sciences, the UK Royal Society, the US National Academy of Sciences and the US National Academy of Medicine, was supposed to focus on the prospects of HGE. Just before the Summit began, news broke that He Jiankui, a Chinese researcher and invited speaker at the Summit, created the world’s first genetically edited babies resulting from the use of CRISPR/Cas9 in embryos (Regalado, 2018 ; Lovell-Badge, 2019 ). Although an independent investigation of the case is still pending, his experiments have now been reviewed in detail by some scholars (e.g., Greely, 2019 , 2021 ; Kirksey, 2020 ; Davies, 2020 ; Musunuru, 2019 ). These experiments were globally criticized, since they did not follow suitable safety procedures or ethical guidelines (Wang and Yang, 2019 ; Lovell-Badge, 2019 ; Krimsky, 2019 ), nor considered the recommendations previously put forward by international reports (NASEM, 2017 ; Nuffield Council on Bioethics, 2018 ) and legal frameworks (Araki and Ishii, 2014 ; Isasi et al., 2016 ). Different reactions were triggered, including another call by scientists for a global moratorium on clinical human genome editing, to allow time for international discussions to take place on its appropriate uses (Lander et al., 2019 ) or an outright ban on the technology (Botkin, 2019 ). There were also calls for a measured analysis of the possible clinical applications of human genome editing, without the imposition of a moratorium (Daley et al., 2019 ; Dzau et al., 2018 ).

Most countries currently have legal frameworks to ban or severely restrict the use of heritable genome editing technologies (Araki and Ishii, 2014 ; Isasi et al., 2016 ; Baylis et al., 2020 ). However, since He’s experiment, the possibility that researchers might still attempt (with some likelihood of success) to use the technology in human embryos, became a growing concern, particularly since some scientists have already announced their interest in further clinical experiments (Cyranoski, 2019 ). For many, He’s experiments highlighted the ongoing risks associated with the use of modern genome editing technology without proper safety protocols and regulatory frameworks at an international level (Ranisch et al., 2020 ). This has triggered the need to develop clear and strict regulations to be implemented if these tools are to be used in the future. This incident also led to the formation of several working groups, including the establishment of an international commission on the Clinical Use of Human Germline Genome Editing set up by the US National Academy of Medicine, the US National Academy of Sciences, and the UK’s Royal Society. In 2020, the commission published a comprehensive report on HGE, proposing a translational pathway from research to clinical use (National Academy of Medicine, National Academy of Sciences, and the Royal Society, 2020 ). Likewise, a global expert Advisory Committee was established by the World Health Organization (WHO) with the goal of developing recommendations on governance mechanisms for human genome editing. Although the committee insisted in an interim recommendation that “it would be irresponsible at this time for anyone to proceed with clinical applications of human germline genome editing” (WHO, 2019 ), it did not express fundamental concerns on the possibility that some forms of HGE will one day become a reality. In 2021, the WHO’s Advisory Committee issued some publications, including a “Framework for governance” report and a “Recommendations” report (WHO, 2021 ). Building on a set of procedural and substantive values and principles, the “Framework for Governance” report discusses a variety of tools and institutions necessary for developing appropriate national, transnational, and international governance and oversight mechanisms for HGE. Specifically, the report considers the full spectrum of possible applications of human genome editing (including epigenetic editing and human enhancement) and addresses specific challenges associated with current, possible and speculative scenarios. These range from somatic gene therapy for the prevention of serious hereditary diseases to potentially more controversial applications reminiscent of the He Jiankui case (e.g., the use of HGE in reproductive medicine outside regulatory controls and oversight mechanisms). Additionally, the “Recommendations” report proposes among other things whistleblowing mechanisms to report illegal or unethical research. It also highlights the need for a global human genome editing registry, that should also cover basic and preclinical research on different applications of genetic manipulation, including HGE. The report also emphasises the need of making possible benefits of human genome editing widely accessible.

The idea of a human genome editing registry has also been supported by the European Group on Ethics in Science and New Technologies (EGE), an advisory board to the President of the European Commission. After an initial statement on genome editing published in 2016, still calling for a moratorium on editing of human embryos (EGE, 2016 ), the EGE published a comprehensive Opinion in 2021 (EGE, 2021 ). Although the focus of this report is on the moral issues surrounding genome editing in animals and plants, HGE is also discussed. Similar to the WHO Advisory Committee, the EGE recommends for HGE not to be introduced prematurely into clinical application and that measures should be taken to prevent HGE’s use for human enhancement.

Overall, when reviewing reports and initiatives produced since 2015, common themes and trajectories can be identified. A key development is the observation that the acceptance of the fundamental permissibility of such interventions appears to be increasing. This constitutes an important change from previous positions, reflecting the fact that human germline interventions have long been considered a ‘red line’ or at least viewed with deep scepticism (Ranisch and Ehni, 2020 ). In particular, while there is agreement that it would be premature to bring HGE into a clinical context, key concerns expressed by authoritative international bodies and committees are now associated with acceptable uses of the technology, rather than its use per se. Consideration is now being given to the conditions and objectives under which germline interventions could be permissible, instead of addressing the fundamental question of whether HGE may be performed at all. The question of permissibility is often linked to the stage of technological development. These developments are remarkable, since the key ethical aspects of genome editing are now frequently confined to questions of safety or cost–benefit ratios, rather than categorical considerations.

Another common issue can also be found in recent reports: the question of involving society in the debate. There is consensus on the fact that the legitimacy and governance of HGE should not be left solely to scientists and other experts but should involve society more broadly. Since germline interventions could profoundly change the human condition, the need for a broad and inclusive public debate is frequently emphasized (Iltis et al., 2021 ; Scheufele et al., 2021 ). The most striking expression of the need for public engagement and a “broad societal consensus” can be found in the final statement by the 2015 International Summit on Human Gene Editing organizing committee, as previously quoted (NASEM, 2015 ). Furthermore, the EGE and others also stresses the need for an inclusive societal debate before HGE can be considered permissible.

The pleas for public engagement are, however, not free of tension. For example, the NASEM’s 2017 report was criticised for supporting HGE bypassing the commitment for the broad societal consensus (Baylis, 2017 ). Regarding HGE, some argue that only a “small but vocal group of scientists and bioethicists now endorse moving forward” (Andorno et al., 2020 ). Serious efforts to engage the public on the permissibility and uses of HGE have yet to be made. This issue not only lacks elaboration on approaches to how successful public participation can occur, but also how stop short of presenting views on how to translate the public’s views into ethical considerations and policy (Baylis, 2019 ).

Potential uses of heritable genome editing technology

HGE is expected to allow a range of critical interventions: (i) preventing the transmission of genetic variants associated with severe genetic conditions (mostly single gene disorders); (ii) reducing the risk of common diseases (mostly polygenic diseases), with the promise of improving human health; and (iii) enhancing human capabilities far beyond what is currently possible for human beings, thereby overcoming human limitations. The identification of different classes of potential interventions has shifted the debate to the applications considered morally permissible beyond the acceptable use of HGE (Dzau et al., 2018 ). Specifically, there are differences in the limits of applicability suggested by some of the key cornerstone publications discussed above. For example, the NASEM ( 2017 ) report suggests limiting the use of HGE to the transmission of genetic variants linked to severe conditions, although in a very regulated context. In a very similar way, the 2020 report from the International Commission on the Clinical Use of Human Germline Genome Editing suggests that the initial clinical use of HGE should be limited to the prevention of serious monogenic diseases. By contrast, the 2018 Nuffield Council on Bioethics Report does not seem to limit the uses of genome editing to specific applications, though suggests that applications should be aligned with fundamental guiding ethical principles and need to have followed public debate (Savulescu et al., 2015 ). The same report also discusses far-reaching and speculative uses of HGE that might achieve “other outcomes of positive value” (Nuffield Council on Bioethics, 2018 ). Some of these more speculative scenarios include “built-in genetic resistance or immunity to endemic disease”; “tolerance for adverse environmental conditions” and “supersenses or superabilities” (Nuffield Council on Bioethics, 2018 , p. 47).

There have been different views on the value of HGE technology. Some consider that HGE should be permissible in the context of therapeutic applications, since it can provide the opportunity to treat and cure diseases (Gyngell et al., 2017 ). For example, intervention in severe genetic disorders is considered as therapeutic and hence morally permissible, or even obligatory. Others consider HGE to be more like a public health measure, which could be used to reduce the prevalence of a disease (Schaefer, 2020 ). However, others maintain that reproductive uses of HGE are not therapeutic because there is no individual in a current state of disease which needs to be treated, rather a prospective individual to be born with a specific set of negative prospective traits (Rulli, 2019 ).

Below, HGE is discussed in the context of reproductive uses and conditions of clinical advantage over existent reproductive technologies. The HGE applications are explored regarding their potential for modifying one or more disease-related genes relevant to the clinical context. Other uses associated with enhancement of physical and mental characteristics, which are considered non-clinical (although the distinction is sometimes blurred), are also discussed.

Single gene disorders

An obvious application of HGE interventions is to prevent the inheritance of genetic variants known to be associated with a serious disease or condition. Its potential use for this purpose could be typically envisaged through assisted reproduction, i.e., as a process to provide reproductive options to couples or individuals at risk of transmitting genetic conditions to their offspring. Critics of this approach often argue that other assisted reproductive technologies (ARTs) and preimplantation screening technologies e.g., preimplantation genetic diagnosis (PGD), not involving the introduction of genetic modifications to germline cells, are already available for preventing the transmission of severe genetic conditions (Lander, 2015 ; Lanphier et al., 2015 ). These existent technologies aim to support prospective parents in conceiving genetically related children without the condition that affect them. In particular, PGD involves the creation of several embryos by in vitro fertilization (IVF) treatment that will be tested for genetic anomalies before being transferred to the uterine cavity (Sermon et al., 2004 ). In Europe, there is a range in the regulation of the PGD technology with most countries having restrictions of some sorts (Soini, 2007 ). The eligibility criteria for the use of PGD also vary across countries, depending on the range of heritable genetic diseases for which it can be used (Bayefsky, 2016 ).

When considering its effectiveness, PGD presents specific limitations, which include the rare cases in which either both prospective parents are homozygous carriers of a recessive genetic disease, or one of the parents is homozygous for a dominant genetic disease (Ranisch, 2020 ). In these cases, all embryos produced by the prospective parents will be affected by the genetic defect, and therefore it will not be possible to select an unaffected embryo after PGD. Currently, beyond adoption of course, the options available for these prospective parents include the use of a third-party egg or sperm donors.

Overall, given the rarity of cases in which it is not applicable, PGD is thought to provide a reliable option to most prospective parents for preventing severe genetic diseases to be transmitted to their offspring, except in very specific cases. HGE interventions have been suggested to be an alternative method to avoid single gene disorders in the rare cases in which selection techniques such as PGD cannot be used (Ranisch, 2020 ). It has also been proposed to use tools such as CRISPR/Cas9 to edit morphologically suitable but genetically affected embryos, and thus increase the number of embryos available for transfer (de Wert et al., 2018 ; Steffann et al., 2018 ). Moreover, HGE interventions are considered by some as a suitable alternative to PGD, even when the use of PGD could be possible. One argument in this respect is that, although not leading to the manifestation of the disease, the selected embryos can still be carriers of it. In this respect, differently from PGD, HGE interventions can be used to eliminate unwanted, potential future consequences of genetic diseases (i.e., by eliminating the critical mutation carried out in the selected embryo), with the advantage of reducing the risks of further propagation of the disease in subsequent future generations (Gyngell et al., 2017 ).

Overall, HGE interventions are thought to offer a benefit over PGD in some situations by providing a broader range of possible interventions, as well as by providing a larger number of suitable embryos. The latter effect is usually important in the cases where unaffected embryos are small in number, making PGD ineffective (Steffann et al., 2018 ). Whether these cases provide a reasonable ground to justify research and development on the clinical use of HGE remain potentially contentious. Some authors have suggested that the number of cases in which PGD cannot be effectively used to prevent transmission of genetic disorders is so marginal that clinical application of HGE could hardly be justified (Mertes and Pennings, 2015 ). Particularly when analyzing economic considerations (i.e., the allocation of already scarce resources towards clinical research involving expensive techniques with limited applicability) and additional risks associated with direct interventions. In either case of HGE being used as an alternative or a complementary tool to PGD, PGD will most likely still be used to identify those embryos that would manifest the disease and would hence require subsequent HGE.

The PGD technique, however, is not itself free of criticism and possible moral advantages of HGE over PGD have also been explored (Hammerstein et al., 2019 ; Ranisch, 2020 ). PGD remains ethically controversial since, identifying an unaffected embryo from the remaining embryos (which will not be used and ultimately discarded) amounts to the selection of ‘healthy’ embryos rather than ‘curing’ embryos affected by the genetic conditions. On the other hand, given a safe and effective application of the technology, the use of HGE is considered by many morally permissible to prevent the transmission of genetic variants known to be associated with serious illness or disability (de Miguel Beriain, 2020 ). One question that remains is whether HGE and PGD have a differing or equal moral permissibility or, at least, comparable. On issues including human dignity and autonomy, it was argued that HGE and PGD interventions can be considered as equally morally acceptable (Hammerstein et al., 2019 ). This equal moral status was, however, only valid if HGE is used under the conditions of existent gene variants in the human gene pool and to promote the child health’s best interest in the context of severe genetic diseases (Hammerstein et al., 2019 ). Because of selection and ‘therapy’, moral assessments resulted in HGE interventions being considered to some extent preferable to PGD, once safety is carefully assessed (Gyngell et al., 2017 ; Cavaliere, 2018 ). Specifically, PGD’s aim is selective and not ‘therapeutic’, which could be said to contradict the aims of traditional medicine (MacKellar and Bechtel, 2014 ). In contrast to PGD’s selectivity, HGE interventions are seen as ‘pre-emptively therapeutic’, and therefore closer to therapy than PGD (Cavaliere, 2018 ). However, it is also argued that HGE does not have curative aims, and thus it is not a therapeutic application, as there is no patient involved in the procedure to be cured (Rulli, 2019 ). On balance, there appears to be no consensus on which of the approaches, HGE and PGD, is morally a better strategy to prevent the transmission of single gene disorders, with a vast amount of literature expressing diverse positions when considering different scenarios (Delaney, 2011 ; Gyngell et al., 2017 ; Cavaliere, 2018 ; Ranisch, 2020 ; Rehmann-Sutter, 2018 ; Sparrow, 2021 ).

Polygenetic conditions

HGE is also argued to have the potential to be used in other disorders which have a polygenic disposition and operate in combination with environmental influences (Gyngell et al., 2017 , 2019 ). Many common diseases, which result from the involvement of several genes and environmental factors, fall into this category. Examples of common diseases of this type includes diabetes, coronary artery disease and different types of cancers, for which many of the genes involved were identified by studies of genome wide association (e.g., Wheeler and Barroso, 2011 ; Peden and Farral, 2011 ). These diseases affect the lives of millions of people globally, severely impacting health and often leading to death. Furthermore, these diseases have a considerable burden on national health systems. Currently, many of these diseases are controlled through pharmaceutical products, although making healthier life choices about diet and exercise can also contribute to preventing and managing some of them. Despite the interest, the use of PGD in polygenic conditions would hardly be feasible, due to the number of embryos needed to select the preferred genotype and available polygenic predictors (Karavani et al., 2019 ; Shulman and Bostrom, 2014 ).

In theory, HGE could be a potentially useful tool to target different genes and decrease the susceptibility to multifactorial conditions in current and future generations. The application of HGE to polygenic conditions is often argued by noting that the range of applicability of the technique (well beyond single gene disorders) would justify and outweigh the cost needed to develop it. However, to do so, a more profound knowledge of genetic interactions, of the role of genes and environmental factors in diverse processes would be needed to be able to modify such interconnected systems with limited risk to the individual (Lander, 2015 ). Besides, it is now understood that, depending on the genetic background, individuals will have different risks of developing polygenetic diseases (risk-associated variants), but hardly any certainty of it. In other words, although at the population level there would most likely be an incidence of the disease, it is not possible to be certain of the manifestation of the disease in any specific individual. As a result, the benefits of targeting a group of genes associated to a disease in a specific individual would have to be assessed in respect to the probability of incidence of the disease. The risk-benefit ratio for HGE is considerably increased for polygenic conditions compared to monogenic disorders. Additionally, the risks of adverse effects, e.g., off-target effects, increases with the number of genes targeted for editing. The latter effects make the potential benefits of HGE in polygenic diseases more uncertain than in single gene disorders.

Genetic enhancement

A widespread concern regarding the use of HGE is that such interventions could be used not only to prevent serious diseases, but also to enhance desirable genetic traits. Currently, our knowledge on how to genetically translate information into specific phenotypes is very limited and some argue that it might never be technically feasible to achieve comprehensive genetic enhancements using current gene editing technologies (Janssens, 2016 ; Ranisch, 2021 ). Similar to many diseases, in which different genetic and other factors are involved, many of the desirable traits to be targeted by any enhancement will most likely be the result of a combination of several different genes influenced by environment and context. Moreover, the implications for future generations of widespread genetic interventions in the human population and its potential impact on our evolutionary path are difficult to assess (Almeida and Diogo, 2019 ). Nevertheless, others argue that genetic enhancement through HGE could be possible in the near future (de Araujo, 2017 ).

There has been much discussion regarding the meaning of the terms and the conceptual or normative difference between ‘therapy’ and ‘enhancement’ (for an early discussion: Juengst, 1997 ; Parens, 1998 ). There are mainly three different meanings of ‘enhancement’ used in the literature. First, ‘enhancement’ is sometimes used to refer to measures that go beyond therapy or prevention of diseases, i.e., that transcend goals of medicine. Second, ‘enhancement’ is used to refer to measures that equip a human with traits or capacities that they typically do not possess. In both cases, the term points to equally controversial and contrasting concepts: on the one hand, those of ‘health’, ‘disease’ or ‘therapy’, and on the other, those of ‘normality’ or ‘naturalness’. Third, ‘enhancement’ is sometimes also used as an umbrella-term describing all measures that have a positive effect on a person’s well-being. According to this definition, the cure, or prevention of a disease is then also not opposed to an enhancement. Here again, this use refers to the controversial concept of ‘well-being’ or a ‘good life’.

It is beyond the scope of this article to provide a detailed review of the complex debate about enhancement (for an overview: Juengst and Moseley, 2019 ). However, three important remarks can be made: first, although drawing a clear line between ‘enhancement’ and ‘therapy’ (or ‘normality’, etc.) will always be controversial, some cases can be clearly seen as human enhancement. This could include modifications to augment human cognition, like having a greater memory, or increasing muscle mass to increase strength, which are not considered essential for human health (de Araujo, 2017 ).

Second, it is far from clear whether a plausible account of human enhancement would, in fact, be an objectivist account. While authors suggest that there is some objectivity regarding the conditions that constitute a serious disease (Habermas, 2003 ), the same might not be true for what constitutes an improvement of human functioning. It may rather turn out that an enhancement for some might be seen as a dis-enhancement for others. Furthermore, the use of the HGE for enhancement purposes can be considered at both an individual and a collective level (Gyngell and Douglas, 2015 ; Almeida and Diogo, 2019 ), with a range of ethical and biological implications. If HGE is to be used for human enhancement, this use will be in constant dependence on what we perceive as ‘normal’ functioning or as ‘health’. Therefore, factors such as cultural and societal norms will have an impact on where such boundaries are drawn (Almeida and Diogo, 2019 ).

Third, it should be noted that from an ethical perspective the conceptual question of what enhancement is, and what distinguishes it from therapy, is less important than whether this distinction is ethically significant in the first place. In this context, it was pointed out that liberal positions in bioethics often doubt that the distinction between therapy and enhancement could play a meaningful role in determining the limits of HGE (Agar, 1998 ). The consideration of genetic intervention for improving or adding traits considered positive by individuals have raised extreme positions. Some welcome the possibility to ameliorate the human condition, whilst others consider it an alarming attempt to erase aspects of our common human ‘nature’. More specifically, some authors consider HGE a positive step towards allowing humans the opportunity to obtain beneficial traits that otherwise would not be achievable through human reproduction, thus providing a more radical interference in human life to overcome human limitations (de Araujo, 2017 ; Sorgner, 2018 ). The advocates of this position are referred to as ‘bioliberals’ or ‘transhumanists’ (Ranisch and Sorgner, 2014 ), and its opponents are referred to as ‘bioconservatives’ (Fukuyama, 2002 ; Leon, 2003 ; Sandel, 2007 ). Transhumanism supports the possibility of humans taking control of their biology and interfering in their evolution with the use of technology. Bioconservatism defends the preservation and protection of ‘human essence’ and expresses strong concerns about the impact of advanced technologies on the human condition (Ranisch and Sorgner, 2014 ).

For the general public, HGE used in a clinical context seems to be less contentious compared when used as a possible human enhancement tool. Specifically, some surveys indicate that the general-public typically exhibits a reduced support for the use of genome editing interventions for enhancement purposes compared to therapeutic purposes (Gaskell et al., 2017 ; Scheufele et al., 2017 ). In contrast, many technologies and pharmaceutical products developed in the medical context to treat patients are already being used by individuals to ‘enhance’ some aspect of their bodies. Some examples include drugs to boost brain power, nutritional supplements, and brain-stimulating technologies to control mood, even though their efficiency and safety is not clear. This could suggest that views on enhancement may vary depending on the context and on what is perceived as an enhancement by individuals. It may be informative to carry out detailed population studies to explore whether real ethical boundaries and concerns exist, or whether these are purely the result of the way information is processed and perceived.

Heritable genome editing: Mapping the ethical debate

Even though genome editing methods have only been developed in the last decade, the normative implication of interventions into the human germline have been discussed since the second half of the 20th century (Walters et al., 2021 ). Some even argue that, virtually, all the ethical issues raised by genetic engineering were already being debated at that time (Paul, 2005 ). This includes questions about the distinction between somatic and germline interventions, as well as between therapy and enhancement (e.g., Anderson, 1985 ). Nevertheless, as it has been widely noted, it is difficult to draw clear lines between these two categories (e.g., McGee, 2020 ; Juengst, 1997 ), and alternative frameworks have been proposed, particularly in the context of HGE (Cwik, 2020 ). Other questions include the normative status of human nature (e.g., Ramsey, 1970 ), the impossibility of consent from future generations (e.g., Lappe, 1991 ), possible slippery slopes towards eugenics (e.g., Howard and Rifkin, 1977 ), or implications for justice and equality (e.g., Resnik, 1994 ).

When discussing the ethics of HGE, roughly three types of considerations can be distinguished: (i) pragmatic, (ii) sociopolitical, and iii) categorical (Richter and Bacchetta, 1998 ; cf. Carter, 2002 ). Pragmatic considerations focus on medical or technological aspects of HGE, such as the safety or efficacy of interventions, risk–benefit ratio, possible alternatives or the feasibility of responsible translational research. Such considerations largely depend on the state of science and are thus always provisional. For example, if high-risk technologies one day evolve into safe and reliable technologies, some former pragmatic considerations may become obsolete. Sociopolitical aspects, on the other hand, are concerned with the possible societal impact of technologies, e.g., how they can promote or reduce inequalities, support or undermine power asymmetries, strengthen, or threaten democracy. Similar to pragmatic considerations, sociopolitical reasons depend on specific contexts and empirical factors. However, these are in a certain sense ‘outside’ the technology—even though technologies and social realities often have a symbiotic relationship. While sociopolitical considerations can generate strong reasons against (or in favour of) implementing certain technologies, most often these concerns could be mitigated by policies or good governance. Categorical considerations are different and more akin to deontic reasons. They emphasise categorical barriers to conduct certain deeds. It could be argued, for instance, that the integrity of the human genome or the impossibility to obtain consent from future generation simply rule out certain options to modify human nature. Such categorical considerations may persist despite technological advances or changing sociopolitical conditions.

Comparing the bioethical literature on genetic engineering from the last century with the ongoing discussions shows a remarkable shift in the ethical deliberation. In the past, scholars from the field of medical ethics, as well as policy reports, used to focus on possible categorical boundaries for germline interventions and on possible sociopolitical consequences of such scenarios. For instance, the influential 1982 report “Splicing Life” from the US President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioural Research prominently discussed concerns about ‘playing God’ against the prospects of genetically engineering human beings, as well as possible adverse consequences of such interventions. Although this study addresses potential harms, pragmatic arguments played only a minor role, possibly due to the technical limitations at the time.

With the upcoming availability of effective genome editing techniques, the focus on the moral perspective seems to have been reversed. Increasingly, the analysis of the permissibility of germline interventions is confined to questions of safety and efficacy. This is demonstrated by the 2020 consensus study report produced by an international commission convened by the US National Academy of Medicine, the US National Academy of Sciences, and the UK’s Royal Society, which aimed at defining a translational pathway for HGE. Although the report recognizes that HGE interventions does not only raise pragmatic questions, ethical aspects were not explicitly addressed (National Academy of Medicine, National Academy of Sciences, and the Royal Society, 2020 ).

Similarly, in 2019, a report on germline interventions published by the German Ethics Council (an advisory body to the German government and parliament) emphasizes that the “previous categorical rejection of germline interventions” could not be maintained (Deutscher Ethikrat, 2019 , p. 5). The German Ethics Council continues to address ethical values and societal consequences of HGE. However, technical progress and the development of CRISPR/Cas9 tools seem to have changed the moral compass in the discussion about germline interventions.

For a comprehensive analysis of HGE to focus primarily on pragmatic arguments such as safety or efficacy would be inadequate. In recent years, developments in the field of genome editing have occurred at an incredibly fast pace. At the same time, there are still many uncertainties about the efficacy of the various gene editing methods and unexpected effects in embryo editing persist (Ledford, 2015 ). Social and political implication also remain largely unknown. To date, it has been virtually impossible to estimate how deliberate interventions into the human germline could shape future societies and to conduct a complete analysis of the safety aspects of germline interventions.

Moreover, as the EGE notes, we should be cautious not to limit the complex process of ethical decision-making to pragmatic aspects such as safety. The “‘safe enough’ narrative purports that it is enough for a given level of safety to be reached in order for a technology to be rolled out unhindered, and limits reflections on ethics and governance to considerations about safety” (EGE, 2021 , p. 20). Consequently, the EGE has highlighted the need to engage with value-laden concepts such as ‘humanness’, ‘naturalness’ or ‘human diversity’ when determining the conditions under which HGE could be justified. Even if a technology has a high level of safety, its application may still contradict ethical values or lead to undesirable societal consequences. Efficacy does not guarantee compatibility with well-established ethical values or cultural norms.

While concepts such as ‘safety’ or ‘risk’ are often defined in scientific terms, this does not take away the decision of what is ethically desirable given the technical possibilities. As Hurlbut and colleagues put it in the context of genome editing: “Limiting early deliberation to narrowly technical constructions of risk permits science to define the harms and benefits of interest, leaving little opportunity for publics to deliberate on which imaginations need widening, and which patterns of winning and losing must be brought into view” (Hurlbut et al., 2015 ). Therefore, if public engagement is to be taken seriously, cultural norms and values of those affected by technologies must also be considered (Klingler et al., 2022 ). This, however, means broadening the narrow focus on pragmatic reasons and allowing categorical as well as sociopolitical concerns in the discourse. Given the current attention on pragmatic reasons in current debates on HGE, it is therefore beneficial to revisit the categorical and sociopolitical concerns that remain unresolved. The following sections provide an overview of relevant considerations that can arise in the context of HGE and that underline many of the societal concerns and values crucial for public engagement.

Human genome ‘integrity’

Heritability seems to be one of the foremost considerations regarding germline genome editing, as it raises relevant questions on a ‘natural’ human genome and its role in ‘human nature’ (Bayertz, 2003 ). This follows an ongoing philosophical debate on ‘human nature’, at least as defined by the human genome. This has ensued a long debate on the value of the human genome and normative implications associated with its modification (e.g., Habermas, 2003 ). Although a comprehensive discussion of these topics goes beyond the scope of this paper, the human genome is viewed by many as playing an important role in defining ‘human nature’ and providing a basis for the unity of the human species (for discussion: Primc, 2019 ). Considering the implications for the individual and the collective, some affirm the right of all humans to inherit an unmodified human genome. For some authors, germline modification is considered unethical, e.g., a “line that should not be crossed” (Collins, 2015 ) or a “crime against humanity” (Annas et al., 2002 ).

The Universal Declaration on the Human Genome and Human Rights (UDHGHR) states that “the human genome underlies the fundamental unity of all members of the human family, as well as the recognition of their inherent dignity and diversity. In a symbolic sense, it is the heritage of humanity” (Article 1, UNESCO, 1997 ). The human genome is viewed as our uniquely human collective ‘heritage’ that needs to be preserved and protected. Critics of heritable genetic interventions argue that germline manipulation would disrupt this natural heritage and therefore would threaten human rights and human equality (Annas, 2005 ). Heritable human genome editing creates changes that can be heritable to future generations. For many, this can represent a threat to the unity and identity of the human species, as these modifications could have an impact on the human’s gene pool. Any alterations would then affect the evolutionary trajectory of the human species and, thus, its unity and identity.

However, the view of the human genome as a common heritage is confronted with observations of the intrinsic dynamism of the genome (Scally, 2016 ). Preservation of the human genome, at least in its current form, would imply that the genome is static. However, the human genome is dynamic and, at least in specific periods of environmental pressure, must have naturally undergone change, as illustrated by human evolution (Fu and Akey, 2013 ). The genome of any individual includes mutations that have occurred naturally. Most of them seem to be neither beneficial nor detrimental to the ability of an individual to live or to his/her health. Others can be detrimental and limiting to their wellbeing. It has been shown that, on average, each human genome has 60 new mutations compared to their parents (Conrad et al., 2011 ). At the human population level, a human genome can have in average 4.1–5 million variants compared to the ‘reference’ genome (Li and Sadler, 1991 ; Genomes Project C, 2015 ). The reference genome itself is thus a statistical entity, representing the statistic distribution of the probability of different gene variants in the whole genome. Human genomic variation is at the basis of the differences in the various physical traits present in humans (e.g., eye colour, height, etc.), as well as specific genetic diseases. Thus, the human population is comprised of genomes with a pattern of variants and not of ‘one’ human genome that needs to be preserved (Venter et al. 2001 ). The human genome has naturally been undergoing changes throughout human history. An essentialist view of nature seems to be the basis for calling for the preservation of genome integrity. However, in many ways, this view is intrinsically challenged by the interpretation portrayed by evolutionary biology of our genetic history already more than a century ago. Nevertheless, despite the dynamic state of the human genome, this in itself cannot justify the possibility of modifying the human genome. It is also worth considering that the integrity of the human genome could also be perceived in a ‘symbolic’ rather than biological literal meaning. Such an interpretation would not require a literally static genome over time, but instead suggest a boundary between ‘naturally’ occurring variation and ‘artificially’ induced change. This is rather a version of the ‘natural’/unnatural argument, rather than an argument for a literally unchanged genetic sequence.

The modification of the human genome raises complex questions about the characterization of the human species genome and if there should be limits on interfering with it. The options to modify the human genome could range from modifying only the genes that are part of the human gene pool (e.g., those genes involved in severe genetic diseases such as Huntington’s disease) to adding new variants to the human genome. Regarding variants which are part of the common range of variation found in the human population (although it is not possible to know all the existent variations), the question becomes whether HGE could also be used in any of them (e.g., even the ones providing some form of enhancement) or only in disease-associated variants and thus be restricted to the prevention of severe genetic diseases. In both cases, the integrity of the human genome is expected to be maintained with no disruption to human lineage. However, it could be argued that this type of modification is defending a somewhat conservative human nature argument, since it is considering that a particular genetic make-up is ‘safe’ or would not involve any relevant trade-offs. In contrast, a different conclusion could be drawn on the integrity of the human genome when introducing genotypical and phenotypical traits that do not lie within the common range of variation found in the population (Cwik, 2020 ). In all cases, since the implications of the technology are intergenerational and consequently, it will be important to carry out an assessment of the risks that we, as a species, are willing to take when dealing with disease and promoting health. For this, we will need to explore societal views, values and cultural norms associated with the human genome, as well as possibly existing perceptions of technology tampering with ‘nature’. To support such an assessment, it would be useful to draw on a firm concept of human nature and the values it implies, beyond what is implied by genetic aspects.

Human dignity

In several of the legally binding and non-binding documents addressing human rights in the biomedical field, human dignity is one of the key values emphasized. There are concerns that heritable genome interventions might conflict with the value of human dignity (Calo, 2012 ; Melillo, 2017 ). The concerns are considered in the context of preserving the human genome (Nordberg et al. 2020 ). More specifically, the recommendation on Genetic Engineering by the Council of Europe (1982) states that “ the rights to life and to human dignity protected by Articles 2 and 3 of the European Convention on Human Rights imply the right to inherit a genetic pattern which has not been artificially changed” (Assembly, 1982 ). This is supported by the Oviedo Convention on Human Rights and Biomedicine (1997), where Article 13 prohibits any genetic intervention with the aim of introducing a modification in the genome of any descendants. The Convention is the only international legally binding instrument that covers human germline modifications among the countries which have ratified it (Council of Europe, 1997 ). However, there have been some authors disputing the continued ban proposed by the Oviedo Convention (Nordberg et al. 2020 ). Such authors have focused on the improvements of safety and efficacy of the technology in contrast to authors focusing on its value for human dignity (Baylis and Ikemoto, 2017 ; Sykora and Caplan, 2017 ). The latter authors seem to highlight the concept of human dignity to challenge heritable interventions to the human genome.

But a question in debate has been to demonstrate how ‘human dignity’, described in such norms, relates to heritable genome interventions. The concept of the human genome as common genetic heritage, distinguishing humans from other species seems one of the main principles implied by such norms. In this view, the human genome determines who belongs to the human species and who does not, and thus confers an individual the dignity of being a human by association. This creates an inherent and strong link between the concept of human genome and the concept of human dignity and its associated legal rights (Annas, 2005 ). It could be argued that a genetic modification to an individual may make it difficult for him/her to be recognized as a human being and therefore, preservation of the human genome being important for human dignity to be maintained. This simple approach, or at least interpretation, however, ignores the fact that the human genome is not a fixed or immutable entity, as exemplified by human evolution (as discussed in the previous section). As a result, the view that HGE interventions are inherently inadmissible based on the need to preserve human dignity is contested (Beriain, 2018 ; Raposo, 2019 ). More broadly, the idea that biological traits are the basis for equality and dignity, supporting the need for the human genome to be preserved, is often challenged (Fenton, 2008 ).

It is argued that to fully assess the impact of the HGE interventions on human dignity, it will be necessary to have a better understanding of the concept of human dignity in the first place (Häyry, 2003 ; Cutas, 2005 ). For some, however, human dignity is a value that underlies questions of equality and justice. Thus, the dignity-based arguments could uncover relevant questions in the discussion of ethical implications on modifying the human genome (Segers and Mertes, 2020 ). In the Nuffield Council on Bioethics Report (2018) principles of social justice and solidarity, as well as welfare, are used to guide the debate on managing HGE interventions. Similarly, the concept of human dignity could, therefore, provide the platform upon which consideration of specific values could be discussed, broaden the debate on HGE to values shared by society.

Right of the child: informed consent

In many modern societies, every individual, including children, have the rights to autonomy and self-determination. Therefore, each person is entitled to decide for themselves in decisions relating to their body. These rights are important for protecting the physical integrity of a person. When assessing the implication of allowing individuals to take (informed) decisions relative to the use of heritable genetic interventions on someone else’s body, it is useful to reflect on the maturity of existing medical practices and, more broadly, on the additional complexities associated with the heritability of any such intervention.

In modern health-care systems, informed consent provides the opportunity for an individual to exercise autonomy and make an informed decision about a medical procedure, based on their understanding of the benefits and risks of such procedure. Informed consent is thus a fundamental principle in medical (research) ethics when dealing with human subjects (Beauchamp and Childress, 2019 ).

Heritable genome interventions present an ethical constraint on the impossibility of future generations of providing consent to an intervention on their genome (Smolenski, 2015 ). In other words, future generations cannot be involved in a decision which could limit their autonomy, since medical or health-related decisions affecting them are placed on the present generation (and, in the case of a child to be born, more specifically, on his/her parents). However, many other actions taken by parents of young children also intentionally influence the lives of those children and have been doing so for millennia (Ranisch, 2017 ). Although these actions may not involve altering their genes, many of such actions can have a long-lasting impact on a child’s life (e.g., education and diet). However, it could be argued that they do not have the irreversible effect that HGE will have in the child and future generations. In cases where parents act to expand the life choices of their children by eliminating disease (e.g., severe genetic diseases), this would normally be thought to outweigh any possible restriction on autonomy. In these cases, if assuming HGE benefits will outweigh risks regarding safety and efficacy, the use of HGE could be expected to contribute to the autonomy of the child, as him/her would be able in the future to have a better life, not constrained by the limitations of the disease. As a result, even if it is accepted that these technologies may in one way reduce the autonomy of future generations, some believe that this will often be outweighed by other effects increasing autonomy (Gyngell et al., 2017 ). In other words, it is reasonable to suppose that, when taken by parents based on good information and understanding of risks and impacts, the limitation in the autonomy of unborn children associated with heritable genetic interventions would be compensated by the beneficial effects of increasing their autonomy when born (Gyngell et al., 2017 ).

It has often been emphasized that possible genetic interventions must not curtail the future possibilities of offspring to live their lives according to their own idea of a good life. This view originated in the liberal tradition and is associated with the “right to an open future”, defended by Joel Feinberg ( 1992 ). That is an anticipatory autonomy right that parents can violate, even though the offspring could exercise it only in the future. Feinberg has discussed the right to an open future in the context of religious education. However, various authors have applied this argument to the question of permissible and desirable genetic interventions (Buchanan et al., 2000 ; Glover, 2006 ; Agar, 1998 ). Accordingly, germline modifications or selection would have to allow the offspring to have a self-determined choice of life plans. It would therefore be necessary to provide offspring with genetic endowments that represent the so-called all-purpose goods. These goods are “useful and valuable in carrying out nearly any plan of life or set of aims that humans typically have” (Buchanan et al., 2000 , p. 167). While this claim is certainly appealing, in reality it will be difficult to identify phenotypes that will only broaden and do not narrow the spectrum of life plans. Take, for example, body size: a physique favourable for a basketball player would at the same time be less favourable in successfully riding horses as a professional jockey and vice versa. Increasing some opportunities often means reducing other ones.

The arguments of informed consent and open future need to be explored outside the realm of severe genetic diseases by considering other scenarios (including scenarios of genetic enhancement). Hereby, the effects of the interventions on the autonomy of future generations can be assessed more comprehensively. As for enhancement, decisions outside the realm of health can be more controversial, as the traits that parents see fit to generate enhancement may inadvertently condition a child’s choices in the future in an undesirable way.

If HGE is to be used, questions on how the consent and information should be provided to parents to fully equip them to decide in the best interests of the child will need to be assessed (Evitt et al., 2015 ). This is evident if considering the informed consent used in the study conducted by He Jiankui. One of the many criticisms of the study was the inadequacy of the informed consent process provided to the parents, which did not meet regulatory or ethical standards (Krimsky, 2019 ; Kirksey, 2020 ). This raises questions on how best to achieve ethical and regulatory compliance regarding informed consent in applications of HGE (Jonlin, 2020 ).

Discrimination of people with disabilities

For many years, there has been an effort to develop selective reproduction technologies to prevent genetic diseases or conditions leading to severe disabilities. These forms of reproductive genetic disease prevention are based on effectively filtering and eradicating embryos or foetuses affected by genetic diseases. There are divergent views regarding the use of these technologies. For example, the disability rights movement argues that the use of technologies such as prenatal testing (PNT) and PGD discriminates against people living with a disability (Scully, 2008 ; Asch and Barlevy, 2012 ). The key arguments presented supporting this view are: (i) the limited value of a genetic trait in respect to the life of an embryo (Parens and Asch, 2000 ) and (ii) the ‘expressivist’ argument (Buchanan, 1996 ; Shakespeare, 2006 ). The first argument is based on the critique that a disabling trait is viewed as being more significant than the life of an embryo/foetus. This argument was initially used in the context of prenatal testing and selective termination, and has also been applied in the context of new technologies like PGD (Parens and Asch, 2000 ). The second, the ‘expressivist’ argument, argues that the use of these technologies expresses negative or discriminatory views on the disabling conditions they are targeting and subsequently on the people living with these conditions (Asch and Wasserman, 2015 ). The expressivist argument, however, has been challenged by stressing the importance of differentiating between the disability itself and the people living with disability (Savulescu, 2001 ). The technology’s use is aimed at reducing the incidence of disability, and it does not have a position of value on the people that have a specific condition.

When applying the same arguments to the use of HGE in comparison with other forms of preventing heritable genetic diseases, some important considerations can be made. Regarding the first argument, in contrast to selective reproduction technologies, HGE may allow the removal of the disabled trait with the aim of ensuring survival of the affected embryo. However, most likely, PGD would be used before and after the editing of the embryos to help the identification of the ones requiring intervention and verifying the efficiency of the genetic intervention (de Miguel Beriain, 2018 ; Ranisch, 2020 ). Similarly, the expressivist argument continues to be challenged if the application of human HGE is envisaged in the context of severe genetic diseases (e.g., Tay-Sachs and Huntington’s disease). It has been argued that the choice to live without a specific genotype neither implies discriminating people living with a respective condition nor considering the life of people living with the disease not worth living or less valuable (Savulescu, 2001 ). In other words, the expressivist argument is not a valid or a sufficiently strong ethical argument for prospective parents not to have the option to have a future child without a genetic disease.

It is worth noting that the debate on the use of reproduction technologies for the prevention of genetic diseases is not at all new, and that modern HGE techniques only serve to highlight ethical concerns that have been expressed for a long time. In the case of preventing genetic diseases, the application of both arguments to HGE intervention could be considered not to provide sufficiently strong ethical arguments to limit the use of the technology in the future. However, it is worth exploring whether scientific innovations like HGE are either ameliorating or reinvigorating ethical concerns expressed so far, for example in creating a future that respects or devalues disability as a part of the human condition. Perhaps even more importantly, given their potential spectrum of possible intervention and efficacy, it is important to reflect on whether the broad use of HGE could have an impact on concepts of disability and ‘normality’ as a whole distorting an already unclear ethical line between clinical and non-clinical interventions. Moreover, research work exploring the relationship between disability and identity indicated that personhood with disability can be an important component to people’s identity and interaction with the world. In the case of heritable human genome editing, it is not yet known how this technology will impact the notions of identity and personhood in people who had their germline genome modified (Boardman and Hale, 2018 ). For further progress on these issues public engagement might be important to gather different views and perceptions on the issue.

Justice and equality

Beside the limits of applicability, another common ethical concern associated with the use of genome editing technologies, as with many new technologies, is the question of accessibility (Baumann, 2016 ). Due to the large investments that will need to be made for continuing development of the technology, there is a (perceived) risk of it becoming an expensive technology that only a few wealthy individuals in any population (and/or only citizens in comparatively rich countries) can access. In addition, there is concern that patenting of genome editing technologies will delay widespread access or lead to unequal distribution of corresponding benefits (Feeney et al., 2018 ). This may, consequently, contribute to further increases in existing disparities, since individuals or countries with the means of accessing better health treatments may have economic advantages (Bosley et al., 2015 ). This could enhance inequality at different levels, depending on the limits of applicability of the technology. Taken to its extreme, the use of the technology could allow germline editing to create and distinguish classes of individuals that could be defined by the quality of their manipulated genome.

The concern that the possibility of germline interventions in humans could entrench or even increase inequalities has accompanied the discussion about ethics of genetic interventions from the very beginning until today (e.g. Resnik, 1994 ). In ‘Remaking Eden’ Lee Silver envisioned a divided future society, consisting of a genetically enhanced class, the “genRich”, and a genetic underclass, the “naturals” (Silver, 1997 ). Françoise Baylis recently echoed such concerns regarding future HGE interventions, namely that “unequal access to genome-editing technologies will both accentuate the vagaries of the natural lottery and introduce an unjust genetic divide that mirrors the current unjust economic and social divide between rich and poor individuals” (Baylis, 2019 , p. 67). At the same time, the possibility to genetically intervene in the ‘natural lottery’ has also been associated with the hope of countering natural inequalities and increase equality of opportunities. Robert Sinsheimer may be among the first to envision such a ‘new’ individualistic type of ‘eugenics’ that “would permit in principle the conversion of all of the unfit to the highest genetic level” (Sinsheimer, 1969 , p. 13). More recently, in the book ‘From chance to choice: Genetics and justice’ (2000) it is argued that “equality of opportunity will sometimes require genetic interventions and that the required interventions may not always be limited to the cure or prevention of disease” (Buchanan et al., 2000 , p. 102). When discussing issues related to justice and equality, it will be important to involve a broad spectrum of stakeholders to better evaluate the economic effects of the commercialization of the technology.

Conclusions

With ongoing technological developments and progress with guiding and regulating its acceptable use, the possibility of HGE interventions in the human genome is closer than ever to becoming a reality. The range of HGE applicability can go from preventing the transmission of genetic variants associated with severe genetic conditions (mostly single gene disorders but also, to a lesser extent, polygenic diseases) to genetic enhancements. The permissibility of HGE has often been considered on the basis of possible uses, with therapeutic uses generally considered more acceptable than non-therapeutic ones (including human enhancement). When compared with other technologies with similar therapeutic uses (e.g., PGD) already in use, HGE presents similarities and differences. However, from an ethical acceptability perspective, there is currently no consensus on whether HGE is more or less acceptable than PGD.

An important conclusion of this study is that, along with the technological development of genome germline editing techniques, a shift in the focus of analyses on its applicability has been observed. More specifically, the emphasis on pragmatic considerations seems to have increased substantially compared with the previous emphasis on categorical and sociopolitical arguments. Many of the most recent publications from authoritative advisory committees and institutions discuss the permissibility of HGE interventions primarily on the basis of pragmatic arguments, in which safety and efficacy are the main focus. Since germline interventions could profoundly change the human condition, the need for a broad and inclusive public debate on this topic has also been frequently emphasized. However, limited consideration has been given to approaches to carry out such action effectively, and on how to consider their outcomes in relevant policies and regulations.

It is currently not entirely clear whether: (i) the pragmatic position championed by such authoritative sources builds on the premise that the ethical debate has reached sufficient maturity to allow a turning point; (ii) the lack of progress has somewhat hampered further consideration of issues still considered controversial; (iii) regulatory pressure is somewhat de facto pushing forward the introduction of such technologies despite critical, unresolved ethical issues. Based on the analysis presented in this paper, a combination of the latter factors (ii and iii) seems more likely. In engaging the public in societal debates on the acceptability of such technologies, unresolved questions are likely to re-emerge. Specifically, it is possible that categorical and sociopolitical considerations will gain renewed focus during public engagement. In other words, when involving the public in discussions on HGE, it is possible that cultural values and norms, not only questions of safety and efficacy, will re-emerge as crucial to the acceptance of the technology (What is meant by natural? What is understood by humanity? etc.).

HGE interventions put into question specific biological and moral views of individuals, including views on the value of the human genome, on human dignity, on informed consent, on disability and on societal equality and justice. The range of ethical issues affected by the introduction of such technology, often still characterised by non-convergent, and at times conflicting, positions, illustrate the importance of further consideration of these issues in future studies and public engagement activities. As a result, society’s moral uncertainties will need to be assessed further to support the regulation of HGE technologies and form a well-informed and holistic view on how they can serve society’s common goals and values.

Data availability

This statement is not applicable.

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This work was supported by Fundação para Ciência e a Tecnologia (FCT) of Portugal [UIDP/00678/2020 to M.A]. We thank Dr. Michael Morrison for his comments and Dr. Gustav Preller for his proofreading of this manuscript.

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Article Contents

Introduction, human enhancement, genetic engineering, conclusions.

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Human enhancement: Genetic engineering and evolution

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Mara Almeida, Rui Diogo, Human enhancement: Genetic engineering and evolution, Evolution, Medicine, and Public Health , Volume 2019, Issue 1, 2019, Pages 183–189, https://doi.org/10.1093/emph/eoz026

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Genetic engineering opens new possibilities for biomedical enhancement requiring ethical, societal and practical considerations to evaluate its implications for human biology, human evolution and our natural environment. In this Commentary, we consider human enhancement, and in particular, we explore genetic enhancement in an evolutionary context. In summarizing key open questions, we highlight the importance of acknowledging multiple effects (pleiotropy) and complex epigenetic interactions among genotype, phenotype and ecology, and the need to consider the unit of impact not only to the human body but also to human populations and their natural environment (systems biology). We also propose that a practicable distinction between ‘therapy’ and ‘enhancement’ may need to be drawn and effectively implemented in future regulations. Overall, we suggest that it is essential for ethical, philosophical and policy discussions on human enhancement to consider the empirical evidence provided by evolutionary biology, developmental biology and other disciplines.

Lay Summary: This Commentary explores genetic enhancement in an evolutionary context. We highlight the multiple effects associated with germline heritable genetic intervention, the need to consider the unit of impact to human populations and their natural environment, and propose that a practicable distinction between ‘therapy’ and ‘enhancement’ is needed.

There are countless examples where technology has contributed to ameliorate the lives of people by improving their inherent or acquired capabilities. For example, over time, there have been biomedical interventions attempting to restore functions that are deficient, such as vision, hearing or mobility. If we consider human vision, substantial advances started from the time spectacles were developed (possibly in the 13th century), continuing in the last few years, with researchers implanting artificial retinas to give blind patients partial sight [ 1–3 ]. Recently, scientists have also successfully linked the brain of a paralysed man to a computer chip, which helped restore partial movement of limbs previously non-responsive [ 4 , 5 ]. In addition, synthetic blood substitutes have been created, which could be used in human patients in the future [ 6–8 ].

The progress being made by technology in a restorative and therapeutic context could in theory be applied in other contexts to treat non-pathological conditions. Many of the technologies and pharmaceutical products developed in a medical context to treat patients are already being used by humans to ‘enhance’ some aspect of their bodies, for example drugs to boost brain power, nutritional supplements, brain stimulating technologies to control mood or growth hormones for children of short stature. Assistive technology for disabled people, reproductive medicine and pharmacology, beside their therapeutic and restorative use, have a greater potential for human ‘enhancement’ than currently thought. There are also dual outcomes as some therapies can have effects that amount to an enhancement as for example, the artificial legs used by the South African sprinter Oscar Pistorius providing him with a competitive advantage.

This commentary will provide general ethical considerations on human enhancement, and within the several forms of so-called human biomedical enhancement, it will focus on genetic engineering, particularly on germline (heritable) genetic interventions and on the insights evolutionary biology can provide in rationalizing its likely impact. These insights are a subject often limited in discussions on genetic engineering and human enhancement in general, and its links to ethical, philosophical and policy discussions, in particular [ 9 ]. The rapid advances in genetic technology make this debate very topical. Moreover, genes are thought to play a very substantial role in biological evolution and development of the human species, thus making this a topic requiring due consideration. With this commentary, we explore how concepts based in evolutionary biology could contribute to better assess the implications of human germline modifications, assuming they were widely employed. We conclude our brief analysis by summarizing key issues requiring resolution and potential approaches to progress them. Overall, the aim is to contribute to the debate on human genetic enhancement by looking not only at the future, as it is so often done, but also at our evolutionary past.

The noun ‘enhancement’ comes from the verb ‘enhance’, meaning ‘to increase or improve’. The verb enhance can be traced back to the vulgar Latin inaltiare and late Latin inaltare (‘raise, exalt’), from ‘ altare ’ (‘make high’) and altus (‘high’), literally ‘grown tall’. For centuries human enhancement has populated our imagination outlined by stories ranging from the myths of supernormal strengths and eternal life to the superpowers illustrated by the 20th century comic books superheroes. The desire of overcoming normal human capacities and the transformation to an almost ‘perfect’ form has been part of the history of civilization, extending from arts and religion to philosophy. The goal of improving the human condition and health has always been a driver for innovation and biomedical developments.

In the broadest sense, the process of human enhancement can be considered as an improvement of the ‘limitations’ of a ‘natural version’ of the human species with respect to a specific reference in time, and to different environments, which can vary depending on factors such as, for example, climate change. The limitations of the human condition can be physical and/or mental/cognitive (e.g. vision, strength or memory). This poses relevant questions of what a real or perceived human limitation is in the environment and times in which we are living and how it can be shifted over time considering social norms and cultural values of modern societies. Besides, the impact that overcoming these limitations will have on us humans, and the environment, should also be considered. For example, if we boost the immune system of specific people, this may contribute to the development/evolution of more resistant viruses and bacteria or/and lead to new viruses and bacteria to emerge. In environmental terms, enhancing the longevity of humans could contribute to a massive increase in global population, creating additional pressures on ecosystems already under human pressure.

Two decades ago, the practices of human enhancement have been described as ‘biomedical interventions that are used to improve human form or functioning beyond what is necessary to restore or sustain health’ [ 10 ]. The range of these practices has now increased with technological development, and they are ‘any kind of genetic, biomedical, or pharmaceutical intervention aimed at improving human dispositions, capacities, or well-being, even if there is no pathology to be treated’ [ 11 ]. Practices of human enhancement could be visualized as upgrading a ‘system’, where interventions take place for a better performance of the original system. This is far from being a hypothetical situation. The rapid progress within the fields of nanotechnology, biotechnology, information technology and cognitive science has brought back discussions about the evolutionary trajectory of the human species by the promise of new applications which could provide abilities beyond current ones [ 12 , 13 ]. If such a possibility was consciously embraced and actively pursued, technology could be expected to have a revolutionary interference with human life, not just helping humans in achieving general health and capabilities commensurate with our current ones but helping to overcome human limitations far beyond of what is currently possible for human beings. The emergence of new technologies has provided a broader range of potential human interventions and the possibility of transitioning from external changes to our bodies (e.g. external prosthesis) to internal ones, especially when considering genetic manipulation, whose changes can be permanent and transmissible.

The advocates of a far-reaching human enhancement have been referred to as ‘transhumanists’. In their vision, so far, humans have largely worked to control and shape their exterior environments (niche construction) but with new technologies (e.g. biotechnology, information technology and nanotechnology) they will soon be able to control and fundamentally change their own bodies. Supporters of these technologies agree with the possibility of a more radical interference in human life by using technology to overcome human limitations [ 14–16 ], that could allow us to live longer, healthier and even happier lives [ 17 ]. On the other side, and against this position, are the so-called ‘bioconservatives’, arguing for the conservation and protection of some kind of ‘human essence’, with the argument that it exists something intrinsically valuable in human life that should be preserved [ 18 , 19 ].

There is an ongoing debate between transhumanists [ 20–22 ] and bioconservatives [ 18 , 19 , 23 ] on the ethical issues regarding the use of technologies in humans. The focus of this commentary is not centred on this debate, particularly because the discussion of these extreme, divergent positions is already very prominent in the public debate. In fact, it is interesting to notice that the ‘moderate’ discourses around this topic are much less known. In a more moderate view, perhaps one of the crucial questions to consider, independently of the moral views on human enhancement, is whether human enhancement (especially if considering germline heritable genetic interventions) is a necessary development, and represents an appropriate use of time, funding and resources compared to other pressing societal issues. It is crucial to build space for these more moderate, and perhaps less polarized voices, allowing the consideration of other positions and visions beyond those being more strongly projected so far.

Ethical and societal discussions on what constitutes human enhancement will be fundamental to support the development of policy frameworks and regulations on new technological developments. When considering the ethical implications of human enhancement that technology will be available to offer now and in the future, it could be useful to group the different kinds of human enhancements in the phenotypic and genetic categories: (i) strictly phenotypic intervention (e.g. ranging from infrared vision spectacles to exoskeletons and bionic limbs); (ii) somatic, non-heritable genetic intervention (e.g. editing of muscle cells for stronger muscles) and (iii) germline, heritable genetic intervention (e.g. editing of the C–C chemokine receptor type 5 (CCR5) gene in the Chinese baby twins, discussed later on). These categories of enhancement raise different considerations and concerns and currently present different levels of acceptance by our society. The degree of ethical, societal and environmental impacts is likely to be more limited for phenotypic interventions (i) but higher for genetic interventions (ii and iii), especially for the ones which are transmissible to future generations (iii).

The rapid advances in technology seen in the last decades, have raised the possibility of ‘radical enhancement’, defined by Nicholas Agar, ‘as the improvement of human attributes and abilities to levels that greatly exceed what is currently possible for human beings’ [ 24 ]. Genetic engineering offers the possibility of such an enhancement by providing humans a profound control over their own biology. Among other technologies, genetic engineering comprises genome editing (also called gene editing), a group of technologies with the ability to directly modify an organism’s DNA through a targeted intervention in the genome (e.g. insertion, deletion or replacement of specific genetic material) [ 25 ]. Genome editing is considered to achieve much greater precision than pre-existing forms of genetic engineering. It has been argued to be a revolutionary tool due to its efficiency, reducing cost and time. This technology is considered to have many applications for human health, in both preventing and tackling disease. Much of the ethical debate associated with this technology concerns the possible application of genome editing in the human germline, i.e. the genome that can be transmitted to following generations, be it from gametes, a fertilized egg or from first embryo divisions [ 26–28 ]. There has been concern as well as enthusiasm on the potential of the technology to modify human germline genome to provide us with traits considered positive or useful (e.g. muscle strength, memory and intelligence) in the current and future environments.

Genetic engineering: therapy or enhancement and predictability of outcomes

To explore some of the possible implications of heritable interventions we will take as an example the editing (more specifically ‘deletion’ using CRISPR genome editing technology) of several base pairs of the CCR5 gene. Such intervention was practised in 2018 in two non-identical twin girls born in China. Loss of function mutations of the CCR5 had been previously shown to provide resistance to HIV. Therefore, the gene deletion would be expected to protect the twin baby girls from risk of transmission of HIV which could have occurred from their father (HIV-positive). However, the father had the infection kept under control and the titre of HIV virus was undetectable, which means that risk of transmission of HIV infection to the babies was negligible [ 29 ].

From an ethical ground, based on current acceptable practices, this case has been widely criticized by the scientific community beside being considered by many a case of human enhancement intervention rather than therapy [ 29 , 30 ]. One of the questions this example helps illustrate is that the ethical boundary between a therapy that ‘corrects’ a disorder by restoring performance to a ‘normal’ scope, and an intervention that ‘enhances’ human ability outside the accepted ‘normal’ scope, is not always easy to draw. For the sake of argument, it could be assumed that therapy involves attempts to restore a certain condition of health, normality or sanity of the ‘natural’ condition of a specific individual. If we take this approach, the question is how health, normality and sanity, as well as natural per se, are defined, as the meaning of these concepts shift over time to accommodate social norms and cultural values of modern societies. It could be said that the difficulty of developing a conceptual distinction between therapy and enhancement has always been present. However, the potential significance of such distinction is only now, with the acceleration and impact of technological developments, becoming more evident.

Beyond ethical questions, a major problem of this intervention is that we do not (yet?) know exactly the totality of the effects that the artificial mutation of the CCR5 may have, at both the genetic and phenotypic levels. This is because we now know that, contrary to the idea of ‘one gene-one trait’ accepted some decades ago, a gene—or its absence—can affect numerous traits, many of them being apparently unrelated (a phenomenon also known as pleiotropy). That is, due to constrained developmental interactions, mechanisms and genetic networks, a change in a single gene can result in a cascade of multiple effects [ 31 ]. In the case of CCR5, we currently know that the mutation offers protection against HIV infection, and also seems to increase the risk of severe or fatal reactions to some infectious diseases, such as the influenza virus [ 32 ]. It has also been observed that among people with multiple sclerosis, the ones with CCR5 mutation are twice as likely to die early than are people without the mutation [ 33 ]. Some studies have also shown that defective CCR5 can have a positive effect in cognition to enhance learning and memory in mice [ 34 ]. However, it’s not clear if this effect would be translated into humans. The example serves to illustrate that, even if human enhancement with gene editing methods was considered ethically sound, assessing the totality of its implications on solid grounds may be difficult to achieve.

Genetic engineering and human evolution: large-scale impacts

Beyond providing the opportunity of enhancing human capabilities in specific individuals, intervening in the germline is likely to have an impact on the evolutionary processes of the human species raising questions on the scale and type of impacts. In fact, the use of large-scale genetic engineering might exponentially increase the force of ‘niche construction’ in human evolution, and therefore raise ethical and practical questions never faced by our species before. It has been argued that natural selection is a mechanism of lesser importance in the case of current human evolution, as compared to other organisms, because of advances in medicine and healthcare [ 35 ]. According to such a view, among many others advances, natural selection has been conditioned by our ‘niche-construction’ ability to improve healthcare and access to clean water and food, thus changing the landscape of pressures that humans have been facing for survival. An underlying assumption or position of the current debate is that, within our human species, the force of natural selection became minimized and that we are somehow at the ‘end-point’ of our evolution [ 36 ]. If this premise holds true, one could argue that evolution is no longer a force in human history and hence that any human enhancement would not be substituting itself to human evolution as a key driver for future changes.

However, it is useful to remember that, as defined by Darwin in his book ‘On the Origin of the Species’, natural selection is a process in which organisms that happen to be ‘better’ adapted to a certain environment tend to have higher survival and/or reproductive rates than other organisms [ 37 ]. When comparing human evolution to human genetic enhancement, an acceptable position could be to consider ethically sound those interventions that could be replicated naturally by evolution, as in the case of the CCR5 gene. Even if this approach was taken, however, it is important to bear in mind that human evolution acts on human traits sometimes increasing and sometimes decreasing our biological fitness, in a constant evolutionary trade-off and in a contingent and/or neutral—in the sense of not ‘progressive’—process. In other worlds, differently from genetic human enhancement, natural selection does not ‘ aim ’ at improving human traits [ 38 ]. Human evolution and the so-called genetic human enhancement would seem therefore to involve different underlying processes, raising several questions regarding the implications and risks of the latter.

But using genetic engineering to treat humans has been proposed far beyond the therapeutic case or to introduce genetic modifications known to already occur in nature. In particular, when looking into the views expressed on the balance between human evolution and genetic engineering, some argue that it may be appropriate to use genetic interventions to go beyond what natural selection has contributed to our species when it comes to eradicate vulnerabilities [ 17 ]. Furthermore, when considering the environmental, ecological and social issues of contemporary times, some suggest that genetic technologies could be crucial tools to contribute to human survival and well-being [ 20–22 ]. The possible need to ‘engineer’ human traits to ensure our survival could include the ability to allow our species to adapt rapidly to the rate of environmental change caused by human activity, for which Darwinian evolution may be too slow [ 39 ]. Or, for instance, to support long-distance space travel by engineering resistance to radiation and osteoporosis, along with other conditions which would be highly advantageous in space [ 40 ].

When considering the ethical and societal merits of these propositions, it is useful to consider how proto-forms of enhancement has been approached by past human societies. In particular, it can be argued that humans have already employed—as part of our domestication/‘selective breeding’ of other animals—techniques of indirect manipulation of genomes on a relatively large scale over many millennia, albeit not on humans. The large-scale selective breeding of plants and animals over prehistoric and historic periods could be claimed to have already shaped some of our natural environment. Selective breeding has been used to obtain specific characteristics considered useful at a given time in plants and animals. Therefore, their evolutionary processes have been altered with the aim to produce lineages with advantageous traits, which contributed to the evolution of different domesticated species. However, differently from genetic engineering, domestication possesses inherent limitations in its ability to produce major transformations in the created lineages, in contrast with the many open possibilities provided by genetic engineering.

When considering the impact of genetic engineering on human evolution, one of questions to be considered concerns the effects, if any, that genetic technology could have on the genetic pool of the human population and any implication on its resilience to unforeseen circumstances. This underlines a relevant question associated with the difference between ‘health’ and biological fitness. For example, a certain group of animals can be more ‘healthy’—as domesticated dogs—but be less biologically ‘fit’ according to Darwin’s definition. Specifically, if such group of animals are less genetically diverse than their ancestors, they could be less ‘adaptable’ to environmental changes. Assuming that, the human germline modification is undertaken at a global scale, this could be expected to have an effect, on the distribution of genetically heritable traits on the human population over time. Considering that gene and trait distributions have been changing under the processes of evolution for billions of years, the impact on evolution will need to be assessed by analysing which genetic alterations have been eventually associated with specific changes within the recent evolutionary history of humans. On this front, a key study has analysed the implications of genetic engineering on the evolutionary biology of human populations, including the possibility of reducing human genetic diversity, for instance creating a ‘biological monoculture’ [ 41 ]. The study argued that genetic engineering will have an insignificant impact on human diversity, while it would likely safeguard the capacity of human populations to deal with disease and new environmental challenges and therefore, ensure the health and longevity of our species [ 41 ]. If the findings of this study were considered consistent with other knowledge and encompassing, the impact of human genetic enhancements on the human genetic pool and associated impacts could be considered secondary aspects. However, data available from studies on domestication strongly suggests that domestication of both animals and plans might lead to not only decreased genetic diversity per se, but even affect patterns of variation in gene expression throughout the genome and generally decreased gene expression diversity across species [ 42–44 ]. Given that, according to recent studies within the field of biological anthropology recent human evolution has been in fact a process of ‘self-domestication’ [ 45 ], one could argue that studies on domestication could contribute to understanding the impacts of genetic engineering.

Beyond such considerations, it is useful to reflect on the fact that human genetic enhancement could occur on different geographical scales, regardless of the specific environment and geological periods in which humans are living and much more rapidly than in the case of evolution, in which changes are very slow. If this was to occur routinely and on a large scale, the implications of the resulting radical and abrupt changes may be difficult to predict and its impacts difficult to manage. This is currently highlighted by results of epigenetics studies, and also of the microbiome and of the effects of pollutants in the environment and their cumulative effect on the development of human and non-human organisms alike. Increasingly new evidence indicates a greater interdependence between humans and their environments (including other microorganisms), indicating that modifying the environment can have direct and unpredictable consequences on humans as well. This highlight the need of a ‘systems level’ approach. An approach in which the ‘bounded body’ of the individual human as a basic unit of biological or social action would need to be questioned in favour of a more encompassing and holistic unit. In fact, within biology, there is a new field, Systems Biology, which stresses the need to understand the role that pleiotropy, and thus networks at multiple levels—e.g. genetic, cellular, among individuals and among different taxa—play within biological systems and their evolution [ 46 ]. Currently, much still needs to be understood about gene function, its role in human biological systems and the interaction between genes and external factors such as environment, diet and so on. In the future if we do choose to genetically enhance human traits to levels unlikely to be achieved by human evolution, it would be crucial to consider if and how our understanding of human evolution enable us to better understand the implications of genetic interventions.

New forms of human enhancement are increasingly coming to play due to technological development. If phenotypic and somatic interventions for human enhancement pose already significant ethical and societal challenges, germline heritable genetic intervention, require much broader and complex considerations at the level of the individual, society and human species as a whole. Germline interventions associated with modern technologies are capable of much more rapid, large-scale impacts and seem capable of radically altering the balance of humans with the environment. We know now that beside the role genes play on biological evolution and development, genetic interventions can induce multiple effects (pleiotropy) and complex epigenetics interactions among genotype, phenotype and ecology of a certain environment. As a result of the rapidity and scale with which such impact could be realized, it is essential for ethical and societal debates, as well as underlying scientific studies, to consider the unit of impact not only to the human body but also to human populations and their natural environment (systems biology). An important practicable distinction between ‘therapy’ and ‘enhancement’ may need to be drawn and effectively implemented in future regulations, although a distinct line between the two may be difficult to draw.

In the future if we do choose to genetically enhance human traits to levels unlikely to be achieved by human evolution, it would be crucial to consider if and how our understanding of humans and other organisms, including domesticated ones, enable us to better understand the implications of genetic interventions. In particular, effective regulation of genetic engineering may need to be based on a deep knowledge of the exact links between phenotype and genotype, as well the interaction of the human species with the environment and vice versa .

For a broader and consistent debate, it will be essential for technological, philosophical, ethical and policy discussions on human enhancement to consider the empirical evidence provided by evolutionary biology, developmental biology and other disciplines.

This work was supported by Fundação para a Ciência e a Tecnologia (FCT) of Portugal [CFCUL/FIL/00678/2019 to M.A.].

Conflict of interest : None declared.

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Genetic Engineering

• First Online: 28 March 2021

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• David B. Resnik 13  

Part of the book series: The International Library of Bioethics ((ILB,volume 86))

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In this chapter I will apply the PP to ethical and policy issues related to genetic engineering of microbes, plants, animals, and human beings. I will argue that the PP can provide some useful insights into these issues, due to the scientific and morally uncertainty surrounding the consequences of genetic engineering for public health, the environment, society, and patients.

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By “genetic engineering” I mean technologies that involve direct modification or alteration of the genomes of cells or organisms. Changes brought about by genetic engineering might or might not be inheritable, depending on the type of change and the organism. Modification of the genomes of somatic cells in humans (discussed below) does not normally result in inheritable genetic changes, but modification of human germ cells, sperm, eggs, or embryos does (Resnik et al. 1999 ). Modification of bacterial genomes always results in inheritable genetic changes because bacteria are unicellular organisms. Ooplasm transfer, nuclear transfer, and reproductive cloning in human beings raise important ethical and social issues, but these procedures are not genetic engineering, according to my definition, because their purposes is not modify genomes, even though they involve the manipulation of genetic material. Synthetic biology uses genetic engineering methods to design cells, organisms, and biological system that do not already exist in the natural world (Biotechnology Innovation Organization 2020b ).

Some viruses encode their genetic information in RNA (ribonucleic acid).

A polymer is a large molecule.

James Watson (1928–) and Francis Crick (1916–2004) won the Nobel Prize in Physiology of Medicine in 1962 for discovering the structure of DNA. Their model was confirmed by Rosalind Franklin’s x-ray crystallography data, Watson and Crick did not name Franklin as an author on the paper that described their model of the structure of DNA. Franklin (1920–1958) was also not awarded the Nobel Prize for her contribution, because she died of ovarian cancer in 1958, and the Nobel Prize is not awarded posthumously (Maddox 2003 ).

Because mitochondria have their own DNA, scientists have speculated that mitochondria were at one time independent organisms that became incorporated into primordial, unicellular organisms (Alberts et al. 2015 ).

Prokaryotes are single-celled organisms with no distinct cell nucleus or organelles.

Mitochondria replicate independently of the cell.

Most higher life forms, including most plants, mammals, and human beings, are diploid (Alberts et al. 2015 ).

Many species of plants and animals that reproduce sexually can also propagate asexually. Growing a new plant from a cutting is a form of asexual propagation.

Plant stem cells can also generate different tissue types.

Berg, Gilbert, and Sanger won the Nobel Prize in chemistry in 1980 for their development of recombinant DNA techniques (Nobel Prize.org 2021 ).

Doudna and Charpentier won the Nobel Prize in Chemistry in 2000 for the discovery of CRISPR (Ledford and Callaway 2020 ).

Laboratory animals are used to produce monoclonal antibodies. An antigen is introduced into the animal, which produces antibodies in its lymphocyte cells. These cells are cultured and then antibodies are isolated. Since these antibodies would be rejected by the human immune system, the cells are genetically modified so that they produce antibodies with a human protein component, or humanized antibodies. The genetically modified cells are then cultured and humanized antibodies are isolated for production (GenScript 2020 ).

Somatic cells are cells other than the reproductive or germ cells, such as skin, nerve, muscle, liver or bone marrow cells.

Monsanto has developed GM crops (known as Bt crops) that produce Bacillus thuringiensis toxins, which are deadly to insects. Farmers were already using these toxins as pesticides were Bt crops were developed (Resnik 2012 ).

Monsanto has developed GM crops (known as “Roundup Ready” crops) that are immune to the effects of glyphosate, the active ingredient in the widely-used herbicide Roundup ™. Farmers can control weeds with damaging their crops by spraying their crops with Roundup (Resnik 2012 ).

Golden rice, for example, contains more beta carotene than normal rice (McDivitt 2019 ).

In 2018, 228 million people worldwide contracted malaria and 405,000 people died from the disease (World Health Organization 2020a ). About 390 million people contract the dengue virus each year and about 4000 die from the disease (World Health Organization 2020b ).

Oxitec has also genetically engineered diamondback moths (Plutella xylostella) to control these populations. Diamondback moths are a destructive pests that feed on cauliflower, cabbage, broccoli and canola (Campbell 2020a ).

E.g. Bt crops. See Footnote 12.

These are the sorts of problems encountered by the natural law approaches to morality, discussed in Chapter 3 .

Most defenders of the slippery slope argument in genetic only apply it to using genome editing in humans, but it could be applied to other applications of genetic engineering.

I am assuming that GM microbes will not be intentionally released into the environment, which would create risks not discussed here. Scientists have developed GM microbes to clean up oil spills but have not deployed them yet, mostly due to regulatory issues. In nature, microbes already play an important role in cleaning up oil spills (Ezezika and Singer 2010 ).

The reproduction rate is how many people infected persons infect. R 0  = 1 means that an infected person infects one more person on average; R 0  = 2 means an infected person infects two people on average.

It is worth noting, however, that a voluntary moratorium was a reasonable option when this technology was emerging in the 1970s.

As noted in Chapter 6 , a black market for alcohol emerged during Prohibition era in the US (1919–1933). The desire to avoid creating a black market for any product is an relevant to regulatory actions that involve prohibitions.

As a side note, members of Greenpeace broke into a research farm in Australia in 2011 and destroyed an entire crop of GM wheat. Members of another environmental damaged a crop of golden rice in the Philippines (Zhang et al. 2016 ).

To date, 156 Nobelists have signed the petition (Nobel Prize Winners 2016 ).

For a review of the GM food safety literature, also see Domingo ( 2016 ).

It is worth noting the long-term animal studies pose some scientific and technical challenges because most of the rodent species used in these types of experiments have a lifespan of about three years and normally develop tumors and other health problems as they age. So, it can be difficult to determine whether an adverse effect in a laboratory animal is due to an exposure to a GM food or the natural aging process. A two-year study published by Séralini et al. ( 2012 ) claiming that mice fed a diet of Roundup Ready GM corn had more tumors than mice fed the normal diet (the control group) was later retracted by the journal due to serious methodological flaws that undermined the validity of the data (Resnik 2015a ).

See Footnote 12.

Davidson ( 2001 ) defends a principle of charity for interpreting language. The basic idea here is that one should interpret a speaker’s statements as being rational, other things being equal. Interpreting disagreements about GM foods/crops as based on differing value priorities portrays these disagreements as rational, rather than based on irrational fear or ignorance.

It is also worth noting that bans on GM plants can create black markets because of the high demand for these products.

As of the writing of this book, Kenya is currently rethinking its ban on GM crops (Meeme 2019 ).

Most of the debate about chimeras so far has focused on inserting human cells into early animal embryos (or blastocysts), not on inserting human genes into animals.

It is also worth noting that a ban would probably create a black market because demand for GM animals and animal products it high.

There is a potential regulatory gap in the genetic engineering of animals for meat or animal products. Although regulations and ethical guidelines require IACUCs to review and oversee genetic engineering of animals for research conducted at academic institutions, there are no such requirements for genetic engineering of animals for non-research purposes, such as meat production. One could argue that companies that genetically engineer animals for non-research purposes should form ethics committees similar to IACUCs to oversee these activities.

Anderson led the research team that conducted the world’s first human gene therapy clinical trial. The experiment used an adenovirus vector to insert the adenosine deaminase gene into the T-cells of two young children with combined immunodeficiency. The trial showed that the procedure was safe and effective even if did not cure the patients (Blaese et al. 1995 ). In 2006, Anderson was convicted of molesting and sexually abusing a girl over a four-year period, beginning when she was 10 years old, and he served 12 years in prison. Anderson maintains that he is innocent and that his conviction was based on falsified evidence (Begley 2018 ).

See Footnote 29.

An example of somatic genetic enhancement would be a transferring a gene to an adult male to stimulate production of testosterone to enhance athletic and sexual performance.

It is worth noting that not everyone regards genetic enhancement immoral or morally questionable. The transhumanist movement embraces various forms of enhancement to benefit mankind and allow people to express creative freedom (Harris 2007 ; Bostrom 2008 , 2010 ; More and Vita-More 2013 ; Porter 2017 ; Rana and Samples 2019 ).

Some have attempted to define health in terms of a normal range of variation for an organism. In medicine, a normal physiological trait is a trait that falls within a range of variation for healthy functioning of the organism (Boorse 1977 ; Schaffner 1993 ). For example, normal fasting blood sugar levels range from 60 mg/dL to 100 mg/dL (WebMD 2020 ). Fasting blood sugar levels that are too high cause diabetes and levels that are too low cause hypoglycemia, both of which are unhealthy conditions. However, normality cannot be equated with the statistical norm for a population, since the statistical norm might be unhealthy. If most people in a population have a fasting blood sugar greater than 100 mg/dL, we would not say that a fasting blood sugar greater than 100 mg/dL is normal, even though it would be the statistical norm for that population. Thus, the concept of a normal range of variation cannot be defined statistically and depends on a broader concept of health, which may be influenced by moral, social, and cultural factors.

Some argue that “gene therapy” is a misleading term because it implies that the genetic interventions are likely to benefit the patient or human subject, when often they do not (Henderson et al. 2006 ).

See Resnik ( 2018a ) for discussion of additional safety protections for subjects enrolled in clinical research.

In 1996, the US Congress passed a ban, known as the Dickey-Wicker amendment, on the use of federal funds to create human embryos for research (Green 2001 ). Though the ban has been interpreted differently by different administrations, it is still in effect.

For further discussion of creating embryos for research, see Green ( 2001 ).

I will assume that parents who are willing to use medical technology to prevent the birth of children with genetic diseases view abortion as morally acceptable, at least for this purpose.

Prenatal genetic testing can also be used to avoid giving birth to children with chromosomal abnormalities, such as Trisomy 21 (Down Syndrome).

Embryos that are not implanted would be destroyed. I am assuming that parents would view this as morally acceptable.

See Resnik et al. ( 1999 ) and National Academies of Sciences, Engineering, and Medicine ( 2017 ) for additional examples of monogenic disorders that GGE might be used to prevent.

The concept of a parent can be confusing here, because people who related to the child genetically might not be related socially. The concept of a parent can be even more confusing when surrogate pregnancy is used to produce children, since woman who gestates and gives birth to the child might not be genetically related to the child, if she is carrying a fetus created by another couple in vitro.

This is one of the themes of the science fiction movie GATTACA.

This cost estimate is based on dividing the total cost of the Human Genome Project--$3 billion—by three. The Human Genome Project was a US-funded research project that took place from 1990 to 2003. Although sequencing the human genome was the primary goal of the project, it also included other activities, such as studies of human diseases, model organisms, genetic technologies, computational methods, and ethical issues (Human Genome Project 2020 ).

Interestingly, two of the scientists who called for the moratorium, David Baltimore and Paul Berg, participated in the Asilomar conference on recombinant DNA (discussed earlier).

These studies could include the creation of human embryos to study the safety and efficacy of GGE methods and techniques (Liang et al. 2015 ).

This is an example of the problem of incoherence discussed in Chapter 4 .

Alopecia areata is a condition that leads to hair loss. It is thought to have a genetic basis (McIntosh 2017 ).

The moratorium would not apply to GGE for research purposes.

The moratorium would not apply to research on embryos created by GGE, which would be necessary to obtain the knowledge needed to better understand the safety and efficacy of using GGE to produce children (Liang et al. 2015 ; Baltimore et al. 2015 ).

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Resnik, D.B. (2021). Genetic Engineering. In: Precautionary Reasoning in Environmental and Public Health Policy. The International Library of Bioethics, vol 86. Springer, Cham. https://doi.org/10.1007/978-3-030-70791-0_7

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DNA And Genetic Engineering Research Paper

This sample DNA and genetic engineering research paper features: 10100 words (approx. 33 pages), an outline, and a bibliography with 23 sources. Browse other research paper examples for more inspiration. If you need a thorough research paper written according to all the academic standards, you can always turn to our experienced writers for help. This is how your paper can get an A! Feel free to contact our writing service for professional assistance. We offer high-quality assignments for reasonable rates.

Introduction

An introduction to biotechnology and genetic engineering, early concepts of inheritance, gregor mendel: the father of genetics, hugo devries: the mutation theory of evolution, morgan and muller: the first genetic experiments, the discovery of the dna molecule, chromosomes: compact dna, dna structure: the double helix, dna replication, the rna molecule, transcription: dna to rna, translation: protein synthesis, dna sequencing, the human genome project: living in the postgenomic era, the origin of genetic engineering, modern genetic engineering, individualized medicine, dna consciousness, future directions.

• Bibliography

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Anthropology has studied humankind in numerous capacities: morphologically, culturally, archaeologically, and philosophically. However, the knowledge gained by understanding the DNA molecule has increased our knowledge of humankind on a genetic and molecular level. In addition, with the completion of the Human Genome Project in 2003, the entire human genome has been sequenced and is now available for analysis. This is important to anthropologists because it allows the field to go beyond the bones and into the DNA.

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Genetic engineering may provide scientific ways to explore the chemical record provided by DNA. Anthropologists will be able to view and explore the past, the present, and conceivably the future of any species, including our own, by the scientific examination of DNA. In addition, understanding DNA and genetic engineering will potentially provide anthropologists with analytical data to explain our genetic relationship to other primates. This type of data will serve to strengthen and further clarify earlier DNA homology studies that have already provided empirical evidence of our close genetic relationships to chimpanzees and gorillas. In the future, this technology can be used to determine our genetic relationship to Neanderthals and Cro-Magnons.

The genetic study of Homo sapiens sapiens is possible because the DNA molecule provides a chemical record of humankind’s genetic makeup and evolutionary history as a process of time. This chemical record will allow examination because DNA is present in every cell in the body and is universal to all life-forms on this planet. All current conglomerations of DNA in all living species are a result of genetic variation and natural selection within populations throughout ongoing organic evolution.

The two terms biotechnology and genetic engineering are used somewhat synonymously. However, the two have different origins and initially they had slightly different applications. Biotechnology, by conventional definitions, is the intentional alteration of other living things (i.e., plants and animals) for the purpose of benefiting humankind. This has been done throughout the history of our species. In fact, the word clone is Greek for “twig,” because small sprouting twigs were removed from mature trees and planted in order to grow new trees.

Examples of early biotechnology include breeding animals that have desirable characteristics in order to increase the chances of producing offspring with those characteristics. It was noted even as far back as ancient times that if a fast male horse was bred with a fast female horse, most of the offspring would be fast.

Another example of early biotechnology would be the intentional pollination of specific crops that are more disease resistant and yield better fruition, while purposely not pollinating other crops lacking those desired characteristics.

Historically this method of biotechnology was limited to controlling what type of particular male specimen bred with a particular female specimen in an attempt to procure favorable genetic characteristics in the resulting offspring. In many ways, these practices were an early form of eugenics.

Genetic engineering is similar to biotechnology in that there is an alteration of an organism’s characteristics. In contrast to biotechnology, the process of genetic engineering denotes the intentional alteration of the actual DNA by using applications of new scientific technology that make changes at a molecular level. This means that a change is made in the actual genetic constitution of a cell by introducing, modifying, or eliminating specific genes by applying modern molecular-biologic techniques.

Another distinction is that biotechnology has traditionally been applied to agriculture for improving food products and livestock, whereas genetic engineering has more applications in medicine and anthropology. However, modern biotechnology has integrated genetic-engineering techniques as opposed to just utilizing breeding strategies to achieve those improvements. Due to the fact that biotechnology currently applies genetic-engineering techniques, the two terms are now frequently used interchangeably.

An alternative way to view the effects that biotechnology and genetic engineering could have on a modern population requires the natural manipulation of individuals through human intervention (using eugenics and euthenics or proliferagenics). The desired or beneficial genetic results can now be accelerated with genetic engineering.

From a historical perspective, humankind long ago began to alter the process of natural selection of animals and plants to yield beneficial results. Now, with the advent of genetic engineering, humankind has the ability to accelerate that process even more. In fact, one can speculate that humankind may eventually possess control over its own evolution.

The possibility that humankind may have direct control over its own evolution, by using genetic engineering and DNA nanotechnology, is known as emerging teleology. Emerging teleology is the theory that scientists can direct evolution by using genetic engineering and DNA nanotechnology—a technique that uses molecular recognition to create self-assembling branched DNA complexes, which in turn yields the engineering of functional systems at a molecular level. This concept of emerging teleology was first proposed by philosopher and anthropologist H. James Birx in 1991.

In conclusion, we have to ask ourselves, what is genetic engineering expected to accomplish for humankind? Or what has genetic engineering accomplished for humankind already? As mentioned earlier, understanding DNA can potentially help anthropologists to better understand the genetic relationships among species. Currently, several genetic-engineering techniques are already in use. Modern genetic-engineering applications include the use of genetically modified cells or microorganisms that can accomplish three major benefits:

• Cells or organisms can be engineered to producemedically beneficial substances. The most common example of this is the production of insulin. In 1987, the FDA approved the use of the first genetically engineered vaccine, which was used for Hepatitis B.
• Genetically modified organisms can be engineered thatwill help in the study of human diseases. An example of this is the use of “knockout mice,” which has helped scientists to understand diseases like cancer.
• Gene therapy allows the possibility of curing geneticallyinherited diseases by making corrections to the genetic defect at the level of the gene responsible. This can be achieved by inserting the correct gene(s) or by deleting the defective gene(s).

Although these three major benefits offer the potential to help millions of people—and already have—controversy will ultimately arise over the direct, nonmedical application of genetic engineering to enhance normal physiological functions in humans.

Genomics is the study of the genetic makeup of a species. A genome project of a species is a comprehensive identification and classification of a species’s genetic makeup. Genome projects of several microorganisms have been completed including many viral and bacterial genomes (e.g., Haemophilus influenza and Mycoplasma genitalium genomes were sequenced and completed in 1995). In addition, the Mouse Genome Project was completed in 1996 and the Human Genome Project was completed in 2003. Currently, other primate genome projects are underway, including the Chimpanzee Genome Project and the Neanderthal Genome Project.

In order to understand and conceptualize how understanding the DNA molecule and genetic engineering will impact many areas, including medicine and anthropology, one needs to first appreciate the history leading up to this marvelous technology. In addition, we need to stop and think about how the DNA molecule was discovered and what new technology enabled humankind to accomplish that important discovery. Finally, we need to be aware of the ideas that were proposed to be responsible for the phenomenon of inheritance before the discovery of the DNA molecule.

Before the DNA molecule was discovered, there were only ideas and theories about heredity and inheritance. The most enduring dogma was the idea of “pangenesis,” which held that all of the cells throughout the human body shed gemmules. These gemmules were believed to be able to collect in the reproductive organs periodically before fertilization and reproduction.

The term pangenesis came from the Greek word pan, meaning whole or encompassing, and genesis/genos, meaning birth/origin. Pangenesis was found in Greek writings in the 5th century BCE and was advocated (and in some ways espoused) by Hippocrates (460–370 BCE). This idea was accepted by fellow Greek thinkers Plato (428–347 BCE) and Aristotle (384–322 BCE). However, Aristotle later attempted to refute pangenesis with his idea of entelechy.

Aristotle proposed the concept of entelechy to explain the manner in which an organism inherits and expresses its traits, which according to this idea are determined by a “vital inner force.” He also noted the idea of “having one’s end within,” meaning that an organism’s essential potential can be actualized by its own vital inner force, or entelechy. Aristotle also believed that this vital force was possessed by males in their semen and that females merely possessed the raw material to be formed.

Pangenesis and entelechy were both prevalent and accepted as facts throughout the Middle Ages by great thinkers such as Albertus Magnus (1193–1280), his student Thomas Aquinas (1225–1274), and Roger Bacon (1220–1294). In the later part of the Middle Ages, a physician named Paracelsus (1493–1541), also known by the name Philippus Theophrastus Aureolus Bombastus von Hohenheim, proposed that semen was actually an extract of the human body, which contained all of the organs in what he called an “ideal form.” He believed that this was the biological link between parent and offspring. He was close.

Jean-Baptiste de Lamarck (1744–1829) proposed a theory that he called inheritance of acquired characters through use and disuse. In his theory, he proposed that changes in an organism’s physiology (over the course of its life span) were acquired and modified through the use of a particular function and then became a permanent and adaptable modification in what he called the germ-line. According to Lamarck, this modification was impressed on the parent form and then transmitted to the offspring, who would, as a result of this process, express this modification as a permanent characteristic that could be altered subsequently through use or disuse.

The acceptance of pangenesis and gemmules appeared as a provisional hypothesis by Charles Darwin (1809–1882) in his publication On the Origin of Species (1859), and later again in The Variation of Animals and Plants Under Domestication (1868). However, Darwin was unaware of the DNA molecule (which was not yet discovered) or of the works of Gregor Mendel (which were published during Darwin’s lifetime, and received but never read by him); therefore Darwin continued to comprehend his theory of evolution according to those concepts of his time— pangenesis and gemmules.

Thus, before any scientific explanation could account for the phenomenon of inheritance (or evolution), there were several unfounded ideas that were accepted. These ideas were mainly pangenesis, gemmules, and entelechy. Later theories such as the use and disuse of acquired characteristics were proposed and gained some popularity, but no theoretical model existed that could scientifically or mathematically account for how characteristics were inherited.

Gregor Johann Mendel (1822–1884) was a monk and a mathematician, and known as “the father of genetics” because his seminal works inspired others to study the phenomenon of inheritance. In 1857, he began conducting experiments using pea plants, Pisum sativum. He bred particular plants together and then he meticulously recorded the characteristics of the resulting offspring.

Mendel’s term character was a description of what we now call a phenotype. Typical characters that Mendel studied and measured were the height of the plants and the color of the pea plant’s flowers. Each character possessed different traits; for example, height was measured as tall, normal, or short; and color was measured as white, pink, or red. Therefore, traits were different varieties of phenotype (i.e., the measurable or observable characteristics of the plants).

Mendel’s experiments demonstrated that the traits of a character were distributed in a mathematically predictable pattern. He used these mathematically predictable patterns to devise two important laws known as Mendel’s laws, which he called the law of segregation and the law of independent assortment.

In general, the first law, which was the Mendelian law of segregation (of genetic factors), was hypothesized by Mendel to mean that each trait (e.g., height or color) must have two “factors.” Mendel would later call these factors “alleles.” One factor, or allele, was inherited from each parent, one from the mother and one from the father. Although two alleles are inherited, only one of the alleles was expressed, and therefore, according to Mendel, they were segregated. Today it is known that gametes are sperm and egg cells, which combine their genetic material during fertilization.

Mendel did not know the underlying biological process in cell replication and division at that time. However, it is now known that during the cell cycle, the DNA replicates itself and divides, yielding two identical cells, each with two sets of chromosomes, known as diploids. This process is known as mitosis. In addition, a specialized version of mitosis takes place with the production of the gametes, in which the gametes, known as haploids, have one set of chromosomes each. This process is known as meiosis. When the two separate gametes (or haploids) are joined during fertilization—one from the mother and one from the father—to form a zygote, the alleles (i.e., the DNA) then recombine.

During the course of his experiments, Mendel found that each allele was either dominant or recessive for a specific trait. He elaborated that there were three possibilities. First, if the two alleles were both dominant, then the trait inherited was considered to be homozygous dominant (AA). Second, if the two alleles were both recessive, then the inherited trait was considered to be homozygous recessive (aa). Third, if the two alleles were different, one dominant and one recessive, then the inherited trait was considered to be heterozygous (Aa), or a hybrid. The homozygous dominant, homozygous recessive, and heterozygous combinations could be crossbred and those results could be used to mathematically predict the probability of what type of offspring would result.

The Punnett square was devised by British geneticist Reginald Punnett (1875–1967), who published the first textbook on genetics, Mendelism (1905). He used these Punnett squares to predict the mathematical probability of the outcome of a particular breeding experiment. The results of the Punnett square could be used to predict the probability of possible genotypes of the offspring in a particular cohort given the genotype of the maternal allele and the makeup of the paternal allele.

Mendel’s second law, the Mendelian law of independent assortment (of genetic factors), is where he hypothesized that the inheritance pattern of one trait does not affect the inheritance pattern of another trait (i.e., they assort independently). He justified this with his concept that alleles segregate during gamete formation and then recombine independently of one another. He was incorrect in this assumption. It is now known that there is a multigene interaction and what is known as the blending of inherited traits. This was proven in the early 1900s by Thomas Hunt Morgan (1915/1978) and his colleagues in experiments involving fruit flies.

In essence, Mendel’s second law worked with pea plants because they are much simpler organisms, genetically, than mammals. In addition, the characteristics that he was measuring were not complicated. However, Mendel himself speculated that these laws may only apply to certain species, but he didn’t know why, because the DNA molecule had not been discovered yet. This is the reason why Mendel and others at his time could only study what was being expressed genetically. They did not understand or appreciate the genetic material itself.

In Example 1, a trait that is homozygous dominant (YY) is crossed with a trait that is homozygous recessive (yy). This example yields 100% heterozygous/ hybrid offspring (Yy). In Example 2, two hybrid traits are crossed. This example yields 50% heterozygous offspring, 25% homozygous dominant offspring, and 25% homozygous recessive offspring. This is a classical and simplified example of Punnett squares.

In addition to the two laws that Mendel devised, there are three other elements that made his work significant. First, he demonstrated the value of conducting controlled experiments. Second, he was a mathematician and applied mathematics to analyze and interpret his data. Third, he published his results, which is probably the most significant of all because his findings were not widely acknowledged during his time. However, his works were rediscovered after his death and had a profound effect on the study of inheritance and genetics. His work was of particular significance because this was the first successful mathematical model that had been proposed to explain inheritance.

Hugo Marie DeVries (1848–1935) was a Dutch botanist and is considered to be one of the first geneticists. He is known for his mutation theory of evolution, which was chiefly influenced by Gregor Mendel’s laws of heredity, which he rediscovered in the 1890s, and Charles Darwin’s theory of evolution.

DeVries’s (1905/2007) mutation theory of evolution speculated that new varieties of a species could appear in sudden, single jumps as opposed to slowly changing over time. His theory proposed that differences in an organism’s phenotype could change rapidly from one generation to the next; this also became known as saltationism. He based this theory on his experiments, which involved hybridizing plants. One particular observation was made by DeVries during these experiments that influenced and compelled his mutation theory of evolution. Occasionally an offspring appeared that had different characteristics than both the parents and was also different from the other offspring. Based on this finding, he postulated that new varieties of species could appear in nature spontaneously. By this, he in essence proposed that a mutated gene could equal a new species (i.e., mutation equals speciation). This was opposed to Darwin’s theory of gradualism.

DeVries’s mutation theory of evolution was supplanted in the late 1930s by modern evolutionary synthesis, initiated by Julian Huxley (1887–1975). Huxley first introduced this theory in his book Evolution: The Modern Synthesis (1942). At this time, he attempted to rationalize a unification of several biological specialties (e.g., genetics, systematics, morphology, cytology, botany, paleontology, and ecology) in order to postulate a more rational account of evolution. Julian Huxley’s work was stimulated by population genetics and served to clear up confusion and miscommunication between specialties existing at that time. In addition, modern evolutionary synthesis defended the notion that Mendelian genetics was more consistent with Darwin’s gradualism (and natural selection), as opposed to DeVries’s hypothesis of the mutation theory.

The mutation theory of evolution proposed by DeVries had nothing to do with what we currently acknowledge as genetic mutations. The current definition of a mutation is the process by which a gene undergoes a structural change to create a different form of the original allele, which results in a completely new allele. Therefore, spontaneous changes can occur in the DNA that can (but sometimes do not) cause changes in an organism’s physiology. This change does not give rise to the sudden appearance of a new species; rather it can produce a modification of the erstwhile species. This was later supported by genetic research done on white-eyed and red-eyed fruit flies by Thomas Morgan and colleagues (1915/1978).

DeVries was known for another accomplishment that arose from his experiments when he speculated that the inheritance of specific traits of an organism occured through a transfer of particles, which he termed pangenes (derived from the word pangenesis). The term pangenes was shortened 20 years later by Wilhelm Johannsen (1857–1927) to genes. The term gene is currently defined as a basic unit of inheritance.

There was some debate that surrounded the “rediscovery” of Mendel’s work. In DeVries’s publication on the topic of inheritance, he mentioned Mendel in a footnote but took credit for the concept of particles of inheritance with his idea of pangenes. It was Carl Erich Correns (1864–1933), a German botanist and geneticist, who pointed out Mendel’s priority, which DeVries eventually publicly acknowledged.

As it turned out, Carl Corren was a student of Karl Wilhelm von Nageli (1817–1891), a famous Swiss botanist, who had corresponded with Mendel regarding his findings years earlier. Corren was familiar with Mendel’s work as a result of this association. An even stranger twist to this was that when Nageli and Mendel were collaborating, Nageli had actually discouraged Mendel from doing any future work studying genetics, for what he considered religious and ethical reasons.

Thomas Morgan (1866–1945) was a geneticist who performed experiments on fruit flies ( Drosophila melanogaster ). He chose to conduct experiments on fruit flies because they required few resources, reproduced quickly, had observable characteristics that could be measured, and had only four chromosomes, which made them ideal for genetic research.

As a result of his experiments in the “fruit-fly lab,” Morgan established that genes were arranged in a line on what is known as a chromosome, which is present in every living cell. Since genes were believed to be responsible for inheritance and were now shown to exist on chromosomes, this became known as the chromosomal theory of inheritance, which had been alluded to prior to Morgan but had not been supported scientifically. He also noted that there was recombination of inherited characteristics resulting from the exchange of genes between two chromosomes of a pair, which he called “crossing over.” This of course disproved Mendel’s second law of independent assortment.

Morgan collaborated with three of his very important students: Hermann Muller, Alfred Sturtevant, and Calvin Bridges, all of whom continued performing genetic research on fruit flies. Collectively, from around 1908 to 1914, they were able to establish that chromosomes carry genes, those genes are distinct physical objects that are arranged on the chromosomes, the genes also could change place on the chromosomes, the genes could be mutated, and those mutated genes could be reliably inherited in future generations.

Morgan’s experimental proof that genes were discrete physical objects carried on chromosomes and they govern the patterns of inheritance was of major significance. Prior to this, the gene was a speculation with no scientific evidence to support it. Morgan’s research also illustrated that the sex of a species was inherited just as all other characteristics are inherited. He became aware that it was the chromosomal differences between the sperm and egg cells that correlated with the determination of gender. This was proven by his famous experiments with white-eyed male fruit flies and red-eyed female fruit flies.

A significant discovery, made by Hermann Muller (1890– 1967), was that mutations could be caused by exposure to high-energy radiation. This technique enabled them to perform those significant genetic experiments, and to give validity to the chromosomal theory of heredity. Hermann Muller received a Noble Prize for physiology and medicine for his discovery that X-rays induced mutations. He was also the first to visualize genes as the origin of life. The reason he believed this was because genes (or chromosomes) can replicate themselves. He further speculated that all of natural selection and evolution acted at the level of the gene.

Prior to Morgan and Muller, the first proof that chromosomes carried hereditary material came from American physician and geneticist Walter Sutton (1877–1916), based on his research on grasshopper cells. Sutton was the first to speculate that the Mendelian laws could be applied to the chromosomes at a cellular level, which is now known as the Boveri-Sutton chromosome theory. However, it was Morgan’s genetic research that provided enough reproducible scientific data to support the chromosomal theory of heredity, which became generally accepted by around 1915 (even though some geneticists, such as William Bateson, continued questioning it until about 1921).

In the early 1920s, it was generally accepted that genes were arranged on chromosomes and that this is how the inheritance of characteristics arose. However, no one was sure what chromosomes were chemically made of or how they worked.

In 1928, a British scientist named Frederick Griffith (1871–1941), who was influenced by Mendel’s hypothesis of units of inheritance, theorized that a molecule of inheritance must exist. He began conducting experiments on Streptococcus pneumonia and proposed that an inheritance molecule existed and could be passed on from one bacterium to another by a process called transformation. Griffith’s research on transformation proved how an inheritance molecule could be transferred from one bacterium to another; however, Griffith never discovered what the inheritance molecule was. Nevertheless, his work in turn inspired others to continue looking.

During this time, it was known that genes were arranged on chromosomes responsible for the phenomena of inheritance, but no one was able to prove their makeup. This dispute narrowed down to proteins, lipids, carbohydrates, and nucleic acids. The popular belief was that the inheritance molecule was protein because there were more proteins in existence, whereas only four nucleic acids were known (later a fifth nucleotide would be discovered in RNA). Some postulated that it was proteins and nucleic acids that made up the inheritance molecule, but there was no scientific proof to support any of these arguments.

Friedrich Miescher (1844–1895) discovered nucleic acids in 1868, while studying white blood cells. He called them nuclein because they were located in the nucleus, but no proof existed to support the fact that nucleic acids were responsible for the inheritance of characteristics.

In the early 1940s, a scientist named Oswald Avery (1877–1955) rediscovered Griffith’s work on transformation. Avery had the advantage of newer technology and advances in cellular biology. Avery had begun to conduct experiments that selectively destroyed different components (carbohydrates, proteins, lipids, and deoxyribonucleic acids) of a virulent bacterium, which he injected into a mouse. If the mouse died, he concluded that the bacterium had maintained its virulence (i.e., it was able to replicate its virulence). During his experiments, he found the bacteria were able to maintain their virulence when the carbohydrates, proteins, or lipids were destroyed. However, the bacteria were unable to be virulent when their deoxyribonucleic acids were destroyed. Therefore, Avery was the first scientist to prove that the genetic material responsible for inheritance was composed of nucleic acids.

Avery’s findings were very significant because they proved that genes, which are made out of nucleic acids (i.e., deoxyribonucleic acids or DNA), are responsible for the genetic inheritance of all organisms’ characteristics. However, at this time, no one knew what DNA’s structure was or how it functioned.

In 1952, Erwin Chargaff (1905–2002) published results based on his experiments involving the isolation of nucleic acids from three microorganisms: Serratia marcescens, Bacillus schatz, and Hemophilus influenza type C. He was able to separate the nucleic acids using a technique called adsorption chromatography. He discovered that DNA was composed of two purines, adenine (A) and guanine (G), and two pyrimidines, thymine (T) and cytosine (C).

In addition, Chargaff also pointed out that in any section of DNA, the number of A residues was always equal the number of T residues and that the number of C residues were always equal to the number of G residues. This became know as Chargaff’s rule. Later, Watson and Crick (1953) would correctly propose that A and T actually pair together and that G and C pair together (due to hydrogen bonding), which is known as Watson-Crick base pairing. By analyzing the chemical structures of these molecules, Watson and Crick pointed out that A and T both have two hydrogen bonds available, which is why they pair together. C and G have three hydrogen bonds available, which is the reason they pair together. Therefore, Watson and Crick were able to find the molecular explanation of Chargaff’s rule (A=T and C=G), but they went a step further with Watson-Crick base pairing to explain why this is true.

Shortly after Chargaff was making his discovery, another significant discovery was being made by scientists Maurice Wilkins (1916–2004) and Rosalind Franklin (1920–1958). Their research illustrated that the DNA molecule had a helical shape and was made up of two strands that were connected by ladderlike rungs. They were able to prove this by studying crystallized X-ray patterns of DNA.

On April 25, 1953, Watson and Crick published an article proposing a molecular structure of DNA. They had incorporated the findings of Chargaff, Wilkins, and Franklin, as well as their own, to propose that the helical strands were the sugar-phosphate backbone and that the ladderlike rungs were pairs of nucleotides (A=T and G=C). Therefore, Watson and Crick established that the molecular structure of DNA was in fact a double helix. This was significant because they were then able to explore and propose a model to explain how DNA worked.

It should be pointed out that the structure of DNA was discovered based on the research and results of many scientists. Watson and Crick definitely made this significant discovery, but they gained much insight from the works of Chargaff, Wilkins, and Franklin.

A chromosome is a long, single piece of DNA that contains several genes; in some species 10 to 40 genes and in other species thousands or more genes can be present in just one chromosome. In eukaryotes, the chromosomes are organized structures that consist of DNA and special structural proteins called histones that wind, coil, and compact large DNA sequences so that they fit efficiently in the nucleus. The chromosome does not always stay condensed, but periodically relaxes and uncoils for replication and for the transcription of proteins. Topoisomerase II is a DNA-nicking-closing enzyme that allows the uncoiling of the DNA supercoils during DNA replication and translation.

In prokaryotic cells, the DNA is either organized in clusters with no nucleus or into small circular DNA molecules called plasmids, which do not contain histones. In viral genomes, very simple chromosomes are found and can be made out of DNA or RNA, which are short, linear or circular chromosomes that usually lack structural proteins.

In all animals, DNA in the chromosomes is packed by histones into globular aggregates known as a nucleosomes. The amino-acid sequence of histones shows almost 100% homology across all species, which illustrates their importance in maintaining chromosomal integrity, structure, and function. In addition, it is now known that the genes that code for histones have no introns.

The DNA strand is wound up and packed with eight histones to form a nucleosome, or what is sometimes called “beaded strings.” These units are further coiled into what is called a solenoid, which contains five to six nucleosomes. The solenoids are then condensed into a chromatin fiber, which has histone H1 holding the core together. The chromatin fiber then folds into a series of loops that are held together by a central scaffold (made of nonhistone chromosomal protein), and this configuration is called a looped fiber. The looped fiber is then coiled to form the fully condensed heterochromatin of the chromosomes.

The coiled and condensed heterochromatin pairs up with an identical copy of itself, and each of the two are referred to as a chromatid. Two identical chromatids are attached to each other by a centromere. The centromere divides both chromatids into a long arm and a short arm. During cell division, microtubules attach to the centromere and align the chromosomes in the center of the dividing cell. The chromosomes are then split, yielding two identical cells—each with its own set of chromosomes. This process is known as mitosis.

All four arms of the chromosome (two long arms and two short arms) have a specialized cap known as a telomere, which has several functions (e.g., preventing the ends from sticking together). The chromosomes also show a distribution of two types of bands. G-bands are A-T rich regions and R-bands are G-C rich regions.

As mentioned earlier, the DNA molecule is composed of two purines (A and G) and two pyrimidines (T and C), and all four are nitrogenous bases. These nitrogenous bases are attached to a deoxyribose sugar, which is attached to a phosphate group to form a nucleotide.

In DNA, a nucleotide is any of the four nitrogenous bases attached to a deoxyribose sugar, which, as explained, is attached to a phosphate group. Because there are four different nitrogenous bases (A, T, G, and C) in DNA, there are four different nucleotides. The deoxyribose sugar can bond with a phosphate group from another nucleotide to form a chain. The nitrogenous base portion of the nucleotide can bond with the nitrogenous base from another nucleotide.

Nucleotides attach side by side to make long strands of DNA. They are able to attach in this fashion by the phosphate group of one nucleotide to the deoxyribose sugar of another nucleotide. This strand is formed in what is known as the 5 prime to 3 prime direction and opposite of this strand is a complementary chain which goes in the 3 prime to 5 prime direction. The original strand is attached to the complementary strand by the hydrogen bond discussed earlier: A=T and C=G. Therefore if the original strand is

                                                5 prime-ATGCTC-3 prime,

the complementary stand is

                                                3 prime-TACGAG-5 prime.

When Watson and Crick proposed the structure of the DNA molecule, they stated that the molecule was a double helix held together by ladderlike projections. The backbone of the helix is the deoxyribose sugar and phosphate group. The ladderlike projections are the base pairs A=T, G=C, T=A, and C=G.

One of the phenomenal characteristics of the DNA molecule is that it not only stores genetic information but replicates itself. This process is simply known as replication. Replication starts when the double strand is opened up by a helicase enzyme, which exposes the base sequences. While the base pairs are exposed along the template strand, a new strand of DNA (a complementary strand) is synthesized by DNA polymerase.

Replication occurs continuously from the origin of one strand, called the leading strand, which follows the 3 prime to 5 prime direction. The other strand on the DNA molecule replicated is called the lagging strand and does not replicate continuously, but rather in small sections (~100– 200 bases), which are called Okazaki fragments. These fragments are linked together by DNA ligase. The leading strand replicates a complementary strand with DNA polymerase delta, while the lagging strand makes a complementary strand using DNA polymerase alpha.

The process of replication results in two identical copies (called daughter duplexes) of the original strand of DNA. Each daughter duplex contains one parental strand from the original DNA molecule and one newly synthesized strand. This is known as a semiconservative model. In 1958, Matthew Meselson and Franklin Stahl used a scientific technique with radio-labeled nitrogen bases to prove that the DNA molecule replicates using a semiconservative model.

In healthy cells, there is a set of postreplication-repair enzymes and base-mismatch proofreading systems. These systems remove and replace mistakes made during replication (e.g., a wrong base being inserted into a growing strand). Occasionally, a change in the nucleotide sequence takes place; this is known as a mutation.

In 1977, two scientists, Richard Roberts and Phil Sharp, discovered that there were many regions in the DNA that did not code for anything. Roberts and Sharp called these noncoding interruptions introns (short for intervening sequences ), and the sections that are coding regions are referred to as exons. They also found that mRNA, which was thought to be an exact copy of a transcribed section of DNA during protein synthesis, was actually missing these intron regions.

Introns are believed by some to be “junk DNA” or filler sequences. However, others believe that the extra sequences may stabilize the DNA molecule, or that the introns may be genetic remnants of evolution (vestigial DNA) and may have been expressed in the past but now lies dormant. In addition, it is conceivable that introns may have a function that presently eludes us.

RNA (ribonucleic acid) is a small, single-stranded nucleic acid that is involved in protein synthesis. Single-stranded RNA (and in rare cases double-stranded RNA) are also found in viruses. Besides being single stranded, RNA differs from DNA in two other important ways. First, DNA contains deoxyribose sugar in its backbone, whereas RNA contains ribose sugar. Secondly, in RNA there is no thymine; rather it is replaced with a different nitrogenous base called uracil, which pairs with A on the DNA molecule during protein synthesis (U=A), just as thymine does.

In the early 1980s, Thomas Cech did a significant amount of research on RNA. At that time it was believed that only proteins could act as biological catalysts. Cech was able to prove that RNA could function as a biological catalyst as well. He even discovered what he called ribozymes (later classified as species of RNA), which take part in the synthesis of mRNA, tRNA, and rRNA. Currently nine types of RNA have been identified:

• Heterogeneous nuclear RNA (hnRNA) is transcribed directly from DNA by an enzyme called RNA polymerase. This form of RNA contains all the coding regions (exons) and noncoding regions (introns). Then, hnRNA is processed to yield mRNA for protein synthesis.
• Messenger RNA (mRNA) is the modified version of hnRNA, which has had all of the introns removed, and possesses only the coding regions, which contain a code (the triplet code or codons) that is used for transcribing proteins.
• Transfer RNA (tRNA) is transcribed from coding sequences on the DNA molecule by RNA polymerase III. This type of RNA possesses an anticodon on one of its ends, which matches a particular section of mRNA. On the other end, tRNA has an amino acid attached. In a basic sense, tRNA serves as an adaptor between mRNA and amino acids during protein synthesis.
• Ribosomal RNA (rRNA) exists as several species of rRNA, which are categorized by their sedimentation coefficients that are recorded in Svedberg units (S). A ribosome is composed of two subunits: a large subunit (5S, 5.8S, and 28S) and a small subunit (18S). The ribosome’s function involves holding mRNA in place while the corresponding tRNA attaches amino acids together during protein synthesis.
• Small nuclear RNA (snRNA) is found in RNA-protein complexes called spliceosomes. Their function is to remove introns from hnRNA to produce mRNA. In the disease systemic lupus erythematus, the body produces antibodies to snRNA molecules.
• Small nucleolar RNA (snoRNA) functions in site-specific base modifications in rRNA and snRNA. These modifications include methylation and pseudouridylation.
• Signal recognition particle RNA functions by recognizing particular signal sequences on some proteins and assists in transporting them outside the cell, a process known as exocytosis.
• Micro-RNA (miRNA) is believed to control the
• translation of structural genes. They are proposed to do this by binding to the complementary sequences in the 3 prime untranslated regions of the mRNA.
• Mitochondrial RNA replicates and transcribes independently of the other nuclear DNA and RNA. However, mitochondrial DNA exists as a double-stranded loop (or circle) with an outer, heavy strand and an inner, light strand. Both strands are transcribed by mitochondrial-specific RNA polymerase to produce 37 separate mitochondrial RNA species (mitochondrial rRNA, mitochondrial tRNA, and mitochondrial mRNA).

Many scientists believe that RNA existed before DNA. This is mostly because small forms of RNA can support life (e.g., a virus). However, a virus needs to infect other cells to replicate itself and this is why viruses are known as “obligate intracellular parasites.” Small species of RNA (explained above) are also able to perform biologic activities independently (e.g., they are responsible for protein synthesis from strands of DNA). However, the DNA molecule is a far more stable repository for genetic information and it produces RNA. Therefore, the question of how RNA can exist without DNA to produce it arises. Finally, there is the possibility that both molecules arose at the same time, forming a symbiotic relationship.

The question now arises, how does DNA make RNA? Transcription is the process by which DNA makes a copy of a section of itself; that copy is RNA and is used for protein synthesis. In the DNA molecule, there are genes known as structural genes that code for proteins. Transcription begins when protein transcription factors attach to a promoter site on the DNA molecule. Next, RNA polymerase Pol II attaches to the transcription factors and then “unzips” the double helix. The complex of transcription factors and RNA polymerase Pol II move downstream (3 prime to 5 prime) along the template strand of the DNA, unzipping it as it moves forward and reconnecting the back portion of the double helix, and forming what is called a transcription bubble. During this process, nucleotides are linked together to form a complementary RNA copy of the coding strand of DNA. This is an exact copy of the DNA called hnRNA.

The hnRNA molecule is modified into mRNA, through ribonucleoprotein complexes called spliceosomes, which are several snRNA molecules that remove introns from hnRNA. The new mRNA molecule is then transported from the nucleus to the cytoplasm, where it will be used to make a peptide or peptides, which are used to make proteins and enzymes.

Translation is the process in which a strand of mRNA in conjunction with tRNA and rRNA produces peptides and polypeptides. The old central dogma of molecular biology was that DNA makes mRNA, and mRNA makes proteins.

The current theme is that DNA makes hnRNA, and that becomes mRNA (with the help of snRNA), which works with tRNA and rRNA to make polypeptides that are used to make proteins.

On a strand of mRNA, nucleotides pair up in sets of three (e.g., AUG and AAA, which are called triplet codons or codons). Each codon corresponds to an amino acid (e.g., GCA = alanine). There are 64 possible combinations of codons, but several codons represent the same amino acid (e.g., GCA, GCC, GCU, and GCG all represent alanine). Three of the codons—UAA, UAG, and UGA— represent a “stop” signal on the mRNA. AUG represents methionine, which is a “start” signal. The codons make up what is known as the genetic code. It works on the basis of tRNA, which contains and anticodon on one end and an amino acid on the other end.

A strand of mRNA is composed of a start signal (AUG), a coding region of codons, and a stop signal. Translation takes place in the cytoplasm within the endoplasmic reticulum. This process takes place in three main steps:

• Initiation: During this phase, the small rRNA subunit (which contains initiation factors) and tRNA, with the methionine (MET) amino acid, both attach to the start signal (AUG) on the mRNA. Then the large rRNA subunit attaches to the mRNA. When the small and large subunits are attached together they are referred to as a ribosome.
• Elongation: After initiation is complete and the first tRNA is attached to the strand of mRNA, a second tRNA attaches to the mRNA on the next codon. The second tRNA will correspond to that codon (e.g., the mRNA codon ACG would have tRNA with the anticodon [UGC] and the amino acid threonine [THR] attached). The existing MET amino acid on the mRNA would then form a bond to THR. This bond is a peptidyl transferase reaction, which creates a peptide bond between MET and THR. After that, a third, fourth (and possibly more) amino acids will be connected in this fashion, yielding an elongated chain of amino acids. This process continues throughout the entire coding message of the mRNA molecule.
• Termination: In this final phase, elongation continues until a stop codon is reached and enters into the ribosome (rRNA large and small subunits). When this takes place, a release factor disconnects the amino acid chain (called a peptide or polypeptide), and the ribosome splits into a small and large subunit, both of which separate from the mRNA molecule.

After translation is completed, posttranslational modification occurs, which involves the removal of methionine and peptide cleavage.

DNA sequencing is a scientific method for determining the order of the nucleotide bases in an unknown strand of DNA. The original method was devised in the early 1970s by Walter Gilbert and Allan Maxam, and called MaxamGilbert sequencing. Their method was very labor-intensive and involved the use of hazardous chemicals. In 1975, Frederick Sanger developed a quicker, more reliable, and less hazardous method of DNA sequencing called the Sanger method or chain-termination method. This method involves the use of dideoxynucleotides (ddATP, ddTTP, ddCTP, and ddGTP), which are different from normal nucleotides in that they lack a hydroxyl group. Because they lack a hydroxyl group, they interrupt and stop the normal sequence being produced in the complementary strand from the template DNA, which causes a termination in the chain. This termination takes place at that dideoxynucleotide’s spot (A, T, C, or G). This method is sometimes called the dideoxynucleotide DNA sequencing method, or chaintermination sequencing.

Utilizing this technology, a strand of unknown DNA can be taken, amplified using PCR (PCR is a process that rapidly replicates a piece of DNA), and sequenced. The single-stranded DNA of unknown sequence is used as the template and a complementary strand is made using radioactively labeled nucleotides. Next, the radioactively labeled complementary strand is placed in four separated mixes, each containing DNA polymerase and one of each of the four dideoxynucleotides. The four separate mixes are then run through a polyacrylamide of gel electrophoresis in four separate rows, which separates the small fragments of DNA. These four rows of fragments correspond to the particular dideoxynucleotide used. From this, a deduced sequence of the original template strand can be made. Currently a method using automated sequencing, which uses fluorescent markers instead of radioactively labeled markers, is used.

The groundbreaking technology of PCR and DNA sequencing made sequencing a genome a reality. Without this technology, the Human Genome Project would have taken several decades to complete or may have even been unattainable. DNA sequencing also has applications in diagnostic testing and forensics. It can also be used to identify a specific pathogenic mutation that causes a particular genetic disease.

The Human Genome Project (HGP) was completed in 2003. It had originated as an international project initiated in 1990 by the U.S. Department of Energy and the National Institute of Health. This project had six major goals:

• To identify all 20,000 to 25,000 genes in the human genome.
• To determine all of the sequences of the chemical basepairs that constitute the entire human genome. The approximate number of chemical pairs is estimated at around 3 billion. It is known that there is a large amount of repetition of these base pairs, and therefore an exact number of chemical base pairs at this time can only be estimated.
• To store all of this information and make it available in databases.
• To make improvements on computer-based tools for data analysis of biological problems. The field that currently deals with these issues is called bioinformatics.
• To transfer these related technologies to private biotechnology and genetic engineering sectors to stimulate further research and product development.
• To address the legal, social, and ethical issues that will appear as a result of the completion of the HGP and also the application of genetic engineering.

The completion of the HGP is significant for the field of anthropology because it will improve the study of topics such as germ-line mutations and assist in determining our genetic relationship with Cro-Magnons and Neanderthals, as well as establish the relationship between those two species. The Neanderthal Genome Project was launched in 2006 and upon its completion the Cro-Magnon Genome Project is likely to ensue.

With the completion of the HGP, there are many anticipated improvements in anthropology, medicine, energy, and the environment. However, many ethical and legal concerns will arise as well.

The first experiments involving genetic-engineering techniques were made possible by seminal works of three individuals: Paul Berg, Stanely Cohen, and Herbert Boyer. All three scientists were separately working on research and experiments involving DNA. Eventually, they collaborated, using all of their techniques to coordinate the very first experiments involving removal of a gene from one species and inserting it into the genome of another species.

During the years 1972 to 1973, Paul Berg at Stanford University was the first scientist to complete a successful gene splicing experiment. This research involved the removal of a gene from a viral genome called Simian Virus 40 (SV40), which was a monkey virus. He was initially interested in studying a particular gene because he found that SV40 could cause cancer in mice. The advantage of studying a viral genome was that it was very small— approximately a few hundred genes. This allowed him to easily identify and isolate this gene. He then attached this gene to the DNA of a lambda virus (known as a biological vector), which would then insert this gene into another cell. This was the very first time that a gene or genetic material from one organism, in this case a virus, was removed and spliced into the DNA of another organism, in this case a second virus. The new DNA, which had its original DNA along with the spliced DNA, would continue to function as normal and is known as recombinant DNA.

Recombinant DNA is the artificial or synthetic production of DNA, engineered by combining one or more strands of DNA from one source and attaching it to the strand of DNA of another source. This process yields a novel strand of DNA, known as recombinant DNA, that would normally not have existed. The recombinant DNA can then function normally, replicating itself and producing its sequenced products as all other DNA normally does.

Stanely Cohen was another scientist at Stanford University. His initial research was investigating how the genes in plasmids could make bacteria develop resistance to antibiotics. He implemented techniques allowing him to remove a plasmid, which was a small ring of DNA, from one bacterium and insert it into another bacterium. Once the plasmid was inside the other bacterium it could then produce the products that it normally made in the original bacterium. This process happens naturally between bacteria and was originally observed by Fredrick Griffith, who called it called transformation. However, Cohen was able to intentionally and selectively make this process take place.

Herbert Boyer, a scientist at the University of California, was doing research on a bacterium called Escherichia coli (or E. coli ), which is normally found in the human intestine. His research involved the use of restriction endonucleases (RE), which were originally discovered by Werner Arber, Daniel Nathans, and Hamilton Smith (they received a Nobel Prize in 1978 for isolating RE). It was discovered that bacteria produce RE to defend themselves against viruses, which work by snipping viral DNA into smaller pieces rendering the virus ineffective. Today there are over 800 RE that are used in laboratories for gene splicing and the production of recombinant DNA. The RE attach to very specific sites on the DNA and can be used to isolate and remove specific sections of DNA. After this technique was refined, Boyer later went on to genetically engineer human insulin, which was the first genetically engineered product approved by the FDA in 1978.

In 1973, the first animal gene was cloned, using the techniques refined by Berg, Cohen, and Boyer. Using Boyer’s RE, Cohen’s technique for removing plasmids, and Berg’s splicing techniques, they were then able to successfully remove and fuse a segment of DNA, which contained a gene from a frog ( Xenopus ) with the DNA of the bacterium E. coli.

In a basic sense, the frog gene was removed using RE, then spliced into a plasmid, and then inserted into E. coli. After the resulting DNA was inserted into E. coli, the frog gene was transcribed, producing a specific frog protein that was not previously produced by E. coli. This was the very first time that an animal’s gene was removed, inserted into a bacterial genome, and the product of that animal gene successfully produced.

The transfer of DNA from one organism into another organism is possible because DNA is universal among all organisms and cells on this planet. This means that the DNA in a bacterial cell is made up of the same components as the DNA in a human cell. The organism ( E. coli ) that successfully receives DNA from another organism (the frog gene) is known as a transgenic organism.

The fundamental steps in genetic engineering include the isolation of the DNA, the amplification of the DNA, and the transfer of that DNA into another cell. It is a very complicated process, but a simplification has been made here in order to establish an understanding of the process.

The DNA section of interest is called donor DNA and needs to be isolated from the rest of the DNA. This is done using restriction enzymes, which cut up the DNA into fragments. The restriction enzymes are very specific and cut the DNA at very specific points. Therefore, the DNA of interest can be located and removed.

After the desired section of DNA is isolated, it then needs to be amplified because the amount originally acquired is usually not enough to be effectively transferred. The donor DNA is amplified by a process called the polymerase chain reaction (PCR), invented by Kary Mullis. PCR is a process that rapidly replicates a piece of DNA by using Taq DNA polymerase.

Finally, the isolated and amplified DNA needs to be introduced into the host cell. This is accomplished with biological vectors and nonbiological vectors. Biological vectors are either plasmids or viruses, which were used in the original genetic engineering experiments by Berg and colleagues. Nonbiological vectors include electrochemical poration, biolistics, microinjections, and recombinasemediated cassette exchange (RMCE).

As mentioned, the DNA in all organisms and cells is made out of the same material (nucleotides and sugar phosphates). This is why it is possible to transfer DNA from one organism’s cells into another organism’s cells and this is also why DNA is able to produce its products normally within the new cell after this process is complete.

There are two types of genetic modifications; one involves the addition of genetic material and the other involves the deletion of genetic material or the products it expresses. Deletion is done in one of two ways: knockout and antisense genes.

Gene therapy is classified in one of two ways:

• Germ-line gene therapy: This is a genetic modification done on the sperm or the egg (germ cells), which are known as a haploids because they only contain one set of chromosomes, whereas all other cells in the body (somatic cells) contain two identical sets of chromosomes (two chromatids connected by a centromere). When this type of gene therapy occurs, the defective genes are no longer inherited (i.e., the genetic change is passed on from one generation to the next).
• Non-germ-line gene therapy: This is a genetic modification that is performed on the somatic cells as opposed to the germ cells. This is also called somatic gene therapy. When this type of gene therapy occurs the genetic disease can still be inherited by future generations. This is because the DNA from somatic cells is altered and these cells are not used for reproduction; therefore the defective genetic material in the haploid germ cells will continue to be passed on to future generations.

In addition to modifying germ cells and somatic cells, the techniques of genetic engineering can also be used to genetically clone species. Cloning is when two (and sometimes more) individuals or cells are produced from one genome.

On July 5, 1996, two scientists, Ian Wilmut and Keith Campbell, cloned the first animal from an adult somatic cell by using a technique called nuclear transfer. The animal was a ewe they named “Dolly.” This showed that one cell could be removed from the body of an animal and be used to re-create a second, identical individual animal.

Other projected use of genetic engineering is the possibility of individualized or genetic medicine. Individualized medicine is a futuristic style of medicine in which treatment will be tailored to the unique genetic needs of the patient. This is also known as personalized medicine. There are two major fields involved with the development of individualized medicine—pharmacogenetics and pharmacogenomics. Pharmacogenetics is an aspect of genetic medicine that studies the genetic sensitivity and differential response of a medication for a patient population. Pharmacogenomics is another aspect that is geared toward the manufacturing of pharmaceuticals with methods of genetic engineering.

In the near future, these two fields will change the way medicine is practiced. It is conceivable that during a typical office visit less time could be spent on deciphering somatic complaints and performing a physical exam, and more time on examining the genetics of the patient.

There is the possibility that the DNA molecule may in fact have a form of consciousness of its own, known as DNA consciousness or molecular/chemical consciousness (Grandy, 2006b, 2009a). This form of consciousness would of course be very different from neurological consciousness or human consciousness. In fact, DNA consciousness may underlie our very own conscious process.

This is a realistic possibility considering certain families of gene clusters; Hox and Pax genes are responsible for and oversee the development of our neurological consciousness. If those genes are altered or deleted, neurological consciousness does not develop.

Other ideas that support DNA consciousness are that the DNA molecule replicates itself, produces proteins freely, communicates chemically with other parts of the cell, and interacts with the external environment of the cell. It performs all of these functions independently. In addition, it is the first known molecule to discover itself (i.e., through Homo sapiens sapiens ) .

Genetic-engineering techniques may help us to explore this area by enabling scientists to explore how DNA interacts with itself, other molecules, and the environment; how it is able to freely self-replicate, and how it knows when and when not to produce certain products.

The future applications of genetic engineering are numerous indeed. Most of the immediate impact will be seen in the fields of anthropology and medicine. In medicine, there will be improvements in clinical therapeutics and individualized medicine. This will improve life spans and harness the potential to halt or reverse the aging process.

In anthropology, the completion of genome projects will assist in establishing genetic relationships between humankind and other species. In addition to studying our evolution, we could potentially control our evolution. Therefore, emerging teleology could become a reality.

The potential to alter human genomes could create the first transgenic Homo sapiens and provide the appearance of new species on this planet and elsewhere, a concept known as transhumanism. This could also give rise to new species such as Homo sapiens futurensis (the human of the future as proposed by Birx) or Homo sapiens genomicus (the transgenic human as proposed by Grandy).

It is also conceivable that genetic engineering could potentially equip our species with genes that could improve our ability to survive in outer space. This could give rise to Homo sapiens extraterrestrialis. During space travel, there is also the likelihood of encountering alien microorganisms as well as new types of diseases and aliments secondary to space exposure (Grandy, 2009d). This would open a new area of space medicine.

Ethical questions and fears will arise as well. We should be very cautious while considering the modification of our genome because we only understand a small fraction of the interworkings of the DNA molecule. Currently, scientists do not know how altering or modifying a gene in a genome as complicated as the human genome could affect us or future generations. Other ethical concerns will be raised; for example, what are good genes and what are bad genes? Who will make that determination? Originally, nature was in charge of deciding these issues. However, humankind began circumventing natural selection long ago without being prepared to address these questions.

In addition, our environment is not as dangerous (in a predatory sense) as it once was, and advances in medicine have increased human life spans while also allowing individuals—who would normally have died and not passed on their DNA to future generations—to survive and pass on inferior genes. This has given rise to a weaker gene pool or a failure to improve the species (Grandy, 2009c). Genetic engineering could potentially be a remedy to this situation. However, questions will arise over the nonmedical use of genome improvement.

With all of these possibilities on the horizon, we should always stop to remember the many great scientists and their pioneering research that made this a possibility. We should also keep our own humanity in mind as we attempt to tamper with something that we are only beginning to understand.

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• Darwin, C. (2000). Amherst, NY: Prometheus Books. (Original work published 1887)
• DeVries, H. (2007). Species and varieties: Their origin by mutation (Kindle ed.). New York: Evergreen Review. (Original work published 1905)
• Galton, F. (1990). Hereditary genius: An inquiry into its laws and consequences. New York: Peter Smith. (Original work published 1869)
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• Grandy, J. (2006d). Human Genome Project. In H. J. Birx (Ed.), Encyclopedia of anthropology (Vol. 3, pp. 1223–1226). Thousand Oaks, CA: Sage.
• Grandy, J. (2006e). RNA molecule. In H. J. Birx (Ed.), Encyclopedia of anthropology (Vol. 5, pp. 2026–2027). Thousand Oaks, CA: Sage.
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• v.26(1); 2018 Jan

One small edit for humans, one giant edit for humankind? Points and questions to consider for a responsible way forward for gene editing in humans

Heidi c. howard.

1 Centre for Research Ethics and Bioethics, Uppsala University, Uppsala, Sweden

Carla G. van El

2 Department of Clinical Genetics, Section Community Genetics and EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam, The Netherlands

Francesca Forzano

3 Department of Clinical Genetics, Great Ormond Street Hospital, London, UK

Dragica Radojkovic

4 Laboratory for Molecular Genetics, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia

Emmanuelle Rial-Sebbag

5 UMR 1027, Inserm, Faculté de médecine Université Toulouse 3, Paul Sabatier, Toulouse France

Guido de Wert

7 Department of Health, Ethics and Society, Research Schools CAPHRI and GROW, Maastricht University, Maastricht, The Netherlands

Pascal Borry

6 Centre for Biomedical Ethics and Law, Department of Public Health and Primary Care, Leuven Institute for Genomics and Society, KU Leuven, Kapucijnenvoer 35 Box 7001, 3000 Leuven, Belgium

Martina C. Cornel

Gene editing, which allows for specific location(s) in the genome to be targeted and altered by deleting, adding or substituting nucleotides, is currently the subject of important academic and policy discussions. With the advent of efficient tools, such as CRISPR-Cas9, the plausibility of using gene editing safely in humans for either somatic or germ line gene editing is being considered seriously. Beyond safety issues, somatic gene editing in humans does raise ethical, legal and social issues (ELSI), however, it is suggested to be less challenging to existing ethical and legal frameworks; indeed somatic gene editing is already applied in (pre-) clinical trials. In contrast, the notion of altering the germ line or embryo such that alterations could be heritable in humans raises a large number of ELSI; it is currently debated whether it should even be allowed in the context of basic research. Even greater ELSI debates address the potential use of germ line or embryo gene editing for clinical purposes, which, at the moment is not being conducted and is prohibited in several jurisdictions. In the context of these ongoing debates surrounding gene editing, we present herein guidance to further discussion and investigation by highlighting three crucial areas that merit the most attention, time and resources at this stage in the responsible development and use of gene editing technologies: (1) conducting careful scientific research and disseminating results to build a solid evidence base; (2) conducting ethical, legal and social issues research; and (3) conducting meaningful stakeholder engagement, education and dialogue.

Introduction

Gene editing, which allows for specific location(s) in the genome to be targeted and changed by deleting, adding or substituting nucleotides, is currently the subject of much academic, industry and policy discussions. While not new per se, gene editing has become a particularly salient topic primarily due to a relatively novel tool called CRISPR-Cas9. This specific tool distinguishes itself from its counterparts, (e.g., zinc-finger nucleases and TAL effector nucleases (TALENs)) due to a mixture of increased efficiency (number of sites altered), specificity (at the exact location targeted), ease of use and accessibility for researchers (e.g., commercially available kits), as well as a relatively affordable price [ 1 ]. These attributes make CRISPR-Cas9 an extremely useful and powerful tool that can (and has) been used in research in order to alter the genes in cells from a large range of different organisms, including plants, non-human animals and microorganisms, as well as in human cells [ 2 ]. Ultimately, CRISPR-Cas9 is becoming increasingly available to a larger number of scientists, who have used it, or intend to use it for a myriad of reasons in many different research domains. When such powerful and potentially disruptive technologies or tools (begin to) show a tendency to become widely used, it is common for debate and discussion to erupt. Germane to this debate is the fact that with the advent of CRISPR-Cas9 and other similar tools (e.g., CRISPR Cpf1), the possibility of using the technique of gene editing in a potentially safe and effective manner in humans—whether for somatic or germ line/heritable 1 gene editing—has become feasible in the near to medium future.

With some clinical trials underway, somatic genetic editing for therapeutic purposes is certainly much closer to being offered in the clinic. For example, several clinical trials on HIV are ongoing [ 3 , 4 ]; in 2015 an infant with leukaemia was treated with modified immunes cells (using TALENs) from a healthy donor [ 5 ]. Moreover, in the autumn of 2016, a Chinese group became 'the first to inject a person with cells that contain genes edited using the CRISPR-Cas9 technique' within the context of a clinical trial for aggressive lung cancer [ 6 ]. With such tools, gene editing is being touted as a feasible approach to treat or even cure certain single-gene diseases such as beta-thalassaemia and sickle-cell disease through somatic gene editing [ 3 ].

Beyond somatic cell gene editing, there is also discussion that through the manipulation of germ line cells or embryos, gene editing could be used to trans-generationally 'correct' or avoid single-gene disorders entirely. Notably, (ethical) concerns about heritable gene editing in humans were heightened when in April 2015, a group at Sun Yat-sen University in Guangzhou, China, led by Dr. Junjiu Huang reported they had successfully used gene editing in human embryos [ 7 ]. They used CRISPR-Cas9 to modify the beta-globin gene in non-viable (triplonuclear) spare embryos from in vitro fertility treatments. The authors concluded that while the experiments were successful overall, it is difficult to predict all the intended and unintended outcomes of gene editing in embryos (e.g., mosaicism, off-target events) and that 'clinical applications of the CRISPR-Cas9 system may be premature at this stage' [ 7 ]. Partly in anticipation/response to these experiments and to the increasing use of CRISPR-Cas9 in many different areas, a number of articles were published [ 2 , 8 – 14 ] and meetings were organized [ 9 , 10 , 15 – 17 ] in order to further discuss the scientific, ethical, legal, policy and social issues of gene editing, particularly regarding heritable human gene editing and the responsible way forward.

Internationally, some first position papers on human gene editing were published in 2015 and 2016. Interestingly, these different recommendations and statements do not entirely concur with one another. The United Nations Educational, Scientific and Cultural Organisation (UNESCO) called for a temporary ban on any use of germ line gene editing [ 18 ]. The Society for Developmental Biology 'supports a voluntary moratorium by members of the scientific community on all manipulation of pre- implantation human embryos by genome editing ' [ 19 ]. The Washington Summit (2015) organizers (National Academy of Sciences, the U.S. National Academy of Medicine, the Chinese Academy of Sciences and the U.K.’s Royal Society) recommended against any use of it in the clinic at present [ 17 ] and specified that with increasing scientific knowledge and advances, this stance 'should be revisited on regular basis' [ 17 ]. Indeed, this was done, to some extent, in a follow-up report by the US National Academy of Sciences and National Academy of Medicine, in which the tone of the recommendations appear much more open towards allowing germ line modifications in the clinic [ 20 , 21 ]. Meanwhile, the 'Hinxton group' also stated that gene editing 'is not sufficiently developed to consider human genome editing for clinical reproductive purposes at this time' [ 22 ] and they proposed a set of general recommendations to move the science of gene editing ahead in an established and accepted regulatory framework. Despite these differences, at least two arguments are consistent throughout these guidance documents: (1) the recognition of the need for further research regarding the risks and benefits; and (2) the recognition of the need for on-going discussion and/or education involving a wide range of stakeholders (including lay publics) regarding the potential clinical use and ethical and societal issues and impacts of heritable gene editing. It should be noted, however, that in the 2017 National Academies of Science, and of Medicine Report, the role of public engagement (PE) and dialogue was presented within the context of having to discuss the use of gene editing for enhancement vs. therapy (rather than somatic vs. heritable gene editing, which was the case in the 2015 summit report) [ 20 , 21 ].

Although many stakeholders, including scientists, clinicians and patients are enthusiastic about the present and potential future applications of these more efficient tools in both the research and clinical contexts, there are also important concerns about moving forward with gene editing technologies for clinical use in humans, and to some extent, for use in the laboratory as well. As we have learned from other ethically sensitive areas in the field of genetics and genomics, such as newborn screening, reproductive genetics or return of results, normative positions held by different stakeholders may be dissimilar and even completely incompatible. This might be influenced by various factors, such as commercial pressure, a technological imperative, ideological or political views, or personal values. Furthermore, it is clear that associated values often differ between different stakeholder groups, different cultures and countries (e.g., where some may be more/less liberal), making widespread or global agreement on such criteria very difficult, if not impossible to reach [ 23 , 24 ].

From this perspective, it was important to study the opportunities and challenges created by the use of gene editing (with CRISPR-Cas9 and other similar tools) within the Public and Professional Policy Committee (PPPC) 2 of the European Society of Human Genetics (ESHG; https://www.eshg.org/pppc.0.html ). Our committee advances that ESHG members and related stakeholders should be aware of, and if possible, take part in the current debates surrounding gene editing. Although not all genetics researchers will necessarily use gene editing in their research, and while gene editing as a potential treatment strategy, may appear, initially, somewhat separate from the diagnostics-focused present day Genetics Clinic, we believe that these stakeholders have an important role to play in the discussions around the development of these tools. For one, their expertise in the science of genetics and in dealing with patients with genetic diseases makes them a rare set of stakeholders who are particularly well placed to not only understand the molecular aspects and critically assess the scientific discourse, but also understand current clinic/hospital/health system resources, as well as human/patient needs. Furthermore, in more practical terms, one could consider that clinical genetics laboratories could be involved in the genome sequencing needed to verify for off-target events in somatic gene editing; and that clinical geneticists and/or genetic counsellors could be involved in some way in the offer of such treatment, especially in any counselling related to the genetic condition for which treatment is sought.

The PPPC is an interdisciplinary group of clinicians and researchers with backgrounds in different fields of expertise including Genetics, Health Law, Bioethics, Philosophy, Sociology, Health Policy, Psychology, as well as Health Economics. As a first step, a sub-committee was assigned the task to specifically study the subject of gene editing (including attending international meetings on the subject) and report back to the remaining members. Subsequently, all PPPC members contributed to a collective discussion during the January 2016 PPPC meeting in Zaandam, The Netherlands (15–16 January 2016). At this meeting, a decision was reached to develop an article outlining the main areas that need to be addressed in order to proceed responsibly with human gene editing, including a review of the critical issues for a multidisciplinary audience and the formulation of crucial questions that require answers as we move forward. A first draft of the article was developed by the sub-committee. This draft was further discussed during the 2016 ESHG annual meeting in Barcelona (21–24 May 2016). A second draft was developed and sent out for comments by all PPPC members and a final draft of the article was concluded based on these comments. Although the work herein acts as guidance for further discussion, reflection and research, the ESHG will be publishing separate recommendations on germ line gene editing (accepted during the 2017 annual meeting in Copenhagen, Denmark).

In the context of the ongoing discussion and debate surrounding gene editing, we present herein three crucial areas that merit the most attention at this stage in the responsible development and use of these gene editing technologies, particularly for uses that directly or indirectly affect humans:

• Conducting careful scientific research to build an evidence base.
• Conducting ethical, legal and social issues (ELSI) research.
• Conducting meaningful stakeholder engagement, education, and dialogue (SEED).

Although the main focus of this discussion article is on the use of gene editing in humans (or in human cells) in research and in the clinic for both somatic and heritable gene editing, we also briefly mention the use of gene editing in non-humans as this will also affect humans indirectly.

Conduct ongoing responsible scientific research to build a solid evidence base

The benefits, as well as risks and negative impacts encountered when conducting gene editing in any research context should be adequately monitored and information about these should be made readily available. Particular attention should be paid to the dissemination of the information by reporting and/or publishing both the 'successful' and 'unsuccessful' experiments including the benefits and risks involved in experiments using gene editing in both human and non-human cells and organisms (Table  1 ).

Example of questions that should be addressed regarding building a scientific evidence base for gene editing

An evidence base regarding actual (and potential) health risks and benefits relevant to the use of gene editing in the human context still needs to be built. Therefore, a discussion needs to be held regarding what type of monitoring, reporting and potential proactive search for any physically based risks and benefits should be conducted by researchers using gene editing. Hereby, various questions emerge: are the current expectations and practices of sharing the results of academic and commercial research adequate for the current and future field of gene editing? Should there be a specific system established for the (systematic) monitoring of some types of basic and (pre-) clinical research? If so, which stakeholders/agencies should or could be responsible for this? How could or should an informative long-term medical surveillance of human patients be organized? Following treatment, would patients be obliged to commit to lifelong follow-up? And, if relevant, how could long-term consequences be monitored for future generations? For example, if heritable gene editing was allowed, from logistical and ELSI perspectives, there would be many challenges in attempting to ensure that the initial patients (in whom gene editing was conducted), as well as their offspring would report for some form of follow-up medical check-ups to assess the full impact of gene editing on future generations while still respecting these individuals’ autonomy.

Although the availability of results and potential monitoring are especially important in a biomedical context for all experiments and assays conducted in human cells, and especially in any ex vivo or in vivo trials with humans, relevant and useful information (to the human context and/or affecting humans) can also be gleaned from the results of experiments with non-human animals and even plants. Furthermore, as clearly explained by Caplan et al. [ 2 ], gene editing in insects, plants and non-human animals are currently taking place and may have very concrete and important impacts on human health long before any gene editing experiments are used in any regular way in the health-care setting. As such, while keeping a focus on human use, there should also be monitoring of the results in non-human and non-model organism experiments and potential applications [ 2 ]. Effects might include change of the ecosystem, of microbial environment, (including the microbiome, of parasites and zoonosis, which can involve new combinations with some disappearing, and/or new unexpected ones appearing), change to vegetation, which has a reflection on our vegetal food and on animals’ food and natural niche [ 25 ]. All this will have an impact on the environment, and consequently on organisms (including humans) who are exposed to this altered environment, hence the monitoring of risks and benefits is very important. Especially with gene editing of organisms for human consumption (in essence, genetically modified organisms), it will be important to note that the absence of obvious harms does not mean that there are no harms. Proper studies must be conducted and information regarding these should be made readily available.

Ongoing reflection, research and dialogue on the ELSI of gene editing as it pertains to humans

Research on the ELSI and impacts of human gene editing should be conducted in tandem with the basic scientific research, as well as with any implementations of gene editing in the clinic. Appropriate resources and priority should be granted to support and promote ELSI research; it should be performed unabated, in a meaningful way and by individuals from a diverse range of disciplines (Table  2 ).

Example of questions needed to be addressed for the ethical, legal, and social issues research (ELSI) of gene editing

Ongoing research, reflection and dialogue should address all ELSI 3 salient to gene editing. With respect to gene editing in humans, both somatic and germ line/heritable embryonic gene editing contexts should be addressed. As stated above, we should also study the ELSI of gene editing in non-human and non experimental/model organisms, including issues surrounding the potential (legal and logistical related to implementation) confusions surrounding the use of the terms genetically modified organisms vs. the term gene-edited organisms.

Somatic gene editing

Although somatic gene editing is not free from ethical, legal and social implications—it is, in many respects, similar to more traditional 'gene therapy' approaches in humans—it has been suggested that in many cases, the use of somatic gene editing does not challenge existing ethical, legal and social frameworks as much as heritable gene editing. However, as with any new experimental therapeutic, the unknowns still outweigh what is known and issues of risk assessment and safety, risk/benefit calculation, patient monitoring (potentially for long periods), reimbursement, equity in access to new therapies and the potential for the unjustified draining of resources from more pressing (albeit less novel) therapies, particular protection for vulnerable populations (e.g., fetuses, children (lacking competencies)), and informed consent remain important to study further [ 26 ].

Furthermore, as with any new (disruptive) technology or application, there often remains a gap to be filled between the setting of abstract principles or guidelines and how to apply these in practice. Indeed, important questions and uncertainties surrounding somatic gene editing both in research and in the clinic remain, including, but not limited to: do the established (national and international) legal and regulatory frameworks (e.g., Regulation (EC) no. 1394/2007 on advanced therapy medicinal products) need further shaping/revisions to appropriately address somatic gene editing (including not just issues with the products per se but also for issues related to potential health tourism)? And if so, how would this best be accomplished? Do present clinical trial principles and protocols suffice? How exactly will trials in somatic gene editing be conducted and evaluated? Do we need particular protection or status for patients in such trials? What procedures will be instilled for patients receiving such treatments (e.g., consent, genetic counselling, follow-up monitoring)? Furthermore, to what extent will commercial companies be able to, or be allowed to offer, potentially upon consumer request, treatments based on techniques where so much uncertainty regarding harms remains? Importantly, which health-care professionals will be involved in the provision of somatic gene therapy and the care of patients who undergo such treatments? Who will decide on roles and responsibilities in this novel context? And, based on what criteria will the eligible diseases/populations to be treated be chosen? Indeed, these questions can also all be applied to the context of heritable gene editing, which is discussed below.

Germ line/heritable gene editing

With respect to germ line or heritable gene editing in humans, the ELSI are more challenging than for somatic gene editing, yet they are not all new per se either. Some of these previously discussed concerns include, but are not limited to: issues addressing sanctity of human life, and respect for human dignity, the moral status of the human embryo, individual autonomy, respect and protection for vulnerable persons, respect for cultural and biological diversity and pluralism, disability rights, protection of future generations, equitable access to new technologies and health care, the potential reduction of human genetic variation, stakeholder roles and responsibilities in decision making, as well as how to conduct 'globally responsible' science [ 16 , 2 , 11 , 18 ]. Discussions and debates over some of these topics have been held numerous times in the last three decades, especially within the context of in vitro fertilization, transgenic animals, cloning, pre-implantation genetic diagnosis (PGD), research with stem cells and induced pluripotent stem cells, as well as related to the large scope of discussion around 'enhancement' [ 13 ]. Although it is important to identify and reflect on more general ELSI linked with heritable gene editing and these different contexts, it is also vital to reflect on the ELSI that may be (more) specific to this novel approach. For example, would the fact that for the first time a human (scientist or clinician) would be directly editing the nuclear DNA of another human in a heritable way cause some form of segregation of types of humans? Creators and the created? [ 27 ] Clearly, we need time for additional reflection and discussion on such topics. Distinguishing the ELSI between different yet related contexts will allow for a deeper understanding of the issues and the rationale behind their (un)acceptability by different stakeholders.

A major contextual difference in the current discussions regarding germ line/heritable gene editing is that we have never been so close to having the technology to perform it in humans in a potentially safe and effective manner. Hence, as we move closer to this technical possibility and as we work out the scientific issues of efficiency and safety, the discussions orient themselves increasingly towards the ELSI regarding whether or not we want to even use heritable gene editing in a laboratory or clinical setting, and if so, how we want it to be used, by whom and based on which criteria? This includes, but is not limited to the following questions: should gene editing of human germ line cells, gametes and embryos be allowed in basic research—for the further understanding of human biology (e.g., human development) and without the intention of being used for creating modified human life? Some jurisdictions, such as the UK, have already answered this question, and are allowing this technique in the research setting in human cells in vitro (they will not be placed in a human body, the research will only involve studying the human embryos outside of the body) whereby researchers need to apply for permission to conduct such research. Some believe that allowing this will inevitably lead to the technology being used in the clinic (the so-called 'slippery slope' argument). This, then, brings us to the question at the centre of the debate: should gene editing of germ line cells, gametes or embryos or any other cell that results in a heritable alteration be allowed in humans in a clinical setting? Germane to this issue is another vital question: what, if any, principles or reasoning would justify the use of hereditary gene editing in humans in a clinical context given the current ban on such techniques in many jurisdictions? The new EU clinical trial Regulation (536/2014 Art 90 al.2.) does not allow germ line modification in humans. Should there be leeway for reconsidering this ban in the future in view of the possible benefits of therapeutic germ line gene editing? Should we first understand the risks and benefits of somatic gene editing before even seriously considering heritable gene editing? If we consider that it could be used in some situations, should we only consider using germ line gene editing in the clinic if there are absolutely no other alternatives? Should already established and potentially safer 4 reproductive alternatives, like PGD, be the approaches of choice before even considering germ line gene editing? If we do entertain its use, what, if any criteria, will be safe enough according to different stakeholders (scientists, ethicists, clinicians, policy makers, patients, general public) for it to be legitimate to consider using gene editing for reproductive use? Who will set this safety threshold and based on what risk/benefit calculations? Furthermore, if ever allowed, should heritable human gene editing be permitted only for specific medical purposes with a particular high chance of developing a disease (e.g., only when parents have a-near-100% risk of having a child affected with a serious disorder), and if so, would it matter if the risk is not 100%, but (much) lower? In addition, how can we, or should we define/demarcate medical reasons from enhancement? And, as was posed above for the use in somatic cells, for what medical conditions will gene editing be considered appropriate for use? What will the criteria be and who will decide?

Taking a step back and looking at the issues from a more general perspective, such ELSI research and reflection will need to address, among others, questions that fall under the following themes:

• the balance of risks and benefits for individual patients and also for the larger community and ecosystem as a whole;
• the ethical, governance and legislative frameworks;
• the motivations and interests 'pushing' gene editing to be used;
• the roles and responsibilities of different stakeholders in ensuring the ethically acceptable use of gene editing, including making sure that every stakeholder voice is heard;
• the commercial presence, influence, and impact on (the use of) gene editing;
• the rationale behind the allocation of resources for health care and research and if and which kind of shift might be expected with the new technologies on the rise.

Additional overarching issues relating to ELSI include the need to take a historical perspective and consider previous attempts to deal with genetic technologies and what or how we can learn from these; the need to consider how group actors could or should accept a shared global responsibility when it comes to the governance of gene editing; the potential eugenic tendencies related to new technologies used to eliminate disease phenotypes; the responsibility of current society for future generations; the way different stakeholders may perceive and desire to eliminate (genetic) risk and/or uncertainty by using new technologies such as gene editing; and the potential role(s) different stakeholders, including 'experts', may inadvertently play in propagating a false sense of control over human health.

Although the human context is where much of the attention currently resides, and is indeed, the focus of this article, as mentioned above, we also stress that many concerns and ELSI also stem from the use of gene editing in non-human organisms (plants, insects and microorganisms), the study of which, could inform the human context. More importantly, given that the use of gene editing in these organisms is currently taking place in laboratories and, if released, some of these gene-edited organisms could have a large impact on the environment and society [ 2 ], the ELSI of gene editing in non-human organisms should also be seriously addressed. In this respect, the current debates over definitions and whether plants and non-human animals in which gene editing is performed are considered (legally) genetically modified organisms (GMOs) are particularly important to consider; indeed, this legal stance may be a misleading way to describe the scientific differences in practice. Moreover, the manipulation of definitions may also be used to circumvent the negative press and opinions surrounding GMOs in Europe. Last, but not least, the use of gene editing for the creation of biologic weapons is a possibility that must be discussed and adequately managed [ 2 ].

In order to ensure that the appropriate ELSI research is conducted to answer these myriad questions, ELSI researchers must ensure adequate understanding of scientific facts and possibilities of gene editing, ensure appropriate use of robust methods [ 29 ] to answer specific ELSI questions, as well as learn from previous research on related themes such as (traditional) gene therapy, reproductive technologies, and GMOs. Furthermore, funding will have to be prioritized for ELSI research. National and European funding agencies should ensure that ELSI funding is given in certain proportion to how much gene editing research is being conducted in the laboratory and (pre) clinical domain. In practice, this will mean ensuring that there are adequate review panels for stand-alone ELSI grants, which do not usually fall within any one traditional academic field (e.g., philosophy, law or social sciences). The requirement of including ELSI work packages within science grants may also be useful if such work packages are conducted by ELSI experts (and this is verified by the funding agencies), that they are given enough budget to conduct research and not only offer services, and that the ELSI work package is not co-opted by the science agenda. Spending money on ELSI research has already allowed for the information to be used in more applied ways. Among others, ELSI research has contributed to helping individual researchers understand what kind of research they are (not) allowed to do in certain countries or regions; helped to design appropriate consent forms for research and clinic; and has helped inform policy decisions.

As ELSI are identified, studied and discussed, it will be of utmost importance to communicate these with as many publics as relevant and possible in a clear and comprehensive way so that the largest number of different stakeholders can understand and engage in a discussion about these issues. With respect to engaging non-academic and non-expert audiences in meaningful dialogue, the challenges are greater. Yet, as this is a vital element of conducting science and preparing clinical applications in a responsible manner and stretches beyond the academic focus of ELSI we propose to distinguish a third domain dedicated to such stakeholder engagement, education and dialogue (SEED) described below.

Stakeholder engagement, education and dialogue (SEED)

To deliver socially responsible research (and health care), an ongoing robust and meaningful multidisciplinary dialogue among a diverse group of stakeholders, including lay publics, should be initiated and maintained to discuss scientific and ethically relevant issues related to gene editing. Publics must not only be asked to engage in the discussion, but they should also be given proper information and education regarding the known facts, as well as the uncertainties regarding the use of gene editing in research and in the clinic. In this way, the two focal areas described above will feed into these SEED goals. Stakeholders should also be given the tools to be able to reflect on the ethically relevant issues in order to help informed decision making. Appropriate resources and prioritization should be granted to support and promote SEED (Table  3 ).

Examples of questions to be answered regarding stakeholder, engagement, education and dialogue (SEED) for gene editing

As mentioned in the introduction, the statements addressing gene editing published  by different groups and organizations have highlighted the need for an ongoing discussion about human gene editing among all stakeholders, including experts, and the general public(s) [ 8 , 9 , 17 ], In calling for an 'ongoing international forum to discuss the potential clinical uses of gene editing', the organizing committee of the International Summit on Human Gene Editing stated that

'The forum should be inclusive among nations and engage a wide range of perspectives and expertise – including from biomedical scientists, social scientists, ethicists, health care providers, patients and their families, people with disabilities, policymakers, regulators, research funders, faith leaders, public interest advocates, industry representatives, and members of the general public' [ 17 ].

Hence, this implies that not only should different expertise be represented in this ongoing discussion, but lay publics should also be included. For this to be a meaningful and impactful endeavour, all stakeholders involved should be appropriately informed and educated about the basic science and possibilities of gene editing. Academic/professional silos, differences in language, definitions, approaches and general lack of experience with multi- and inter-disciplinary work are all barriers to involving different expert stakeholders in meaningful exchange and dialogue. Some first constructive steps have included the posting online of meeting and conference presentations on gene editing (e.g., the 3 days of the Washington Summit ( http://www.nationalacademies.org/gene-editing/Gene-Edit-Summit/index.htm .), Eurordis webinars and meetings aimed at informing patients, http://www.eurordis.org/tv ). Beyond this, one important barrier to having a truly meaningful and inclusive multidisciplinary discussion about new technologies is the (potential) lack of knowledge and/or understanding of different publics [ 30 ]. Indeed, it is not reasonable for experts to expect that all concerned stakeholders are properly informed about the science and/or the social and ethical issues, which are important requisites for having meaningful and productive conversations about responsible gene editing. Furthermore, a pitfall we must avoid is using PE with the aim of persuading or gaining acceptance of technologies instead of 'true participation' [ 31 ] and as a means to allow for supporting informed opinions.

Another critical issue is the role and influence of different stakeholders, including the media, in educating and informing the public. What are the roles and responsibilities of different stakeholders in setting up and maintaining responsible engagement and dialogue? What will, and what should be the role of scientists in popular media communications and other SEED activities? Where will the funding for these activities come from? Financial and temporal resources will have to be reserved for such SEED regarding gene editing. Resources will also be needed to conduct further research on the best way to engage different publics and to study whether engagement strategies are successful.

Moreover, before engaging different publics and asking for their feedback, whichever stakeholders take on this task must seriously reflect on the precise reasons for which lay publics are being engaged. What is the goal? And, what method of engagement will best meet these goals? There is also a need for honest evaluation of engagement efforts to report on their impacts and outcomes. Indeed, the purposes of PE in science can vary widely, including, among others, informing, consulting and/or collaborating; [ 32 ] clearly each of these implies different levels of participation by publics, and by extension, different levels of influence on a topic. Importantly, there are a long list of questions that also need to be answered for PE (Table  3 ), including but not limited to how different voices will be weighed and if or how they will be used in any policy or decision making.

The value of PE in the form of public dialogue in a democratic society, (and we would specify its contribution to responsible science) is very well summarized by Mohr and Raman (2012) in a perspective piece on the UK Stem Cell Dialogue: [ 31 ]

'The value of public dialogue in a democratic society is twofold. From a normative perspective, the process of PE is in itself a good thing in that the public should be consulted on decisions in which they have a stake. From a substantive standpoint, PE generates manifold perspectives, visions, and values that are relevant to the science and technologies in question, and could potentially lead to more socially robust outcomes (which may differ from the outcomes envisaged by sponsors or scientists)' [ 31 ].

Particularly for the purposes of gene editing, we consider SEED a way to try to ensure that decisions on a subject that is filled with uncertainties, and could have important implications for society for generations to come, is not left in the hands of a few. We want to underline the need for: lay publics to be informed to support transparency; lay publics to be educated to support autonomy and informed opinion/decision making; different voices and concerns to be heard and considered through ongoing dialogue to help ensure that no one stakeholder group pursue their interests unchecked. Although it is beyond the scope of this article to go into any detail, it is important to take the time to learn from past and ongoing engagement efforts in science in general [ 32 ], as well as in biomedicine, including areas like stem cell research [ 31 ] and genetics [ 30 , 33 ]. For example, we can learn about: how PE can generate value and impact for a society, as well as how to conceive of and evaluate a PE programme [ 32 ]; the nuances around 'representative samples' and if they really are representative [ 31 ]; how letting citizens be the 'architects' rather than just participants of engagement (activities) could help to ward against the generation of 'predetermined outcomes' [ 31 ]; the utility of deliberative PE to 'offer useful information to policy makers [ 30 ]. Given all the different reasons for PE, and given the higher standards expected for PE in recent years [ 34 ] it is to be expected that each PE activity will have to be adjusted for the specific context. There are, also, useful tools for PE from a European funded project called 'PE2020, Public Engagement Innovations for Horizon 2020' [ 35 ], which has as an aim to 'to identify, analyse and refine innovative public engagement (PE) tools and instruments for dynamic governance in the field of Science in Society (SiS)' [ 35 ].

As already mentioned above for ELSI research, funding agencies will have to prioritize resources for these SEED activities, and the strategies we outlined for ELSI, could also apply for SEED.

In the midst of a plethora of debate over gene editing, different stakeholder views, preferences, agendas and messages, it is crucial to focus our limited resources, including human resources, time and finances on the most important areas that will enable and support the responsible use of gene editing. We have identified the following three areas that merit an equitable distribution of attention and resources in the immediate and medium-term future:

• Conducting ELSI research.

Indeed, one way to ensure that each of these three important areas receive adequate financial support to conduct the necessary work would be for international and national funding agencies to announce specific funding calls on gene editing. They could also encourage or require that scientific projects focused on gene editing include ELSI and SEED along with the scientific work packages. Furthermore, understandably, priorities need to be made with respect to resource allocation in the biomedical sciences, especially in such uncertain financial contexts, however, as expressed at the World Science Forum in Budapest in November 2011, we must ward against scarce funding being funnelled to single disciplines since it is common knowledge that much of the most valuable work is now multidisciplinary [ 36 ]. Moreover, at such a time funding entities must not 'expel' the social sciences 'from the temple' but rather, the hard sciences should 'invite them in to help public engagement' [ 36 ].

Acknowledgements

We thank all members of the Public and Professional Policy Committee of the ESHG for their valuable feedback and generosity in discussions. Members of PPPC in 2015–2017 were Caroline Benjamin, Pascal Borry, Angus Clarke, Martina Cornel, Carla van El, Florence Fellmann, Francesca Forzano, Heidi Carmen Howard, Hulya Kayserili, Bela Melegh, Alvaro Mendes, Markus Perola, Dragica Radijkovic, Maria Soller, Emmanuelle Rial-Sebbag and Guido de Wert. We also thank the anonymous reviewers for their constructive comments, which have helped to improve the article. Part of this work has been supported by the Swedish Foundation for Humanities and Social Science under grant M13-0260:1, and the CHIP ME COST Action IS1303.

Compliance with ethical standards

Conflict of interest.

The authors declare that they have no competing interests.

1 In this category, we include the editing of germ line cells, or embryonic cells, or even somatic cells that are edited and promoted to then become germ line cells in such a way that the alterations would be heritable.

2 This group studies salient ethical, legal, social, policy and economic aspects relating to genetics and genomics.

3 Herein, the terms 'ethical', 'legal' and 'social' are used in a broad sense, where, for example, issues such as economic evaluations, public health prioritization and other related areas would also be included. Indeed the first goal of 'SEED' (see below) is also, to some extent, part of ELSI research, however, given the paucity of meaningful PE in the past, combined with strong consensus regarding the current need and importance of such activities, we have chosen to highlight it separately. We also wish to stress the difference between academic ELSI research and the work of ethics review committees. Although both deal with ethical and legal issues, the former has as a main goal to advance research and does not act as a policing body, nor does it have an agenda per se. Furthemore, ELSI research does not only identify issues to be addressed but also works with scientists and policy makers to address the issues responsibly.

4 It is important to note that despite attempts at addressing these issues, even for technologies such as PGD [ 28 ].