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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

Genetic engineering (also called genetic modification) is a process that uses laboratory-based technologies to alter the DNA makeup of an organism. This may involve changing a single base pair (A-T or C-G), deleting a region of DNA or adding a new segment of DNA. For example, genetic engineering may involve adding a gene from one species to an organism from a different species to produce a desired trait. Used in research and industry, genetic engineering has been applied to the production of cancer therapies, brewing yeasts, genetically modified plants and livestock, and more.

Genetic engineering. Genetic engineering has changed over the years, from cloning for analysis and laboratory use to truly synthetic biology for understanding and new biomedical capabilities.

Former Program Director, Genome Technology Program

Division of Genome Sciences

Next-Gen CRISPR and the Future of Gene Editing

Known for co-inventing CRISPR, Emmanuelle Charpentier discusses how advances in gene editing could transform agriculture, medicine and science itself.

This article was produced for The Kavli Prize by Scientific American Custom Media, a division separate from the magazine's board of editors.

• July 18, 2023

The practice of genetic modification is as old as humanity. For thousands of years, humans have bred crops, livestock and even pets that possess desirable traits. This selective process, which alters an offspring’s genome, began long before anyone knew of genes or DNA, and it has shaped the course of human civilization.

The same might one day be said for the gene-editing technology known as CRISPR (clustered regularly interspaced short palindromic repeats). In a decade, scientists have transformed CRISPR from a natural system used by bacteria to block viral attacks into a molecular scalpel for genetic engineering. CRISPR permits researchers to make precise deletions or substitutions in a specific genetic sequence. Its applications have proliferated, and already many have begun to transform approaches to agriculture and disease research and treatment.

Will we be able to use CRISPR as a drug to treat human disease?

There is great interest in this. Right now, CRISPR is being developed to treat certain blood disorders like sickle-cell disease. In that case, hematopoietic stem cells are harvested from the patient, and the disease-related gene is edited with CRISPR outside the body, before the cells are given back to the patient. These cell-based therapies are awaiting approval from the FDA and European regulators, and the first patients are expected to receive treatment with the commercial version in the coming year.

For disorders caused by single genetic mutations, like Huntington’s disease and certain forms of Alzheimer’s disease, the delivery of CRISPR-Cas9 to tissues inside the body is a bottleneck. A delivery system has to be safe, with no secondary effects. It also needs to be precise enough to target a specific tissue and provide the correct amount of CRISPR-Cas9 to cells. People are working to develop delivery systems, such as lipid nanoparticles and lentiviral vectors, but it remains a key challenge.

Could CRISPR be used to combat infectious disease?

Some biotech companies are developing strategies that use CRISPR to target the DNA of certain bacterial species. The idea is that DNA repair mechanisms in bacteria are relatively weak, so DNA cleaved by CRISPR-Cas9 would not be repaired or fully replicated, and the bacteria would not survive. This approach looks nice on paper, but there are a few hurdles to treating bacterial infections, including how to bring CRISPR to the right bacterial species in the body. I do think CRISPR could be a promising way to treat viruses like HIV. Researchers could modify the CCR5 receptor that HIV uses to enter immune cells. This approach would not prevent infection, but it would block viral propagation.

How can CRISPR be used to improve agriculture?

CRISPR offers the possibility of engineering plant crops that will help us face the challenges of climate change. One approach is to challenge plants with the types of stresses we think will be encountered in the future, such as rising temperatures and drought. Researchers then sequence the genomes of the plants that can resist those stresses and identify the mutations that confer resistance. They can then use CRISPR to reproduce the mutation that allows a plant crop to resist such challenges. CRISPR could also be used to custom-design plants optimized for a farmer’s soil type—a kind of personalized agriculture. The challenges of climate change are coming faster than we can react to them. If we don’t apply these technologies, there will be a part of the world without enough food.

How can we ensure that the scientific enterprise remains vibrant in the future?

Since the pandemic, a lot of PhD students have skipped a postdoc to go directly into startups and biotechs. Biotechs can be innovative, but we have to make sure that basic research is sustained. In the past, at least in Europe, labs were given core funding to do research without the need to constantly write grants. This model could provide some balance. Also, I think a lot of young researchers don’t want the pressure of being a group leader, so they go to a company where they can be part of a team. Maybe public institutions should evolve to be more like companies, with smaller groups that work together in an environment where everyone is supported, and success is evaluated at the level of the institute and its projects, not the individual.

Could microbes harbor other mechanisms that we could exploit technologically?

Bacteria are in a constant war with viruses. To survive, they have evolved novel defense systems. CRISPR-Cas9 is one of those, but we continue to discover others on a regular basis. The technologies we use in molecular biology and genetics have primarily come from basic research performed on microorganisms, and often on bacterial defense systems. Nature has a lot to offer and much of it is likely better than anything we could imagine.

To learn more about the work of Kavli Prize Laureates, visit kavliprize.org . To explore more of the biggest questions in science, click  here .

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SYSTEMATIC REVIEW article

What do people think about genetic engineering a systematic review of questionnaire surveys before and after the introduction of crispr.

• 1 i3S–Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
• 2 ICBAS–Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal

The advent of CRISPR-Cas9 in 2012 started revolutionizing the field of genetics by broadening the access to a method for precise modification of the human genome. It also brought renewed attention to the ethical issues of genetic modification and the societal acceptance of technology for this purpose. So far, many surveys assessing public attitudes toward genetic modification have been conducted worldwide. Here, we present the results of a systematic review of primary publications of surveys addressing public attitudes toward genetic modification as well as the awareness and knowledge about the technology required for genetic modification. A total of 53 primary publications (1987–2020) focusing on applications in humans and non-human animals were identified, covering countries in four continents. Of the 53 studies, 30 studies from until and including 2012 (pre-CRISPR) address gene therapy in humans and genetic modification of animals for food production and biomedical research. The remaining 23 studies from after 2013 (CRISPR) address gene editing in humans and animals. Across countries, respondents see gene therapy for disease treatment or prevention in humans as desirable and highly acceptable, whereas enhancement is generally met with opposition. When the study distinguishes between somatic and germline applications, somatic gene editing is generally accepted, whereas germline applications are met with ambivalence. The purpose of the application is also important for assessing attitudes toward genetically modified animals: modification in food production is much less accepted than for biomedical application in pre-CRISPR studies. A relationship between knowledge/awareness and attitude toward genetic modification is often present. A critical appraisal of methodology quality in the primary publications with regards to sampling and questionnaire design, development, and administration shows that there is considerable scope for improvement in the reporting of methodological detail. Lack of information is more common in earlier studies, which probably reflects the changing practice in the field.

Introduction

The advent of CRISPR-Cas9 in 2012 started revolutionizing the field of genetics by democratizing the access to a method for precise modification of the mammalian genome ( Camporesi and Cavaliere, 2016 ; Barrangou and Horvath, 2017 ). The finding that the technique is straightforward and of low cost—while being precise and efficient—underlies the wide uptake of CRISPR-Cas9 by research groups and industries ( Camporesi and Cavaliere, 2016 ; Nordberg et al., 2018 ). This has resulted in an explosion of laboratories engaging in research using genetic modification of organisms, including applications in clinical practice, biomedical research, food production, and for environmental purposes ( Nordberg et al., 2018 ; Brokowski and Adli, 2019 ). The possibility of CRISPR-Cas9 application to human embryos has nonetheless raised concern among scientists and in society and led to revisit previous regulations on human genetic manipulation, such as Article 13 of the Oviedo Convention, the Universal Declaration on the Human Genome and Human Rights, and the EU Charter of Fundamental Rights ( Nordberg et al., 2018 ). The first years of CRISPR-Cas9 were marked by uncertainty, and an international moratorium on human germline manipulation was adopted by a range of countries ( Isasi et al., 2016 ; Boggio et al., 2019 ; Brokowski and Adli, 2019 ). However, in 2018, media announced the first case of human embryo manipulation that resulted in the birth of the first gene-edited twin babies and the expected arrival of another gene-edited baby in the summer of 2019 ( Hirsch et al., 2019 ; Meagher et al., 2020 ). This story initiated a frenzy of media articles, generally characterized by strong and general disapproval, conveying concern that scientists were “crossing the line” and almost unanimous rejection by members of the scientific community ( Nordberg et al., 2018 ; Morrison and de Saille, 2019 ). The discussion around CRISPR-Cas9 has also reignited concerns about gene editing of animals, including those used for food, and their potential release into the environment and the food supply chain ( Caplan et al., 2015 ).

By the time the CRISPR-Cas9 technique became available, the question of genetic modification of living organisms had already been discussed for more than 3 decades. Following the first study by Thomas and Capecchi in 1987, where recombinant DNA could be transferred as a tool to mammalian cells, the first international conference in 1975 led to the creation of the Recombinant Advisory Committee (RAC) to discuss ethical and societal issues related to the application of this new biotechnology tool ( Hurlbut et al., 2015 ; Rufo and Ficorilli, 2019 ). Subsequent landmark events where genetic engineering was applied to humans, such as the first clinical introduction of retrovirus in gene-modified cells by Rosenberg in 1989 ( Hanna et al., 2017 ), the death of Jesse Gelsinger in 1999 after gene therapy intervention to treat a metabolic disorder ( Caplan, 2019 ), and the death of X-SCID patients in a gene therapy trial in 2002 ( Couzin and Kaiser, 2005 ), were reflected in public distrust and a delay in the development of gene therapy over the first decade of the 21st century. Other major scientific milestones include the first genome-edited embryos ( Liang et al., 2015 ), human clinical trials with genome editing therapies ( ClinicalTrials.gov, 2016a ; ClinicalTrials.gov, 2016b ; ClinicalTrials.gov, 2018 ), the genome-edited human babies referred to above, and the attribution of the 2020 Nobel Prize in Chemistry to Jennifer Doudna and Emmanuelle Charpentier for their work leading to the CRISPR technology ( Royal Swedish Academy of Science, 2020 ).

As it makes gene editing much easier and more widely applicable, CRISPR-Cas9 comes across as a technology perceived as both promising and threatening and, as such, is particularly interesting in the context of initiatives such as RRI (Responsible Research and Innovation), which aim to open up research to society ( Shelley-Egan et al., 2020 ). The underlying objective is to align the research and development of new technologies with societal values and priorities. Understanding public knowledge and awareness of a new technology is an important part of the process, as is the measurement of citizens’ attitudes toward such development, for two main reasons. First, in representative democracies, questionnaires are important sources of information about how citizens position themselves in specific issues. Second, it is important to understand how receptive citizens are to adopting new technologies in their daily lives.

Opinion surveys measure the views of society within a given context in relation to a certain topic, often with a cross-sectional approach that measures opinions at a specific time-point and allows for comparison, such as between countries or regions but not over time ( Stockemer, 2019a ; Stockemer, 2019b ). When used as research instruments, surveys of public opinion are designed to provide quantitative information that allows researchers to answer underlying research questions by assessing the attitudes of surveyed people ( Haddock and Maio, 2008 ). A critical appraisal of the study methodology is an important complement to a systematic review of study outcomes. Despite being most common in reviews of randomized clinical trials, critical appraisal is relevant for many types of studies, including quantitative, qualitative, mixed-methods, and surveys ( National Health and Medical Research Council, 2000a ; National Health and Medical Research Council, 2000b ; Moher et al., 2009 ; Crowe and Sheppard, 2011 ; Nolan et al., 2012 ; Pace et al., 2012 ; Oluka et al., 2014 ). An important aspect of methodological quality is the survey instrument, that is, the set of questions and the accompanying measurement scales such as Likert and semantic differential scales, which are constructs that need to be evaluated in terms of validity and reliability before the survey is administered ( Haddock and Maio, 2008 ; Boateng et al., 2018 ; Hair et al., 2019 ). In systematic reviews of quantitative questionnaire studies, critical appraisal also includes the validity and how representative the sample is of the population under study, how the variables have been defined, whether potential biases are considered, and other factors that may interfere with result interpretation ( COGEM, 2018 ).

The aim of the present systematic review is to map the existing body of evidence concerning public attitudes toward genetic modification since the first survey on the topic was applied nearly 35 years ago. The review includes 53 primary publications covering countries in Asia, Europe, North America, South America, and Oceania, integrating public attitudes and awareness and knowledge about genetic modification. Our approach is comprehensive as it includes cross-sectional surveys measuring public opinions on matters of biotechnology and genetic engineering when applied to humans and other animals and introduces critical appraisal as a means to assess the methodology quality surrounding questionnaire design, development, and administration together with population sampling and the main limitations and successes drawn from studies in this type of analysis. This systematic review will complement existing narrative reviews and perspective papers on the topic, such as Lassen et al. (2006) ; Condit (2010) ; Howell et al. (2020) .

Methodology

Web of Science (WOS) was selected as the primary source for scholarly publications, focusing the search to identify surveys done with citizens on three different themes: gene therapy , genetically modified animals (GM animals) , and genome editing . The search was conducted between July and November 2019 and reviewed again in February 2020 and August 2022. This database search was complemented with Google search engine to look specifically for the gray literature that could not be found through WOS, namely, governmental reports and other studies not published in academic journals. Although not peer-reviewed by academic scholars, their relevance for policy advising means this type of literature is worth considering ( Haddaway et al., 2015 ; Piasecki et al., 2018 ). For the WOS search, the themes gene therapy and GM animals included only publications until 2012 since this was the year of the advent of CRISPR-Cas9 biotechnology, which changed the terminology of scientific articles from “genetic modification” to “genome editing.” Conversely and likewise, for the genome editing theme, only studies from 2013 onward were included. All WOS databases were investigated: WOS Core Collection, Current Contents Connect, Derwent Innovations Index, KCI—Korean Journal Database, MEDLINE ® , Russian Science Citation Index, and SciELO Citation Index. Pilot studies were searched using different combinations of keywords until the identification of the final Boolean strings to be used for the searching process was completed (see Supplementary Material ). For this, the numbers of publications retrieved from WOS for a specific combination of strings were analyzed, and only the ones with the highest numbers were considered. For GM animals , the different combinations of strings yielded the highest number of all, while for gene therapy and genome editing themes, it was irrelevant to add more string terms since it would always yield equal or lower numbers of publications. These allowed us to conduct the search in a broadened way, finding the most publications possible for each theme and discarding unintended ones. As for the Google search, the terms used included the theme name, adding “public” plus “attitude” terms, and the search results were screened thoroughly until the titles of the links showed redundancy in the upcoming search pages. After the identification of websites conveying multiple surveys, these were also used as a source to search for additional gray literature studies.

The screening process is described in the PRISMA flowchart presented in Figure 1 . All WOS publications that featured surveys with the general public regarding genetic modification of humans or animals were included in an Endnote library. All publications only addressing genetic modification of plants or crops were excluded from the library, and so were publications in the format of reviews and meeting or conference abstracts. All publications without access to its full-text or PDF document or not written in English were equally excluded. From the initial set of 2,981 publications, following duplicate removal and implementation of the exclusion criteria, 60 publications were left. After a careful reading of these, 33 publications reporting qualitative rather than quantitative studies and/or with low sample sizes (lower than 100 respondents) were excluded. To the WOS final list of 27 publications, 26 from the gray literature not meeting the exclusion criteria were added, equaling a total of 53 primary publications eligible for the systematic review.

FIGURE 1 . PRISMA flowchart and exclusion criteria used for the search and selection of primary publications in the systematic review.

Survey parameters

The systematic review followed the PICOS guidelines (population, intervention, comparator, outcome, and study design) for the evaluation of studies, resulting from the initial search, except for the intervention index since we were not performing any statistical or meta-analysis ( Centre for Reviews and Dissemination, 2009a ; Centre for Reviews and Dissemination, 2009b ). Population concerned the number of participants featured in the surveys and the country where the surveys took place. Comparison concerned the differences and similarities of public attitudes toward genetic modification procedures among citizens of different countries, comparison between years, and comparison of the type of questions and terminology used by surveyors. Outcomes analyzed were as follows: percentage of agreement with genetic modification in broad terms and for specific applications in humans and animals, the reasoning behind those attitudes, and respondents’ level of knowledge and/or the level of familiarity with biotechnology and/or genetic engineering topics. For more details, please see Supplementary Table S1 .

Critical appraisal of primary publications

All included primary publications were evaluated with regard to the methodological quality of the studies they reported. This was done by assessing if certain indicators were present or absent and by evaluating how well-described and appropriate they were for the studies in question ( Supplementary Table S2 ).

The critical appraisal addressed the following: content of questionnaires —whether authors generated their own items or adapted them from previous surveys; validity— cross-checking between authors and/or external advisers and testing with the target population for both clarity and efficacy of measuring concepts; reliability —trustworthiness of the same items and constructs used within the surveys; sampling —representativeness and randomness; risk of bias —potential response, non-response, and selection bias; and ethical practices —details on informed consent obtained, if there were incentives given to respondents, and disclosure of any ethical statements by authors either related to ethical approval of studies or the potential conflict of interests experienced.

The search, selection, and first analysis were performed by the first author. Feedback was obtained by the other two authors. The critical appraisal was performed by PDR and IASO, while MSA performed the co-authorship network analysis (see Supplementary Material ).

Of the 53 primary publications identified in this review, the 30 studies conducted prior to the advent of CRISPR-Cas9 technology in 2012 represent the pre-CRISPR period ( Supplementary Tables S3, S4 ), whereas the 23 studies conducted from 2013 onward represent the CRISPR period ( Supplementary Table S5 ). Pre-CRISPR studies were conducted between 1987 and 2010 and comprised 25 surveys with questions assessing attitudes toward the genetic modification of animals (GM animals) and 14 surveys assessing attitudes toward the genetic modification of humans. In the CRISPR period, eight survey studies addressed the genetic modification of animals, and 15 addressed the genetic modification of humans.

Generally speaking, the surveys conducted in the pre-CRISPR period focused on the opinion of the general public toward the genetic modification of animals for use in medical applications, food products derived from such animals (meat and milk), and the genetic modification of humans as gene therapy applications for the cure, prevention, and reduction of the risk of diseases. Some of these surveys also included additional aspects of human genetic modification, such as adults and children, prevention and therapy, and modification to change characteristics not related to diseases.

Table 1 summarizes the number of approvers of the genome editing technology in both periods in a proportion of 10 citizens, considering the previously mentioned applications and the region where the surveys took place.

TABLE 1 . Number of approvers of the genetic modification of humans and animals in pre-CRISPR (1987–2012) and CRISPR (2013–2022) periods. The number of approvers in both periods is given for a total of 10 respondents for each primary publication included in the systematic review. Studies are listed according to their year of publication and include information about authors, country(ies) of survey administration, and the genetic modification of animals and humans’ features. For the pre-CRISPR period, studies with approvers of GM animals for transplants, meat, and milk in a total of 10 respondents and approvers of the genetic modification of humans for somatic and germline applications, and disease and enhancement settings are both represented. For the CRISPR period, studies with approvers of GE animals for transplants/medicines, milk, and welfare purposes in a total of 10 respondents and with approvers of GE humans for somatic and germline applications, and disease and enhancement settings are both represented.

Genetically modified animals in pre-CRISPR and CRISPR periods

A) Pre-CRISPR: GM animals for food purposes are mostly rejected, and medical applications are seen ambivalently worldwide.

Overall, 25 of the 30 surveys from the pre-CRISPR period covered the genetic modification of animals (GM animals). In a quick overview of Table 1 , we can see that transplants and medicines face a higher approval from respondents than food products derived from GM animals. For all cases of food derived from GM animals, either to obtain “leaner meat,” “meat less fatty,” or simply “meat from these animals,” the approval rate is very low among respondents in almost all countries analyzed, and this trend is consistent from 1987 to 2006, although there are some studies where approval for meat consumption of GM animals reaches more than half of the respondents (the US in 1987, Japan in 1997, Thailand and India in 1997 and 2000, and Australia in 2000; Figure 2A ). Approval of GM animals for organ transplantation and medicines dropped considerably between 1991 and 2010 in Europe. The lowest approval reached 4 in every 10 European citizens in 1996 and 2002 and only 3 in every 10 citizens in 2005, according to Eurobarometer ( Figure 2A ). Conversely, medicines derived from GM cows gained approval among Europeans between 2002 and 2010, according to Eurobarometer ( Figure 3A ). Australians and New Zealanders are among the lowest approvers of GM animals worldwide for both medical and food purposes, and their approval has been decreasing in surveys after the 2000s ( Figures 2A , 3A ). A similar trend is seen for citizens from the US who rejected meat derived from GM pigs in all surveys conducted after 2000 ( Figure 2A ). Japanese citizens were the most surveyed public in the pre-CRISPR period, regarding attitudes toward GM animals, which they approved slightly more for food—meat and milk—than for medical purposes (organs for transplantation in pigs ( Figure 2A ) and mice for cancer research ( Supplementary Figure S5 ), going against the general trend. A note of remark is their decrease in approval for the meat of GM pigs from 1997 to 2003, as well as for transplants and medicines ( Figure 2A ). The use of GM mice for cancer research is seen as “to be encouraged” more than GM pigs for transplants among Japanese citizens ( Table 1 –pre-CRISPR). In two studies of single European countries, in Germany, less than half of the citizens supported GM laboratory animals for cancer research, and Swedish citizens categorically rejected GM salmon for food consumption ( Supplementary Figure S5 ), similar to their choice regarding GM pigs ( Figure 2A ).

FIGURE 2 . Public support for gene modification in pigs worldwide for a proportion of 10 citizens upon survey inquiry in pre-CRISPR (A) and CRISPR (B) periods. (B) CRISPR: Animal welfare in focus and genome-edited animals for food applications continue to be less approved than for medical applications.

FIGURE 3 . Public support for gene modification in cows worldwide for a proportion of 10 citizens upon survey inquiry in pre-CRISPR (A) and CRISPR (B) periods.

The CRISPR period surveys on attitudes toward GM animals represent a total of eight surveys worldwide over a 10-year period, with the highest number conducted in the US ( Funk and Heferon, 2018a ; Kohl et al., 2019 ; Lull et al., 2019 ; McConnachie et al., 2019 ). Table 1 (CRISPR period) shows that US citizens approve of the genetic modification of animals for human health purposes, in this case, genome-edited pigs for transplants of organs to humans (6 in 10) and genome-edited mosquitoes to eradicate the spreading of diseases into humans (7 in 10). Upon examining Oceanic countries, Australian citizens are more supportive of GE cows for medicines than for meat- and milk-derived products, while New Zealanders are profound rejecters of GE animals for both applications ( Figure 3B ). Regarding the approval for genome-edited pigs for food consumption, Brazilian citizens are mostly rejecters (only 4 in 10) in contrast to US citizens, where more than half support gene editing either for derived products such as meat from GE pigs or meat and milk from GE cows ( Figures 2B , 3B ). A new type of question present in surveys from the CRISPR era deals with the genetic engineering of animals for improved animal welfare. Here, we can see that US citizens frankly approve of “GE cows to become hornless” as a way to avoid invasive and painful dehorning ( Figure 3B ). The majority of citizens in New Zealand approve of GE pigs for better animal health and safety, whereas among Brazilian citizens, the approval for GE pigs to “reduce boar taint in pigs” (as an alternative to invasive and painful castration) is below half of the respondents ( Figure 2B ). The only study covering genome editing in wildlife reported a profound rejection among US citizens ( Table 1 ; Supplementary Figure S5 –CRISPR period) because this was perceived as a risk for both humans and nature.

Genetic modification of humans in pre-CRISPR and CRISPR periods

A) CRISPR: Somatic genetic modification for therapy is a yes, while enhancement is a no.

Overall, the genetic modification of humans for gene therapy purposes receives medium to high acceptance worldwide ( Table 1 ; Figure 4A ). Only three exceptions can be identified: two related to disease prevention, where 4 in every 10 New Zealand respondents agree with it for “preventing stomach cancer by modifying a person’s genetic code,” and 2 in every 10 United Kingdom citizens approve it to prevent baldness ( Table 1 ). The same low proportion of United Kingdom citizens approved of gene therapy to treat aggressive behavior and alcoholism identified as diseases ( Figure 4A ). The overall greatest support for gene therapy is found among Thai citizens, followed by Australians, New Zealanders, and Israeli and Japanese citizens in the 1990s to cure fatal diseases and United Kingdom citizens in the 2000s for genetic diseases like cystic fibrosis and heart diseases ( Table 1 ; Figure 4A ). On the other side of the genetic modification of humans, enhancement is mostly rejected by all citizens surveyed during the pre-CRISPR period, with the only exceptions being in 1995 and 2000 studies, where Thai and Indian citizens show high approval to “make people more ethical” and the ambivalence demonstrated by US citizens in 1987 toward “changing the genetic makeup of human cells” as well as European Union respondents in 2010 regarding human enhancement ( Table 1 ; Figure 4A ).

FIGURE 4 . Public support for gene modification in human adults worldwide for a proportion of 10 citizens upon survey inquiry in pre-CRISPR (A) and CRISPR (B) periods.

Germline genetic modification for therapy purposes gained high approval, similar to somatic genetic modification. Once again, there are exceptions, and these involve citizens from New Zealand in 2005 and Europeans in 2010. For New Zealanders, this represents a drop from much higher levels in the second half of the 1990s (almost 8 in every 10 citizens supporting it to cure fatal disease ( Figure 5A ); then, 10 years later, the number decreased to 4 in 10 citizens for approving GE for serious defects and further decreased to 2 for minor defects and to 1 in every 10 citizens for preventing aggression and violence ( Table 1 ; Figure 6A )). Among the most approving respondents of the germline genome modification for therapy are Thai respondents, followed closely by Australian and Indian citizens ( Figure 5A ).

FIGURE 5 . Public support for gene modification in human germline cells worldwide for a proportion of 10 citizens upon survey inquiry in pre-CRISPR (A) and CRISPR (B) periods.

FIGURE 6 . Public support for gene modification in human adults and human germline cells for preventing disease worldwide for a proportion of 10 citizens upon survey inquiry in pre-CRISPR (A) and CRISPR (B) periods.

Germline genetic modification for enhancement purposes is approved largely by Thai and Indian citizens to improve the physical characteristics and intelligence level “that children would inherit” ( Table 1 ; Figure 5A ). All the other countries surveyed about this rejection of those applications, particularly for the improvement of intelligence, cosmetic modifications in children, and determination of sex in an unborn baby ( Table 1 ).

B) CRISPR: Genome editing of humans for therapy is considered more acceptable in somatic than in germline modifications, but enhancement is opposed.

Surveys in the CRISPR period inquired citizens about genome editing of humans for therapy, similar to that in the pre-CRISPR period, with results showing strong approval worldwide. At this point, Europeans are the most approving of GE to cure diseases, although by a low margin when compared with Chinese and US citizens and with New Zealand citizens following closely. For the prevention of diseases, all citizens surveyed demonstrate an equally high approval rate of 8 in every 10 citizens ( Figure 6B ). In children, the approval rate of gene therapy was only assessed in China and showed to be similarly high among citizens ( Table 1 ).

Similar to the pre-CRISPR period, genetic enhancement of human beings was generally rejected by citizens worldwide ( Figures 4A, B ). Intelligence and the change in skin color were purposes profoundly rejected by Chinese citizens ( Table 1 ). The only case with less than a majority rejecting enhancement (genome editing of “human body cells to change one’s appearance”) was among Australians and to “prolong life” among United Kingdom citizens ( Figure 4B ).

Overall, GE in the human germline, as in the cases of unborn babies and embryos to cure serious diseases, gained approval among citizens ( Figure 5B ). US citizens were the most surveyed public in the CRISPR period, and multiple surveys conducted consecutively from 2016 to 2018 demonstrate a growth in approval of this type of genetic intervention for disease during this period, increasing from 3 to 5 in every 10 citizens in two surveys conducted in 2016 to 6 and 7 in every 10 citizens in surveys conducted in 2017 and 2018, respectively. The remaining studies include European and Chinese publics, and approval rates fall between the highest and the lowest of the US studies ( Figure 5B ; Table 1 ). In fact, 7 in every 10 citizens from the Netherlands approve GGE to avoid hereditary neuromuscular disease, while only 3 in every 10 citizens agree with it for HIV resistance ( Table 1 ). Australian citizens are the most approving of GE in germ cells and embryos, whereas US citizens have lower approval rates, between 3 in every 10 citizens in 2016 and 5 in every 10 citizens in 2018 that approve genetic interventions in unborn babies ( Figure 5B ). Likewise, this is similar for “prevention of disease” scenarios ( Figure 6B ).

Finally, the idea of genetic enhancement of unborn babies is not approved by members of the public anywhere in the world. It was even completely rejected among Europeans and US citizens in a survey conducted in 2017 ( Figure 5B ), and although the surveys conducted demonstrate a higher approval rate among Europeans 1 year later, still less than half of the participants agree with germline genetic enhancement, which is similar to the responses of Australian and Chinese citizens ( Figure 5B ; Table 1 ).

Awareness and knowledge correlation with public attitudes toward the genetic modification of humans and animals

Overall, the more aware or knowledgeable inquired publics are about topics of science and technology, in general, biotechnology, genetics, genetic modification, and gene editing, the most approving they are of genetic modification in humans and animals. In total, 44 surveys assessed the awareness and knowledge of participants about genetic modification topics, and from these, 17 surveys assessed only awareness (level of familiarity) and eight surveys assessed only knowledge (the level of education of respondents) about these topics.

From the total of surveys administered during the pre-CRISPR period, almost none showed a significant correlation between the awareness and knowledge of citizens about topics of science and their approval of genetic modification of humans or animals ( OTA, 1987 ; Macer, 1992 ; Ng et al., 2000 ; Hallman et al., 2002 ; Nayga et al., 2006 ). There was, however, in the United Kingdom in 2007, a survey that demonstrated a significant correlation between higher awareness of citizens to genes and genetics and lower approval of gene therapy in humans ( Barnett et al., 2007 ). Surveys measuring awareness and knowledge of genetics demonstrated a tendency or association between approval of gene therapy in humans and higher awareness or knowledge of these topics ( Macer et al., 1995 ; Sturgis et al., 2005 ; Sato et al., 2006 ). Curiously, a tendency for citizens to reject GM animals when they are more aware of the technology can be observed ( Macer et al., 1997 ; Ng et al., 2000 ; Inaba and Macer, 2003a ; Inaba and Macer, 2003b ). In terms of knowledge, the attitude of citizens showed a tendency to approve when the knowledge was higher ( OTA, 1987 ; Commission of the European Communities, 1991 ; Commission of the European Community, 1993 ; European Commission Directorate-General ScienceResearch and Development XII, 1996 ; Hallman et al., 2002 ; Hallman et al., 2003 ; Puduri et al., 2005 ), except for one study with German respondents ( Hampel et al., 2000 ).

In the CRISPR period, no studies demonstrated a significant correlation between the approval of GE animals or GE humans and awareness or knowledge about the topics among citizens. Nevertheless, there was a tendency for citizens who were more aware of scientific topics to show increased acceptance of gene therapy in humans and GE animals ( Funk et al., 2016 ; STAT and Harvard, 2016 ; Scheufele et al., 2017 ; Funk and Heferon, 2018b ; Funk and Heferon, 2018a ; Lakomý et al., 2018 ; Uchiyama et al., 2018 ; Critchley et al., 2019 ; Lull et al., 2019 ; Chikhazhe 2015; McConnachie et al., 2019 ), except for one study finding no correlation ( Yunes et al., 2019 ).

Methodological quality: reporting of critical issues

This section presents the results of critical appraisal of the methodology, as reported in the primary publications selected for analysis, to provide an indication of the methodological quality ( Petticrew and Roberts, 2005 ). All data are summarized in Supplementary Table S2 .

Questionnaire development

Surveys may be the result of original item generation or adaptation of items used in previous surveys. For pre-CRISPR surveys, there was an approximately even distribution between the eight studies originally generating their own items and the 10 that adapted existing studies. For studies in the CRISPR period, generating own items was much more common (11 versus 4). As for the remaining 18 surveys that have information available both in the pre-CRISPR and CRISPR periods, a hybrid approach was followed.

The validity of a survey instrument is reflected by how well it measures what it is supposed to measure. Face validity (whether it appears to measure what it should) and content validity (if it is understandable to respondents) were the most reported types in 29 and 37 studies, respectively ( Boateng et al., 2018 ; Hair et al., 2019 ). Construct validity, to check if the construct used is suitable, appears mostly in the form of hypothesis testing in 16 pre-CRISPR and 14 CRISPR surveys.

Reliability is about how reproducible survey instrument data are across different applications of the survey. Most papers (32 of the 53) included in the review did not report this parameter. Among the papers that did, the most used was Cronbach’s alpha index to measure internal consistency and split-half reliability, where samples are divided into halves or thirds to ensure that there is not a significant difference between groups of individuals studied.

Sampling: method, response rate, and weighing

The methodology of sampling participants for surveys is very diverse across the different surveys analyzed. CRISPR surveys were conducted mostly online, and pre-CRISPR surveys overlap between telephone, face-to-face, and mail responses. Quota sampling from databases (rather than random sampling) was more common in CRISPR surveys than in pre-CRISPR surveys (10 vs. 3). Weighing of the sample was used to overcome potential sampling bias but was reported in less than half of the studies. In the studies where weighing was reported, the correction tool mostly used was based on demographics for surveys in both time periods. The majority of the studies report a medium response rate (25%–75% of invited participants responded). CRISPR studies show a medium to high response rate compared with pre-CRISPR studies, for which response rates were generally low to medium. Multinational surveys such as Eurobarometer and intercontinental surveys demonstrate a different response rate per country, and therefore, sample weighing was used. Furthermore, an equal number of pre-CRISPR and CRISPR surveys did not report on the response rate (7 each).

Methodology accountability and reporting

Only half of the studies provide information on bias, and this is transversal to both pre-CRISPR and CRISPR studies. The most commonly referred by authors in the studies from the systematic review is recruitment bias, with under- or over-representation of certain demographic groups for education, age, gender, race, and socio-economic status. Some studies report techniques to avoid bias, namely, the use of random digit dialing to avoid inadequate telephone surveys ( OTA, 1987 ), demographic comparisons to the census to avoid sample distortions ( OTA, 1987 ), standardization of questionnaires and their delivery ( Macer et al., 1995 ), use of open responses ( Macer et al., 1995 ; Macer et al., 2000 ), background campaigning ( McCaughey et al., 2019 ), online survey to have a more robust sample ( Weisberg et al., 2017 ), online tools to avoid age bias ( Wang et al., 2017 ), and not mentioning the survey nature to avoid self-selection bias ( McConnachie et al., 2019 ; Yunes et al., 2019 ). In CRISPR studies, authors report about ethical practices taken during survey conduction, whereas this is mostly not reported in pre-CRISPR studies. Such practices involve obtaining informed consent from participants, voluntary participation invitation, obtaining a privacy statement, or even the chance of withdrawal from the study. Formal ethics approval for the study was only reported for 10 studies from the total of publications in the systematic review. Finally, incentives to participants in order to increase their willingness to participate were disclosed in nine studies.

This systematic review of 53 primary publications on attitudes toward genetic modification in humans and non-human animals provides a comprehensive picture of studies in Europe, North America, Asia, and Oceania over 35 years. The review shows some variation between countries but a clear pattern in how different applications are viewed, which does not change substantially over time.

There is an overall positive attitude to gene therapy for medical purposes in humans, both for adults and children, and both as treatment for a fatal genetic disease and as prevention from developing a disease that would otherwise be likely to occur. This is transversal from the early studies before the 1990s to the most recent studies, with little variation among the public and regardless of their origin. This is in agreement with international and national policies ( Walters, 1991 ; Horst, 2007 ; DH-Bio, Committee on Bioethics, 2015 ; Polcz and Lewis, 2016 ; Nicol et al., 2017 ), and indeed, several clinical trials of somatic gene therapy are underway ( EASAC, 2017 ; Karagyaur et al., 2019 ). Key challenges in the use of these therapies in the clinic raised by scholars regard their definition and regulation ( Nicol et al., 2017 ; Sherkow et al., 2018 ) and were partly recognized in some of the public opinion surveys, including the “need for strict regulation” in somatic therapy (Eurobarometer, 2010) and the need for FDA approval to proceed ( STAT and Harvard, 2016 ).

The differentiation between germline and somatic cells becomes important over time. Surveys administered pre-CRISPR hardly ever distinguish between the correction of genes carrying disease for the individual and those that can be passed onto future generations. In contrast, post-CRISPR surveys address this directly not just by questioning explicitly about germline and unborn babies but also when asking both about germline versus somatic therapy and adult versus prenatal therapy. Overall, somatic gene therapy is widely accepted in most surveys, whereas there is much ambivalence about germline gene therapy, with higher support to prevent future health issues in unborn babies and lower support if the purposes are non-health-related issues like physical and psychological characteristics. The ethics of germline gene editing experienced a spike of interest with the advent of the CRISPR-Cas9 technology ( National Academy of Sciences, 2017 ; Nordberg et al., 2018 ; Brokowski and Adli, 2019 ; Morrison and de Saille, 2019 ), and the ethical issues are discussed by the general public and the scientific community in distinct ways. The surveyed public often mentions unnaturalness, messing with nature, and humans playing God in the creation of designer babies as main arguments to reject germline gene editing and health benefits as a reason to accept it. Researchers, on the other hand, primarily refer to technical hurdles and uncertainties, such as off-target effects and mosaicism, as the background of ethical questions related to unintended consequences and safety and also the problem of introducing irreversible changes to the genome of future individuals whose consent cannot be obtained ( Bosley et al., 2015 ; Gyngell et al., 2017 ; National Academy of Sciences, 2017 ; Brokowski and Adli, 2019 ; Morrison and de Saille, 2019 ). Many scholars defend that, while germline gene editing will eventually be inevitable, the technology should not be pursued in the clinic except when no other alternative exists to prevent a severe or deadly genetically transmitted disease and only after the technology has proven to be safe to proceed to clinical trials ( Bosley et al., 2015 ; Gyngell et al., 2017 ; Brokowski, 2018 ; Browkoski and Adli, 2019 ; Morrison and de Saille, 2019 ). Others argue that research on gene editing could improve the understanding of genetic diseases and should be used for single-gene disorders and other disorders arising from polygenic traits ( Gyngell et al., 2017 ). Scholars have defended the adoption of a moratorium on germline gene editing more than once: following the first edit on human cells and after the birth of the first gene-edited babies in late November 2018, respectively ( Baltimore et al., 2015 ; EASAC, 2017 ; Brokowski and Adli, 2019 ; Lander, 2019 ), often justified by the precautionary principle and taking into account the unpredictability of an emerging new form of technology ( Nordberg et al., 2018 ).

A third relevant point is the differentiation between therapy and enhancement. Across countries, citizens are generally opposed to genetic modification for the purpose of enhancement. When asked to distinguish between different types of enhancement, intelligence or psychological features were favored over physical abilities and appearance in US and British studies. Across the countries where there is some support for non-therapeutic gene editing, the most supported purpose is improved human health. This is in line with the establishment of a purpose for genome editing beforehand and the clear distinction between what is a disease and what is a deviation from a societal norm ( Brokowski and Adli, 2019 ). As for current guidelines, the US National Academies of Sciences, Engineering, and Medicine exclude the use of genome modification for any type of enhancement under any circumstance ( National Academy of Sciences, 2017 ; Brokowski and Adli, 2019 ). The reasons for this are also aligned with the slippery-slope argument that gene editing will ultimately lead to social harm by the creation of new genetically modified humans that may lead to “new forms of inequality, discrimination, and societal conflict” if regulation fails to limit germline gene editing to therapeutic uses ( Gyngell et al., 2017 ).

With regard to GM animals, the aspect that stands out as a continued trend is the way acceptance differs between different purposes. Overall, GM animals appear as generally not acceptable for food purposes, be it for leaner or healthier meat, as in the case of GM pigs, or to produce more milk, as in the case of GM cows. In 2007, Novoselova et al. highlighted the important role of consumers in the potential integration of GM products derived from animals into the food chain, pointing out the perception of healthy and safe food, as well as understanding of environmental and ethical concerns as key issues ( Novoselova et al., 2007 ). This perception is based on arguments that “genetic modification is intrinsically wrong” for food applications ( Frewer, 2003 ), with many people even questioning the usefulness of such applications ( Macnaghten, 2004 ). Risk and benefit perceptions regarding food are affected by many factors which interact in complex ways; specifically, with regard to animals, this is further complicated by the duality of the animal as a friend and food ( Ueland et al., 2012 ). As for GM pigs or GM sheep, for medical purposes such as organs for transplantation and derived products to help with diseases, the acceptance is higher. Furthermore, among professionals who are involved with animal research, support for GM pigs in medical applications like xenotransplantation was greater than that for food applications ( Schuppli and Weary, 2010 ). Although this would overcome the shortage of human organs for transplantation, this discussion is again reflecting current and older moral reservations regarding the mixing of tissues from human and non-human species, as well as the unnaturalness and invasiveness of the process and ultimately the risk for human health ( Einsieddel, 2005 ; EASAC, 2017 ; Luna, 2017 ; de Graeff et al., 2019 ). Similarly, it has been found over the years of public opinion surveys that public perceptions of risk are higher when they concern GM animals rather than GM crops/microorganisms and are also perceived as riskier and having more ethical concerns if the context is food applications rather than medical applications as the latter tend to be evaluated on a more specific or case-by-case basis ( Frewer, 2003 ; Frewer et al., 2011 ). The two differences that appear when comparing surveys from before and after the introduction of CRISPR-Cas9 technology are largely associated with the type of questions that were asked. In pre-CRISPR surveys, most respondents see laboratory research in animal models like GM mice as useful but not morally acceptable. This reflects an ambivalence between what is perceived to be a valuable objective (the study of human disease) and the concerns over animals’ welfare ( Spencer, 1999 ; EASAC, 2017 ; de Graeff et al., 2019 ). In the CRISPR surveys that include animal applications, the questions are about applications where genetic modification is done to avoid animal welfare problems, and while people mention some concerns, in particular about potential suffering, overall, they see it as something good. However, they also reveal an unwillingness to consume products derived from these animals, similar to respondents in pre-CRISPR surveys. This follows the usual perception of risks and ethical concerns where the public has also been found to be willing to pay less for GM foods than conventional ones ( Frewer et al., 2011 ). Impacts on human health by the introduction of genetically modified species in the food chain, unnaturalness, and potential ecosystem disturbance are also recognized as moral issues of these interventions ( Nuffield Council of Bioethics, 2016 ; EASAC, 2017 ; Nordberg et al., 2018 ; de Graeff et al., 2019 ). Impacts on biodiversity and sustainability are repeatedly identified ethical concerns about the genetic modification of animals, together with animal welfare, tampering with nature, and unnaturalness ( Frewer et al., 2004 ; MacNaghten, 2004 ; Schuppli and Weary, 2010 ; Frewer et al., 2011 ). Furthermore, GM animals are also seen more negatively than GM plants, and the perception that the technology is unnatural has increased over the years ( Frewer, 2017 ).

Across many surveys, there is a correlation with support for gene technology: the higher the awareness and knowledge levels, the higher the support as well. This lends some support for the deficit model, according to which education and an improved public understanding of science would lead to a higher acceptance of food that is genetically engineered and gene therapy as a clinical treatment approach ( Uzogara, 2000 ; Gottweis, 2002 ). However, in most cases, this relationship is weak, and awareness and knowledge levels toward genetic engineering or modification and biotechnology are generally not considered predictive of public attitude ( Priest, 2000 ; Gottweis, 2002 ; Chen and Chern, 2004 ; Saher et al., 2006 ; Wheeler, 2008 ; Frewer et al., 2011 ). In this context, it is relevant to consider the role of social media. Huber et al. (2019) found that the use of social media news and trust in science was positively correlated across data from 20 countries. They also found that trust in science was more strongly related to social media news use than traditional media news. However, an important caveat highlighted by the authors is that their analysis did not consider the quality of the information. The social media discussion of COVID-19 has made the question of whether what is disseminated is verified scientific information or misinformation/fake news increasingly critical. Radrizzani et al. (2023) surveyed a sample of the United Kingdom public about how their trust in science had been affected by the introduction of the first COVID-19 vaccines. They found that it was much more common for people to report that not only their trust had increased than that it had decreased but also that trust decreased among those who had little trust in science to begin with. In the US, Xiao et al. (2021) found that individuals who get most news from social media had greater beliefs in conspiracies in general and in COVID-19-related conspiracies in particular. Social media may also play a different role in survey research, as illustrated by studies covered by our systematic review, such as McCaughey et al., 2016 , Wang et al., 2017 ; McCaughey et al., 2019 , that included online social media as a method for participant recruitment and response to surveys.

The critical appraisal of methodological quality shows that most studies provide low- to medium-quality information. Only two publications ( Magnusson and Hursti, 2002 ; Kohl et al., 2019 ) fulfill all the criteria recommended for questionnaire surveys ( Petticrew and Roberts, 2005 ; Malhotra, 2006 ; Stockemer, 2019a ; Stockemer, 2019b ). Most studies report or demonstrate the consideration of two to three of the criteria but typically not on the aspects considered more relevant for ensuring the methodological quality, such as the item generation method and response rate. Characteristics of greater relevance, such as validity, reliability, risk of bias, and sampling, are reported at a much lower frequency than what is desired. Poor methodological quality may justify the exclusion of studies from a systematic review. We nevertheless included all surveys in this systematic review because, first, our priority was comprehensiveness and, second, in order to be able to highlight the issue of study quality, which is not yet receiving as much attention in reviews of social science research as it does in biomedical research. Although not reporting does not necessarily mean that the practice was absent, it does, at least, suggest limited attention to the methodology. Lack of information is more common in earlier studies, which probably reflects the changing practice in the field. One also needs to distinguish between survey reports in the gray literature, which focus on reporting the results, from articles in scholarly journals with peer review, where a discussion of methods and issues such as the risk of bias are expected to be an integral part of reporting. Finally, the lack of information regarding formal ethics approval might simply mean that the context in which the study was implemented was considered exempt from formal approval, even though mentioning the exemption would be expected.

To the best of our knowledge, our study is unique in comprehensiveness. First, it includes publications covering almost 35 years and addressing attitudes to human and non-human genetic modifications. Although the 2020 systematic review by Delhove et al. undertook a similar approach in terms of timespan and definition of primary publications, it covers only attitudes to human genetic modification ( Delhove et al., 2020 ). The limitations to our study include the choice of databases, studies, and information to include. We used WOS as the source database and Google web search for publication retrieval. It is possible that other databases would have generated a somewhat different outcome in terms of selected publications. We chose only to include studies of the general public, excluding studies of only specific publics ( Frewer et al., 1997 ; Chen and Chern, 2004 ; Napier et al., 2004 ). Additionally, we must admit some delay regarding the change in terminology from “genetic modification” to “genome editing” that occurred with the advent of CRISPR in 2012 and which was considered in our literature search (see Methodology). In terms of analysis of results, we opted to only assess the influence of awareness and knowledge in public attitudes and did not include other parameters that could have had an influence here, like trust in organizations, demographics (e.g., socio–economic status), and religious index. The reason to only include awareness and knowledge is because these variables have been continuously assessed, and therefore, we could have a parallel view of how they would have influenced public opinions toward genetic modification over time. Finally, the present paper includes only a qualitative analysis of quantitative results, and we did not perform a meta-analysis.

Future perspectives

Public consultation is critical in controversial matters in relation to genetics and biotechnology, especially when applications will potentially directly influence citizens’ lives and, therefore, have to ensure accurate representation ( Halpern et al., 2019 ). Although cross-sectional surveys such as those we analyzed are important because they provide an overview of how public opinion evolved during the last 35 years, real comprehensive initiatives of public engagement and societal debate on genome modification beforehand are indispensable ( Tait et al., 2017 ; Jasanoff and Hurlbut, 2018 ; Wirz et al., 2020 ). This could include a citizen policy approach, such as that described for climate action policy ( Wintle et al., 2017 ; O’Grady, 2020 ). This would be particularly important in the context of policy-making for CRISPR-Cas9 technology implementation. The design of citizen engagement initiatives with multiple stakeholders in the discussion of genome editing driven by the intervention of some associations already in place like the Association for Responsible Research and Innovation in Genome Editing (ARRIGE) may elevate the dialog and contribute to the adoption of a participatory governance framework that may resemble such reflections ( Montoliu et al., 2018 ; Hirsch et al., 2019 ; Pereira and Völker, 2020 ). This path would also entail the best opportunity for scientists and policymakers to consolidate RRI practices in an era where the speed of technology implementation is key but responsibility for its adoption is mandatory ( Tait et al., 2017 ; Shelley-Egan et al., 2020 ).

The surveys we analyzed varied widely in methodology, and more standardized approaches across countries and over time would be important for such future studies. Good examples to follow are Eurobarometer surveys and international surveys that demand a higher collaboration between teams and offer a consistent overview that may transform a cross-sectional view into a more longitudinal one, allowing for more robust hypothesized theories over time ( Stockemer, 2019a ; Stockemer, 2019b ). Co-authorship analysis for the studies included in the present review ( Supplementary Figure S2 ) enabled addressing the connectedness of the authors involved. Although some extensive networks can be seen, most studies seem authored by independent groups of researchers. More collaborations may benefit methodological consistency in future studies.

Additionally, the bioethics literature on biotechnology recognizes a wider range of issues than those that have been covered in the public attitude surveys, such as eugenics, access to technology, funding of genome technologies, and social justice. These are subjects that impact the public and which they often care about, and should be included in future studies as well ( Isasi et al., 2016 ; Nuffield Council of Bioethics, 2016 ; Brokowski and Adli, 2019 ). In policy-making, principles such as solidarity, social justice, and the welfare of future generations are worth considering in the case of GE ( Halpern et al., 2019 ; Mulvihill et al., 2017 ). Finally, it is important to include an assessment of technology awareness and knowledge as part of the survey. Many surveys indicate low levels of knowledge and awareness, and these factors seem to be related to opinion, at least to some extent.

Data availability statement

The original contributions presented in the study are included in the article/ Supplementary Material ; further inquiries can be directed to the corresponding authors.

Author contributions

PR: conceptualization, data curation, formal analysis, investigation, methodology, resources, software, validation, visualization, writing–original draft, and writing–review and editing. MA: conceptualization, data curation, formal analysis, methodology, supervision, validation, writing–original draft, writing–review and editing, software, and visualization. IO: conceptualization, data curation, formal analysis, methodology, supervision, validation, writing–original draft, writing–review and editing, funding acquisition, project administration, and resources.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This project has received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska-Curie Grant, agreement no. 765269.

Acknowledgments

The authors would like to thank the librarian at i3S, Anabela Costa, for her guidance on the methodology for the search and selection of primary publications to feature in this systematic review. The authors also wish to thank Cord Brakebusch for the coordination of IMGENE as part of the European Union’s Horizon 2020 Research and Innovation Program under the Marie Sklodowska-Curie Grant, agreement no. 765269, which enabled the funding of this project.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Supplementary material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fgeed.2023.1284547/full#supplementary-material

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Keywords: systematic review, public attitude, genetic engineering, genome editing, CRISPR, questionnaires, surveys

Citation: Ramos PD, Almeida MS and Olsson IAS (2023) What do people think about genetic engineering? A systematic review of questionnaire surveys before and after the introduction of CRISPR. Front. Genome Ed. 5:1284547. doi: 10.3389/fgeed.2023.1284547

Received: 28 August 2023; Accepted: 27 October 2023; Published: 19 December 2023.

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*Correspondence: Pedro Dias Ramos, [email protected] ; Maria Strecht Almeida, [email protected] ; Ingrid Anna Sofia Olsson, [email protected]

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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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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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The interplay of ethics and genetic technologies in balancing the social valuation of the human genome in unesco declarations, 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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Almeida, M., Ranisch, R. Beyond safety: mapping the ethical debate on heritable genome editing interventions. Humanit Soc Sci Commun 9 , 139 (2022). https://doi.org/10.1057/s41599-022-01147-y

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genetic engineering , the artificial manipulation, modification, and recombination of DNA or other nucleic acid molecules in order to modify an organism or population of organisms. The term genetic engineering is generally used to refer to methods of recombinant DNA technology , which emerged from basic research in microbial genetics . The techniques employed in genetic engineering have led to the production of medically important products, including human insulin , human growth hormone , and hepatitis B vaccine , as well as to the development of genetically modified organisms such as disease-resistant plants.

The term genetic engineering initially referred to various techniques used for the modification or manipulation of organisms through the processes of heredity and reproduction . As such, the term embraced both artificial selection and all the interventions of biomedical techniques, among them artificial insemination , in vitro fertilization (e.g., “test-tube” babies), cloning , and gene manipulation. In the latter part of the 20th century, however, the term came to refer more specifically to methods of recombinant DNA technology (or gene cloning ), in which DNA molecules from two or more sources are combined either within cells or in vitro and are then inserted into host organisms in which they are able to propagate .

The possibility for recombinant DNA technology emerged with the discovery of restriction enzymes in 1968 by Swiss microbiologist Werner Arber . The following year American microbiologist Hamilton O. Smith purified so-called type II restriction enzymes , which were found to be essential to genetic engineering for their ability to cleave a specific site within the DNA (as opposed to type I restriction enzymes, which cleave DNA at random sites). Drawing on Smith’s work, American molecular biologist Daniel Nathans helped advance the technique of DNA recombination in 1970–71 and demonstrated that type II enzymes could be useful in genetic studies. Genetic engineering based on recombination was pioneered in 1973 by American biochemists Stanley N. Cohen and Herbert W. Boyer, who were among the first to cut DNA into fragments, rejoin different fragments, and insert the new genes into E. coli bacteria , which then reproduced.

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How genetic engineering will reshape humanity

A book excerpt and interview with jamie metzl, author of “hacking darwin”.

NEW GENETIC technologies are exhilarating and terrifying. Society might overcome diseases by tweaking individual genomes or selecting specific embryos to avoid health problems. But it may also give rise to "superhumans" who are optimised for certain characteristics (like intelligence or looks) and exacerbate inequalities in society.

What is certain is that people will be able to make decisions about their lives in ways that were impossible in the past, when we relied more on random evolution than deliberation. In the words of Jamie Metzl, we are "Hacking Darwin," the title of his latest book. It is a thoughtful romp through new genetic technologies, with insights on what it means for individuals, society and even great-power politics.

The theme draws together discrete strands of Mr Metz's diverse background. He's worked for the United Nations on humanitarian issues in Cambodia and served on America's National Security Council under President Bill Clinton. He's been an executive at a biotechnology company, a partner at large investment fund in New York and a candidate for Congress from Missouri. But perhaps even more relevantly, he is the author of two sci-fi novels on genetics, "Genesis Code" and "Eternal Sonata."

As part of The Economist’s Open Future project, we asked Mr Metzl about genetic engineering, inequality and the new “liberal agenda”. Below the interview is an excerpt from his book, on the history of eugenics.

The Economist: What are the ways in which people are able to "hack Darwin" today and over the next 15 years or so?

Jamie Metzl: We have always fought against the inherent cruelty of natural selection, one of the two essential pillars of Darwinian evolution. We are now beginning to hack away at the second pillar, random mutation. Our growing understanding of how genes and biology function is opening the door to incredible medical applications like using genome sequencing and gene therapies to fight cancer and other diseases. But the healthcare applications of genetic technologies are only a station along the way to where these technologies are taking us.

Our ability to select embryos during in vitro fertilisation (IVF)—based on informed genetic predictions of both health-related traits and intimate characteristics like height, IQ and personality style—will grow over the coming years. We’ll use stem cell technologies to expand the number of eggs that prospective mothers can use in IVF and therefore the range of reproductive options for parents. We’ll deploy gene editing tools far more precise than today’s CRISPR systems to make heritable genetic changes to our future offspring. Over the coming decades, Darwin’s original concept of random mutation and natural selection will gradually give way to a process that is far more self-guided than anything Darwin could have imagined.

The Economist: Changing the nature of what it means to be human has huge consequences. What are the main ones?

Mr Metzl: We have internalised the idea that information technology is variable, which is why we expect each generation of our phones and computers to be better than the last. It’s harder for us to come to grips with the idea that our biology could be as variable as our IT, even though we understand intellectually that somehow we evolved from single cell organisms to complex humans over the past 3.8 billion years. Starting to see all of life, including our own, as increasingly manipulable will force us to think more deeply about what values will guide us as we begin altering biology more aggressively.

If we want to avoid dividing our species into genetic have and have-nots—a dangerous reduction in our diversity—or a genetic determinism that undermines our humanity, we’ll need to start living our values. But though we need to be mindful of the dangers, we must also keep in mind that these technologies have the potential to do tremendous good. Someday they might well help us avoid extinction level events like dangerous synthetic pathogens, a warmer climate, the fallout from a nuclear war or the eventual expiration of our sun.

The Economist: Do we have the ethical framework to handle this? If not, what might it look like if things go wrong?

Mr Metzl: We create beautiful art, philosophy and universal concepts like human rights but wipe out millions of each other in wars and genocides and still today invest massive amounts of our collective wealth in tools of mass murder. The “better angels of our nature” remain primary drivers in our development of genetic technologies, but the dark side of human nature could also be empowered through these same tools. We need a very strong ethical and cultural framework to increase the odds that we’ll use these technologies wisely, not least because access to them will be decentralised and democratised.

Although the positive possibilities far outweigh the negatives, it would be crazy to ignore the many ways things could go wrong. Like Icarus, we could fly too close to the sun and get burned if we hubristically assume we know more than we actually do. Our gene drives could crash ecosystems. We could use these tools to undermine our common identity as a species and social cohesion. The good news is that while the technologies are new, the values we’ll need to use them wisely are often old.

The Economist: What sort of regulations need to be in place to "enable" these technologies—and what rules should "constrain" them?

Mr Metzl: Genetic technologies touch the source code of what it means to be human and must be regulated. This job is all the more difficult because the technology is racing forward faster than the governance structures around them can keep up. On both the national and international levels, we’ll need enough governance and regulation to prevent abuses and promote public safety while not so much to impede beneficial research and applications.

To avoid dangerous medical tourism, every country should have a national regulatory system in place that aligns with international best practices and the country’s own values and traditions. We also have to start developing global norms that can ultimately underpin flexible international standards and regulations. These systems must be guided by core values rather than inflexible rules because what may now seem unthinkable, like actively selecting and even editing our future offspring, will increasingly become normalised over time. We urgently need to start preparing for what is coming.

The Economist: This takes the issue of human liberty to a new level (people should be free to change themselves or offspring), as well as the potential for unbridgeable inequalities (not just of wealth or life outcomes, but of capabilities encoded in oneself and family). How must the idea of liberalism adapt to address this? What does the "liberal agenda" look like for the 21st century vis-à-vis “hacking Darwin”?

Mr Metzl: If and when it becomes possible for some parents to give their children enhanced IQs, lifespans and resistance to disease, we will have to ask what this means for everyone else. Some will see these parents as first-adopters paving the way for everyone else, like the first privileged people buying smartphones. Others will call them usurpers laying the foundation for dangerously divided societies.

Whatever the case, differences within and between societies, fuelled by competition, will drive adoption of these technologies and present societies with stark choices. Too few regulations could lead to a dangerous genetic engineering free-for-all and arms race. But trying to ban genetic manipulations would increasingly require the trappings of the most oppressive police states. Some liberal societies may choose to provide a basic level of access to assisted reproduction and genetic-engineering services to everyone, not least to save the expense of lifetime care for people who would otherwise be born with preventable genetic diseases.

Societies already struggling to define the balance between the parental and state interests in the context of abortion will have an even tougher time drawing this line for parent-driven assisted reproduction. But if we thought the debates over abortion and genetically modified crops were contentious, wait until the coming debate over genetically modified people arrives. If we don’t want this to tear us asunder, we must all come together in a public process to figure out the best ways forward.

The disgraceful history of eugenics

Excerpted from “Hacking Darwin: Genetic Engineering and the Future of Humanity” by Jamie Metzl (Sourcebooks, 2019)

The term eugenics combines the Greek roots for good and birth. Although coined in the nineteenth century, the concept of selective breeding and human population culling has a more ancient history. Infanticide was written into Roman law and practiced widely in the Roman Empire. “A father shall immediately put to death,” Table IV of the Twelve Tables of Roman Law stated, “a son who is a monster, or has a form different from that of the human race.” In ancient Sparta, city elders inspected newborns to ensure that any who seemed particularly sickly would not survive. The German tribes, pre-Islamic Arabs, and ancient Japanese, Chinese, and Indians all practiced infanticide in one form or another.

The 1859 publication of Darwin’s The Origins of Species didn’t just get scientists thinking about how finches evolved in the Galapagos but about how human societies evolved more generally. Applying Darwin’s principles of natural selection to human societies, Darwin’s cousin and scientific polymath Sir Francis Galton theorized that human evolution would regress if societies prevented their weakest members from being selected out. In his influential books Hereditary Talent and Character (1885) and then Hereditary Genius (1889), he outlined how eugenics could be applied positively by encouraging the most capable people to reproduce with each other and negatively by discouraging people with what he considered disadvantageous traits from passing on their genes. These theories were embraced by mainstream scientific communities and championed by luminaries like Alexander Graham Bell, John Maynard Keynes, Woodrow Wilson, and Winston Churchill.

Although his work was partly in the spirit of the Victorian England times, Galton was then and even more now what we would call a racist. “The science of improving stock,” he wrote, “takes cognizance of all the influences that tend in however remote degree to give the more suitable races or strains of blood a better chance of prevailing speedily over the less suitable than they otherwise would have had.” In 1909, Galton and his colleagues established the journal Eugenics Review, which argued in its first edition that nations should compete with each other in “race-betterment” and that the number of people in with “pre-natal conditions” in hospitals and asylums should be “reduced to a minimum” through sterilization and selective breeding.

Galton’s theories gained increasing prominence internationally, particularly in the New World. Although eugenics would later accrue sinister connotations, many of the early adopters of eugenic theories were American progressives who believed science could be used to guide social policies and create a better society for all. “We can intelligently mold and guide the evolution in which we take part,” progressive theologian Walter Rauschenbusch wrote. “God,” Johns Hopkins economic professor Richard Ely asserted, “works through the state.” Many American progressives embraced eugenics as a way of making society better by preventing those considered “unfit” and “defective” from being born. “We know enough about eugenics so that if that knowledge were applied, the defective classes would disappear within a decade,” University of Wisconsin president Charles Van Hise opined.

In the United States, the “science” of eugenics became intertwined with disturbing ideas about race. Speaking to the 1923 Second International Congress of Eugenics, President Henry Osborn of New York’s American Museum of Natural History argued that scientists should:

“ascertain through observation and experiment what each race is best fitted to accomplish… If the Negro fails in government, he may become a fine agriculturist or a fine mechanic… The right of the state to safeguard the character and integrity of the race or races on which its future depends is, to my mind, as incontestable as the right of the state to safeguard the health and morals of its peoples. As science has enlightened government in the prevention and spread of disease, it must also enlighten government in the prevention of the spread and multiplication of worthless members of society, the spread of feeblemindedness, of idiocy, and of all moral and intellectual as well as physical diseases”.

Major research institutes like Cold Spring Harbor, funded by the likes of the Rockefeller Foundation, the Carnegie Institution of Washington, and the Kellogg Race Betterment Foundation, provided a scientific underpinning for a progressive eugenics movement growing in popularity as a genetic determinism swept the country. The American Association for the Advancement of Science put its full weight behind the eugenics movement through its trend-setting publication, Science. If Mendel showed there were genes for specific traits, the thinking went, it was only a matter of time before the gene dictating every significant human trait would be found. Ideas like these moved quickly into state policies.

Indiana in 1907 became the first U.S. state to pass a eugenics law making sterilization mandatory for certain types of people in state custody. Thirty different states and Puerto Rico soon followed with laws of their own. In the first half of the twentieth century, approximately sixty thousand Americans, mostly patients in mental institutions and criminals, were sterilized without their acquiescence. Roughly a third of all Puerto Rican women were sterilized after providing only the flimsiest consent. These laws were not entirely uncontroversial, and many were challenged in courts. But the U.S. Supreme Court ruled in its now infamous 1927 Buck v. Bell decision, that eugenics laws were constitutional. “Three generations of imbeciles,” progressive Supreme Court justice Oliver Wendell Holmes disgracefully wrote in the decision, “are enough.”

As the eugenics movement played out in the United States, another group of Europeans was watching closely. Nazism was, in many ways, a perverted heir of Darwinism. German scientists and doctors embraced Galton’s eugenic theories from the beginning. In 1905, the Society for Racial Hygiene was established in Berlin with the express goal of promoting Nordic racial “purity” through sterilization and selective breeding. An Institute for Hereditary Biology and Racial Hygiene was soon opened in Frankfurt by a leading German eugenicist, Otmar Freiherr von Verschuer.

Eugenic theories and U.S. efforts to implement them through state action were also very much on Adolf Hitler’s mind as he wrote his ominous 1925 manifesto, Mein Kampf, in Landsberg prison. “The stronger must dominate and not mate with the weaker,” he wrote:

“Only the born weakling can look upon this principle as cruel, and if he does so it is merely because he is of a feebler nature and narrower mind; for if such a law did not direct the process of evolution then the higher development of organic life would not be conceivable at all… Since the inferior always outnumber the superior, the former would always increase more rapidly if they possessed the same capacities for survival and for the procreation of their kind; and the final consequence would be that the best in quality would be forced to recede into the background. Therefore a corrective measure in favor of the better quality must intervene…for here a new and rigorous selection takes place, according to strength and health”.

One of the first laws passed by the Nazis after taking power in 1933 was the Law for the Prevention of Hereditary Defective Offspring, with language based partly on the eugenic sterilization law of California. Genetic health courts were established across Nazi Germany in which two doctors and a lawyer helped determine each case of who should be sterilized.

Over the next four years, the Nazis forcibly sterilized an estimated four hundred thousand Germans. But simply sterilizing those with disabilities was not enough for the Nazis to realize their eugenic dreams. In 1939, they launched a secret operation to kill disabled newborns and children under the age of three. This program was then quickly expanded to include older children and then adults with disabilities considered to have lebensunwertes leben, or lives unworthy of life.

Making clear the conceptual origins of these actions lay in scientifically and medically legitimated eugenics, medical professionals oversaw the murder of an ever-widening group of undesirables in “gassing installations” around the country. This model then expanded from euthanizing the disabled and people with psychiatric conditions to criminals and to those considered to be racial inferiors, including Jews and Roma, as well as homosexuals. It was not by accident that Joseph Mengele, the doctor who decided who would be sent to the gas chambers at Auschwitz, was a former star student of von Verschuer at the Frankfurt Institute for Hereditary Biology and Racial Hygiene.

By the mid-1930s, the American scientific community was pulling away from eugenics. In 1935, the Carnegie Institution concluded the science of eugenics was not valid and withdrew its funding for the Eugenics Records Office at Cold Spring Harbor. Reports of Nazi atrocities amplified by the 1945–46 Nuremberg trials put the nail in the coffin of the eugenics movement in the West. Although eugenics laws were finally scrapped from the books only in the 1960s in the United States and the 1970s in Canada and Sweden, very few people were forcibly sterilized after the war.

But as new technologies more recently began to revolutionize the human reproduction process and create new tools for assessing, selecting, or genetically engineering preimplanted embryos, many critics raised the specter of eugenics.

The parallels between the ugly eugenics of the late nineteenth century and the first half of the twentieth and what’s beginning to happen today are not insignificant. In both cases, a science at an early stage of development and with sometimes uncertain accuracy was or is being used to make big decisions—forced sterilization of the “feeble-minded” in the old days, not selecting a given embryo for implantation or terminating a pregnancy based on genetic indications today. In both cases, scientists and government officials seek to balance individual reproductive liberty with broader societal goals. In both cases, future potential children lose the opportunity to be born. In both cases, societies and individuals make culturally biased but irrevocable decisions about which lives are worth living and which are not. These parallels offer us a powerful warning.

But if we collectively paint all human genetic engineering with the brush of Nazi eugenics, we could kill the incredible potential of genetics technologies to help us live healthier lives. […] That there probably is an element of eugenics in decisions being made today on the future of human genetic engineering should push us to be careful and driven by positive values, but the specter of past abuses should not be a death sentence for this potentially life-affirming technology or the people it could help.

It’s not that hard to imagine future scenarios when humans would need to genetically alter ourselves in order to survive a rapid change in our environment resulting from global warming or intense cooling following a nuclear war or asteroid strike, a runaway deadly virus, or some kind of other future challenge we can’t today predict. Genetic engineering, in other words, could easily shift from being a health or lifestyle choice to becoming an imperative for survival. Preparing responsibly for these potential future dangers may well require we begin developing the underlying technologies today, while we still have time.

Thinking about genetic choice in the context of imagined future scenarios is, in many ways, abstract. But potentially helping a child live a healthier, longer life is anything but. Every time a person dies, a lifetime of knowledge and relationships dissolves. We live on in the hearts of our loved ones, the books we write, and the plastic bags we’ve thrown away, but what would it mean if people lived a few extra healthy years because they were genetically selected or engineered to make that possible? How many more inventions could be invented, poems written, ideas shared, and life lessons passed on? What would we as individuals and as a society be willing to pay, what values might we be willing to compromise, to make that possible? What risks would we individually and collectively be willing to take on? Our answers to these questions will both propel us forward and present us with some monumental ethical challenges.

___________

Excerpted from “Hacking Darwin: Genetic Engineering and the Future of Humanity.” Copyright © 2019 by Jamie Metzl. Used with permission of Sourcebooks. All rights reserved.

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NCGGE - 2025

The Department of Genetic Engineering at SRM IST, started in the year 2004 is commemorating 20 years of its journey in education and research by organizing a “National Conference on Genetics and Genetic Engineering (NCGGE) – 20 years of Accomplishments” during Feb 6th and 7th, 2025. The conference will have 4 sections namely: “Animal and Human Genetics”; “Genomics and Computational Biology”; “Plant Molecular Biology and Genetics” and “Microbial Genetics”. Best Research Student Awards, Best Research Scholar Awards and Young Scientist Awards will also be conferred upon meritorious researchers. We have also planned to conduct five pre-conference workshops on topics like “Quantitative real-time PCR”, “Neuroscience of behaviour”, etc. for the benefit of student community. We are pleased to inform that we are planning to publish full-length research/review manuscripts from selected quality abstracts from the upcoming conference.

Pre Conference Workshop

Hands-on training on chromosome banding techniques, workshop on molecular docking & molecular dynamics simulation, workshop on exploring the neuroscience of behaviour in animal models, hands-on workshop on in vitro assays for screening anti-cancer drugs, conference format.

Leading national experts from academia and industry in the field of genetics and genetic engineering will deliver insightful lectures in the conference. Researchers from around the country will be sharing their ideas, solutions on topics pertaining to the fields genetics, genetic engineering, genomics and their applications in life sciences. Apart from the invited talks from eminent scientists there will be oral presentation sessions and poster presentation sessions for PhD researchers and students.

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Contributions are invited from researchers, scientists, students, faculty members to submit their high quality research work. All the accepted abstracts will be published in the conference proceedings with ISBN number. Selected full papers will be published in selected SCI & Scopus indexed journals.

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Potential authors are invited to submit their abstracts (no more than 250 words) via email to [email protected] . The document should be formatted in MS Word, using Time New Roman font, size 12, and 1.5 line spacing. The abstract should include the following details: the title of the abstract, authors names, affiliation with numerical superscripts, the corresponding author marked with asterisks ( * ), email address and 4-6 keywords.

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Prof. Deepak Modi

FNASc, NIRRCH,Mumbai

DR.S Gopalakrishnan

IARI,New Delhi

Dr. Manoj Prasad

FNA, NIPGR, New Delhi

Dr. Nagarajan Muruganadam

ICMR- RMRC, Port Blair

Dr. Syed Dastgar

Dr. Subeer S.Majumdar

FNA, FASc, FNASc Gujarat Biotechnology University, Gandhinagar

Dr.C.Vishwanathan

IARI, New Delhi

Dr. Vinod Scaria

Vishwanath Cancer Care Foundation, Banglore

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Ethical considerations of gene editing and genetic selection

Jodie rothschild.

1 Rothschild Biomedical Communications, Seattle WA, USA

For thousands of years, humans have felt the need to understand the world around them—and ultimately manipulate it to best serve their needs. There are always ethical questions to address, especially when the manipulation involves the human genome. There is currently an urgent need to actively pursue those conversations as commercial gene sequencing and editing technologies have become more accessible and affordable. This paper explores the ethical considerations of gene editing (specifically germline) and genetic selection—including the hurdles researchers will face in trying to develop new technologies into viable therapeutic options.

1. BACKGROUND

1.1. gene editing.

Artificial manipulation of genes is a relatively new science, and a number of watershed moments have provided the foundation for the current state of genetic engineering. Researchers first discovered that nonspecific alterations to Drosophila DNA could be introduced using radiation 1 and chemicals 2 in 1927 and 1947, respectively. Greater understanding of the structure of the DNA molecule (such as the work of Watson, Crick, and Franklin, leading to the discovery of DNA’s double‐helix structure 3 ) and the cellular processes that govern its transcription, translation, replication, and repair (such as the function of ligases 4 and restriction enzymes 5 ) led to the first splicing experiments 6 and, ultimately, the first recombinant DNA 7 in the early 1970s. DNA recombination techniques were used extensively in the budding yeast Saccharomyces cerevisiae 8 , 9 beginning in the early 1980s, allowing researchers to study functional eukaryotic genomics. And in a significant advancement, the development of polymerase chain reaction (PCR) allowed scientists to amplify DNA, producing millions of copies from a single strand. 10

Around the same time, a number of laboratories created the first transgenic mice, 11 and about five years later, the first knockout mice were created. 12 Targeted gene editing was further advanced by the discovery that engineered endonucleases could create site‐specific double‐stranded breaks (DSBs), which in turn induce homologous recombination (HR), 13 , 15 the most common type of homology‐directed repair (HDR). When the Human Genome Project was declared complete in 2003, 15 it became possible to identify (and thus, theoretically, target) any human gene of interest.

The three main techniques for gene editing involve molecules that recognize and bind to specific DNA sequences; researchers can use custom molecules to affect genetic and epigenetic changes on essentially any gene. For example, these molecules can be combined with endonucleases, creating DSBs which can be repaired using either nonhomologous end joining (NHEJ), which often results in small random indel mutations, or HDR, which, when donor DNA with homology to either side of the cleavage site is present, can be used to create new or “repaired” versions of a target gene. The site‐specific DNA recognition molecule can also be combined with an effector molecule to up‐ or downregulate gene expression.

1.1.1. ZFPs/ZFNs

In the late 1970s and early 1980s, there was a large focus on understanding transcription factor IIIA (TFIIIA), the first eukaryotic transcription factor to be described. In 1983, researchers determined that zinc is required for TFIIIA function, 16 and in 1985 came the discovery that the zinc‐binding portions of the proteins are actually repeating motifs, independently folded to create finger‐like domains that grip the DNA. 17 This class of proteins is now referred to as zinc finger proteins (ZFPs), and several similar proteins have been discovered in the proteomes of a number of different organisms. Because each zinc finger recognizes three base pairs, 18 , 19 , 20 a peptide can be created to recognize a target gene by joining the appropriate zinc fingers in a linear fashion.

A 1994 paper describes a ZFP that was engineered to recognize and suppress an oncogene, as well as a ZFP that acted (in a different cell system) as a promoter of another gene by recognizing its activation domain. 21 The same paper suggests that ZFPs can be bound to effector proteins as a means of controlling gene expression.

Building on this idea, researchers fused a ZFP to the nonspecific cleavage domain of the Fok1 restriction enzyme. 22 The resulting heterodimer, known as a zinc finger nuclease (ZFN), can recognize a specific DNA sequence and produce a targeted DSB. As previously mentioned, these DSB can either be repaired via NHEJ, resulting in small indels, or HDR, which can be harnessed to insert an alternate or repaired gene. Fok1 must dimerize, so ZFNs must be created in pairs (one targeting the 3’ strand and the other targeting the 5’ strand) which improves target specificity—though efficiency remains relatively low (G‐rich sequences are especially difficult to target).

Ex vivo and in vivo delivery of ZFNs is relatively easy given their small size and the small size of the ZFN cassettes (which allows for the use of a variety of vectors). However, while ZFNs were certainly novel at the time they were developed, they are incredibly difficult and expensive to engineer, making them less practical in general than newer technologies.

1.1.2. TALEs/TALENs

In 2009, two different laboratories described a newly identified DNA‐binding motif: the transcription activator‐like effector (TALE), a protein secreted by the plant pathogen Xanthomonas . 23 , 24 Each TALE includes a DNA‐binding region composed of tandem repeats with repeat‐variable diresidues (RVDs) at positions 12 and 13; each RVD recognizes an individual nucleotide.

Like ZFPs, synthetic TALEs can be designed to affect gene regulation, 25 combined with effector proteins, or fused to endonucleases 26 , 27 , 28 to create TALE nucleases (TALENs); as with ZFNs, because Fok1 is the endonuclease used, TALENs must be created in pairs.

TALE nucleases are much larger than ZFNs, and so can be more difficult to deliver efficiently (especially in vivo). However, for myriad reasons (including the nature of their relative interactions with the DNA and the fact that each RVD recognizes a single base), TALE‐based chimeras (especially TALENs) can be built with higher specificity and greater targeting capacity than ZFP‐based chimeras. In addition, TALENs can be produced significantly more cheaply, easily, and with greater efficiency than ZFNs.

1.1.3. CRISPR‐Cas

In 1987, a laboratory in Osaka accidentally discovered an unusual palindromic repeat sequence in the E. coli genome they were studying, unique in that it was regularly interspaced. 29 These DNA motifs were further identified in various bacterial genomes by multiple laboratories over the next 20 years; their function, however, was still unknown. By 2005, three groups had independently determined that the spacer sequences were actually derived from phage DNA, 30 , 31 , 32 and the possibility of the genes playing a role in bacterial immunity was first suggested. 30 , 33 By this time, the scientific community referred to this unusual array as clustered regularly interspaced short palindromic repeats, or CRISPR. Meanwhile, researchers in the Netherlands had identified several other genes located near the CRISPR locus that appeared to be functionally associated with the CRISPR genes; 34 these would turn out to be the CRISPR associated proteins (Cas) that make up an integral part of the CRISPR‐Cas system.

In 2007, the CRISPR‐Cas system was identified as being a prokaryotic defense against pathogens. 35 As a part of a self‐/non–self‐determination mechanism of adaptive immunity, prokaryotes integrate a segment (generally 32‐38 base pairs) of phage DNA into their own genome, creating the spacers in the CRISPR arrays. After the CRISPR genes are transcribed, endoribonucleases cleave the resulting CRISPR RNA (pre‐crRNA), resulting in shorter RNA units composed of a single spacer sequence and the palindromic repeat (crRNA); depending on the organism, a trans‐activating crRNA (tracrRNA) may also be transcribed. The RNA forms a ribonucleoprotein (RNP) complex with the associated Cas proteins; any phage DNA containing the spacer sequence will be identified by the guiding RNA and cleaved by the endonuclease function of the Cas protein(s). The protospacer is the homologous sequence in the invading DNA, and is followed by a short protospacer adjacent motif (PAM); because the PAM is not incorporated in the CRISPR array, the CRISPR‐Cas complex is able to recognize the foreign DNA as non‐self (and thus will not cleave the prokaryotic cell's own DNA). 36

In 2012, Jennifer Doudna, Emmanuelle Charpentier, and others on their team engineered a synthetic chimera of the tracrRNA and crRNA (now known as single guide RNA, or sgRNA), which was able to direct Cas9 to create a targeted, site‐specific double‐stranded break. 37 By 2013, investigators had established that the CRISPR‐Cas9 was an effective, facile, and multiplexable method of editing the human genome. 38 , 39 , 40 , 41

Newer CRISPR‐based editing methods do not reply on unpredictable NHEJ or donor DNA. For example, endonuclease‐deficient Cas proteins can be fused to base‐editing enzymes; 42 first described in 2016, researchers have recently reported a high‐fidelity base editor with no off‐target mutations (OTMs). 43 Epigenetic techniques are also being explored using CRISPR‐Cas technology, 44 , 45 including linking endonuclease‐deficient Cas proteins to effector molecules. And prime editing addresses genetic disorders caused by multibase variances (such as sickle‐cell and Tay‐Sachs); in this case, the impaired Cas9 is fused to an engineered reverse transcriptase. 46

ZFNs and TALENs do maintain some advantages: CRISPR requires a PAM sequence, and sgRNA spacer sequences are usually only about 20 base pairs, meaning an inherently reduced targeting capacity (though researchers have recently begun exploring the effects of increased sgRNA length on cleavage efficiency and target specificity 47 ). CRISPR vectors are also necessary larger, making delivery more difficult. Overall, however, CRISPR is generally the preferred method of genetic and epigenetic manipulation, especially as improvements are made to the technology. CRISPR’s main advantage over its predecessors lies in the fact that rather than a complex protein as the DNA recognition molecule, the CRISPR system relies on a guide RNA. CRISPR kits are thus significantly cheaper, easier, and more efficiently produced than either ZFNs or TALENs.

1.2. Gene selection

Genetic selection happens in nature—natural selection is the mechanism that drives Darwinian evolution. Humans have also been practicing artificial selection for thousands of years, selecting for phenotypic traits when breeding plants and animals. New technologies have been developed over the last 53 years that allow selection of an embryo based on various criteria such as sex, ploidy, and polymorphisms.

1.2.1. Preimplantation genetic testing

Preimplantation genetic testing (PGT) encompasses various techniques used to screen embryos prior to transfer. Originally all referred to as preimplantation genetic diagnosis (PGD), there are actually three types of PGT: aneuploidy detection, now called PGT‐A; monogenic disorder detection, now called PGT‐M; and structural rearrangement detection, now called PGT‐SR.

Preimplantation genetic testing was ideated eleven years before the birth of the first in vitro fertilization (IVF) baby in 1978. Rabbit blastocysts were stained and observed using a fluorescence microscope; screening for sex chromatin allowed for the identification of the female embryos. 48 Because of the mutagenic potential of the preparation, the embryos were not implanted; a year later, cells from the trophoblasts of rabbit blastocysts were stained and sorted for sex, and the biopsied embryos transferred and allowed to grow to full term (at which point sex was confirmed). 49

Researchers then began to explore various methods of extracting a single embryonic cell for PGT: a blastomere biopsy (BB) removed during cleavage stage, 50 trophectoderm biopsy (TB), 51 and polar body biopsy. 52 Meanwhile, polymerase chain reaction (PCR) was developed in 1985 and quickly recognized as a potential tool for PGT when it was used to amplify the portion of the β‐globin locus that includes the Dde I site (absence of which is diagnostic for sickle‐cell anemia). 53 The blastomere biopsy technique and PCR were brought together in 1990 when two human pregnancies were established using sex selected embryos to eliminate the risk of inheriting recessive x‐linked conditions. 54

Fluorescence in situ hybridization (FISH) was the first cytogenetic technique to be used for PGT. Fluorochrome‐labeled site‐specific probes were hybridized to sample DNA, revealing aneuploidy and translocations; in 1993, two laboratories used FISH to identify X‐chromosomes, Y‐chromosomes, and aneuploidy. 55 , 56 However, the technique was limited by the number of chromosomes that could be assessed and by its inability to detect monogenic disorders.

Researchers then turned to comparative genomic hybridization (CGH) in 1999. 57 , 58 CGH can be thought of as competitive FISH: Sample and reference DNA are each labeled with a different color fluorophore, denatured, and allowed to hybridize to a metaphase spread. The DNA is then microscopically analyzed for differences in fluorescence intensity, indicating copy‐number variation (CNV).

While it was a vast improvement over its predecessor, CGH was time‐consuming (requiring embryos to be freeze‐thawed), labor‐intensive, and limited in its sensitivity. The next generation of CGH technology, array CGH (aCGH), addressed these limitations. 59 Like traditional CGH, aCGH allows for 24‐chromosome analysis; however, rather than human observation, fluorescence intensity evaluation is performed by a computer, locus by locus, with high specificity and resolution.

A number of other cytogenetic techniques for comprehensive chromosome screening (CCS) have since been developed: digital PCR (or dPCR, wherein a sample‐containing PCR solution is separated into tens of thousands of droplets and the reaction occurs separately in each partition), which can detect CNV, aneuploidy, mutations, and rare sequences; quantitative real‐time PCR (qPCR), in which a preamplification step prior to real‐time PCR allows for rapid detection of aneuploidy in all 24 chromosomes; single nucleotide polymorphism (SNP) array (which involves hybridizing fluorescent nucleotide probes to sample DNA and comparing the resulting fluorescence to a bioinformatic reference), which can detect imbalanced translocation, aneuploidy, and monogenic (and some multifactorial) disease; and next‐generation sequencing (NGS), the high‐throughput, massively parallel DNA sequencing technologies that allow for significantly quicker and cheaper sequencing than the Sanger method and make it possible to screen for everything from SNPs to aneuploidy.

Researchers and IVF laboratories use different combinations of FISH and/or the various CCS techniques.

1.2.2. Other prenatal testing

Often, IVF is not feasible, necessitating postimplantation prenatal testing (when indicated by family history and other risk factors). Amniocentesis, chorionic villus sampling (CVS), and percutaneous umbilical cord sampling (PUBS) were initially paired with karyotyping, which can detect sex, aneuploidy, and some types of structural chromosomal disorders. Karyotyping was superseded by chromosomal microarray techniques (aCGH and SNP array) and, more recently, low‐pass genome sequencing, as these technologies allow detection of CNVs as well as aneuploidy. 60

Amniocentesis is a procedure in which an ultrasound‐guided needle is inserted transabdominally in order to aspirate amniotic fluid. Applications of amniocentesis extend beyond genetic testing, such as assessment of fetal lung maturity, detection of Rh incompatibility, and decompression of polyhydramnios (accumulation of amniotic fluids).

Prior to 15 weeks’ gestation, the prenatal testing method of choice is CVS, a technique that involves analysis of samples taken from placental tissue. The CVS procedure is ultrasound‐guided and can be performed either transabdominally or transcervically (associated with higher miscarriage rates). CVS carries the risks of miscarriage, amniotic fluid leakage, and limb reduction defects and is limited by the possibility of placental mosaicism and maternal cell contamination.

Percutaneous umbilical cord sampling is a rarely used procedure, performed between 24 and 32 weeks’ gestation, in which fetal blood from the umbilical cord is obtained. Because of the high potential for complications, PUBS is generally reserved for cases in which the pregnancy is deemed high‐risk for genetic disorders and other testing methods (amniocentesis, CVS, and ultrasound) are unable to provide the needed information or have been inconclusive. PUBS is also used to provide more information about fetal health (such as blood gas levels and infection).

In 1997, the presence of cell‐free fetal DNA (cffDNA) in maternal blood was established using PCR amplification with Y‐chromosome probes. 61 This led to the development of noninvasive prenatal testing (NIPT) of cffDNA. NIPT has been shown to be an accurate and sensitive technique for the detection of some aneuploidies (such as trisomy 21 62 ), less so for others. 63 Because cffDNA comes from the placenta, placental mosaicism can result in inaccurate results. Further, NIPT detects all cell‐free DNA in the mother's blood, including her own; maternal mosaicism or malignancies can also contribute to inaccuracies. As such, NIPT is considered a screening test, rather than a diagnostic test.

2. ETHICS OF GENE EDITING

On November 25, 2018, news broke that Jiankui He of Southern University of Science and Technology in Shenzhen, China had registered a clinical trial in which he planned to implant human embryos which had been modified using CRISPR‐Cas9. 64 Within days, the world learned that not only had edited embryos been implanted, two baby girls, Lulu and Nana, had already been born. 65

He used CRISPR‐Cas9 to create a nonspecific sequence alteration in the CCR5 gene. CCR5 is a seven‐transmembrane–spanning G protein–coupled CC chemokine (β chemokine) receptor. When expressed on the surface of a human T cell, CCR5 is the main coreceptor (along with CD4) for the human immunodeficiency virus (HIV). A naturally occurring 32–base pair deletion (with heterozygote allele frequencies of about 10% in people with European origin), known as CCR5∆32 , has been shown to disable the protein; 66 heterozygosity of the CCR5∆32 allele has been shown to slow disease progression, while homozygosity significantly increases disease resistance. He's goal was to knock out CCR5 , with the desired outcome of creating HIV‐resistant babies (it should be noted that HIV infection in CCR5∆32 +/+ individuals has been increasingly reported, associated with X4‐trophic HIV strains—that is, strains that rely exclusively on coreceptor CXCR4 for endocytosis, rather than CCR5 67 ).

He presented the details of his investigation 68 at the Second International Summit on Human Genome Editing, being held “to discuss scientific, medical, ethical, and governance issues associated with recent advances in human gene‐editing research.” 69 While his manuscript describing the trial was not accepted by any publications, excerpts are available to the public, and various media outlets (and some experts) have been able to view the paper and supplementary data in their entirety. Enough is now known about He's work that it can serve as the basis of a conversation about the ethics surrounding germline gene editing. There are a number of issues—those inherent in the technologies themselves, as well as scientific hurdles that need to be overcome—before initiating clinical trials, to ensure that they are carried out as ethically as possible.

2.1. Not all sequence variations are created equally

CCR5∆32 has been researched extensively, but is one of only a few CCR5 variants studied. In his abstract, He claims that his team has reproduced this natural variant, but this is not the case: Two embryos were implanted, one of which (Nana) had frameshift mutations on both alleles (a 1–base pair insertion and a 4–base pair deletion, respectively) and the other of which (Lulu) showed a 15–base pair deletion on only one allele. Frameshift mutations have a high probability of disrupting protein structure (and thus function). The 15–base pair deletion, however, will result in five missing amino acids when the protein is translated, and its effect on the protein's function is unknown. He's team could have frozen the embryos, duplicated the sequence alterations in other cell lines, and tested whether or not the genetic changes actually conferred disease resistance, before actually implanting the embryos, but it does not appear that they made an effort to fully understand the actual effect of the alterations they had made. 64 With all of the risks associated with the CRISPR editing process, embryos should not be implanted if the scientists are unsure of the effects.

2.2. Mosaicism

A CRISPR‐Cas vector is inserted into a zygote soon after fertilization. If the CRISPR‐induced mutagenesis only occurred during the single‐cell stage, each successive round of cleavage would yield genetically identical cells. However, while the half‐life of the Cas proteins themselves may not be long, the vectors will remain and continue to be transcribed for days. During this time, the embryo will continue to divide, eventually forming a blastocyst of a few hundred cells. Uneven distribution of the plasmid and the RNPs means that there is a significant potential for mosaicism.

In He's laboratory, three to five cells were removed from each blastocyst, and their genomes sequenced. If Lulu's embryo were made up of identical cells (with one wild type allele and one with a 15–base pair deletion) as He had reported, the Sanger chromatogram should have shown two sets of peaks, approximately the same height. However, it appears likely that there were actually three different combinations of alleles: two normal copies, one normal copy and one with a 15–base pair deletion, and one normal copy and an unknown large insertion. Similarly, while Nana's embryo should have shown two alterations, the Sanger chromatogram revealed three. 70

The suspicion of mosaicism is borne out when sequencing of samples from the cord blood, umbilical cords, and placentas are reviewed. Just as with the embryo sequencing, rampant mosaicism is evident. It is reasonable to assume that the girls’ bodies are mosaic as well, but for an unknown reason, He's team did not test any cells from the girls themselves. 70 There is therefore the possibility that not all of the cells in Nana's body will have modifications to both CCR5 alleles, meaning it is possible that Nana is not actually resistant to HIV.

Mosaicism can have myriad effects: Even a few mutated cells in an organ can cause disease, a single cell can develop into a tumor, and any allelic variation in germ cells will be inherited by the following generation. There is no way to sequence a cell's genome without destroying the cell itself; as such, it is currently impossible to rule out mosaicism in a blastocyst.

2.3. Off‐target effects

As efficient as CRISPR is, there is a high probability of OTMs. He's team reported that in addition to the CCR5 gene edits, there was only one OTM, a 1–base pair insertion in a noncoding region of Chromosome 1 in Lulu's genome. This was based on their relatively limited sequencing, however; as noted above, mosaicism cannot be ruled out. (It should also be noted that there were flaws in the sequencing itself, so there may be other alterations that were missed in the screening, on top of the mosaicism. 70 )

2.4. Other consequences of target gene modification

When undertaking to knock out a gene in an embryo, it is vital to understand all of the functions of that gene.

CCR5 is a chemokine receptor that mediates leukocyte chemotaxis, and thus helps mount immune response. It is therefore unsurprising that homozygosity for the CCR5∆32 variant has been shown to be significantly correlated with more symptomatic infection and higher mortality rates in patients with West Nile virus, 71 influenza A, 71 , 72 and tick‐borne encephalitis. 73 It has also been shown to be associated with upregulation of certain CC chemokine ligands, and in turn associated with progressive reduction in survival time for patients with multiple sclerosis (MS). 74 Is it ethical to create a sequence variation that confers resistance to one illness, while increasing the likelihood of succumbing to another?

Public health conversations will need to change as well. It is possible, for example, that some with a CCR5 edit will engage in riskier sexual practices, or that some with a PCSK9 edit (which is associated with decreased levels of low‐density lipoprotein cholesterol, or LDL, in the blood 75 , 76 ) will be less likely to make behavioral changes such as increased exercise and diet modification.

2.5. Which genes/diseases to target?

Many who have viewed He's work have questioned why he chose to focus on CCR5 and HIV resistance. HIV prevalence in China is relatively low, 77 and current treatments can keep viral loads at almost undetectable levels. He stated that his research could help tamp down the HIV/AIDS epidemic; the most hard‐hit areas (such as Africa), however, would likely not gain much benefit from gene‐editing technologies.

Per a December 2018 poll, 78 Americans draw the line at so‐called enhancement, but favor the use of genetic engineering to address disease and disability. Which diseases and disabilities to target, however, is still an open discussion. Some questions that may help inform that decision: Should there be a focus on infectious disease resistance? Only fatal conditions? Will we decide that there is a need to quantify the degree of suffering? If an effective treatment already exists, should we still seek prevention through genetic modification? Is childhood versus adulthood onset of illness an important factor? Not all sequence variants are guaranteed to cause disease (eg, BRCA genes); should they be considered? What about orphan diseases? And should certain types of disabilities be prioritized over others?

2.6. OTHER ISSUES

2.6.1. clinical research ethics.

The history of research using human subjects has been blemished by unethical treatment of the subjects themselves. From Imperial Japan to the Tuskegee Institute, examples of atrocities committed in the name of medical science can be found across the world. As a result, a number of guidelines have been developed to facilitate ethical research going forward. 79 Nazi Germany engaged in abominable human experimentation during World War II; in 1947, the Nuremberg Military Tribunal (during which Nazi physicians and administrators were tried for war crimes and crimes against humanity) resulted in the Nuremberg Code, a statement aimed at preventing such abuses in the future. Stemming from a reaction to the same offenses, the World Medical Association produced Ethical Principles for Medical Research Involving Human Subjects —known as the Declaration of Helsinki—in 1964 (it has been modified a few times since), which in 1982 was adapted by the Council for International Organizations of Medical Sciences into a manual, Proposed International Ethical Guidelines for Biomedical Research Involving Human Subjects , as a guideline for World Health Organization (WHO) member countries. (Individual countries have created their own guidelines, as well. In the United States, for example, the National Research Act of 1974 established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research—often referred to as the Belmont commission—which issued the 1979 Ethical Principles and Guidelines for the Protection of Human Subjects of Research , now known as the Belmont Report. The National Research Act of 1974 also established a set of regulations regarding human subject research; by 1991, after various updates and additions, the government decided that the regulations should become a “Common Rule” covering all federally connected research, codified in Title 45, Part 46 of the Code of Federal Regulations.)

This article will not delve into all of He's ethical missteps as regards his research (such as the fact that he registered the trial with the Chinese Clinical Trial Registry in November 2018, after the twins had already been born). However, there are a few key issues, directly addressed by at least one of these major reports, which can be considered in terms of guiding future ethics discussions regarding gene‐editing clinical trials.

First and foremost, clinical trial participants should be informed of all of the associated risks and benefits. There is significant ambiguity as to the informed consent process in He's study. First, the experiment was misleadingly couched as an HIV vaccine trial. 65 , 80 It is also unclear how much the parents in He's study understood about risks such as mosaicism or increased susceptibility to other infections. The investigator is responsible for keeping participants informed throughout the study; it does not appear that in this case they were informed of the mosaicism present in both embryos (in his presentation at the human genome editing summit, He said only that the parents had been informed about one OTM 68 and does not even mention the mosaicism in his manuscript 70 ). It is likely that were the parents fully informed, they would have decided not to implant one or both embryos. This raises another question: Should parents be the ones to make such a decision, or is that the responsibility of the researchers and doctors?

The selection of the study participants is an issue, as well: The first inclusion criterion is that the participants must be a married couple wherein the husband is HIV‐positive and the wife is HIV‐negative. 81 Father‐to‐child transmission of HIV is rare (especially when the father is on antiretroviral therapy and the mother is on preexposure prophylaxis), but it is possible; for this reason, many couples opt for sperm washing (to separate the sperm from the virus), followed by either in vitro fertilization (IVF) or intrauterine implantation (IUI). While there is no explicit law against HIV‐positive parents accessing these procedures, it is unlikely that it would be approved by hospitals’ ethics committees. 82 Chinese couples often travel to other countries (such as Thailand) for the procedure, but it can cost hundreds of thousands of yuan. 83 The couples selected for He's study may have seen participation as their only chance to have children—indeed, He described the father as having “lost hope for life.” 68 This makes them particularly vulnerable to exploitation. (This may also have informed their decision to implant both embryos rather than just the one that had alterations to both alleles.)

Study participants should be able to voluntarily withdraw from the research at any point; He's informed consent form stipulates that were the couple to withdraw from the study (at any point between the implantation of the embryo in the first IVF cycle and 28 days postbirth), they would be responsible for reimbursing the laboratory for all project costs (and that if reimbursement was not received within 10 calendar days of withdrawal, a substantial fine—more than the average annual income of a Chinese citizen—would be imposed). 80 This is sufficiently cost prohibitive as to prevent a subject from withdrawing from the study.

It is unclear whether He's research actually underwent an ethics review process: In his manuscript, He claims that the Medical Ethics Committee of the Shenzhen Harmonicare Women's and Children's Hospital approved the study in March 2017, but only elaborates by stating that his team was “… told that the committee held a comprehensive discussion of risks and benefits… During the study, the director of the ethics committee was constantly updated about the state of the clinical trial.” 84 The hospital has since denied that the study was reviewed at all, and claims that the signatures on the approval were forged. 85 What is clear is that a number of regulations were violated or circumvented, including the guidelines for embryo research which allow an edited embryo to be cultured for no more than 14 days and prohibit its implantation, 86 as well as the aforementioned limitations on assisted reproductive services for HIV‐positive parents. 82 It is likely that He switched blood samples and kept many of the IVF technicians and obstetricians in the dark as to the nature of the study to get around these issues. 87

Finally, it is reasonable to consider whether He was qualified to be the investigator on such a trial: He had published one paper about CRISPR (in 2010, before human gene editing was an application of the technology), his background was in physics (he crossed over into biophysics), and he had no medical training. This is especially concerning as biohackers have made available both the equipment and the basic blueprints for home CRISPR editing (see the Other Perspectives section)—including advice on how to obtain human embryos and eventually implant them. 88

2.6.2. Socioeconomic disparities

Multiple polls have shown that the majority of people around the world are opposed to the use of genetic engineering of embryos for enhancement, such as athletic ability and intelligence, or for altering physical characteristics, such as eye color and height. 89 It is easy to conceive of the risk of a new age of eugenics.

But even the application of genetic modification to address medical needs holds the potential for establishing inequality. The technology will remain incredibly expensive for some time, prohibitively so for most people. CCR5 edits lie in an ill‐defined area between medical need and enhancement; an unfair health advantage will be established if such modifications are only accessible to the wealthy. Other kinds of edits may mean the difference between life and death; should potentially life‐saving therapies only be available to those with financial means? Put another way, should those individuals on one side of the growing socioeconomic gap be the only ones protected from the suffering that comes with illnesses such as Alzheimer's disease, Huntington disease, or cystic fibrosis?

2.6.3. Possible stigma

Especially while the concept is still novel, it is difficult to predict how society will feel about gene‐edited babies. Will Nana and Lulu face any sort of backlash? Conversely, if and when gene editing becomes commonplace, will there be a stigma associated with not having been edited in some way, such as still being susceptible to various infectious diseases? Might children like Lulu be less accepted for not carrying a desired modification? He wanted to spare HIV‐infected individuals’ children the stigma and discrimination their parents endured; 90 it is possible that having edited genes has replaced one potential stigma with another.

2.6.4. Insurance

Because gene editing will be a tool to cure and prevent illness, insurance coverage will be an important part of the conversation. First, will insurance cover the editing itself? If so, will germline versus somatic cell editing be an important distinction? Will coverage be based on the targeted illness or disability (and expected associated costs)? And who will decide which edits are considered medically necessary and which are considered elective?

Once babies born from edited embryos are born, more questions arise. Will those whose genes have not been edited to prevent certain illnesses be considered to have preexisting conditions? Will they be expected to pay more for coverage? On the other side of the coin, will those who have had their genes edited (especially when the technology is first rolled out) pay more because of possible off‐target risks or potential negative consequences of editing (eg, the increased susceptibility to influenza associated with CCR5 editing)?

2.6.5. Other perspectives

A full discussion of ethics requires a balanced presentation of various points of view.

There are those who object to continued research into gene editing, especially in zygotes, for myriad reasons. For example, some feel that gene editing is “playing God” and that it is not man's role to make changes to the basic building blocks of humanity; others are concerned about the potential that the technology, once perfected, could be co‐opted to produce designer babies; there is the consideration that opening a market for human eggs for research could lead to exploitation of disadvantaged women; and still others have concerns similar to those who are opposed to embryonic stem cell research—such as the conviction that embryos should not be created for the purpose of research, or that un‐implanted embryos (which they consider potential life) should not be destroyed.

There are also those who believe that not only should research continue, but that even nascent technology such as gene editing should be accessible to the public. 91 Known as biohackers, these scientists and activists laud the efforts like Jiankui He's. 88 Educational and laboratory materials are currently available to essentially anyone. It is even possible to purchase CRISPR kits, 92 and while a new California law requires that such kits are labeled “not for self‐administration” 93 there are currently no laws prohibiting people from doing just that—in fact, the owner of one company was investigated by the California Medical Board for unlicensed practice of medicine after injecting himself with CRISPR, but the investigation was dropped after four months with “no further action… anticipated.” 94

3. GLOBAL DISCUSSIONS ON GERMLINE EDITING

While it is impossible to mandate that all countries follow the same set of guidelines, it is possible to establish guiding principles for the risk‐benefit analyses and ethical discussions each country will undertake in developing their own regulatory framework. Because science moves faster than regulation, the scientific community as a whole can also use these principles to help guide ethically charged research decisions where no regulations yet exist. To that end, various groups have been meeting all over the world to try to come to a consensus on how to proceed with germline editing research and the potential clinical applications thereof.

3.1. Before He’s announcement

In 2015, the International Bioethics Committee (IBC), part of the United Nations Educational, Scientific, and Cultural Organization (UNESCO), released the Report of the IBC on Updating its Reflection on the Human Genome and Human Rights. 95 The report considers other technologies as well, but “recommends a moratorium on genome editing of the human germline.”

Also in 2015, investigators in China announced that they had successfully used CRISPR to edit a nonviable human embryo. 96 This inspired the first International Summit on Human Gene Editing, held December 2015 in Washington, D.C. Hosted by the US National Academy of Sciences, US National Academy of Medicine, the Royal Society of the UK, and the Chinese Academy of Sciences, the summit brought together more than 3500 stakeholders (500 in person and 3000 online) from around the world to discuss human gene editing. At the end of the summit, the organizing committee released a statement advising ongoing global engagement and discussion, and outlined their conclusions regarding gene editing: 97 “(i)ntensive basic and preclinical research is clearly needed and should proceed, subject to appropriate legal and ethical rules and oversight…”; “(m)any promising and valuable clinical applications of gene editing are directed at altering genetic sequences only in somatic cells… [and] they can be… evaluated within existing and evolving regulatory frameworks for gene therapy…”; and “(g)ene editing might also be used, in principle, to make genetic alterations in gametes or embryos…” The statement goes on to address the ethical, legal, and scientific questions surrounding germline editing that have yet to be answered, and warns:

It would be irresponsible to proceed with any clinical use of germline editing unless and until (a) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (b) there is broad societal consensus about the appropriateness of the proposed application. Moreover, any clinical use should proceed only under appropriate regulatory oversight. At present, these criteria have not been met for any proposed clinical use: the safety issues have not yet been adequately explored; the cases of most compelling benefit are limited; and many nations have legislative or regulatory bans on germline modification. However, as scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis.

While this statement in no way gives a green light for trials such as He's, it also does not call for an outright moratorium. In March 2017, another Chinese team published the results of the first use of CRISPR in viable human embryos. 98 Less than two years later, He's work was revealed to the world.

3.2. After He’s announcement

The article about He's trial was published the day before the second International Summit on Human Gene Editing. As they had at the first summit, organizers released a concluding statement on the last day. Surprisingly, not only does the statement again fall short of calling for a moratorium on clinical use of gene editing, the language is even softer than that of the first summit statement:

The variability of effects produced by genetic changes makes it difficult to conduct a thorough evaluation of benefits and risks. Nevertheless, germline genome editing could become acceptable in the future if these risks are addressed and if a number of additional criteria are met. These criteria include strict independent oversight, a compelling medical need, an absence of reasonable alternatives, a plan for long‐term follow‐up, and attention to societal effects. Even so, public acceptability will likely vary among jurisdictions, leading to differing policy responses. The organizing committee concludes that the scientific understanding and technical requirements for clinical practice remain too uncertain and the risks too great to permit clinical trials of germline editing at this time. Progress over the last three years and the discussions at the current summit, however, suggest that it is time to define a rigorous, responsible translational pathway toward such trials.

In December 2018, seeing the need for a more substantial framework of regulatory guidance, the WHO established the Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing, “a global, multi‐disciplinary expert panel to examine the scientific, ethical, social and legal challenges associated with human genome editing… tasked to advise and make recommendations on appropriate institutional, national, regional and global governance mechanisms for human genome editing.” 99 They have established the Human Genome Editing Registry to collect information on human clinical trials involving genome editing, and the WHO has supported the advisory committee's interim recommendation that “it would be irresponsible at this time for anyone to proceed with clinical applications of human germline genome editing.” 100

In 2019, the US National Academies of Medicine and Science, together with the Royal Society, convened the International Commission on the Clinical Use of Human Germline Genome Editing. The goal of commission is: 101

… with the participation of science and medical academies around the world, to develop a framework for scientists, clinicians, and regulatory authorities to consider when assessing potential clinical applications of human germline genome editing. The framework will identify a number of scientific, medical, and ethical requirements that should be considered, and could inform the development of a potential pathway from research to clinical use—if society concludes that heritable human genome editing applications are acceptable.

The commission's final report is scheduled to be released in the spring of 2020.

As the science progresses, there are clearly significant conversations yet to be had.

CONFLICT OF INTEREST

The authors have stated explicitly that there are no conflicts of interest in connection with this article.

Rothschild J. Ethical considerations of gene editing and genetic selection . J Gen Fam Med . 2020; 21 :37–47. 10.1002/jgf2.321 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]