research paper about genetic engineering

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• Published: 29 October 2020

The genome editing revolution: review

• Ahmad M. Khalil   ORCID: orcid.org/0000-0002-1081-7300 1  

Journal of Genetic Engineering and Biotechnology volume  18 , Article number:  68 ( 2020 ) Cite this article

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Development of efficient strategies has always been one of the great perspectives for biotechnologists. During the last decade, genome editing of different organisms has been a fast advancing field and therefore has received a lot of attention from various researchers comprehensively reviewing latest achievements and offering opinions on future directions. This review presents a brief history, basic principles, advantages and disadvantages, as well as various aspects of each genome editing technology including the modes, applications, and challenges that face delivery of gene editing components.

Genetic modification techniques cover a wide range of studies, including the generation of transgenic animals, functional analysis of genes, model development for diseases, or drug development. The delivery of certain proteins such as monoclonal antibodies, enzymes, and growth hormones has been suffering from several obstacles because of their large size. These difficulties encouraged scientists to explore alternative approaches, leading to the progress in gene editing. The distinguished efforts and enormous experimentation have now been able to introduce methodologies that can change the genetic constitution of the living cell. The genome editing strategies have evolved during the last three decades, and nowadays, four types of “programmable” nucleases are available in this field: meganucleases, zinc finger nucleases, transcription activator-like effector nucleases, and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) (CRISPR/Cas-9) system. Each group has its own characteristics necessary for researchers to select the most suitable method for gene editing tool for a range of applications. Genome engineering/editing technology will revolutionize the creation of precisely manipulated genomes of cells or organisms in order to modify a specific characteristic. Of the potential applications are those in human health and agriculture. Introducing constructs into target cells or organisms is the key step in genome engineering.

Conclusions

Despite the success already achieved, the genome editing techniques are still suffering certain difficulties. Challenges must be overcome before the full potential of genome editing can be realized.

In classical genetics, the gene-modifying activities were carried out selecting genetic sites related to the breeder’s goal. Subsequently, scientists used radiation and chemical mutagens to increase the probability of genetic mutations in experimental organisms. Although these methods were useful, they were time-consuming and expensive. Contrary to this, reverse genetics goes in the opposite direction of the so-called forward genetic screens of classical genetics. Reverse genetics is a method in molecular genetics that is used to help understanding the function of a gene by analyzing the phenotypic effects of specific engineered gene sequences. Robb et al. [ 68 ] defined and compared the three terms: “genome engineering”, “genome editing”, and “gene editing”. Genome engineering is the field in which the sequence of genomic DNA is designed and modified. Genome editing and gene editing are techniques for genome engineering that incorporate site-specific modifications into genomic DNA using DNA repair mechanisms. Gene editing differs from genome editing by dealing with only one gene.

This review briefly presents the evolution of genome editing technology over the past three decades using PubMed searches with each keyword of genome-editing techniques regarding the brief history, basic principles, advantages and disadvantages, as well as various aspects of each genome editing technology including the modes, future perspective, applications, and challenges.

Genome-wide editing is not a new field, and in fact, research in this field has been active since the 1970s. The real history of this technology started with pioneers in genome engineering [ 36 , 59 ]. The first important step in gene editing was achieved when researchers demonstrated that when a segment of DNA including homologous arms at both ends is introduced into the cell, it can be integrated into the host genome through homologous recombination (HR) and can dictate wanted changes in the cell [ 10 ]. Employing HR alone in genetic modification posed many problems and limitations including inefficient integration of external DNA and random incorporation in undesired genomic location. Consequently, the number of cells with modified genome was low and uneasy to locate among millions of cells. Evidently, it was necessary to develop a procedure by which scientists can promote output. Out of these limitations, a breakthrough came when it was figured out that, in eukaryotic cells, more efficient and accurate gene targeting mechanisms could be attained by the induction of a double stranded break (DSB) at a specified genomic target [ 70 ].

Furthermore, scientists found that if an artificial DNA restriction enzyme is inserted into the cell, it cuts the DNA at specific recognition sites of double-stranded DNA (dsDNA) sequences. Thus, both the HR and non-homologous end joining (NHEJ) repair can be enhanced [ 14 ]. Various gene editing techniques have focused on the development and the use of different endonuclease-based mechanisms to create these breaks with high precision procedures [ 53 , 78 ] (Fig. 1 ). The mode of action of what is known as site-directed nucleases is based on the site-specific cleavage of the DNA by means of nuclease and the triggering of the cell’s DNA repair mechanisms: HR and NHEJ.

Genome editing outcomes. Genome editing nucleases induce double-strand breaks (DSBs). The breaks are repaired through two ways: by non-homologous end joining (NHEJ) in the absence of a donor template or via homologous recombination (HR) in the presence of a donor template. The NHEJ creates few base insertions or deletion, resulting in an indel, or in frameshift that causes gene disruption. In the HR pathway, a donor DNA (a plasmid or single-stranded oligonucleotide) can be integrated to the target site to modify the gene, introducing the nucleotides and leading to insertion of cDNA or frameshifts induction. (Adapted from [ 78 ])

One of the limitations in this procedure is that it has to be activated only in proliferating cells, adding that the level of activity depends on cell type and target gene locus [ 72 ]. Tailoring of repair templates for correction or insertion steps will be affected by these differences. Several investigations have determined ideal homology-directed repair (HDR) donor configurations for specific applications in specific models systems [ 67 ]. The differences in the activities of the DNA repair mechanisms will also influence the efficiency of causing indel mutations through NHEJ or the classical microhomology-mediated end joining (c-MMEJ) pathway, and even the survival of the targeted cells. The production of such repair in the cell is a sign of a characteristic that errors may occur during splicing the ends and cause the insertion or deletion of a short chain. Simply speaking, gene editing tools involve programmed insertion, deletion, or replacement of a specific segment of in the genome of a living cell. Potential targets of gene editing include repair of mutated gene, replacement of missing gene, interference with gene expression, or overexpression of a normal gene.

The human genome developments paved the way to more extensive use of the reverse genetic analysis technique. Nowadays, two methods of gene editing exist: one is called “targeted gene replacement” to produce a local change in an existing gene sequence, usually without causing mutations. The other one involves more extensive changes in the natural genome of species in a subtler way.

In the field of targeted nucleases and their potential application to model and non-model organisms, there are four major mechanisms of site-specific genome editing that have paved the way for new medical and agricultural breakthroughs. In particular, meganucleases (MegNs), zinc finger nucleases (ZFNs), transcription activator-like effector nuclease (TALENs), and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) (CRISPR/Cas-9) (Fig. 2 ).

Schematic diagram of the four endonucleases used in gene editing technologies. a Meganuclease (MegN) that generally cleaves its DNA substrate as a homodimer. b Zinc finger nuclease (ZFN) recognizes its target sites which is composed of two zinc finger monomers that flank a short spacer sequence recognized by the FokI cleavage domain. c Transcription activator-like effector nuclease (TALEN) consists of two monomers; TALEN recognizes target sites which flank a fok1 nuclease domain to cut the DNA. d CRISPR/Cas9 system is made of a Cas9 protein with two nuclease domains: human umbilical vein endothelium cells (HuvC) split nuclease and the HNH, an endonuclease domain named for the characteristic histidine and asparagine residue, as well as a single guide RNA (sgRNA). (Adapted from [ 1 , 51 ]; Gaj et al., 2016 [ 53 ];)

Meganucleases (MegNs)

Meganucleases (MegNs) are naturally occurring endodeoxyribonucleases found within all forms of microbial life as well as in eukaryotic mitochondria and chloroplasts. The genes that encode MegNs are often embedded within self-splicing elements. The combination of molecular functions is mutually advantageous: the endonuclease activity allows surrounding introns and inteins to act as invasive DNA elements, while the splicing activity allows the endonuclease gene to invade a coding sequence without disrupting its product. The high specificity of these enzymes is based on their ability to cleave dsDNA at specific recognition sites comprising 14–40 bp (Fig. 2 a). Unlike restriction enzymes, which provide defenses to bacteria against invading DNA, MegNs facilitate lateral mobility of genetic elements within an organism. This process is referred to as “homing” and gives the name homing endonucleases to these enzymes. The high DNA specificity of MegNs makes them a powerful protein scaffold to engineer enzymes for genome manipulation. A deep understanding of their molecular recognition of DNA is an important prerequisite to generate engineered enzymes able to cleave DNA in specific desired genome sites. Crystallographic analyses of representatives from all known MegNs families have illustrated both their mechanisms of action and their evolutionary relationships to a wide range of host proteins. The functional capabilities of these enzymes in DNA recognition vary widely across the families of MegNs. In each case, these capabilities, however, make a balance between what is called orthogonal requirements of (i) recognizing a target of adequate length to avoid overt toxicity in the host, while (ii) accommodating at least a small amount of sequence drift within that target. Indirect readout in protein-DNA recognition is the mechanism by which the protein achieves partial sequence specificity by detecting structural features on the DNA.

Several homing endonucleases have been used as templates to engineer tools that cleave DNA sequences other than their original wild-type targets.

Meganucleases can be divided into five families based on sequence and structure motifs: LAGLIDADG, GIY-YIG, HNH, His-Cys box, and PD-(D/E) XK [ 74 ]. I-CreI is a homodimeric member of MegNs family, which recognizes and cleaves a 22-bp pseudo-palindromic target (5′-CAAAACGTCGTGAGACAGTTTG-3′). The important role of indirect readout in the central region of the target DNA of these enzymes I-CreI suggested that indirect readout may play a key role in the redesign of protein-DNA interactions. The sequences of the I-CreI central substrate region, four bp (± 1 and ± 2) called 2NN, along with the adjacent box called 5NNN, are key for substrate cleavage [ 64 ]. Changes in 2NN significantly affect substrate binding and cleavage because this region affects the active site rearrangement, the proper protein-DNA complex binding, and the catalytic ion positioning to lead the cleavage.

An exhaustive review of each MegN can be found in Stoddard [ 75 ] as well as in Petersen and Niemann [ 63 ]. Several MegNs have been used as templates to engineer tools that cleave DNA sequences other than their original wild-type targets. This technology have advantages of high specificity of MegNs to target DNA because of their very long recognition sites, ease in delivery due to relatively small size, and giving rise to more recombinant DNA (i.e., more recombinogenic for HDR) due to production of a 3′ overhang after DNA cleavage. This lowers the potential cytotoxicity [ 53 , 78 ].

Meganucleases have several promising applications; they are more specific than other genetic editing tools for the development of therapies for a wide range of inherited diseases resulting from nonsense codons or frameshift mutations. However, an obvious drawback to the use of natural MegNs lies in the need to first introduce a known cleavage site into the region of interest. Additionally, it is not easy to separate the two domains of MegNs: the DNA-binding and the DNA-cleavage domains, which present a challenge in its engineering. Another drawback of MegNs is that the design of sequence-specific enzymes for all possible sequences is time-consuming and expensive. Therefore, each new genome engineering target requires an initial protein engineering step to produce a custom MegN. Thus, in spite of the so many available MegNs, the probability of finding an enzyme that targets a desired locus is very small and the production of customized MegNs remains really complex and highly inefficient. Therefore, routine applications of MegNs in genome editing is limited and proved technically challenging to work with [ 24 ].

Zinc finger nucleases (ZFNs)

The origin of genome editing technology began with the introduction of zinc finger nucleases (ZFNs). Zinc finger nucleases are artificially engineered restriction enzymes for custom site-specific genome editing. Zinc fingers themselves are transcription factors, where each finger recognizes 3–4 bases. Zinc finger nucleases are hybrid heterodimeric proteins, where each subunit contains several zinc finger domains and a Fok1 endonuclease domain to induce DSB formation. The first is zinc finger, which is one of the DNA binding motifs found in the DNA binding domain of many eukaryotic transcription factors responsible for DNA identification. The second domain is a nuclease (often from the bacterial restriction enzyme FokI) [ 6 ]. When the DNA-binding and the DNA-cleaving domains are fused together, a highly specific pair of “genomic scissors” is created (Fig. 2b ). In principle, any gene in any organism can be targeted with a properly designed pair of ZFNs. Zinc finger recognition depends only on a match to DNA sequence, and mechanisms of DNA repair, both HR and NHEJ, are shared by essentially all species. Several studies have reported that ZFNs with a higher number of zinc fingers (4, 5, and 6 finger pairs) have increased the specificity and efficiency and improved targeting such as using modular assembly of pre-characterized ZFs utilizing standard recombinant DNA technology.

Since they were first reported [ 41 ], ZFN was appealing and showed considerable promise and they were used in several living organisms or cultured cells [ 11 ]. The discovery of ZFNs overcame some of the problems associated with MegNs applications. They facilitated targeted editing of the gene by inducing DSBs in DNA at specific sites. One major advantage of ZFNs is that they are easy to design, using combinatorial assembly of preexisting zinc fingers with known recognition patterns. This approach, however, suffered from drawbacks for routine applications. One of the major disadvantages of the ZFN is what is called “context-dependent specificity” (how well they cleave target sequence). Therefore, these specificities can depend on the context in the adjacent zinc fingers and DNA. In other terms, their specificity does not only depend on the target sequence itself, but also on adjacent sequences in the genome. This issue may cause genome fragmentation and instability when many non-specific cleavages occur. It only targets a single site at a time and as stated above. Although the low number of loci does not usually make a problem for knocking-out editing, it poses limitation for knocking in manipulation [ 32 ]. In addition, ZFNs cause overt toxicity to cells because of the off-target cleavages. The off-target effect is the probability of inaccurate cut of target DNA due to single nucleotide substitutions or inappropriate interaction between domains.

Transcription activator-like effector nucleases (TALENs)

The limitations mentioned in the previous section paved the way for the development of a new series of nucleases: transcription activator-like effector nucleases (TALENs), which were cheaper, safer, more efficient, and capable of targeting a specified region in the genome [ 13 ].

In principle, the TALENs are similar to ZFNs and MegNs in that the proteins must be re-engineered for each targeted DNA sequence. The ZFNs and TALENs are both modular and have natural DNA-binding specificities. The TALEN is similar to ZFN in that it is an artificial chimeric protein that result from fusing a non-specific FokI restriction endonuclease domain to a DNA-binding domain recognizing an arbitrary base sequence (Fig. 2c ). This DNA-binding domain consists of highly conserved repeats derived from transcription activator-like effectors (TALE). When genome editing is planned, a pair of TALEN is used like ZFNs. The TALE protein made of three domains: an amino-terminal domain having a transport signal, a DNA-binding domain which is made of repeating sequences of 34 amino acids arranged in tandem, and a carboxyl-terminal domain having a nuclear localization signal and a transcription activation domain. Of the 34 amino acids, there is a variable region of two amino acid residues located at positions 12 and 13 called repeat variable di-residues (RVD). This region has the ability to confer specificity to one of the any four nucleotide bps [ 15 ].

Unlike ZFNs, TALENs had advantages in that one module recognizes just one nucleotide in its DNA-binding domain, as compared with 3 bps recognized by the first single zinc finger domains [ 39 ]. So, interference of the recognition sequence does not occur even when several modules are joined. In theory, because cleavage of the target sequence is more specific than ZFN, it became possible to target any DNA sequence of any organism genome. This difference facilitates creation of TALEN systems which recognize more target sequences. Another benefit of the TALEN system over ZFN’s for genome editing is that the system is more efficient in producing DSBs in both somatic cells and pluripotent stem cells [ 35 ]. In addition, TALENs exhibit less toxicity in human cell lines due to off-target breaks that result in unwanted changes and toxicity in the genome. Another advantage of TALENs is a higher percentage of success in genome editing through cytoplasmic injection of TALEN mRNA in livestock embryos than observed with ZFN induction [ 39 ]. In addition, TALENs have been more successfully used in plant genome engineering [ 88 ]. It is hoped that TALENs will be applied in the generation of genetically modified laboratory animals, which may be utilized as a model for human disease research [ 24 , 39 ].

The TALEN-like directed development of DNA binding proteins was employed to improve TALEN specificity by phage-assisted continuous evolution (PACE). The improved version was used to create genetically modified organisms [ 34 ]. Nucleases which contain designable DNA-binding sequences can modify the genomes and have the promise for therapeutic applications. DNA-binding PACE is a general strategy for the laboratory evolution of DNA-binding activity and specificity. This system can be used to generate TALEN with highly improved DNA cutting specificity, establishing DB-PACE as a diverse approach for improving the accuracy of genome editing tools. Thus, similar to ZFN, TALEN is used for DSBs as well as for knocking in/knocking out. In comparison with the ZFN, two important advantages for this editing technique have been reported: first, the simple design, and second, the low number of off-target breaks [ 35 ].

In spite of the improvement and simplification of the TALEN method, it is complicated for whom not familiar with molecular biological experiments. Moreover, it is confronted with some limitations, such as their large size (impeding delivery) in comparison to ZFN [ 24 , 39 ]. The superiority of TALEN relative to ZFN could be attributed to the fact that in the TALEN each domain recognizes only one nucleotide, instead of recognizing DNA triplets in the case of ZEF. The design of TALEN is commonly more obvious than ZNF. This results in less intricate interactions between the TALEN-derived DNA-binding domains and their target nucleotides than those among ZNF and their target trinucleotides [ 35 , 39 ].

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)

The CRISPR/Cas system is the most recent platform in the field of genome editing. The system was developed in 2013 and is known as the third generation genomic editing tools. The clustered regularly interspaced short palindromic repeats, which are sometimes named “short regularly spaced repeats” were discovered in the 1980s. Computational analysis of these elements showed they were found in more than 40% of sequenced bacteria and 90% of archaea [ 37 , 56 ]. The acronym CRISPR was suggested, and a group of genes adjacent to the CRISPR locus, which was termed “CRISPR-associated system”, or Cas was established [ 37 ]. Cas proteins coded by these genes carry functional domains similar to endonucleases, helicases, polymerases, and nucleotide-binding proteins. In addition, the role of CRISPRs as bacterial and archaeal adaptive immunity system against invading bacteriophages and other and in DNA repair was realized [ 17 , 77 ].

Unlike the two previous technologies (ZFN and TALEN), in which the recognition of the DNA site was based on the sequence recognition by artificial proteins requiring interaction between protein and DNA, the DNA recognition of the CRISPR/Cas system is based on RNA-DNA interactions. This offers several advantages over ZFNs and TALENs. These include easy design for any genomic targets, easy prediction regarding off-target sites, and the probability of modifying several genomic sites simultaneously (multiplexing). CRISPR-Cas systems are diverse and have been classified thus far into two classes, six types, and over 20 subtypes based on locus arrangement and signature cas genes [ 33 , 44 , 51 ]. Types I, III, and IV, with multiprotein crRNA-effector complexes, are class 1 systems; types II, V, and VI, with a single protein-crRNA effector complex, are class 2. All CRISPR-Cas systems require Cas proteins and crRNAs for function, and CRISPR- cas expression is a prerequisite to acquire new spacers, process pre-crRNA, and assemble ribonucleoprotein crRNA interference complexes for target degradation. Herein, we will focus on the CRISPR-Cas9 technology, the reader should keep in mind other available variants of the system such as CRISPR-Cas6 [ 5 ], CRISPR-Cas12a, -Cas12b [ 42 ], as well as the most recently discovered c2c2 (Cas13a) and c2c6 (Cas13b [ 19 , 69 ]. The CRISPR/Cas9 system is made of Cas9 nuclease and single-guide RNA (sgRNA). The sgRNA is an engineered single RNA molecule containing crispr RNA and tracr RNA parts. The sgRNA recognizes the target sequence by standard Watson-Crick base pairing. It has to be followed by a DNA motif called a protospacer adjacent motif (PAM). The commonly used wild-type Streptococcus pyogenes Cas (SpCas9) protein has a specific PAM sequence, 5’-NGG-3’, where “N” can be any nucleotide base followed by two guanine (“G”) nucleobases. This sequence is located directly downstream of the target sequence in the genomic DNA, on the non-target strand. Targeting is constrained to every 14 bp (12 bp from the seed sequence and 2 bp from PAM) [ 15 ]. SpCas9 variants may increase the specificity of genome modifications at DNA targets adjacent to NGG PAM sequences when used in place of wild-type SpCas9.

DNA cleavage is performed by Cas9 nuclease and can result in DSB in the the case of a wild-type enzyme, or in a SSB when using mutant Cas9 variants called nickases (Fig. 2d ). It should be emphasized that the utilization of this approach in editing eukaryotes’ genome only needs the manipulation of a short sequence of RNA, and there is no need for complicated manipulations in the protein domain. This enables a faster and more cost-effective design of the DNA recognition moiety compared with ZFN and TALEN technologies. Applications of CRISPR-Cas9 systems are variable like those for ZFNs, TALENs, and MegNs. But, because of the relative simplicity of this system, its great efficiency and high tendency for multiple functions and library construction, it can be applied to different species and cell types [ 35 ].

As shown in Fig. 3 , in all CRISPR/Cas systems, immunity occurs in three distinct stages [ 77 , 81 ]: (1) adaptation or new spacer acquisition, (2) CRISPR transcription and processing (crRNA generation), and (3) interference or silencing. The advantages of the CRISPR/Cas system superseded those of both of the TALEN and ZFN tools, the ZFN in particular. This is due to its target design simplicity since the target specificity depends on ribonucleotide complex formation and non-protein/DNA recognition. In addition, the CRISPR/Cas approach is more efficient because changes can be introduced directly by injecting RNAs that encode the Cas protein and gRNA into developing embryos. Moreover, multigene mutations can be induced simultaneously by injecting them with multiple gRNAs. This is an example that explains the rapid spread of CRISPR/Cas 9 application in various fields. Still, the system has certain drawbacks. Although the CRISPR/Cas9 is much less complicated than TALEN, in terms of execution and construction, the off-target effect in CRISPR/Cas9 is higher than TALEN. Since the DSB results only after accurate binding of a pair of TALEN to the target sequence, the off-target effect problem is considered to be low. These two are different in restriction of target sequence. CRISPR/Cas9 is much more efficient than TALEN in multiple simultaneous modification. Table 1 compares the three main systems of site-directed synthetic nuclease employed in genome editing: ZFN, TALEN, and CRISPR/Cas9.

Schematic representation of CRISPR loci and targeting of DNA sequence, which include Cas genes, a leader sequence, and several spacer sequences derived from engineered or foreign DNA that are separated by short direct repeat sequences. The three major steps of CRISPR-Cas immune systems. In the adaptation phase, Cas proteins excise specific fragments from foreign DNA and integrate it into the repeat sequence neighboring the leader at the CRISPR locus. Then, CRISPR arrays are transcribed and processed into multiple crRNAs, each carrying a single spacer sequence and part of the adjoining repeat sequence. Finally, at the interference phase, the crRNAs are assembled into different classes of protein targeting complexes (cascades) that anneal to, and cleave, spacer matching sequences on either invading element or their transcripts and thus destroy them. (Adapted from [ 3 , 53 , 78 ])

The off-target effect is an essential subject for future studies if CRISPR/Cas9 is to achieve its promises as a powerful method for genome editing. Non-specific and unintended genetic modifications (off-target effect) can result from the use of CRISPR/Cas9 system which is one of the drawbacks of this tool. Therefore, this point should be considered for use in researches. One strategy to reduce the off-target activity is to replace the Streptococcus pyogenes Cas9 enzyme (SpyCas9) for a mutant Cas9 nickase (nSpyCas9; ncas9), which cleaves a single strand through the inactivation of a nuclease domain Ruvc or HNH [ 9 ]. Our understanding of off-target effects remains fragmentary. A deeper understanding of this phenomenon is needed. Several approaches that could be followed to characterize the binding domains and consequently Cas9 targeting specificity have been reviewed and summarized [ 83 ].

It has previously been stated that CRISPR/Cas9 system needs both gRNA and PAM to detect its target sequence of interest by integration of a gRNA component that binds to complementary double-stranded DNA sequences. Cell culture studies have shown that off-target effects may be due to the incorrect detection of genomic sequences by sgRNA. This, in turn, affects cleavage when the mismatch is in the vicinity of the PAM (up to 8 bases), but if the PAM is too far apart, these effects will be small [ 4 ], even a slight mismatch between sgRNA and target sequences can lead to a failure. Dependence of this method on specific PAM sequences to act functionally limits the number of target loci, and it can reduce off-target breaks [ 86 ]. For this goal, another type of specific PAM-containing nucleases has been prepared to compensate for this limitation. Genetic engineering and enzyme changing have also been able to overcome the limitation [ 42 ]. For a sgRNA, many similar sequences depending on the genome size of the species may exist [ 86 ]. Interestingly, the initial targeting scrutiny of the CRISPR/Cas9-sgRNA complex showed that not every nucleotide base in the gRNA is necessary to be complementary to the target DNA sequence to effect Cas9 nuclease activity. Regarding that where the similar sequences are found in the genome, their breaks could lead to malignancies or even death [ 86 ]. Various methods have been proposed to prevent off-target breaks, among which the double nicking method, the FokI-dCas9 fusion protein method, and the truncated sgRNA method [ 76 ] (Fig. 4 ).

a Summary of the Cas9 nickases methods in efficient genome editing. Two gRNAs target opposite strands of DNA. These double nicks create a DSB that is repaired using non-homologous end joining (NHEJ) or edits via homology-directed repair (HDR) (adapted from www.addgene.org/crispr/nick ). b FokI-dCas 9 fusion protein method. Two FokI-dCas9 fusion proteins are used to adjacent target sites by two different sgRNAs to facilitate FokI dimerization and DNA cleavage. These fusions would have enhanced specificity compared to the standard monomeric Cas9 nucleases and the paired nickase system because they should require two sgRNAs for activity. c Truncated sgRNA method. Cas9 interacting with either a full-length sgRNA (20 nucleotide sequence complementary to target site) or truncated gRNA (less than 15 nucleotide sequence complementary to target site). (Retrieved from blog.addgene.org )

To overcome these problems, researchers explored another generation of base editing technologies, which combine CRISPR and cytidine deaminase (Fig. 5 ). This is a diverse method called CRISPR-SKIP (Fig. 6 ) which uses cytidine deaminase single-base editors to program exon skipping by mutating target DNA bases within splice acceptor sites [ 25 ]. Given its simplicity and precision, CRISPR-SKIP will be widely applicable in gene therapy. Base editing utilizes Cas9 D10A nickases fused to engineered base deaminase enzymes to make single base changes in the DNA sequence without the need of DNA DSB. Also, base editing does not require an external repair template. The Cas9 nickase part of the base editor protein plays a dual function. The first is to target the deaminase activity to the wanted region and the second is to localize the enzyme to certain regions of double-stranded RNA. The deaminase domains in base editors (BEs) occur in two versions: either adenosine deaminase or cytosine deaminase, which catalyze only base transitions (C to T and A to G) and cannot produce base transversions [ 26 , 68 ]. In these base editing tools, the targeted activity of adenosine deaminase can result in an A:T to G:C sequence alteration in a very similar way [ 26 , 68 ].This approach avoided the requirement of breaking DNA to induce an oligonucleotide. In addition, compared to knocking system, it exerted a higher output with lower off-targets [ 40 , 43 ]. Adenosine is deaminated to inosine (I) that is subsequently utilized to repair the nicked strand with a cytosine, and the I:C base pair is resolved to G:C [ 26 ]. More recently, new genome editing technologies have been developed: glycosylase base editors (GBEs), which consist of a Cas9 nickase, a cytidine deaminase, and a uracil-DNA glycosylase (Ung), are capable of transversion mutations by changing C to A in bacterial cells and from C to G in mammalian cells [ 45 , 89 ]. The new BEs can also be designed to minimize unwanted (“off-target”) mutations that could potentially cause undesirable side effects. The novel BE platform may help researchers understand and correct genetic diseases by selective editing of single DNA “alphabets” across nucleobase classes. However, the technique with this new class of transversion BEs is still at an early stage and requires additional optimization, so it would be premature to say this is ready for the clinic applications.

Base editing uses engineered Cas9 variants to induce base changes in a target sequence. Cas9 nickase is fused to a base deaminase domain. The deaminase domain works on a targeted region within the R-loop after target binding and R-loop formation. Simultaneously, the target strand is nicked. DNA repair is started in response to the nick using the strand which contains the deaminated base as a repair template. Repair leads to a transition mutations: C:G to T:A and A:T to G:C for cytosine and adenosine base editors, respectively [ 68 ]

Essential steps in CRISPR-SKIP targeting approach: a Nearly every intron ends with a guanosine (asterisked G). It is hypothesized that mutations that disrupt this highly conserved G within the splice acceptor of any given exon in genomic DNA would lead to exon skipping by preventing incorporation of the exon into mature transcripts base. b In the presence of an appropriate PAM sequence, this G can be effectively mutated by converting the complementary cytidine to thymidine using CRISPR-Cas9 C>T single-base editors. (From [ 25 ])

Gene delivery

From biotechnology’s point of view, the main obstacle that is facing molecular technology is to select the right method that is simple but effective to transfer the gene to the host cell. The components of gene editing have to be transferred to the cell/nucleus of interest using in vivo, ex vivo, or in vitro route. In this regard, several concerns must be considered including physical barriers (cell membranes, nuclear membranes) as well as digestion by proteases or nucleases of the host. Another important issue is the possible rejection by the immune system of the host if the components are delivered in vivo. In general, the gene delivery routes can be categorized in three classes of physical delivery, viral vectors, and non-viral agents. Although the direct delivery of construct plasmids may sound easy and more efficient and specific than the physical and the chemical methods, it proves to be an inappropriate choice because the successful gene delivery system requires the foreign genetic molecule to remain stable within the host cells [ 52 ]. The other possible procedure is to use viruses. However, because plant cells have thick walls, the gene transfer systems for plants involve transient and stable transformation using protoplast-plasmid in vitro [ 54 ]: agrobacterium-mediated transformation, gene gun and viral vectors (transient expression by protoplast transformation), and agro-infiltration [ 1 ]. Viruses may present a suitable vehicle to transfer genome engineering components to all plant parts because they do not require transformation and/or tissue culture for delivering and mutated seeds could easily recovered. For many years, scientists employed different species of Agrobacterium to systematically infect a large number of plant species and generate transgenic plants. These bacterial species have small genome size and this facilitates cloning and agroinfections, and the virus genome does not integrate into plant genomes [ 1 ].

Of the challenges and approaches of delivering CRISPR, it was pointed out [ 18 , 51 ] that although the present genome engineering is in favor of CRISPR tools, TALENs may still be of a primary choice in certain experimental species. For example, TALENs have been utilized in targeted genomic editing in Xenopus tropicalis by knocking-out Klf4 [ 49 , 50 ] or thyroid hormone receptor α [ 23 ]. In addition, TALENs have been utilized to modify genome of human stem cells [ 47 ]. Also TALEN approach has been applied to create amniotic mesenchymal stem cells overexpressing anti-fibrotic interleukin-10 [ 12 ]. Lately, a geminivirus genome has been prepared to deliver various nucleases platforms (including ZFN, TALENs, and the CRISPR/Cas system) and repair template for HR of DSBs [ 62 ].

To deliver the carrying DNA sequence to target cells, non-viral techniques such as electroporation, lipofection, and microinjection can also be used [ 18 ]. In addition, these techniques also reduce off-target cleavages problems. Gene transfer via microinjection is considered the gold standard procedure since its efficiency is approximately 100% [ 85 ]. The advantage of this approach is its high efficacy and less constrains on the size of the delivery. A disadvantage is that it can be employed only in in vitro or ex vivo cargo. Recently, small RNAs, including small interfering RNA (siRNA) and microRNA (miRNA), have been widely adopted in research to replace laboratory animals and cell lines. Development of innovative nanoparticle-based transfer systems that deliver CRISPR/Cas9 constructs and maximize their effectiveness has been tested in the last few years [ 29 , 58 ].

Applications of gene technology

The ability of the abovementioned gene delivery systems to target and manipulate the genome of living organisms has been attractive to many researchers worldwide. Despite all limitations, the interest in this technology has developed its capabilities and enhanced its scope of applications. Genome/gene engineering technology is relatively applicable and has potential to effectively and rapidly revolutionize genome surgery and will soon transform agriculture, nutrition, and medicine. Some of the most important applications are briefly described below.

Plant-based genome editing

The appearance of genome editing has been appealing especially to agricultural experts. One of the major goals for utilizing genome editing tools in plants is to generate improved crop varieties with higher yields and clear-cut addition of valuable traits such as high nutritional value, extended shelf life, stress tolerance, disease and pest resistance, or removal of undesirable traits [ 1 ]. However, several obstacles related to the precision of the genetic manipulations and the incompatibility of the host species have hampered the development of crop improvements [ 2 ]. The use of site-specific nucleases is one of the important promising techniques of gene editing that helped overcome certain limitations by specifically targeting a suitable site in a gene/genome. The employment of the gene editing technologies, including those discussed in this review, seems to be endless ever since their emergence, and several improvements in original tools have further brought accuracy and precision in these methods [ 78 ].

Animal-based genome editing

Recent genome editing techniques has been extensively applied in many organisms, such as bacteria, yeast, and mouse [ 53 , 73 ]. Genetic manipulation tools cover a wide range of fields, including the generation of transgenic animals using embryonic stem cells (ESC), functional analysis of genes, model development for diseases, or drug development. Genome editing techniques have been used in many various organisms. Among the livestock and aquatic species, ZFN is only used for zebrafish, but two other technologies, TALEN and CRISPR, have been used at the cell level in chicken, sheep, pig, and cattle. Engineered endonucleases or RNA-guided endonucleases (RGENs) mediated gene targeting has been applied directly in a great number of animal organisms including nematodes and zebrafish [ 20 , 57 ], as well as pigs [ 71 , 85 ]. Since the first permission to use CRISPR/Cas9 in human embryos and in vivo genome editing via homology-independent targeted integration (HITI), an increasing number of studies have identified striking differences between mouse and human pre-implantation development and pluripotency [ 66 ], highlighting the need for focused studies in human embryos. Therefore, more specific criteria and widely accepted standards for clinical research have to be met before human germline editing would be deemed permissible [ 31 ]. In this regard, results of some research on the human genome editing have been questioned. The “He Jiankui experiments at the beginning of 2019”, which claimed to have created the world’s first genetically edited babies, is simply the most recent example. He Jiankui said he edited the babies’ genes at conception by selecting CRISPR/cas9 to edit the chemokine receptor type 5 (CCR5) gene in cd4+ cells in hopes of making children resistant to the AIDS virus, as their father was HIV-positive. Researchers said He’s actions exposed the twins to unknown health risks, possibly including a higher susceptibility to viral illnesses. For more information on the scientific reactions around the world, the reader may find helpful several excellent sources of information [ 38 , 49 , 79 , 84 ].

• Gene therapy

The original principles of gene therapy arose during the 1960s and early 1970s when restriction enzymes were utilized to manipulate DNA [ 22 ]. Since then, researchers have done great efforts to treat genetic diseases but treatment for multiple mutations is difficult. Different clinical therapy applications have been attempted to overcome these problems. Much of the interest in CRISPR and other gene editing methods revolves around their potential to cure human diseases. It is hoped that eradication of human diseases is not too far to achieve via the CRISPR system because it was employed in other fields of biological sciences such as genetic improvement and gene therapy. It is important to mention that the therapeutic efficiency of gene editing depends on several factors, such as editing efficacy, which varies widely depending on the cell type, senescence status, and cell cycle status of the target [ 69 ]. Other factors that also influence therapeutic effectiveness include cell aptitude, which refers to the feasibility of accomplishing a therapeutic modification threshold, and the efficient transfer of programmable nuclease system to the target tissue, which is only considered to be effective if the engineered nuclease system reaches safely and efficiently to the nucleus of the target cell. Finally, the precision of the editing procedure is another important aspect, which refers to only editing the target DNA without affecting any other genes [ 80 ].

The genome editing tools have enabled scientists to utilize genetically programmed animals to understand the cause of various diseases and to understand molecular mechanisms that can be explored for better therapeutic strategies (Fig. 7 ). Genome editing gives the basis of the treatment of many kinds of diseases. In preliminary experiments, the knocking-in procedure was used to reach this goal. There are examples of gene editing techniques applied in different genetic diseases in cell lines, disease models, and human [ 48 , 53 , 82 ]. These encouraging results suggest the therapeutic capability of these gene editing strategies to treat human genetic diseases including Duchenne muscular dystrophy [ 8 , 28 , 55 ], cystic fibrosis [ 21 ], sickle cell anemia [ 62 ], and Down syndrome [ 7 ]. In addition, this technology has been employed in curing Fanconi anemia by correcting point mutation in patient-derived fibroblasts [ 60 ], as well as in hemophilia for the restoration of factor VIII deficiency in mice [ 61 , 87 ]. The CRISPR tools have also demonstrated promising results in diagnosis and curing fatal diseases such as AIDS and cancer [ 16 , 30 , 84 ].

Outline of the ex vivo and in vivo genome editing procedures for clinical therapy. Top: In the ex vivo editing therapy, cells are removed from a patient to be treated, corrected by gene editing and then re-engrafted back to the patient. To achieve therapeutic success, the target cells must be capable of surviving in vitro and autologous transplantation of the corrected cells. Below: In the in vivo editing therapy, designed nucleases are administered using viral or non-viral techniques and directly injected locally to the affected tissue, such as the eye, brain, or muscle. (Adapted from [ 48 ])

Other applications

The applications mentioned above were more about knock out or modification of genes Gapinske et al. [ 25 ]. However due to inactivate nuclease activity nature of the dCas9, CRISPR can be used in other applications as well. By selecting the target sequence, gene expression can be controlled by inhibiting the transcription rate of RNA polymerase II (polII) or inhibiting the transcription factor binding [ 65 ]. Additionally, combining gene expression inhibitors such as Krüppel-associated box with the inactivated Cas9 has led to generate a special kind of gene inhibitors, which are called CRISPR interference (CRISPRi), and downregulate gene expression [ 46 ]. It is also possible to control gene expression by fusing transcription-activating molecule, the transcription-repressing molecule, or the genome-modifying molecule to dCas9 [ 27 ].

Genome editing is a fast-growing field. Editing nucleases have revolutionized genomic engineering, allowing easy editing of the mammalian genome. Much progress has been accomplished in the improvement of gene editing technologies since their discovery. Of the four major nucleases used to cut and edit the genome, each has its own advantages and disadvantages, and the choice of which gene editing method depends on the specific situation. The current genome editing techniques are still buckling up with problems, and it is difficult to perform genome editing in cells with low transfection efficiency or in some cultured cells such as primary cultured cells. Genotoxicity is an inherent problem of enzymes that act on nucleic acids, though one can expect that highly specific endonucleases would reduce or abolish this issue. Exceptional efforts are needed in future to complement and offer something novel approaches in addition to the already existing ones. It is anticipated that research in gene editing is going to continue and tremendously advance. With the development of next-generation sequencing technology, new extremely important clinical applications, such as manufacturing engineered medical products, eradication of human genetic diseases, treatment of AIDS and cancers, as well as improvement of crop and food, will be introduced. Combination of genomic modifications induced by targeted nucleases to their own self-degradation, self-inactivating vectors may help overcoming confronting limitations discussed above to improve the specificity of genome editing, especially because the frequency of off-target modifications. Our understanding of off-target effects remains poor. This is a vital area for continued study if CRISPR/Cas9 is to realize its promise. Regarding gene cargo delivery systems, this remains the greatest obstacle for CRISPR/Cas9 use, and an all-purpose delivery method has yet to emerge. The union between genome engineering and regenerative medicine is still in its infancy; realizing the full potential of these technologies in reprograming the fate of stem/progenitor cells requires that their functional landscape be fully explored in these genetic backgrounds. Humankind can only wait to see what the potential of these technologies will be. One major question is whether or not the body’s immune response will accept or reject the foreign genetic elements within the cells. Another important concern is that along with the revolutionary advances of this biotechnology and related sciences, bioethical concerns and legal problems related to this issue are still increasing in view of the possibility of human genetic manipulation and the unsafety of procedures involved [ 49 , 50 , 66 ]. The enforcement of technical and ethical guidelines, and legislations should be considered and need serious attention as soon as possible.

Availability of data and materials

Not applicable

Abbreviations

CRISPR-associated protein 9

Clustered regularly interspaced short palindromic repeats

Double-stranded break

Embryonic stem cells

Homology-directed repair

Homology-independent targeted integration

Homologous recombination

Human umbilical vein endothelium cells

Intron-encoded endonuclease

• Meganucleases

Microhomology-mediated end joining

Non-homologous end joining

Phage-assisted continuous evolution

Protospacer adjacent motifs

RNA-guided endonucleases

Repeat variable di-residues

Single guide RNA

Streptococcus pyogenes Cas9

Single-strand break

Transcription activator-like effector nuclease

Zinc finger nucleases

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Article Contents

Introduction, human enhancement, genetic engineering, conclusions.

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Human enhancement: Genetic engineering and evolution

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

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

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

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

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

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

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

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

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

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

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

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

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

Genetic engineering: therapy or enhancement and predictability of outcomes

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

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

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

Genetic engineering and human evolution: large-scale impacts

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

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

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

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

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

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

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

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

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

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

Conflict of interest : None declared.

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Genetic Engineering

• First Online: 28 March 2021

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• David B. Resnik 13  

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

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

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

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

A polymer is a large molecule.

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

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

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

Mitochondria replicate independently of the cell.

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

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

Plant stem cells can also generate different tissue types.

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

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

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

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

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

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

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

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

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

E.g. Bt crops. See Footnote 12.

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

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

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

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

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

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

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

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

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

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

See Footnote 12.

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

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

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

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

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

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

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

See Footnote 29.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The moratorium would not apply to GGE for research purposes.

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

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

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• v.26(1); 2018 Jan

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

Heidi c. howard.

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

Carla G. van El

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

Francesca Forzano

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

Dragica Radojkovic

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

Emmanuelle Rial-Sebbag

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

Guido de Wert

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

Pascal Borry

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

Martina C. Cornel

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

Introduction

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

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

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

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

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

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

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

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

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

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

Conduct ongoing responsible scientific research to build a solid evidence base

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

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

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

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

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

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

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

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

Somatic gene editing

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

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

Germ line/heritable gene editing

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

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

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

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

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

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

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

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

Stakeholder engagement, education and dialogue (SEED)

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

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

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

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

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

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

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

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

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

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

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

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

• Conducting ELSI research.

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

Acknowledgements

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

Compliance with ethical standards

Conflict of interest.

The authors declare that they have no competing interests.

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

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

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

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

132 Genetic Engineering Essay Topic Ideas & Examples

Welcome to our list of genetic engineering essay topics! Here, you will find everything from trending research titles to the most interesting genetic engineering topics for presentation. Get inspired with our writing ideas and bonus samples!

🔝 Top 10 Genetic Engineering Topics for 2024

🏆 best genetic engineering topic ideas & essay examples, ⭐ good genetic engineering research topics, 👍 simple & easy genetic engineering essay topics, ❓ genetic engineering discussion questions, 🔎 genetic engineering research topics, ✅ genetic engineering project ideas.

• Ethical Issues of Synthetic Biology
• CRISPR-Cas9 and Its Applications
• Progress and Challenges in Gene Therapy
• Applications of Gene Editing in Animals
• The Process of Genetic Engineering in Plants
• Genetic Engineering for Human Enhancement
• Genetic Engineering for Improving Crop Yield
• Regulatory Issues of Genetic Editing of Embryos
• Gene Silencing in Humans through RNA Interference
• Gene Drive Technology for Controlling Invasive Species
• The Ethical Issues of Genetic Engineering Many people have questioned the health risks that arise from genetically modified crops, thus it is the politicians who have to ensure that the interests of the people are met and their safety is assured. […]
• The Film “Gattaca” and Genetic Engineering In the film, it is convincing that in the near future, science and technology at the back of genetic engineering shall be developed up to the level which makes the film a reality.
• Gattaca: Ethical Issues of Genetic Engineering Although the world he lives in has determined that the only measure of a man is his genetic profile, Vincent discovers another element of man that science and society have forgotten.
• A Major Milestone in the Field of Science and Technology: Should Genetic Engineering Be Allowed? The most controversial and complicated aspect of this expertise is Human Genetic Engineering- whereby the genotype of a fetus can be altered to produce desired results.
• The Dangers of Genetic Engineering and the Issue of Human Genes’ Modification In this case, the ethics of human cloning and human genes’ alteration are at the center of the most heated debates. The first reason to oppose the idea of manipulation of human genes lies in […]
• Religious vs Scientific Views on Genetic Engineering With the need to increase the global economy, the field of agriculture is one among the many that have been used to improve the commercial production to take care of the global needs for food […]
• Is Genetic Engineering an Environmentally Sound Way to Increase Food Production? According to Thomas & Earl and Barry, genetic engineering is environmentally unsound method of increasing food production because it threatens the indigenous species.
• Human Genetic Engineering: Key Principles and Issues There are many options for the development of events in the field of genetic engineering, and not all of them have been studied. To conclude, human genetic engineering is one of the major medical breakthroughs, […]
• Mitochondrial Diseases Treatment Through Genetic Engineering Any disorders and abnormalities in the development of mitochondrial genetic information can lead to the dysfunction of these organelles, which in turn affects the efficiency of intracellular ATP production during the process of cellular respiration.
• Genetic Engineering: Is It Ethical to Manipulate Life? In the case of more complex operations, genetic engineering can edit existing genes to turn on or off the synthesis of a particular protein in the organism from which the gene was taken.
• Biotechnology and Genetic Engineering Apart from that, there are some experiments that cannot be ethically justified, at least in my opinion, for example, the cloning of human being or the attempts to find the gene for genius.
• Genetic Engineering in the Movie “Gattaca” by Niccol This would not be right at all since a person should be responsible for their own life and not have it dictated to them as a result of a societal construct created on the basis […]
• Genetic Engineering Using a Pglo Plasmid The objective of this experiment is to understand the process and importance of the genetic transformation of bacteria in real time with the aid of extrachromosomal DNA, alternatively referred to as plasmids.
• Managing Diabetes Through Genetic Engineering Genetic engineering refers to the alteration of genetic make-up of an organism through the use of techniques to introduce a new DNA or eliminate a given hereditable material. What is the role of genetic engineering […]
• The Role of Plant Genetic Engineering in Global Security Although it can be conveniently stated that the adequacy, abundance and reliability of the global food supply has a major role to play in the enhancement of human life, in the long run, they influence […]
• Significance of Human Genetic Engineering The gene alteration strategy enables replacing the specific unwanted genes with the new ones, which are more resistant and freer of the particular ailment, hence an essential assurance of a healthy generation in the future.
• Is the World Ready for Genetic Engineering? The process of manipulating genes has brought scientists to important discoveries, among which is the technology of the production of new kinds of crops and plants with selected characteristics. The problem of the advantages and […]
• Genome: Bioethics and Genetic Engineering Additionally, towards the end of the documentary, the narrator and some of the interviewed individuals explain the problem of anonymity that is also related to genetic manipulations.
• Genetic Engineering Is Ethically Unacceptable However, the current application of genetic engineering is in the field of medicine particularly to treat various genetic conditions. However, this method of treatment has various consequences to the individual and the society in general.
• Designer Genes: Different Types and Use of Genetic Engineering McKibben speaks of Somatic Gene Therapy as it is used to modify the gene and cell structure of human beings so that the cells are able to produce certain chemicals that would help the body […]
• A Technique for Controlling Plant Characteristics: Genetic Engineering in the Agriculture A cautious investigation of genetic engineering is required to make sure it is safe for humans and the environment. The benefit credited to genetic manipulation is influenced through the utilization of herbicide-tolerant and pest-safe traits.
• Genetically Engineered Food Against World Hunger I support the production of GMFs in large quality; I hold the opinion that they can offer a lasting solution to food problems facing the world.
• Genetic Engineering in Food: Development and Risks Genetic engineering refers to the manipulation of the gene composition of organisms, to come up with organisms, which have different characteristics from the organic ones.
• Genetic Engineering in the Workplace The main purpose of the paper is to evaluate and critically discuss the ethical concerns regarding the implementation of genetic testing in the workplace and to provide potential resolutions to the dilemmas.
• Designer Babies Creation in Genetic Engineering The creation of designer babies is an outcome of advancements in technology hence the debate should be on the extent to which technology can be applied in changing the way human beings live and the […]
• Genetic Engineering and Eugenics Comparison The main idea in genetic engineering is to manipulate the genetic make-up of human beings in order to shackle their inferior traits. The concept of socially independent reproduction is replicated in both eugenics and genetic […]
• Changing the world: Genetic Engineering Effects Genes used in genetic engineering have a high impact on health and disease, therefore the inclusion of the genetic process alters the genes that influence human behavior and traits.
• Future of Genetic Engineering and the Concept of “Franken-Foods” This is not limited to cows alone but extends to pigs, sheep, and poultry, the justification for the development of genetically modified food is based on the need to feed an ever growing population which […]
• Ecological Effects of the Release of Genetically Engineered Organisms Beneficial soil organisms such as earthworms, mites, nematodes, woodlice among others are some of the soil living organisms that are adversely affected by introduction of genetically engineered organisms in the ecosystem since they introduce toxins […]
• Proposition 37 and Genetically Engineered Foods The discussion of Proposition 37 by the public is based on the obvious gap between the “law on the books” and the “law in action” because Food Safety Law which is associated with the Proposition […]
• Is Genetically Engineered Food the Solution to the World’s Hunger Problems? However, the acceptance of GMO’s as the solution to the world’s food problem is not unanimously and there is still a multitude of opposition and suspicion of their use.
• Benefits of Genetic Engineering as a Huge Part of People’s Lives Genetic Engineering is said to question whether man has the right to manipulate the course and laws of nature and thus is in constant collision with religion and the beliefs held by it regarding life.
• Perfect Society: The Effects of Human Genetic Engineering
• Genetic Engineering and Forensic Criminal Investigations
• Biotechnology Assignment and Genetic Engineering
• Genetic Engineering and Genetically Modified Organisms
• Bio-Ethics and the Controversy of Genetic Engineering
• Health and Environmental Risks of Genetic Engineering in Food
• Genetic Engineering and the Risks of Enforcing Changes on Organisms
• Genetic Engineering and How It Affects Globel Warming
• Cloning and Genetic Engineering in the Food Animal Industry
• Genetic Engineering and Its Impact on Society
• Embryonic Research, Genetic Engineering, & Cloning
• Genetic Engineering: Associated Risks and Possibilities
• Issues Concerning Genetic Engineering in Food Production
• Genetic Engineering, DNA Fingerprinting, Gene Therapy
• Cloning: The Benefits and Dangers of Genetic Engineering
• Genetic Engineering, History, and Future: Altering the Face of Science
• Islamic and Catholic Views on Genetic Engineering
• Gene Therapy and Genetic Engineering: Should It Be Approved in the US
• Exploring the Real Benefits of Genetic Engineering in the Modern World
• Genetic Engineering and Food Security: A Welfare Economics Perspective
• Identify the Potential Impact of Genetic Engineering on the Future Course of Human Immunodeficiency Virus
• Genetic Engineering and DNA Technology in Agricultural Productivity
• Human Genetic Engineering: Designing the Future
• Genetic Engineering and the Politics Behind It
• The Potential and Consequences of Genetic Engineering
• Genetic Engineering and Its Effect on Human Health
• The Moral and Ethical Controversies, Benefits, and Future of Genetic Engineering
• Gene Therapy and Genetic Engineering for Curing Disorders
• Genetic Engineering and the Human Genome Project
• Ethical Standards for Genetic Engineering
• Genetic Engineering and Cryonic Freezing: A Modern Frankenstein
• The Perfect Child: Genetic Engineering
• Genetic Engineering and Its Effects on Future Generations
• Agricultural Genetic Engineering: Genetically Modified Foods
• Genetic Engineering: The Manipulation or Alteration of the Genetic Structure of a Single Cell or Organism
• Analysing Genetic Engineering Regarding Plato Philosophy
• The Dangers and Benefits of Human Cloning and Genetic Engineering
• Genetic Engineering: Arguments of Both Proponents and Opponents and a Mediated Solution
• Genetic and How Genetic Engineering Is Diffusing Individualism
• Finding Genetic Harmony With Genetic Engineering
• What Is Genetic Engineering?
• Do You Think Genetically Modified Food Could Harm the Ecosystems of the Areas in Which They Grow?
• How Agricultural Research Systems Shape a Technological Regime That Develops Genetic Engineering?
• Can Genetic Engineering for the Poor Pay Off?
• How Does Genetic Engineering Affect Agriculture?
• Do You Think It’s Essential to Modify Genes to Create New Medicines?
• How Can Genetic Engineering Stop Human Suffering?
• Can Genetic Engineering Cure HIV/AIDS in Humans?
• How Has Genetic Engineering Revolutionized Science and the World?
• Do You Think Genetic Engineering Is Playing God and That We Should Leave Life as It Was Created?
• What Are Some Advantages and Disadvantages of Genetic Engineering?
• How Will Genetic Engineering Affect the Human Race?
• When Does Genetic Engineering Go Bad?
• What Are the Benefits of Human Genetic Engineering?
• Does Genetic Engineering Affect the Entire World?
• How Does the Christian Faith Contend With Genetic Engineering?
• What Are the Ethical and Social Implications of Genetic Engineering?
• How Will Genetic Engineering Impact Our Lives?
• Why Should Genetic Engineering Be Extended?
• Will Genetic Engineering Permanently Change Our Society?
• What Are People Worried About Who Oppose Genetic Engineering?
• Do You Worry About Eating GM (Genetically Modified) Food?
• What Do You Think of the Idea of Genetically Engineering New Bodily Organs to Replace Yours When You Are Old?
• Should Genetic Engineering Go Ahead to Eliminate Human Flaws, Such as Violence, Jealousy, Hate, Etc?
• Does the Government Have the Right to Limit How Far We Modify Ourselves?
• Why Is Genetic Food Not Well Accepted?
• What Is the Best in the Genetic Modification of Plants, Plant Cell, or Chloroplasts and Why?
• How Do You Feel About Human Gene Editing?
• Does Climate Change Make the Genetic Engineering of Crops Inevitable?
• What Do You Think About Plant Genetic Modification?
• Gene Drives and Pest Control
• The Benefits of Genetically Modified Organisms
• Challenges of Gene Editing for Rare Genetic Diseases
• The Use of Genetic Engineering to Treat Human Diseases
• Ethical Considerations and Possibilities of Designer Babies
• How Genetic Engineering Can Help Restore Ecosystems
• Basic Techniques and Tools for Gene Manipulation
• Latest Advancements in Genetic Engineering and Genome Editing
• Will Engineering Resilient Organisms Help Mitigate Climate Change?
• Creation of Renewable Resources through Genetic Engineering
• Genetic Engineering Approach to Drought and Pest Resistance
• Genetic Engineering Use in DNA Analysis and Identification
• Synthetic Microorganisms and Biofactories for Sustainable Bioproduction
• Stem Cells’ Potential for Regenerative Medicine
• The Role of Genetic Modification in Vaccine Development
• Can Genetic Engineering Help Eradicate Invasive Species Responsibly?
• Genetic Engineering for Enhancing the Body’s Defense Mechanisms
• Advancements in Transplantation Medicine and Creating Bioengineered Organs
• Genetic Editing of Microbes for Environmental Cleanup
• Is It Possible to Develop Living Detection Systems?
• Chicago (A-D)
• Chicago (N-B)

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• Published: 13 May 2024

Integrating population genetics, stem cell biology and cellular genomics to study complex human diseases

• Nona Farbehi   ORCID: orcid.org/0000-0001-8461-236X 1 , 2 , 3   na1 ,
• Drew R. Neavin   ORCID: orcid.org/0000-0002-1783-6491 1   na1 ,
• Anna S. E. Cuomo 1 , 4 ,
• Lorenz Studer   ORCID: orcid.org/0000-0003-0741-7987 3 , 5 ,
• Daniel G. MacArthur 4 , 6 &
• Joseph E. Powell   ORCID: orcid.org/0000-0002-5070-4124 1 , 3 , 7  

Nature Genetics volume  56 ,  pages 758–766 ( 2024 ) Cite this article

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• Population genetics
• Transcriptomics

Human pluripotent stem (hPS) cells can, in theory, be differentiated into any cell type, making them a powerful in vitro model for human biology. Recent technological advances have facilitated large-scale hPS cell studies that allow investigation of the genetic regulation of molecular phenotypes and their contribution to high-order phenotypes such as human disease. Integrating hPS cells with single-cell sequencing makes identifying context-dependent genetic effects during cell development or upon experimental manipulation possible. Here we discuss how the intersection of stem cell biology, population genetics and cellular genomics can help resolve the functional consequences of human genetic variation. We examine the critical challenges of integrating these fields and approaches to scaling them cost-effectively and practically. We highlight two areas of human biology that can particularly benefit from population-scale hPS cell studies, elucidating mechanisms underlying complex disease risk loci and evaluating relationships between common genetic variation and pharmacotherapeutic phenotypes.

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Acknowledgements

Figures were generated with BioRender.com and further developed by A. Garcia, a scientific illustrator from Bio-Graphics. This research was supported by a National Health and Medical Research Council (NHMRC) Investigator grant (J.E.P., 1175781), research grants from the Australian Research Council (ARC) Special Research Initiative in Stem Cell Science, an ARC Discovery Project (190100825), an EMBO Postdoctoral Fellowship (A.S.E.C.) and an Aligning Science Across Parkinson’s Grant (J.E.P., N.F., D.R.N. and L.S.). J.E.P. is supported by a Fok Family Fellowship.

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These authors contributed equally: Nona Farbehi, Drew R. Neavin.

Authors and Affiliations

Garvan Weizmann Center for Cellular Genomics, Garvan Institute of Medical Research, Sydney, New South Wales, Australia

Nona Farbehi, Drew R. Neavin, Anna S. E. Cuomo & Joseph E. Powell

Graduate School of Biomedical Engineering, University of New South Wales, Sydney, New South Wales, Australia

Nona Farbehi

Aligning Science Across Parkinson’s Collaborative Research Network, Chevy Chase, MD, USA

Nona Farbehi, Lorenz Studer & Joseph E. Powell

Centre for Population Genomics, Garvan Institute of Medical Research, University of New South Wales, Sydney, New South Wales, Australia

Anna S. E. Cuomo & Daniel G. MacArthur

The Center for Stem Cell Biology and Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, USA

Lorenz Studer

Centre for Population Genomics, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia

Daniel G. MacArthur

UNSW Cellular Genomics Futures Institute, University of New South Wales, Sydney, New South Wales, Australia

Joseph E. Powell

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All authors conceived the topic and wrote and revised the manuscript.

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Correspondence to Joseph E. Powell .

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D.G.M. is a founder with equity in Goldfinch Bio, is a paid advisor to GSK, Insitro, Third Rock Ventures and Foresite Labs, and has received research support from AbbVie, Astellas, Biogen, BioMarin, Eisai, Merck, Pfizer and Sanofi-Genzyme; none of these activities is related to the work presented here. J.E.P. is a founder with equity in Celltellus Laboratory and has received research support from Illumina. The other authors declare no conflict of interest.

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Farbehi, N., Neavin, D.R., Cuomo, A.S.E. et al. Integrating population genetics, stem cell biology and cellular genomics to study complex human diseases. Nat Genet 56 , 758–766 (2024). https://doi.org/10.1038/s41588-024-01731-9

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Received : 24 January 2023

Accepted : 20 March 2024

Published : 13 May 2024

Issue Date : May 2024

DOI : https://doi.org/10.1038/s41588-024-01731-9

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