genome editing essay

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Yale J Biol Med
• v.90(4); 2017 Dec

Focus: Genome Editing

Genome editing: past, present, and future
.

The CRISPR-Cas genome editing tools have been adopted rapidly in the research community, and they are quickly finding applications in the commercial sector as well. Lest we lose track of the broader context, this Perspective presents a brief review of the history of the genome editing platforms and considers a few current technological issues. It then takes a very limited view into the future of this technology and highlights some of the societal issues that require examination and discussion.

Introduction

This is a marvelous time for genetics, due largely to advances in genetic analysis and genetic manipulation. The impact of innovations in high-throughput DNA sequencing and in genome editing have been felt broadly, from work on model organisms, to evolutionary studies, to improvement of food organisms, to medical applications.


Classically, genetic studies relied on the discovery and analysis of spontaneous mutations. This dependence was true of Mendel, Morgan, Avery, et al . In the mid-twentieth century, Muller [ 1 ] and Auerbach [ 2 ] demonstrated that the rate of mutagenesis could be enhanced with radiation or chemical treatment. Later methods relied on transposon insertions that could be induced in some organisms; but these procedures, like radiation and chemical mutagenesis, produced changes at random sites in the genome. The first targeted genomic changes were produced in yeast and in mice in the 1970s and 1980s [ 3 - 6 ]. This gene targeting depended on the process of homologous recombination, which was remarkably precise but very inefficient, particularly in mouse cells. Recovery of the desired products required powerful selection [ 7 ] and thorough characterization. Because of the low frequency and the absence of culturable embryonic stem cells in mammals other than mice, gene targeting was not readily adaptable to other species.


The current genome editing technologies resolved this issue, making directed genetic manipulations possible in essentially all types of cells and organisms [ 8 , 9 ]. In addition, these methods confirmed Nobel laureate Sydney Brenner’s notion that, “Progress in science depends on new techniques, new discoveries and new ideas, probably in that order.” (http://www.azquotes.com/author/24376-Sydney_Brenner) In this short article, I want to review where the genome editing platforms came from and speculate about where we are headed through their use. I will leave description of the technologies themselves to other contributors.


Genome Editing Platforms

The secret to high-efficiency genome editing is the ability to make a targeted DNA double-strand break (DSB) in the chromosomal sequence of interest. Realization that such a break would stimulate gene targeting and local mutagenesis did not arise de novo , but came from research on DNA damage and repair. Recombination between homologous sequences is stimulated in meiosis by intentional DSBs [ 10 ], and DSBs generated by ionizing radiation lead to sister chromatid crossovers [ 11 ]. Model experiments with highly specific nucleases showed stimulation of homologous repair in yeast and mammalian cells and pointed the way for programmable genome editing [ 12 - 15 ]. Broken ends are also rejoined by a process called nonhomologous end joining (NHEJ) [ 16 ]. The ends are often joined precisely, restoring the original sequence; but occasionally errors are made, leading to local small insertions and deletions (indels). When these mutations occur in a gene, they will frequently inactivate it.


We are currently endowed with three powerful classes of nucleases that can be programmed to make DSBs at essentially any desired target: zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and CRISPR-Cas [ 8 ]. Although the latter platform now dominates in research laboratories around the world, the other two are still in use for research and in various agricultural and medical arenas. All of these platforms arose from investigations into natural biological processes and not from intentions to find genome editing reagents.


ZFNs are hybrids between a DNA cleavage domain from a bacterial protein and sets of zinc fingers that were originally identified in sequence-specific eukaryotic transcription factors. TALENs employ the same bacterial cleavage domain, but link it to DNA recognition modules from transcription factors produced by plant pathogenic bacteria. CRISPR-Cas is a prokaryotic system of acquired immunity to invading DNA or RNA.


Let us take a closer look at components of each of the platforms. ZFNs: The first eukaryotic sequence-specific transcription factor to be characterized was found to have zinc-binding repeats in its DNA-binding domain [ 17 ]. Related sequences from other transcription factors were shown to be peptide modules that made stereotyped contacts with base pair triplets [ 18 ]. Changing a few residues in a single zinc finger altered its DNA-recognition specificity, and fingers could be devised to recognize many different DNA triplets [ 19 ]. TALENs: Some plant pathogenic bacteria secrete into host cells proteins that bind to and regulate the activity of host genes to promote the infection. There is a simple and robust one-to-one code of recognition between modules in the protein and base pairs in the DNA target [ 20 , 21 ]. ZFNs and TALENs: Some bacterial restriction enzymes cut DNA a few base pairs away from their recognition sites. This is because they have physically separable binding and cleavage domains [ 22 ]. The cleavage domain has no inherent sequence specificity, and it can be linked to novel DNA-binding domains, which alters where it cuts [ 23 , 24 ]. One such domain was linked to zinc finger arrays and TALE arrays to generete ZFNs and TALENs.


CRISPR-Cas: This story begins with the discovery of a cluster of odd, short repeats in a bacterial genome [ 25 ]. Between those clustered regularly interspaced short palindromic repeats (CRISPR) are short sequences that were eventually shown to match viral genomes [ 26 - 28 ]. Some CRISPR-associated (Cas) proteins encoded adjacent to the repeat clusters mediate capture of these viral sequences, while others mediate cleavage and inactivation of invading viral genomes, guided by short RNAs (crRNAs) transcribed from the CRISPR arrays [ 29 , 30 ]. The final piece of the puzzle was the identification of the small trans-acting RNA (tracrRNA) that participates in both processing of the crRNAs and cleavage of the invading DNA in Streptococcus pyogenes [ 31 ]. Putting together the crRNA with tracrRNA and the one protein needed for cleavage in this system (Cas9) led to the editing reagent that is now most widely used [ 32 ].


In summary, powerful tools come from unexpected sources.


Genome Editing Issues

Remarkably, all that the genome editing nucleases do is to make a break in chromosomal DNA. The key, of course, is that the break is targeted and thus very specific. Everything that happens after the break, however, depends on cellular DNA repair machinery. The two broad pathways of DSB repair are homology-dependent repair (HDR) in which a donor sequence matching the target is copied, and NHEJ in which putting ends back together can lead to mutations at the break site [ 8 , 9 ]. Most somatic cells in higher eukaryotes generate mutations via NHEJ more frequently than they copy sequences from a user-supplied donor. This bias is acceptable if all you want to do is to knock out a protein coding sequence, but not so good if you want to introduce sequences of your own choice. Limited success has been achieved in modulating the ratio between homologous and non-homologous products [ 33 , 34 ], but no general solution is yet at hand, and the ratio in some cell types is very biased toward NHEJ. Several recent reports suggest that small-molecule inhibitors of key NHEJ activities may be effective [ 35 - 37 ], but more research is needed to produce simple and reliable reagents. Another way to influence the efficiency of homology-dependent events is through design of the donor DNA [ 38 ], linkage of the donor sequence to the guide RNA [ 39 ], and consideration of specific mechanisms to mediate sequence insertions [ 40 , 41 ].


All of the nuclease platforms can be very effective, but none of them has perfect specificity. Recent modifications of both Cas9 protein and guide RNA have enhanced their discrimination against secondary targets [ 42 ]. How much one cares about off-target cleavage and mutagenesis depends on the application. In many model organisms, there are ways to validate the effects of an introduced sequence change, including making independent mutations in the same gene, crossing into a clean background, and complementing with a wild type gene. In cases of organisms that can be rapidly expanded, like crop plants, founder genomes can be fully sequenced, and founder phenotypes can be analyzed thoroughly. Even in some medical applications, off-target mutations may be tolerable, as long as they do not lead to a novel clinical condition.


Looking Ahead


Research advances. It is safe to say that genome editing will continue to be a widely-used tool in research and in commercial and medical applications. One question that arises is whether CRISPR-Cas is the last word in programmable nucleases, or perhaps there is something even better on the horizon. With limited vision into the future, it is difficult to imagine a protein-based system that is fundamentally simpler than recognition by base pairing and cleavage by a single protein. Perhaps the protein could be smaller and be endowed with additional beneficial properties, but that constitutes variations on the same theme rather than something completely novel. Maybe a fully chemically-based reagent could be developed, based on small synthetic compounds that combine DNA recognition with DNA cleavage. Research toward this end has been going on for decades – from triplex-forming oligonucleotides [ 43 ], to peptide nucleic acids [ 44 ], to polyimines [ 45 ] – without producing a platform with adequate cleavage efficiency and recognition range. It seems likely that if novel methods emerge, they will come, like the current ones, from research into natural processes, not from an intent to improve on CRISPR.


A variation on the theme of DSB-induced genome editing is the introduction recently of CRISPR-mediated base editing [ 46 - 49 ]. This platform makes use of Cas9 nickase, that cuts only one strand of the target DNA, linked to a base-modifying activity. Conversion of C to U within a few base pairs of the RNA-guided binding site leads to specific coding changes in that very narrow area. Future uses of this approach include fusions to alternative activities and modeling and correction of human disease alleles.


Medical applications. A few somatic therapies that involve genome editing have been approved for Phase I clinical trials. The earliest trials used ZFNs to knock out the CCR5 co-receptor gene in T cells of HIV-positive patients [ 50 ], thereby making the T cells resistant to the virus. The results were encouraging, and an extension to earlier hematopoietic precursors is planned. TALENs have been used to enhance the efficacy of therapeutic CAR T cells [ 51 ], and at least two trials using CRISPR-Cas9 for this purpose have been approved [ 52 , 53 ]. These examples rely on editing of cells in the laboratory – in some cases cells derived from the person being treated – and transfer to the patient. Such ex vivo treatments allow facile delivery of the editing reagents and preliminary characterization of the edited cells. As stem cell therapies are developed, genome editing is a natural adjunct. Particularly when stem cells are derived in culture from somatic cells of an affected individual, correction of an offending mutation would fall to one of the editing platforms.


In many cases, cell-based therapy is not possible. Clinical trials for treatment of hemophilia and two lysosomal storage diseases, based on in vivo delivery of ZFNs with viral vectors, are under way (see clinicaltrials.gov, and search “Sangamo”). These rely on gene editing in the liver, a comparatively accessible organ. Delivery to other in vivo sites will require novel vector and non-vector approaches, and possibly the development of well-behaved stem cells for particular tissues. Very active research is directed toward treatments for other genetic diseases, including sickle cell disease and muscular dystrophy. In all cases, whether based on ex vivo or in vivo treatment, both safety and efficacy must be demonstrated.


Germline editing. Stimulated by recognition of the ease of CRISPR-based editing and the possibility of misuse of the technology, there is considerable current interest in prospects for human germline genome editing. Such applications would involve delivery of the editing reagents to embryos created by in vitro fertilization. In the future, it may be feasible to engineer gametogenic precursor cells in prospective parents instead. The advantage to germline correction of disease alleles is that they will forever be gone from the lineage of the treated individual. The risk at present is that the attempt to correct may do more harm than good. Current genome editing technology does not have sufficient efficiency and specificity to be reliably safe. Mutations generated at non-target sites in the genome will also affect the treated person and be transmitted through subsequent generations, and their effects will not always be benign or predictable, nor will they be readily reversible.


Continuing research will make germline editing safer and more effective, and it seems inevitable that it will eventually be used. In the meantime, broad discussion of the ethical issues raised by the prospect should be continued [ 54 ]. A thoughtful summary of the practical aspects of both somatic and germline therapies is provided by Kohn et al . [ 55 ].


Gene drives. An application of genome editing that has begun to attract attention is the use in a genetic process called gene drive. In brief, a genetic element can spread itself rapidly through a breeding population by copying itself into genomes that previously lacked it. Even if this element causes a moderately deleterious phenotype, it can expand in frequency. Natural gene drives have been identified, but current interest is focused on ones that are mediated by CRISPR-Cas9 [ 56 ]. Synthetic gene drives have been developed in mosquitoes that serve as vectors for tropical diseases, including a system that produces sterility in females [ 57 ] and one that inactivates genes required for parasite growth [ 58 ]. In principle, these approaches could dramatically reduce disease transmission in areas where disease treatment is challenging. The enormous burden of mosquito-borne diseases on human lives and health, particularly in the developing world, provides strong motivation for containing or eliminating the vectors.


The prospect of intentionally, or even unintentionally, releasing organisms carrying gene drives has evoked appropriate concern [ 59 , 60 ]. It is very difficult to predict the consequences for a broad ecosystem of depleting or removing one of its residents. If a particular mosquito population disappears, what will be the impact on organisms that rely on it, perhaps fish, birds, or plants? Other species will soon fill a vacant niche, but will they have the same influence on their surroundings? Will the drive itself become ineffective by mutation or by adaptation of the target organisms? Reversible gene drives are being developed [ 56 ], but their efficacy has not been tested. Unfortunately, small-scale laboratory tests will be poor predictors of effects in a natural environment, and we will not know the full impact of gene drives intended for benefit until they have actually been released.


Agriculture. Turning to agriculture, both livestock and crop plants are current targets for genome editing. The organisms produced are literally genetically modified, but they differ from earlier GMOs in important ways [ 61 ]. In most cases, no genetic material from another species is introduced, and when it is, it is inserted in a precise genomic location. The changes that are introduced are very often ones that could have occurred naturally, and whole genome sequencing can be done on edited organisms to look for off-target mutations. Because both seeds and semen can be dispersed rapidly into succeeding generations, validated genomes will quickly generate large populations of modified plants or animals.


Among current examples of edited crops are disease resistance in wheat [ 62 ], potatoes that don’t sweeten on storage [ 63 ], and soy plants that produce healthier oil [ 64 ]. The prospects for developing other healthier crops are bright. To address economic and animal welfare issues, dairy cows have been generated that lack horns, due to a genetic modification [ 65 ]. Cows [ 66 ], sheep [ 66 , 67 ], pigs [ 68 ], and other food animals that carry more muscle mass ( i.e. , meat) have also been produced by disruption of a single gene. Genome editing has the advantage over breeding selection that a trait can be introduced in a single generation without disrupting a favorable genetic background. The same beneficial modification can be introduced into different breeds or cultivars that are adapted to different environments, without leading to monoculture. A key question is whether the precise and largely natural genome modifications made by editing will find greater public acceptance than earlier GMOs. As the current resistance is based more on distaste for commercial greed and dominance than on evidence of adverse effects, there is a substantial hurdle to cross.


Beyond food modifications, large animal models of human disease are being produced to facilitate physiological analysis, drug testing and other therapies. It seems likely that genome editing will be applied to companion species, generating new breeds of dogs and cats and correcting genetic susceptibilities in current breeds. Additional work will be needed to uncover the genetic causes for desirable traits, but genetic research in dogs, at least, is making good headway.


Societal issues. Finally, I want to address societal issues that apply to medical and agricultural applications of genome editing. Who will decide what products or treatments are developed, and who will decide who gets them? I call these issues Attribution and Distribution.


In the medical realm, what therapies will be developed based on whom we decide needs to be “fixed”? Devastating diseases, like Huntington’s disease and muscular dystrophy, are obvious candidates. What about hereditary deafness or short stature? People with these conditions are often high-functioning, have strong communities, and do not feel themselves to be in need of “correction” [ 69 ]. To take an absurd example, is skin color a condition that needs altering? This brings us to purely cosmetic changes that some may find desirable – hair color, eye color, height, athletic ability (assuming we know how to engineer these traits genetically). Should these applications be pursued? 1


Once methods are developed, who will benefit? Human therapies based on genome editing are currently complex and expensive. Will only the wealthy be able to afford them? Could we distribute a genetic therapy for sickle cell disease to the large populations in Africa and Asia that are most affected?


These considerations apply to food organisms as well. Will nutritional improvements be made in specialty crops for the developed world, or in staples that predominate in the developing world? In both plants and animals, will we engineer resistance to diseases that are endemic in wealthy, temperate regions or to ones that limit production in developing regions? Ultimately, who will pay for development and distribution of improved crops and livestock – only the marketplace? Or will generous benefactors emerge?


Things are moving fast in genome editing. Many different applications are being pursued, and the only limit seems to be our imagination. In the midst of this excitement, we need to consider what are the best uses of the technology, what adjustments are needed to make the technology safe and effective, and how its advances will be provided to those who would benefit most. Currently, these decisions are driven by market forces, not humanitarian considerations. Are we comfortable with this, or do we need governmental participation at the national and international levels to change the situation? Count me as an advocate for the latter.


Acknowledgments

Many talented people have contributed to the development of genome editing – too many to be cited individually. I want to acknowledge that my understanding of the ethical and societal issues has been enhanced by interactions with Prof. Alta Charo and by presentations by Profs. Ruha Benjamin and Catherine Bliss at the International Summit on Human Gene Editing in Washington, DC, in December 2015. I thank Prof. Paul Sigala and an anonymous reviewer for their comments on earlier versions of the manuscript. Work in my own laboratory is supported by grant GM078571 from the US National Institutes of Health.

Abbreviations

Author contributions.

DC wrote the article.

1 Two very recent papers highlight the interest in human germline editing and the value of research on human embryos [ 70 , 71 ].

• Muller HJ. Artificial transmutation of the gene . Science . 1927; 66 :84–7. [ PubMed ] [ Google Scholar ]
• Auerbach C, Robson JM, Carr JG. Chemical production of mutations . Science . 1947; 105 :243–7. [ PubMed ] [ Google Scholar ]
• Rothstein RJ. One-step gene disruption in yeast . Methods Enzymol . 1983; 101 :202–11. [ PubMed ] [ Google Scholar ]
• Scherer S, Davis RW. Replacement of chromosome segments with altered DNA sequences constructed in vitro . Proc Natl Acad Sci USA . 1979; 76 :4951–5. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Smithies O, Gregg RG, Boggs SS, Koralewski MA, Kucherlapati RS. Insertion of DNA sequences into the human chromosomal beta-globin locus by homologous recombination . Nature . 1985; 317 ( 6034 ):230–4. [ PubMed ] [ Google Scholar ]
• Thomas KR, Folger KR, Capecchi MR. High frequency targeting of genes to specific sites in the mammalian genome . Cell . 1986; 44 :419–28. [ PubMed ] [ Google Scholar ]
• Mansour SL, Thomas KR, Capecchi MR. Disruption of the proto-oncogene int-2 in mouse embryo-derived stem cells: a general strategy for targeting mutations to non-selectable genes . Nature . 1988; 336 :348–52. [ PubMed ] [ Google Scholar ]
• Carroll D. Genome Engineering with Targetable Nucleases . Annu Rev Biochem . 2014; 83 :409–39. [ PubMed ] [ Google Scholar ]
• Gaj T, Gersbach CA, Barbas CF., 3rd ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering . Trends Biotechnol . 2013; 31 ( 7 ):397–405. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Youds JL, Boulton SJ. The choice in meiosis - defining the factors that influence crossover or non-crossover formation . J Cell Sci . 2011; 124 ( Pt 4 ):501–13. [ PubMed ] [ Google Scholar ]
• Latt SA. Sister chromatic exchange formation . Annu Rev Genet . 1981; 15 :11–55. [ PubMed ] [ Google Scholar ]
• Choulika A, Perrin A, Dujon B, Nicolas JF. Induction of homologous recombination in mammalian chromosomes by using the I-SceI system of Saccharomyces cerevisiae . Mol Cell Biol . 1995; 15 :1968–73. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Plessis A, Perrin A, Haber JE, Dujon B. Site-specific recombination determined by I-SceI, a mitochondrial group I intron-encoded endonuclease expressed in the yeast nucleus . Genetics . 1992; 130 :451–60. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rouet P, Smih F, Jasin M. Introduction of double-strand breaks into the genome of mouse cells by expression of a rare-cutting endonuclease . Mol Cell Biol . 1994; 14 :8096–106. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Rudin N, Sugarman E, Haber JE. Genetic and physical analysis of double-strand break repair and recombination in Saccharomyces cerevisiae . Genetics . 1989; 122 :519–34. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chapman JR, Taylor MR, Boulton SJ. Playing the end game: DNA double-strand break repair pathway choice . Mol Cell . 2012; 47 ( 4 ):497–510. [ PubMed ] [ Google Scholar ]
• Miller J, McLachlan AD, Klug A. Repetitive zinc-binding domains in the protein transcription factor IIIA from Xenopus oocytes . EMBO J . 1985; 4 :1609–14. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Pavletich NP, Pabo CO. Zinc finger-DNA recognition: crystal structure of a Zif268-DNA complex at 2.1 A resolution . Science . 1991; 252 :809–17. [ PubMed ] [ Google Scholar ]
• Pabo CO, Peisach E, Grant RA. Design and selection of novel Cys2His2 zinc finger proteins . Annu Rev Biochem . 2001; 70 :313–40. [ PubMed ] [ Google Scholar ]
• Boch J, Scholze H, Schornack S, Landgraf A, Hahn S, Kay S, et al. Breaking the code of DNA binding specificity of TAL-Type III effectors . Science . 2009; 326 :1509–12. [ PubMed ] [ Google Scholar ]
• Moscou MJ, Bogdanove AJ. A simple cipher governs DNA recognition by TAL effectors . Science . 2009; 326 :1501. [ PubMed ] [ Google Scholar ]
• Li L, Wu LP, Chandrasegaran S. Functional domains in FokI restriction endonuclease . Proc Natl Acad Sci USA . 1992; 89 :4275–9. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kim YG, Cha J, Chandrasegaran S. Hybrid restriction enzymes: zinc finger fusions to FokI cleavage domain . Proc Natl Acad Sci USA . 1996; 93 :1156–60. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kim YG, Chandrasegaran S. Chimeric restriction endonuclease . Proc Natl Acad Sci USA . 1994; 91 ( 3 ):883–7. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Ishino Y, Shinagawa H, Makino K, Amemura M, Nakata A. Nucleotide sequence of the iap gene, responsible for alkaline phosphatase isozyme conversion in Escherichia coli, and identification of the gene product . J Bacteriol . 1987; 169 ( 12 ):5429–33. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Bolotin A, Quinquis B, Sorokin A, Ehrlich SD. Clustered regularly interspaced short palindrome repeats (CRISPRs) have spacers of extrachromosomal origin . Microbiology . 2005; 151 ( Pt 8 ):2551–61. [ PubMed ] [ Google Scholar ]
• Mojica FJ, Diez-Villasenor C, Garcia-Martinez J, Soria E. Intervening sequences of regularly spaced prokaryotic repeats derive from foreign genetic elements . J Mol Evol . 2005; 60 ( 2 ):174–82. [ PubMed ] [ Google Scholar ]
• Pourcel C, Salvignol G, Vergnaud G. CRISPR elements in Yersinia pestis acquire new repeats by preferential uptake of bacteriophage DNA, and provide additional tools for evolutionary studies . Microbiology . 2005; 151 ( Pt 3 ):653–63. [ PubMed ] [ Google Scholar ]
• Barrangou R, Fremaux C, Deveau H, Richards M, Boyaval P, Moineau S, et al. CRISPR provides acquired resistance against viruses in prokaryotes . Science . 2007; 315 ( 5819 ):1709–12. [ PubMed ] [ Google Scholar ]
• Barrangou R, Marraffini LA. CRISPR-Cas systems: prokaryotes upgrade to adaptive immunity . Mol Cell . 2014; 54 ( 2 ):234–44. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Deltcheva E, Chylinski K, Sharma CM, Gonzales K, Chao Y, Pirzada ZA, et al. CRISPR RNA maturation by trans-encoded small RNA and host factor RNase III . Nature . 2011; 471 ( 7340 ):602–7. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity . Science . 2012; 337 :816–21. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Beumer KJ, Trautman JK, Bozas A, Liu JL, Rutter J, Gall JG, et al. Efficient gene targeting in Drosophila by direct embryo injection with zinc-finger nucleases . Proc Natl Acad Sci USA . 2008; 105 :19821–6. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Bozas A, Beumer KJ, Trautman JK, Carroll D. Genetic analysis of zinc-finger nuclease-induced gene targeting in Drosophila . Genetics . Forthcoming 2009 [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chu VT, Weber T, Wefers B, Wurst W, Sander S, Rajewsky K, et al. Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells . Nat Biotechnol . 2015; 33 ( 5 ):543–8. [ PubMed ] [ Google Scholar ]
• Maruyama T, Dougan SK, Truttmann MC, Bilate AM, Ingram JR, Ploegh HL. Increasing the efficiency of precise genome editing with CRISPR-Cas9 by inhibition of nonhomologous end joining . Nat Biotechnol . 2015; 33 ( 5 ):538–42. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Singh P, Schimenti JC, Bolcun-Filas E. A mouse geneticist’s practical guide to CRISPR applications . Genetics . 2015; 199 ( 1 ):1–15. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Richardson CD, Ray GJ, DeWitt MA, Curie GL, Corn JE. Enhancing homology-directed genome editing by catalytically active and inactive CRISPR-Cas9 using asymmetric donor DNA . Nat Biotechnol . 2016; 34 ( 3 ):339–44. [ PubMed ] [ Google Scholar ]
• Lee K, Mackley VA, Rao A, Chong AT, Dewitt MA, Corn JE, et al. Synthetically modified guide RNA and donor DNA are a versatile platform for CRISPR-Cas9 engineering . eLife . 2017:6. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Paix A, Folkmann A, Seydoux G. Precision genome editing using CRISPR-Cas9 and linear repair templates in C. elegans . Methods . 2017 [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Sakuma T, Nakade S, Sakane Y, Suzuki KT, Yamamoto T. MMEJ-assisted gene knock-in using TALENs and CRISPR-Cas9 with the PITCh systems . Nat Protoc . 2016; 11 ( 1 ):118–33. [ PubMed ] [ Google Scholar ]
• Tycko J, Myer VE, Hsu PD. Methods for Optimizing CRISPR-Cas9 Genome Editing Specificity . Mol Cell . 2016; 63 ( 3 ):355–70. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Chin JY, Glazer PM. Repair of DNA lesions associated with triplex-forming oligonucleotides . Mol Carcinog . 2009; 48 :389–99. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Kim KH, Nielsen PE, Glazer PM. Site-specific gene modification by PNAs conjugated to psoralen . Biochemistry . 2006; 45 :314–23. [ PubMed ] [ Google Scholar ]
• Doss RM, Marques MA, Foister S, Chenoweth DM, Dervan PB. Programmable oligomers for minor groove DNA recognition . J Am Chem Soc . 2006; 128 :9074–9. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Hess GT, Fresard L, Han K, Lee CH, Li A, Cimprich KA, et al. Directed evolution using dCas9-targeted somatic hypermutation in mammalian cells . Nat Methods . 2016; 13 ( 12 ):1036–42. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Komor AC, Kim YB, Packer MS, Zuris JA, Liu DR. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage . Nature . 2016; 533 ( 7603 ):420–4. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Ma Y, Zhang J, Yin W, Zhang Z, Song Y, Chang X. Targeted AID-mediated mutagenesis (TAM) enables efficient genomic diversification in mammalian cells . Nat Methods . 2016; 13 ( 12 ):1029–35. [ PubMed ] [ Google Scholar ]
• Nishida K, Arazoe T, Yachie N, Banno S, Kakimoto M, Tabata M, et al. Targeted nucleotide editing using hybrid prokaryotic and vertebrate adaptive immune systems . Science . 2016; 353 ( 6305 ):aaf8729. [ PubMed ] [ Google Scholar ]
• Tebas P, Stein D, Tang WW, Frank I, Wang SQ, Lee G, et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV . N Engl J Med . 2014; 370 ( 10 ):901–10. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Menger L, Sledzinska A, Bergerhoff K, Vargas FA, Smith J, Poirot L, et al. TALEN-Mediated Inactivation of PD-1 in Tumor-Reactive Lymphocytes Promotes Intratumoral T-cell Persistence and Rejection of Established Tumors . Cancer Res . 2016; 76 ( 8 ):2087–93. [ PubMed ] [ Google Scholar ]
• Cyranoski D. Chinese scientists to pioneer first human CRISPR trial . Nature . 2016; 535 :476–7. [ PubMed ] [ Google Scholar ]
• Kaiser J. First proposed human test of CRISPR passes initial safety review . Science . 2016 [ Google Scholar ]
• Committee on Human Gene Editing S, Medical, and Ethical Considerations. Human Genome Editing: Science, Ethics, and Governance . Washington (DC): The National Academies Press; 2017. [ PubMed ] [ Google Scholar ]
• Kohn DB, Porteus MH, Scharenberg AM. Ethical and regulatory aspects of genome editing . Blood . 2016; 127 ( 21 ):2553–60. [ PubMed ] [ Google Scholar ]
• Gantz VM, Bier E. The dawn of active genetics . BioEssays . 2016; 38 ( 1 ):50–63. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Hammond A, Galizi R, Kyrou K, Simoni A, Siniscalchi C, Katsanos D, et al. A CRISPR-Cas9 gene drive system targeting female reproduction in the malaria mosquito vector Anopheles gambiae . Nat Biotechnol . 2016; 34 ( 1 ):78–83. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Gantz VM, Jasinskiene N, Tatarenkova O, Fazekas A, Macias VM, Bier E, et al. Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi . Proc Natl Acad Sci USA . 2015; 112 ( 49 ):E6736–43. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Akbari OS, Bellen HJ, Bier E, Bullock SL, Burt A, Church GM, et al. BIOSAFETY. Safeguarding gene drive experiments in the laboratory . Science . 2015; 349 ( 6251 ):927–9. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Esvelt KM, Smidler AL, Catteruccia F, Church GM. Concerning RNA-guided gene drives for the alteration of wild populations . eLife . 2014:3. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Carroll D, Van Eenennaam AL, Taylor JF, Seger J, Voytas DF. Regulate genome-edited products, not genome editing itself . Nat Biotechnol . 2016; 34 ( 5 ):477–9. [ PubMed ] [ Google Scholar ]
• Zhang Y, Bai Y, Wu G, Zou S, Chen Y, Gao C, et al. Simultaneous modification of three homoeologs of TaEDR1 by genome editing enhances powdery mildew resistance in wheat . Plant J . 2017; 91 ( 4 ):714–24. [ PubMed ] [ Google Scholar ]
• Clasen BM, Stoddard TJ, Luo S, Demorest ZL, Li J, Cedrone F, et al. Improving cold storage and processing traits in potato through targeted gene knockout . Plant Biotechnol J . 2016; 14 ( 1 ):169–76. [ PubMed ] [ Google Scholar ]
• Demorest ZL, Coffman A, Baltes NJ, Stoddard TJ, Clasen BM, Luo S, et al. Direct stacking of sequence-specific nuclease-induced mutations to produce high oleic and low linolenic soybean oil . BMC Plant Biol . 2016; 16 ( 1 ):225. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Carlson DF, Lancto CA, Zang B, Kim ES, Walton M, Oldeschulte D, et al. Production of hornless dairy cattle from genome-edited cell lines . Nat Biotechnol . 2016; 34 ( 5 ):479–81. [ PubMed ] [ Google Scholar ]
• Proudfoot C, Carlson DF, Huddart R, Long CR, Pryor JH, King TJ, et al. Genome edited sheep and cattle . Transgenic Res . 2015; 24 ( 1 ):147–53. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Crispo M, Mulet AP, Tesson L, Barrera N, Cuadro F, dos Santos-Neto PC, et al. Efficient Generation of Myostatin Knock-Out Sheep Using CRISPR/Cas9 Technology and Microinjection into Zygotes . PLoS One . 2015; 10 ( 8 ):e0136690. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Wang K, Ouyang H, Xie Z, Yao C, Guo N, Li M, et al. Efficient Generation of Myostatin Mutations in Pigs Using the CRISPR/Cas9 System . Sci Rep . 2015; 5 :16623. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• Solomon A. Far from the Tree: Parents, Children and the Search for Identity . New York: Scribner; 2012. [ Google Scholar ]
• Ma H, Marti-Gutierrez N, Park SW, Wu J, Lee Y, Suzuki K, et al. Correction of a pathogenic gene mutation in human embryos . Nature . 2017; 548 :413–9. [ PubMed ] [ Google Scholar ]
• Fogarty NM, McCarthy A, Snijders KE, Powell BE, Kubikova N, Blakeley P, et al. Genome editing reveals a role for OCT4 in human embryogenesis . Nature . 2017; 550 :67–73. [ PMC free article ] [ PubMed ] [ Google Scholar ]

Featured Topics

Featured series.

A series of random questions answered by Harvard experts.

Explore the Gazette

Read the latest.

Science is making anti-aging progress. But do we want to live forever?

Epic science inside a cubic millimeter of brain

What is ‘original scholarship’ in the age of AI?

Perspectives on gene editing.

Illustration by Dan Mitchell

Mary Todd Bergman

Harvard Correspondent

Harvard researchers, others share their views on key issues in the field

Medicine is at a turning point, on the cusp of major change as disruptive technologies such as gene, RNA, and cell therapies enable scientists to approach diseases in new ways. The swiftness of this change is being driven by innovations such as CRISPR gene editing , which makes it possible to correct errors in DNA with relative ease.

Progress in this field has been so rapid that the dialogue around potential ethical, societal, and safety issues is scrambling to catch up.

This disconnect was brought into stark relief at the Second International Summit on Human Genome Editing , held in Hong Kong in November, when exciting updates about emerging therapies were eclipsed by a disturbing announcement. He Jiankui, a Chinese researcher, claimed that he had edited the genes of two human embryos, and that they had been brought to term.

There was immediate outcry from scientists across the world, and He was subjected to intense social pressure, including the removal of his affiliations, for having allegedly disregarded ethical norms and his patients’ safety.

Yet as I. Glenn Cohen, faculty director of the Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics at Harvard Law School, has said, gene editing comes in many varieties, with many consequences. Any deep ethical discussion needs to take into account those distinctions.

Human genome editing: somatic vs. germline

The germline editing He claimed to have carried out is quite different from the somatic gene therapies that are currently changing the frontiers of medicine. While somatic gene editing affects only the patient being treated (and only some of his or her cells), germline editing affects all cells in an organism, including eggs and sperm, and so is passed on to future generations. The possible consequences of that are difficult to predict.

Somatic gene therapies involve modifying a patient’s DNA to treat or cure a disease caused by a genetic mutation. In one clinical trial, for example, scientists take blood stem cells from a patient, use CRISPR techniques to correct the genetic mutation causing them to produce defective blood cells, then infuse the “corrected” cells back into the patient, where they produce healthy hemoglobin. The treatment changes the patient’s blood cells, but not his or her sperm or eggs.

Germline human genome editing, on the other hand, alters the genome of a human embryo at its earliest stages. This may affect every cell, which means it has an impact not only on the person who may result, but possibly on his or her descendants. There are, therefore, substantial restrictions on its use.

Germline editing in a dish can help researchers figure out what the health benefits could be, and how to reduce risks. Those include targeting the wrong gene; off-target impacts, in which editing a gene might fix one problem but cause another; and mosaicism, in which only some copies of the gene are altered. For these and other reasons, the scientific community approaches germline editing with caution, and the U.S. and many other countries have substantial policy and regulatory restrictions on using germline human genome editing in people.

But many scientific leaders are asking: When the benefits are believed to outweigh the risks, and dangers can be avoided, should science consider moving forward with germline genome editing to improve human health? If the answer is yes, how can researchers do so responsibly?

CRISPR pioneer Feng Zhang of the Broad Institute of Harvard and MIT responded immediately to He’s November announcement by calling for a moratorium on implanting edited embryos in humans. Later, at a public event on “Altering the Human Genome” at the Belfer Center at Harvard Kennedy School (HKS), he explained why he felt it was important to wait:

“The moratorium is a pause. Society needs to figure out if we all want to do this, if this is good for society, and that takes time. If we do, we need to have guidelines first so that the people who do this work can proceed in a responsible way, with the right oversight and quality controls.”

Professors at the University’s schools of medicine, law, business, and government saw He’s announcement as a turning point in the discussion about heritable gene therapies and shared their perspectives on the future of this technology with the Gazette.

Here are their thoughts, issue by issue:

Aside from the safety risks, human genome editing poses some hefty ethical questions. For families who have watched their children suffer from devastating genetic diseases, the technology offers the hope of editing cruel mutations out of the gene pool. For those living in poverty, it is yet another way for the privileged to vault ahead. One open question is where to draw the line between disease treatment and enhancement, and how to enforce it, considering differing attitudes toward conditions such as deafness.

Robert Truog , director of the Center for Bioethics at Harvard Medical School (HMS), provided context:

“This question is not as new as it seems. Evolution progresses by random mutations in the genome, which dwarf what can be done artificially with CRISPR. These random mutations often cause serious problems, and people are born with serious defects. In addition, we have been manipulating our environment in so many ways and exposing ourselves to a lot of chemicals that cause unknown changes to our genome. If we are concerned about making precise interventions to cure disease, we should also be interested in that.

“To me, the conversation around Dr. He is not about the fundamental merits of germline gene editing, which in the long run will almost certainly be highly beneficial. Instead, it’s about the oversight of science. The concern is that with technologies that are relatively easy to use, like CRISPR, how does the scientific community regulate itself? If there’s a silver lining to this cloud, I think it is that the scientific community did pull together to be critical of this work, and took the responsibility seriously to use the tools available to them to regulate themselves.”

When asked what the implications of He’s announcement are for the emerging field of precision medicine, Richard Hamermesh, faculty co-chair of the Harvard Business School/Kraft Precision Medicine Accelerator, said:

“Before we start working on embryos, we have a long way to go, and civilization has to think long and hard about it. There’s no question that gene editing technologies are potentially transformative and are the ultimate precision medicine. If you could precisely correct or delete genes that are causing problems — mutating or aberrant genes — that is the ultimate in precision. It would be so transformative for people with diseases caused by a single gene mutation, like sickle cell anemia and cystic fibrosis. Developing safe, effective ways to use gene editing to treat people with serious diseases with no known cures has so much potential to relieve suffering that it is hard to see how anyone could be against it.

“There is also commercial potential and that will drive it forward. A lot of companies are getting venture funding for interesting gene therapies, but they’re all going after tough medical conditions where there is an unmet need — [where] nothing is working — and they’re trying to find gene therapies to cure those diseases. Why should we stop trying to find cures?

“But anything where you’re going to be changing human embryos, it’s going to take a long time for us to figure out what is appropriate and what isn’t. That has to be done with great care in terms of ethics.”

George Q. Daley  is dean of HMS, the Caroline Shields Walker Professor of Medicine, and a leader in stem cell science and cancer biology. As a spokesperson for the organizing committee of the Second International Summit on Human Genome Editing, he responded swiftly to He’s announcement in Hong Kong. Echoing those remarks, he said:

“It’s time to formulate what a clinical path to translation might look like so that we can talk about it. That does not mean that we’re ready to go into the clinic — we are not. We need to specify what the hurdles would be if one were to move forward responsibly and ethically. If you can’t surmount those hurdles, you don’t move forward.

“There are stark distinctions between editing genes in an embryo to prevent a baby from being born with sickle cell anemia and editing genes to alter the appearance or intelligence of future generations. There is a whole spectrum of considerations to be debated. The prospect includes an ultimate decision that we not go forward, that we decide that the benefits do not outweigh the costs.”

Asked how to prevent experiments like He’s while preserving academic freedom, Daley replied:

“For the past 15 years, I have been involved in efforts to establish international standards of professional conduct for stem cell research and its clinical translation, knowing full well that there could be — and has been — a growing number of independent practitioners directly marketing unproven interventions to vulnerable patients through the internet. We advocated so strongly for professional standards in an attempt to ward off the risks of an unregulated industry. Though imperfect, our efforts to encourage a common set of professional practices have been influential.

“You can’t control rogue scientists in any field. But with strongly defined guidelines for responsible professional conduct in place, such ethical violations like those of Dr. He should remain a backwater, because most practitioners will adhere to generally accepted norms. Scientists have a responsibility to come together to articulate professional standards and live by them. One has to raise the bar very high to define what the standards of safety and efficacy are, and what kind of oversight and independent judgment would be required for any approval.

“We have called for an ongoing international forum on human genome editing, and that could take many shapes. We’ve suggested that the national academies of more countries come together — the National Academy of Sciences in the U.S. and the Royal Society in the U.K. are very active here — because these are the groups most likely to have the expertise to convene these kinds of discussions and keep them going.”

Cohen , speaking to the legal consequences of germline human genome editing, said:

“I think we should slow down in our reaction to this case. It is not clear that the U.S. needs to react to Dr. He’s announcement with regulation. The FDA [Food and Drug Administration] already has a strong policy on germline gene editing in place. A rider in the Consolidated Appropriations Act of 2016 — since renewed — would have blocked the very same clinical application of human germline editing He announced, had it been attempted in the U.S.

“The scientific community has responded in the way I’d have liked it to. There is a difference between ‘governance’ and ‘self-governance.’ Where government uses law, the scientific community uses peer review, public censure, promotions, university affiliations, and funding to regulate themselves. In China, in Dr. He’s case, you have someone who’s (allegedly) broken national law and scientific conventions. That doesn’t mean you should halt research being done by everyone who’s law-abiding.

“Public policy or ethical discussion that’s divorced from how science is progressing is problematic. You need to bring everyone together to have robust discussions. I’m optimistic that this is happening, and has happened. It’s very hard to deal with a transnational problem with national legislation, but it would be great to reach international consensus on this subject. These efforts might not succeed, but ultimately they are worth pursuing.”

Professor Kevin Eggan of Harvard’s Department of Stem Cell and Regenerative Biology said, “The question we should focus on is: Will this be safe and help the health of a child? Can we demonstrate that we can fix a mutation that will cause a terrible health problem, accurately and without the risk of harming their potential child? If the answer is yes, then I believe germline human genome editing is likely to gain acceptance in time.

“There could be situations where it could help a couple, but the risks of something going wrong are real. But at this point, it would be impossible to make a risk-benefit calculation in a responsible manner for that couple. Before we could ever move toward the clinic, the scientific community must come to a consensus on how to measure success, and how to measure off-target effects in animal models.

“Even as recently as this past spring and fall, the results of animal studies using CRISPR — the same techniques Dr. He claimed to have used — generated a lot of confusion. There is disagreement about both the quality of the data and how to interpret it. Until we can come to agreement about what the results of animal experiments mean, how could we possibly move forward with people?

“As happened in England with mitochondrial replacement therapy, we should be able to come to both a scientific and a societal consensus of when and how this approach should be used. That’s missing.”

According to Catherine Racowsky, professor of obstetrics, gynecology and reproductive biology at Brigham and Women’s Hospital, constraints on the use of embryos in federally funded research pose barriers to studying the risks and benefits of germline editing in humans. She added:

“Until the work is done, carefully and with tight oversight, to understand any off-target effects of replacing or removing a particular gene, it is inappropriate to apply the technology in the clinical field. My understanding of Dr. He’s case is that there wasn’t a known condition in these embryos, and by editing the genes involved with HIV infection, he could also have increased the risks of susceptibility to influenza and West Nile viruses.

“We need a sound oversight framework, and it needs to be established globally. This is a technology that holds enormous promise, and it is likely to be applied to the embryo, but it should only be applied for clinical purposes after the right work has been done. That means we must have consensus on what applications are acceptable, that we have appropriate regulatory oversight, and, perhaps most importantly, that it is safe. The only way we’re going to be able to determine that these standards are met is to proceed cautiously, with reassessments of the societal and health benefits and the risks.”

Asked about public dialogue around germline human genome editing, George Church , Robert Winthrop Professor of Genetics at HMS, said:

“With in vitro  fertilization (IVF), ‘test tube babies’ was an intentionally scary term. But after Louise Brown, the first IVF baby, was born healthy 40 years ago, attitudes changed radically. Ethics flipped 180 degrees, from it being a horrifying idea to being unacceptable to prevent parents from having children by this new method. If these edited twins are proven healthy, very different discussions will arise. For example, is a rate of 900,000 deaths from HIV infection per year a greater risk than West Nile virus, or influenza? How effective is each vaccine?”

Science, technology, and society

Sheila Jasanoff , founding director of the Science, Technology, and Society program at HKS, has been calling for a “global observatory” on gene editing, an international network of scholars and organizations dedicated to promoting exchange across disciplinary and cultural divides. She said:

“The notion that the only thing we should care about is the risk to individuals is very American. So far, the debate has been fixated on potential physical harm to individuals, and not anything else. This is not a formulation shared with other countries in the world, including practically all of Europe. Considerations of risk have equally to do with societal risk. That includes the notion of the family, and what it means to have a ‘designer baby.’

“These were not diseased babies Dr. He was trying to cure. The motivation for the intervention was that they live in a country with a high stigma attached to HIV/AIDS, and the father had it and agreed to the intervention because he wanted to keep his children from contracting AIDS. AIDS shaming is a fact of life in China, and now it won’t be applied to these children. So, are we going to decide that it’s OK to edit as-yet-to-be children to cater to this particular idea of a society?

“It’s been said that ‘the genie is out of the bottle’ with germline human genome editing. I just don’t think that’s true. After all, we have succeeded in keeping ‘nuclear’ inside the bottle. Humanity doesn’t lack the will, intelligence, or creativity to come up with ways for using technology for good and not ill.

“We don’t require students to learn the moral dimensions of science and technology, and that has to change. I think we face similar challenges in robotics, artificial intelligence, and all kinds of frontier fields that have the potential to change not just individuals but the entirety of what it means to be a human being.

“Science has this huge advantage over most professional thought in that it has a universal language. Scientists can hop from lab to lab internationally in a way that lawyers cannot because laws are written in many languages and don’t translate easily. It takes a very long time for people to understand each other across these boundaries. A foundational concept for human dignity? It would not be the same thing between cultures.

“I would like to see a ‘global observatory’ that goes beyond gene editing and addresses emerging technologies more broadly.”

To learn more:

Technology and Public Purpose project, Belfer Center for Science and International Affairs, Harvard Kennedy School of Government, https://www.belfercenter.org/tapp/person

Concluding statement from the Second International Summit on Human Genome Editing. http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=11282018b

A global observatory for gene editing: Sheila Jasanoff and J. Benjamin Hurlbut call for an international network of scholars and organizations to support a new kind of conversation. https://www.nature.com/articles/d41586-018-03270-w

Building Capacity for a Global Genome Editing Observatory: Institutional Design. http://europepmc.org/abstract/MED/29891181

Glenn Cohen’s blog: How Scott Gottlieb is Wrong on the Gene Edited Baby Debacle. http://blog.petrieflom.law.harvard.edu/2018/11/29/how-scott-gottlieb-is-wrong-on-the-gene-edited-baby-debacle/

Gene-Editing: Interpretation of Current Law and Legal Policy. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651701/

Forum: Harvard T.H. Chan School of Public Health event on the promises and challenges of gene editing, May 2017: https://theforum.sph.harvard.edu/events/gene-editing/

Petrie-Flom Center Annual Conference: Consuming Genetics: Ethical and Legal Considerations of New Technologies: http://petrieflom.law.harvard.edu/events/details/2019-petrie-flom-center-annual-conference

Share this article

You might like.

Nobel laureate details new book, which surveys research, touches on larger philosophical questions

Researchers publish largest-ever dataset of neural connections

Symposium considers how technology is changing academia

Excited about new diet drug? This procedure seems better choice.

Study finds minimally invasive treatment more cost-effective over time, brings greater weight loss

How far has COVID set back students?

An economist, a policy expert, and a teacher explain why learning losses are worse than many parents realize

Human Genome Editing: Science, Ethics, and Governance (2017)

Chapter: summary.

Genome editing 2 is a powerful new tool for making precise additions, deletions, and alterations to the genome—an organism’s complete set of genetic material. The development of new approaches—involving the use of meganucleases; zinc finger nucleases (ZFNs); transcription activator-like effector nucleases (TALENs); and, most recently, the CRISPR/Cas9 system—has made editing of the genome much more precise, efficient, flexible, and less expensive relative to previous strategies. With these advances has come an explosion of interest in the possible applications of genome editing, both in conducting fundamental research and potentially in promoting human health through the treatment or prevention of disease and disability. The latter possibilities range from restoring normal function in diseased organs by editing somatic cells to preventing genetic diseases in future children and their descendants by editing the human germline.

As with other medical advances, each such application comes with its own set of benefits, risks, regulatory frameworks, ethical issues, and societal implications. Important questions raised with respect to genome editing include how to balance potential benefits against the risk of unintended

___________________

1 This summary does not include references. Citations for the discussion presented in the summary appear in the subsequent report chapters.

2 The term “genome editing” is used throughout this report to refer to the processes by which the genome sequence is changed by adding, replacing, or removing DNA base pairs. This term is used in lieu of “gene editing” because it is more accurate, as the editing could be targeted to sequences that are not part of genes themselves, such as areas that regulate gene expression.

harms; how to govern the use of these technologies; how to incorporate societal values into salient clinical and policy considerations; and how to respect the inevitable differences, rooted in national cultures, that will shape perspectives on whether and how to use these technologies.

Recognizing both the promise and concerns related to human genome editing, the National Academy of Sciences and the National Academy of Medicine convened the Committee on Human Gene Editing: Scientific, Medical, and Ethical Considerations to carry out the study that is documented in this report. While genome editing has potential applications in agriculture and nonhuman animals, this committee’s task was focused on human applications. The charge to the committee included elements pertaining to the state of the science in genome editing, possible clinical applications of these technologies, potential risks and benefits, whether standards can be established for quantifying unintended effects, whether current regulatory frameworks provide adequate oversight, and what overarching principles should guide the regulation of genome editing in humans.

OVERVIEW OF GENOME-EDITING APPLICATIONS AND POLICY ISSUES

Genome-editing methods based on protein recognition of specific DNA sequences, such as those involving the use of meganucleases, ZFNs, and TALENs, are already being tested in several clinical trials for application in human gene therapy, and recent years have seen the development of a system based on RNA recognition of such DNA sequences. CRISPR (which stands for clustered regularly interspaced short palindromic repeats) refers to short, repeated segments of DNA originally discovered in bacteria. These segments provided the foundation for the development of a system that combines short RNA sequences paired with Cas9 (CRISPR associated protein 9, an RNA-directed nuclease), or with similar nucleases, and can readily be programmed to edit specific segments of DNA. The CRISPR/Cas9 genome-editing system offers several advantages over previous strategies for making changes to the genome and has been at the center of much discussion concerning how genome editing could be applied to promote human health. Like the use of meganucleases, ZFNs, and TALENs, CRISPR/Cas9 genome-editing technology exploits the ability to create double-stranded breaks in DNA and the cells’ own DNA repair mechanisms to make precise changes to the genome. CRISPR/Cas9, however, can be engineered more easily and cheaply than these other methods to generate intended edits in the genome.

The fact that these new genome-editing technologies can be used to make precise changes in the genome at a high frequency and with considerable accuracy is driving intense interest in research to develop safe and

effective therapies that use these approaches and that offer options beyond simply replacing an entire gene. It is now possible to insert or delete single nucleotides, interrupt a gene or genetic element, make a single-stranded break in DNA, modify a nucleotide, or make epigenetic changes to gene expression. In the realm of biomedicine, genome editing could be used for three broad purposes: for basic research, for somatic interventions, and for germline interventions.

Basic research can focus on cellular, molecular, biochemical, genetic, or immunological mechanisms, including those that affect reproduction and the development and progression of disease, as well as responses to treatment. Such research can involve work on human cells or tissues, but unless it has the incidental effect of revealing information about an identifiable, living individual, it does not involve human subjects as defined by federal regulation in the United States. Most basic research on human cells uses somatic cells—nonreproductive cell types such as skin, liver, lung, and heart cells—although some basic research uses germline (i.e., reproductive) cells, including early-stage human embryos, eggs, sperm, and the cells that give rise to eggs and sperm. These latter cases entail ethical and regulatory considerations regarding how the cells are collected and the purposes for which they are used, even though the research involves no pregnancy and no transmission of changes to another generation.

Unlike basic research, clinical research involves interventions with human subjects. In the United States and most other countries with robust regulatory systems, proposed clinical applications must undergo a supervised research phase before becoming generally available to patients. Clinical applications of genome editing that target somatic cells affect only the patient, and are akin to existing efforts to use gene therapy for disease treatment and prevention; they do not affect offspring. By contrast, germline interventions would be aimed at altering a genome in a way that would affect not only the resulting child but potentially some of the child’s descendants as well.

A number of the ethical, legal, and social questions surrounding gene therapy and human reproductive medicine provide a backdrop for consideration of key issues related to genome editing. When conducted carefully and with proper oversight, gene therapy research has enjoyed support from many stakeholder groups. But because such technologies as CRISPR/Cas9 have made genome editing so efficient and precise, they have opened up possible applications that have until now been viewed as largely theoretical. Germline editing to prevent genetically inherited disease is one example. Potential applications of editing for “enhancement”—for changes that go beyond mere restoration or protection of health—are another.

Because genome editing is only beginning to transition from basic research to clinical research applications, now is the time to evaluate the full

range of its possible uses in humans and to consider how to advance and govern these scientific developments. The speed at which the science is developing has generated considerable enthusiasm among scientists, industry, health-related advocacy organizations, and patient populations that perceive benefit from these advances. It is also raising concerns, such as those cited earlier, among policy makers and other interested parties to voice concerns about whether appropriate systems are in place to govern the technologies and whether societal values will be reflected in how genome editing is eventually applied in practice.

Public input and engagement are important elements of many scientific and medical advances. This is particularly true with respect to genome editing for potential applications that would be heritable—those involving germline cells—as well as those focused on goals other than disease treatment and prevention. Meaningful engagement with decision makers and stakeholders promotes transparency, confers legitimacy, and improves policy making. There are many ways to engage the public in these debates, ranging from public information campaigns to formal calls for public comment and incorporation of public opinion into policy.

APPLICATIONS OF HUMAN GENOME EDITING

Genome editing is already being widely used for basic science research in laboratories; is in the early stages of development of clinical applications that involve somatic (i.e., nonreproductive) cells; and in the future might be usable for clinical applications involving reproductive cells, which would produce heritable changes.

Basic Science Laboratory Research

Basic laboratory research involving genome editing of human cells and tissues is critical to advancing biomedical science. Genome-editing research using somatic cells can advance understanding of molecular processes that control disease development and progression, potentially facilitating the ability to develop better interventions for affected people. Laboratory research involving genome editing of germline cells can help in understanding human development and fertility, thereby supporting advances in such areas as regenerative medicine and fertility treatment.

The ethical issues associated with basic science research involving genome editing are the same as those that arise with any basic research involving human cells or tissues, and these issues are already addressed by extensive regulatory infrastructures. There are, of course, enduring debates about limitations of the current system, particularly with respect to how it addresses the use of gametes, embryos, and fetal tissue, but the regula-

tions are considered adequate for oversight of basic science research, as evidenced by their longevity. Special considerations may come into play for research involving human gametes and embryos in jurisdictions where such research is permitted; in those cases, the current regulations governing such work will apply to genome-editing research as well. Overall, then, basic laboratory research in human genome editing is already manageable under existing ethical norms and regulatory frameworks at the local, state, and federal levels.

Clinical Uses of Somatic Cell Editing for Treatment and Prevention of Disease and Disability

An example of the application of genome editing to alter somatic (nonreproductive) cells for purposes of treating or preventing disease is a recently authorized clinical trial involving patients whose advanced cancer has failed to respond to such conventional treatments as chemotherapy and radiation. In this study, genome editing is being used to program patients’ immune cells to target the cancer.

Somatic cells are all those present in the tissues of the body except for sperm and egg cells and their precursors. This means that the effects of genome editing of somatic cells are limited to treated individuals and are not inherited by their offspring. The idea of making genetic changes to somatic cells—referred to as “gene therapy”—is not new, and genome editing for somatic applications would be similar. Gene therapy has been governed by ethical norms and subject to regulatory oversight for some time, and this experience offers guidance for establishing similar norms and oversight mechanisms for genome editing of somatic cells.

Somatic genome-editing therapies could be used in clinical practice in a number of ways. Some applications could involve removing relevant cells—such as blood or bone marrow cells—from a person’s body, making specific genetic changes, and then returning the cells to that same individual. Because the edited cells would be outside the body (ex vivo), the success of the editing could be verified before the cells were replaced in the patient. Somatic genome editing also could be performed directly in the body (in vivo) by injecting a genome-editing tool into the bloodstream or target organ. Technical challenges remain, however, to the effective delivery of in vivo genome editing. Gene-editing tools introduced into the body might not find their target gene within the intended cell type efficiently. The result could be little or no health benefit to the patient, or even unintended harm, such as inadvertent effects on germline cells, for which screening would be necessary. Despite these challenges, however, clinical trials of in vivo editing strategies are already under way for hemophilia B and mucopolysaccharidosis I.

The primary scientific and technical, ethical, and regulatory issues associated with the use of somatic gene therapies to treat or prevent disease or disability concern only the individual. The scientific and technical issues of genome editing, such as the as-yet incompletely developed standards for measuring and evaluating off-target events, can be resolved through ongoing improvements in efficiency and accuracy, while the ethical and regulatory issues would be taken into account as part of existing regulatory frameworks that involve assessing the balance of anticipated risks and benefits to a patient.

Overall, the committee concluded that the ethical norms and regulatory regimes developed for human clinical research, gene transfer research, and existing somatic cell therapy are appropriate for the management of new somatic genome-editing applications aimed at treating or preventing disease and disability. However, off-target effects will vary with the platform technology, cell type, target gene, and other factors. As a result, no single standard for somatic genome-editing efficiency or specificity—and no single acceptable off-target rate—can be defined at this time. For this reason, and because, as noted above, somatic genome editing can be carried out in a number of different ways, regulators will need to consider the technical context of the genome-editing system as well as the proposed clinical application in weighing anticipated risks and benefits.

Germline Editing and Heritable Changes

Although editing of an individual’s germline (reproductive) cells has been achieved in animals, there are major technical challenges to be addressed in developing this technology for safe and predictable use in humans. Nonetheless, the technology is of interest because thousands of inherited diseases are caused by mutations in single genes. 3 Thus, editing the germline cells of individuals who carry these mutations could allow them to have genetically related children without the risk of passing on these conditions. Germline genome editing is unlikely to be used often enough in the foreseeable future to have a significant effect on the prevalence of these diseases but could provide some families with their best or most acceptable option for averting disease transmission, either because existing technologies, such as prenatal or preimplantation genetic diagnosis, will not work in some cases or because the existing technologies involve discarding affected embryos or using selective abortion following prenatal diagnosis.

At the same time, however, germline editing is highly contentious precisely because the resulting genetic changes could be inherited by the next

3 OMIM, https://www.omim.org (accessed January 5, 2017); Genetic Alliance, http://www.diseaseinfosearch.org (accessed January 5, 2017).

generation, and the technology therefore would cross a line many have viewed as ethically inviolable. The possibility of making heritable changes through the use of germline genome editing moves the conversation away from individual-level concerns and toward significantly more complex technical, social, and religious concerns regarding the appropriateness of this degree of intervention in nature and the potential effects of such changes on acceptance of children born with disabilities. Policy in this area will require a careful balancing of cultural norms, the physical and emotional well-being of children, parental autonomy, and the ability of regulatory systems to prevent inappropriate or abusive applications.

In light of the technical and social concerns involved, the committee concluded that heritable genome-editing research trials might be permitted, but only following much more research aimed at meeting existing risk/benefit standards for authorizing clinical trials and even then, only for compelling reasons and under strict oversight. It would be essential for this research to be approached with caution, and for it to proceed with broad public input.

In the United States, authorities currently are unable to consider proposals for this research because of an ongoing prohibition on the U.S. Food and Drug Administration’s (FDA’s) use of federal funds to review “research in which a human embryo is intentionally created or modified to include a heritable genetic modification.” 4 In a number of other countries, germline genome-editing trials would be prohibited entirely. If U.S. restrictions on such trials were allowed to expire or if countries without legal prohibitions were to proceed with them, it would be essential to limit these trials only to the most compelling circumstances, to subject them to a comprehensive oversight framework that would protect the research subjects and their descendants, and to institute safeguards against inappropriate expansion into uses that are less compelling or well understood. In particular, clinical trials using heritable genome editing should be permitted only if done within a regulatory framework that includes the following criteria and structures:

• absence of reasonable alternatives;
• restriction to preventing a serious disease or condition;
• restriction to editing genes that have been convincingly demonstrated to cause or to strongly predispose to the disease or condition;
• restriction to converting such genes to versions that are prevalent in the population and are known to be associated with ordinary health with little or no evidence of adverse effects;

4 Consolidated Appropriations Act of 2016, Public Law 114-113 (adopted December 18, 2015).

• availability of credible preclinical and/or clinical data on risks and potential health benefits of the procedures;
• ongoing, rigorous oversight during clinical trials of the effects of the procedure on the health and safety of the research participants;
• comprehensive plans for long-term, multigenerational follow-up that still respect personal autonomy;
• maximum transparency consistent with patient privacy;
• continued reassessment of both health and societal benefits and risks, with broad ongoing participation and input by the public; and
• reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition.

Even those who will support this recommendation are unlikely to arrive at it by the same reasoning. For those who find the benefits sufficiently compelling, the above criteria represent a commitment to promoting well-being within a framework of due care and responsible science. Those not completely persuaded that the benefits outweigh the social concerns may nonetheless conclude that these criteria, if properly implemented, are strict enough to prevent the harms they fear. It is important to note that such concepts as “reasonable alternatives” and “serious disease or condition” embedded in these criteria are necessarily vague. Different societies will interpret these concepts in the context of their diverse historical, cultural, and social characteristics, taking into account input from their publics and their relevant regulatory authorities. Likewise, physicians and patients will interpret them in light of the specifics of individual cases for which germline genome editing may be considered as a possible option. Starting points for defining some of these concepts exist, such as the definition of “serious disease or condition” used by the FDA. 5 Finally, those opposed to heritable editing may even conclude that, properly implemented, the above criteria are so strict that they would have the effect of preventing all clinical trials involving germline genome editing.

Use of Genome Editing for “Enhancement”

Although much of the current discussion around genome editing focuses on how these technologies can be used to treat or prevent disease and

5 While not drafted with the above criteria in mind, the FDA definition of “serious disease or condition” is “a disease or condition associated with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible if it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day-to-day functioning, or the likelihood that the disease, if left untreated, will progress from a less severe condition to a more serious one” (21 CFR 312.300(b)(1)).

disability, some aspects of the public debate concern other purposes, such as the possibility of enhancing traits and capacities beyond levels considered typical of adequate health. In theory, genome editing for such enhancement purposes could involve both somatic and germline cells. Such uses of the technologies raise questions of fairness, social norms, personal autonomy, and the role of government.

To begin, it is necessary to define what is meant by “enhancement.” Formulating this definition requires a careful examination of how various stakeholders conceptualize “normal.” For example, using genome editing to lower the cholesterol level of someone with abnormally high cholesterol might be considered prevention of heart disease, but using it to lower cholesterol that is in the desirable range is less easily characterized, and would either intervention differ from the current use of statins? Likewise, using genome editing to improve musculature for patients with muscular dystrophy would be considered a restorative treatment, whereas doing so for individuals with no known pathology and average capabilities just to make them stronger but still within the “normal” range might be considered enhancement. And using the technology to increase someone’s muscle strength to the extreme end of human capacity (or beyond) would almost certainly be considered enhancement.

Regardless of the specific definition, there is some indication of public discomfort with using genome editing for what is deemed to be enhancement, whether for fear of exacerbating social inequities or of creating social pressure for people to use technologies they would not otherwise choose. Precisely because of the difficulty of evaluating the benefit of an enhancement to an individual given the large role of subjective factors, public discussion is needed to inform the regulatory risk/benefit analyses that underlie decisions to permit research or approve marketing. Public discussion also is needed to explore social impacts, both real and anticipated, as governance policy for such applications is developed. The committee recommends that genome editing for purposes other than treatment or prevention of disease and disability should not proceed at this time, and that it is essential for these public discussions to precede any decisions about whether or how to pursue clinical trials of such applications.

Public Engagement

Public engagement is always an important part of regulation and oversight for new technologies. As noted above, for somatic genome editing, it is essential that transparent and inclusive public policy debates precede any consideration of whether to authorize clinical trials for indications that go beyond treatment or prevention of disease or disability (e.g., for enhancement). With respect to heritable germline editing, broad participation and

input by the public and ongoing reassessment of both health and societal benefits and risks are particularly critical conditions for approval of clinical trials.

At present, a number of mechanisms for public communication and consultation are built into the U.S. regulatory system, including some designed specifically for gene therapy, whose purview would include human genome editing. In some cases, regulatory rules and guidance documents are issued only after extensive public comment and agency response. Discussion is fostered by the various state and federal bioethics commissions, which typically bring together technical experts and social scientists in meetings that are open to the public. And the National Institutes of Health’s Recombinant DNA Advisory Committee offers a venue for general public discussion of gene therapy, for review of specific protocols, and for transmission of advice to regulators. Other countries, such as France and the United Kingdom, have mechanisms that involve formal polling or hearings to ensure that diverse and informed viewpoints are heard.

PRINCIPLES TO GUIDE THE GOVERNANCE OF HUMAN GENOME EDITING

One of the charges to the committee was to identify principles that many countries might be able to use to govern human genome editing. The principles identified by the committee are detailed in Box S-1 . The committee recommends that any nation considering governance of human genome editing consider incorporating these principles—and the responsibilities that flow therefrom—into its regulatory structures and processes.

RECOMMENDATIONS

In light of the considerations detailed above, the committee made a series of recommendations targeted to basic research and to clinical applications, both somatic and germline. A summary of the key messages in these recommendations is found in Box S-2 .

This page intentionally left blank.

Genome editing is a powerful new tool for making precise alterations to an organism's genetic material. Recent scientific advances have made genome editing more efficient, precise, and flexible than ever before. These advances have spurred an explosion of interest from around the globe in the possible ways in which genome editing can improve human health. The speed at which these technologies are being developed and applied has led many policymakers and stakeholders to express concern about whether appropriate systems are in place to govern these technologies and how and when the public should be engaged in these decisions.

Human Genome Editing considers important questions about the human application of genome editing including: balancing potential benefits with unintended risks, governing the use of genome editing, incorporating societal values into clinical applications and policy decisions, and respecting the inevitable differences across nations and cultures that will shape how and whether to use these new technologies. This report proposes criteria for heritable germline editing, provides conclusions on the crucial need for public education and engagement, and presents 7 general principles for the governance of human genome editing.

READ FREE ONLINE

Welcome to OpenBook!

You're looking at OpenBook, NAP.edu's online reading room since 1999. Based on feedback from you, our users, we've made some improvements that make it easier than ever to read thousands of publications on our website.

Do you want to take a quick tour of the OpenBook's features?

Show this book's table of contents , where you can jump to any chapter by name.

...or use these buttons to go back to the previous chapter or skip to the next one.

Jump up to the previous page or down to the next one. Also, you can type in a page number and press Enter to go directly to that page in the book.

Switch between the Original Pages , where you can read the report as it appeared in print, and Text Pages for the web version, where you can highlight and search the text.

To search the entire text of this book, type in your search term here and press Enter .

Share a link to this book page on your preferred social network or via email.

View our suggested citation for this chapter.

Ready to take your reading offline? Click here to buy this book in print or download it as a free PDF, if available.

Get Email Updates

Do you enjoy reading reports from the Academies online for free ? Sign up for email notifications and we'll let you know about new publications in your areas of interest when they're released.

An epigenome editing toolkit to dissect the mechanisms of gene regulation

This article is also available in Italiano .

A study from the Hackett group at EMBL Rome led to the development of a powerful epigenetic editing technology, which unlocks the ability to precisely program chromatin modifications

Understanding how genes are regulated at the molecular level is a central challenge in modern biology. This complex mechanism is mainly driven by the interaction between proteins called transcription factors, DNA regulatory regions, and epigenetic modifications – chemical alterations that change chromatin structure. The set of epigenetic modifications of a cell’s genome is referred to as the epigenome.

In a study just published in Nature Genetics , scientists from the Hackett Group at EMBL Rome have developed a modular epigenome editing platform – a system to program epigenetic modifications at any location in the genome. The system allows scientists to study the impact of each chromatin modification on transcription, the mechanism by which genes are copied into mRNA to drive protein synthesis. 

What is chromatin?

Inside the cell’s nucleus, DNA is wrapped around positively charged proteins called histones that strongly adhere to the negatively charged DNA. The individual units of DNA with accompanying histones are called nucleosomes, which assemble in a highly ordered structure, called chromatin. Chromatin structure is known to play a major role in gene regulation, since it influences the accessibility of DNA regulatory regions to transcription factors, proteins that help turn gene expression on or off. However, the extent to which chemical modifications of DNA and histones, collectively referred to as ‘chromatin marks’, contribute to transcription regulation has so far remained unclear.

Chromatin modifications are thought to contribute to the regulation of key biological processes such as development, response to environmental signals, and disease.

To understand the effects of specific chromatin marks on gene regulation, previous studies have mapped their distribution in the genomes of healthy and diseased cell types. By combining this data with gene expression analysis and the known effects of perturbing specific genes, scientists have ascribed functions to such chromatin marks. 

However, the causal relationship between chromatin marks and gene regulation has proved difficult to determine. The challenge lies in dissecting the individual contributions of the many complex factors involved in such regulation – chromatin marks, transcription factors, and regulatory DNA sequences.

Scientists from the Hackett Group developed a modular epigenome editing system to precisely program nine biologically important chromatin marks at any desired region in the genome. The system is based on CRISPR – a widely used genome editing technology that allows researchers to make alterations in specific DNA locations with high precision and accuracy. 

Such precise perturbations enabled  them to carefully dissect cause-and-consequence relationships between chromatin marks and their biological effects.  The scientists also designed and employed a ‘reporter system’, which allowed them to measure changes in gene expression at single-cell level and to understand how changes in the DNA sequence influence the impact of each chromatin mark. Their results reveal the causal roles of a range of important chromatin marks in  gene regulation.

For example, the researchers  found a new role for H3K4me3, a chromatin mark that was previously believed to be a result of transcription. They observed that H3K4me3 can actually increase transcription by itself if artificially added to specific DNA locations. “This was an extremely exciting and unexpected result that went against all our expectations,” said Cristina Policarpi, postdoc in the Hackett Group and leading scientist of the study. “Our data point towards a complex regulatory network, in which multiple governing factors interact to modulate the levels of gene expression in a given cell. These factors include the pre-existing structure of the chromatin, the underlying DNA sequence, and the location in the genome.” 

Hackett and colleagues are currently exploring avenues to leverage this technology through a promising start-up venture. The next step will be to confirm and expand these conclusions by targeting genes across different cell types and at scale.  How chromatin marks influence transcription across the diversity of genes and downstream mechanisms, also remains to be clarified.  

“Our modular epigenetic editing toolkit constitutes a new experimental approach to dissect the reciprocal relationships between the genome and epigenome,” said Jamie Hackett, Group Leader at EMBL Rome. “The system could be used in the future to more precisely understand the importance of epigenomic changes in influencing gene activity during development and in human disease. On the other hand, the technology also unlocks the ability to program desired gene expression levels in a highly tunable manner. This is an exciting avenue for precision health applications and may prove useful in disease settings.”

Un sistema di editing epigenetico per analizzare il meccanismo di regolazione dei geni

Uno studio del gruppo di jamie hackett dello european molecular biology laboratory (embl) di roma ha portato allo sviluppo di una potente tecnologia di editing epigenetico, che consente di programmare con precisione le modifiche della cromatina..

Comprendere la regolazione dei geni a livello molecolare è una sfida centrale della biologia moderna. Questo complesso meccanismo è guidato principalmente dall’interazione tra fattori di trascrizione, regioni regolatrici del DNA e modifiche epigenetiche – alterazioni chimiche che cambiano la struttura della cromatina. 

In uno studio appena pubblicato su Nature Genetics , gli scienziati del gruppo di Jamie Hackett all’EMBL di Roma hanno sviluppato una piattaforma modulare per l’editing epigenetico – un sistema che permette di programmare modifiche epigenetiche in qualunque posizione del genoma. Questa tecnologia consente di studiare l’impatto di ciascuna modifica della cromatina sulla trascrizione – il meccanismo attraverso cui i geni vengono copiati in una molecola di mRNA per guidare la sintesi delle proteine. 

Cos'è la cromatina

All’interno del nucleo della cellula, il DNA è avvolto da proteine a carica positiva chiamate istoni che si legano al DNA che ha carica negativa. Le singole unità di DNA e istoni, chiamate nucleosomi, si assemblano in una struttura altamente ordinata – la cromatina.   È noto che la struttura della cromatina svolge un ruolo importante nella regolazione dei geni, poiché influenza l’accesso dei fattori di trascrizione (le proteine che accendono e spengono i geni) alle regioni regolatrici del DNA. Tuttavia non è chiaro in che modo le modifiche chimiche sul DNA e sugli istoni contribuiscono alla regolazione della trascrizione.

Le modifiche della cromatina contribuiscono alla regolazione di processi biologici chiave come lo sviluppo, la risposta ai segnali ambientali e le malattie.

Per comprendere l’effetto specifico di queste modifiche epigenetiche sulla regolazione dei geni, alcuni studi precedenti hanno mappato la loro distribuzione nel genoma di cellule sane e malate. Combinando questi dati con l’analisi dell’espressione genica gli scienziati hanno potuto solo dedurre la funzione di alcune modifiche della cromatina. 

Tuttavia, stabilire una relazione causale tra le modifiche della cromatina e la regolazione genica non è semplice, poiché è necessario analizzare il contributo dei singoli fattori coinvolti nel processo – oltre alle modifiche della cromatina anche i fattori di trascrizione e le sequenze di DNA regolatrici.

I ricercatori del gruppo di Hackett hanno sviluppato un sistema modulare di editing epigenetico che consente di programmare con precisione nove modifiche epigenetiche biologicamente importanti in qualsiasi regione del genoma. Il sistema è basato su CRISPR, una tecnologia ampiamente utilizzata dai ricercatori per alterare regioni specifiche del DNA con elevata precisione e accuratezza.

Questo sistema ha permesso di analizzare in maniera precisa le relazioni di causa-effetto tra le modifiche della cromatina e il loro effetto biologico. I ricercatori hanno inoltre utilizzato geni reporter  per misurare i livelli di espressione genica in  singole cellule e capire come i cambiamenti nella sequenza del DNA influenzano  l’effetto ultimo  delle modifiche della cromatina sulla trascrizione. I risultati hanno rivelato il contributo specifico di alcune importanti modifiche epigenetiche nella regolazione genica. 

Ad esempio, i ricercatori hanno scoperto un nuovo ruolo di H3K4me3, una modifica della cromatina che generalmente si pensava fosse una conseguenza dell’attività trascrizionale. I risultati dello studio hanno mostrato che invece H3K4me3 è in grado di aumentare la trascrizione quando viene depositata in corrispondenza di alcuni geni. 

“Si tratta di un risultato estremamente eccitante e inaspettato, che va contro tutte le nostre previsioni”, ha commentato Cristina Policarpi, postdoc del Gruppo Hackett e prima autrice dello studio. “I nostri dati suggeriscono una complessa rete di regolazione, in cui molteplici fattori intervengono per modulare i livelli di espressione genica nella cellula. Questi fattori includono lo stato preesistente della cromatina, la sequenza del DNA e la posizione dei geni nel genoma.” 

Il prossimo passo per il gruppo di Hackett sarà confermare ed estendere queste conclusioni analizzando un gran numero di  geni in diversi tipi di cellule e di organismi.  Resta da chiarire il meccanismo attraverso cui le modifiche della cromatina influenzano la trascrizione e interagiscono  con gli altri elementi regolatori.

“Il nostro kit di editing epigenetico costituisce un nuovo approccio sperimentale per analizzare le relazioni reciproche tra genoma ed epigenoma”, ha dichiarato Jamie Hackett, Group Leader dell’EMBL di Roma. “Il sistema potrebbe essere utilizzato per comprendere con maggiore precisione l’importanza dei cambiamenti epigenetici nell’influenzare l’attività dei geni durante lo sviluppo e nelle malattie umane. D’altra parte, la tecnologia apre anche la possibilità di programmare e modulare con un’elevata precisione i livelli di espressione genica desiderati. Si tratta di una strada entusiasmante per le applicazioni nella medicina di precisione e potrebbe rivelarsi utile in alcune patologie.”

Source article(s)

Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications.

Policarpi C., et al.,

Nature Genetics 9 May 2024

10.1038/s41588-024-01706-w

Related links

• Hackett group

Tags: chromatin , dna , emblem , epigenetic , epigenetics , gene , gene regulation , genetics , genome , innovation , invention , rome , technology transfer

EMBL Press Office

Meyerhofstraße 1 69117 Heidelberg Germany

[email protected] +49 6221 387-8726

More from this category

Father’s gut microbes affect the next generation

Researchers aim to use quantum computing to assemble and analyse pangenomes 

A universal framework for spatial biology

When AI meets biology

Read the latest Issue

Issue 101 Winter 2023

Why time is of the essence in development

Deciphering the data deluge: how large language models are transforming scientific data curation

Impact of access to imaging technologies on scientific achievements

Looking for past print editions of EMBLetc. ? Browse our archive, going back 20 years.

Subscribe to our e-newsletter

Newsletter archive.

• Reference Manager
• Simple TEXT file

People also looked at

Original research article, ethics, patents and genome editing: a critical assessment of three options of technology governance.

• 1 Research Unit “Ethics of Genome Editing”, Institute of Ethics and History of Medicine, University of Tübingen, Tübingen, Germany
• 2 Bioethics Institute Ghent (BIG), Ghent University, Ghent, Belgium

Current methods of genome editing have been steadily realising the once remote possibilities of making effective and realistic genetic changes to humans, animals and plants. To underpin this, only 6 years passed between Charpentier and Doudna’s 2012 CRISPR-Cas9 paper and the first confirmed (more or less) case of gene-edited humans. While the traditional legislative and regulatory approach of governments and international bodies is evolving, there is still considerable divergence, unevenness and lack of clarity. However, alongside the technical progress, innovation has also been taking place in terms of ethical guidance from the field of patenting. The rise of so-called “ethical licensing” is one such innovation, where patent holders’ control over genome editing techniques, such as CRISPR, creates a form of private governance over possible uses of gene-editing through ethical constraints built into their licensing agreements. While there are some immediately apparent advantages (epistemic, speed, flexibility, global reach, court enforced), this route seems problematic for, at least, three important reasons: 1) lack of democratic legitimacy/procedural justice, 2) voluntariness, wider/global coordination, and sustainability/stability challenges and 3) potential motivational effects/problems. Unless these three concerns are addressed, it is not clear if this route is an improvement on the longer, slower traditional regulatory route (despite the aforementioned problems). Some of these concerns seem potentially addressed by another emerging patent-based approach. Parthasarathy proposes government-driven regulation using the patent system, which, she argues, has more transparency and legitimacy than the ethical licensing approach. This proposal includes the formation of an advisory committee that would guide this government-driven approach in terms of deciding when to exert control over gene editing patents. There seem to be some apparent advantages with this approach (over traditional regulation and over the ethical licensing approach mentioned above—speed and stability being central, as well as increased democratic legitimacy). However, problems also arise—such as a “half-way house” of global democratic legitimacy that may not be legitimate enough whilst still compromising speed of decision-making under the “ethical licensing” approach). This paper seeks to highlight the various advantages and disadvantages of the three main regulatory options—traditional regulation, ethical licensing and Parthasarathy’s approach—before suggesting an important, yet realistically achievable, amendment of TRIPS and an alternative proposal of a WTO ethics advisory committee.

Introduction

Compared to previous techniques of genetic intervention, CRISPR (clustered regularly interspaced short palindromic repeats), and in particular CRISPR-Cas9, has been steadily changing the discourse on gene modification from one of future possibilities to that of emerging realities. There have been a number of promising developments of the CRISPR tools in research (e.g., research on heritable disease (DMD) and infectious disease (HIV); corrections of genetic bases to some heart defects, and to beta thalassaemia). Throughout this time, there have also been developments that have caused concern (e.g., 2015 embryo gene-editing experiments) and, in November 2018, some outrage. To underscore the revolutionary advances in technical capacity, only 6 years passed between Charpentier and Doudna’s 2012 paper outlining the CRISPR-Cas9 technique, and He Jiankui’s case of reproductive human gene-editing ( Jinek et al., 2012 ; Cyranoski and Ledford, 2018 ). He’s gene-editing of twin girls was an attempt to confer immunity to HIV. This case has been significant not only for its extension of gene-editing to humans, but also due to the ethical and legal guidelines ignored in the process ( Feeney, 2019 ).

While the traditional legislative and regulatory approach of governments and international bodies is evolving ( Baylis et al., 2020 ), there is still considerable divergence, unevenness and lack of clarity ( Nordberg et al., 2020 ). Nevertheless, besides in technical progress, innovation has also been taking place in the proposals of new forms of ethical guidance and regulation for gene-editing—from the field of patenting. Guerrini et al. (2017) have noted the rise of so-called ‘ethical licensing’ where institutions, researchers and companies have used their patent control over CRISPR techniques (especially in the case of the foundational patents) to create an emerging form of private governance over some uses of gene-editing. Unlike the partial, ineffective patchwork of uncoordinated and outdated regulatory and legislative systems across different jurisdictions at the international level, the patent system has global scope through the 1994 TRIPS Agreement ( Feeney et al., 2018 ). While there are some immediately apparent advantages (epistemic, speed, flexibility, global reach, and court enforcement), this route seems problematic for, at least, three important reasons: 1) lack of democratic legitimacy/procedural justice, 2) voluntariness, wider/global coordination, and sustainability/stability challenges and 3) potential motivational effects/problems. Unless at least these three concerns are addressed, it is not clear if this route is an improvement on the longer, slower traditional regulatory route.

Some of these concerns seem potentially to be addressed by another emerging patent-based approach. Parthasarathy (2018) proposes government-driven regulation using the patent system, which, she argues, has more transparency and legitimacy than the ethical licensing approach. Her proposal includes the formation of an advisory committee that would guide this government-driven approach in terms of deciding when to exert control over gene editing patents. There seem to be some apparent advantages with this approach over the traditional regulation and ethical licensing approaches—speed and stability being central, as well as increased democratic legitimacy. However, problems also arise—such as a “half-way house” of global democratic legitimacy that may not be legitimate enough whilst still compromising the speed of decision-making under the ethical licensing approach.

In both patent-based suggestions, it must also be examined whether, or to what degree, this focus lessens the urgency for, or interferes with, the more robust, regulatory/legislative approach. This paper seeks to highlight the various advantages and disadvantages of the three main options—traditional regulation, ethical licensing and Parthasarathy’s approach. We will argue that ethical licensing, if it occurs and the objectives are just and ethical, is to be welcomed. However, this method itself cannot be sufficient as it would just as easily permit unethical objectives. Even if the objectives were ethical, stability and democratic accountability would still be problematic. A prominent concern would also be that this route would slow down the urgency for seeking more traditional regulatory options, whilst at the same time increasing the power of biotechnological companies. Finally, we suggest an additional proposal, entailing an important, but still realistically achievable, amendment of TRIPS and an alternative proposal of a WTO ethics advisory committee that can, and should, be put in place to guide signatory countries worldwide. Throughout, we do not promote this or any patent-related route as the sole, or necessarily optimal, approach to regulating new technologies, such as genome editing, but rather that it may usefully be part of a range of responses, including working alongside forms of traditional regulation. If and where the latter is insufficient, the patent-based route, including our proposal, can be considered beneficial additions to the field.

Background—Technological Progress and Regulatory Inertia?

In the October 2010 issue of Scientific American, an article by Stephen S. Hall entitled “Revolution Postponed” outlined a number of areas that had not progressed as speedily as was predicted during the heady days of the Human Genome Project ( Hall, 2010 ). While such arguments are not particularly accurate or fair—for instance advance in basic research has been immense—there is no doubt as to their accuracy for the decade that immediately followed that article. With major milestones occurring in the 2015 case of CRISPR gene-editing of nonviable human embryos and the 2017 case of the CRISPR correction of the genetic basis of the congenital heart condition hypertrophic cardiomyopathy, only 6 years passed between Charpentier and Doudna’s seminal 2012 paper outlining the CRISPR-Cas9 technique, and the first confirmed case of gene-edited humans ( Jinek et al., 2012 ; Cyranoski and Ledford, 2018 ). In 2018, Jiankui He claimed to have performed germ-line reproductive gene-editing of twin girls—Lulu and Nana—by inserting a variant of the CCR5 gene in an attempt to confer immunity to the human immunodeficiency virus (this was followed with a later claim of a third gene-edited child). Increasing the speed of technical advance puts pressure on ethics and law to catch up.

However, in this case, it was not just areas of ongoing ethical disagreement and still forming ethical values and principles that gave rise to moral unease. It was also the discarding of well-established values and principles that gave rise to moral outrage. From safety concerns and lack of medical necessity to charges of eugenics, He’s case highlighted that we no longer have the silver lining of slow technical progress for further moral reflection before potentially problematic genetic interventions are attempted ( Feeney, 2019 ). While the genome editing techniques of Zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) already had potential, CRISPR has revolutionised what was usually termed genetic engineering by making it cheaper, more accurate and more efficient. This is not to suggest that CRISPR-Cas9 is the only gene-editing technique in use. ZFNs and TALENs are still considered as major contemporary forms of genome editing technologies ( Gaj et al., 2013 ; Li et al., 2020 ). Nor, does “more” efficient and accurate mean efficient and accurate (a line is straight or it is not—more straight suggests still not straight).

Nevertheless, the “CRISPR Revolution” has also meant that the ethical discussions over the previous decades, on what changes, if any, we can morally make to humans is less one of future speculation and more one of imminent or current application. Moving beyond well-established clinical research ethics, new ethical issues arise, for instance, in arguments that favour somatic, as opposed to germline, interventions; the latter are arguably problematic insofar as they can affect future generations in unpredictable and irreversible ways ( Ranisch and Ehni, 2020 ). Other concerns include the risk of the use or misuse of the technology for enhancement purposes ( WHO, 2021 ) as well as issues of social justice between those who have their genomes edited, and the rest ( Baylis, 2019 ). Since the Chinese case, claims by a Russian biochemist have raised the prospect of more such interventions in the future ( Kravchenko, 2019 ). Others will surely follow.

While it appears that He was severely sanctioned by the Chinese authorities ( Cyranoski, 2020 ), his case exposed the lack of a clear and coherent international legal or regulatory structure. In fact, the only international ethical instrument with legal force in relation to gene-editing is the Convention on Human Rights and Biomedicine (the Oviedo Convention). However, this only covers countries party to the Council of Europe, and then only those who sign and ratify it. Moreover, this Convention entered into force in 1999, suggesting that there are, at least some, aspects to it that are long out of date, including any consideration of CRISPR or other contemporary genome editing techniques. The Council of Europe’s Committee on Bioethics (DH-BIO) recent examination of Article 13 of the Oviedo Convention in light of gene editing technologies did not embark upon a wider exploration of the ethical and legal issues arising in recent years, confining itself to relatively minor adjustments and clarifications 1 . It is not clear that minor revisions will be sufficient. This is not unique to the Oviedo Convention. As Parthasarathy (2018) notes “when it comes to editing genes in humans and other organisms, the United States and the United Kingdom—along with many other countries—rely on laws and policies that cover existing genetic engineering technologies”. Nordberg et al. (2020) highlight how the current legislative and regulatory framework in Europe incorporates some general principles advanced by the United Nations Educational, Scientific and Cultural Organization (UNESCO). While this may constitute some degree of soft law applicable in the EU arena, Nordberg et al. highlight that some considerable divergence still exists between national regulations and well as lack of clarity regarding the available legal tools.

The lack of clarity on the international level with regarding to the legislative and regulatory options regarding human genome editing is compounded by a lack of empirical work (or lack of rigour in such work) in contemporary discussions. Françoise Baylis et al. (2020) highlight a failure of such discussions to properly acknowledge and accurately portray the existing legislation, regulations, and guidelines on research in human genome editing. Indeed, according to the review of some of the literature by Baylis et al., the expected Chinese reaction to reproductive human genome editing could have ranged from permissive regulation to outright prohibition. However, as the authors observe, there is some degree of consensus in the global setting. With regard to emerging policy on heritable human genome editing, Baylis et al. (2020) found a “broad prevalent agreement” in the international setting which suggests “that development of international consensus on heritable human genome editing is conceivable”. Unsurprisingly, the rough consensus is prohibition. Nevertheless, this international consensus may soon be moving in a new direction that is reflected in a recent Report written largely in response to the gene-edited twins in China. The International Commission on the Clinical Use of Human Germline Genome Editing’s 2020 Heritable Human Genome Editing Report concluded that implanting edited embryos to establish a pregnancy was not justifiable, at this time. Research into heritable human genome editing could proceed, subject to stringent guidelines for carefully progressing toward clinical research and clinical application, such as on monogenetic disorders. In this respect, the Report seeks to offer a translational pathway for the approval of human heritable genome editing in limited cases, where such stringent criteria are met (e.g. where no developmental abnormalities are detected). Furthermore, this could feed into the appropriate WHO governance and monitoring mechanisms for heritable and non-heritable genome editing in clinical use and research in humans. Amongst other things, this would give rise to increasing complexity for legislation and regulation in the different countries—including those that may currently have some form of rough consensus. Outright prohibition is—in one sense—easy: you ban it. But permitting some uses, while temporarily or permanently banning others is not so straightforward and may also break the aforementioned consensus. Noting germline genome editing that is not for reproductive purposes, Baylis et al. (2020) observed a greater international divergence than in the case of its heritable version. As the technology becomes more established, it is plausible, at least, to suggest that some of the initial prohibition standpoints may also soften in the case of heritable changes.

The greater the divergence in international governance (whether in relation to germline or potentially heritable editing), the greater is the risk of unscrupulous actors, companies or indeed states moving genome editing operations to other locations where there are no prohibitions or other restrictions. There may be countries or regions that, while agreeing in principle with a cautious WHO global governance and monitoring mechanism, may not have the local regulatory infrastructure to police rogue actors. Such countries may have legislation in place but no enforcement capability. Similarly, other places may not have the resources to divert to spending time on either legislating on or regulating human genome technologies, let alone enforcing them ( Baylis et al., 2020 ). Other states may be under severe geo-political pressures that creates space for rogue actors to operate. A clinic in Ukraine is purportedly planning to sell CRISPR enhancements ( Knoepfler 2021 ). It is more likely that the Ukrainian government is preoccupied with its conflict with Russia and Russian supporting separatists, than it is eagerly supporting a CRISPR “wild west” in the eastern edge of Europe. It is also not beyond the realms of probability that countries that continue to be at odds with a “western consensus” in terms of military expansionism or vaccine development outside of basic ethical standards, may take entirely regional—not “global”—approaches to human genome governance. A new cold war may arise in the development of human genome editing technologies—a not unlikely prospect given the potential military applications of the technology. “Ethics dumping” may not only be a risk for countries who are unprepared in terms of human genome editing policy—it may be a deliberate political decision ( Schroeder et al., 2019 ).

Appropriately robust and well-balanced international legislation will likely be slow in its development, and subject to persistent moral disagreement ( Nordberg et al., 2020 ). The fact that the Oviedo Convention, now two decades old, is the only international legally binding form of legislation, and applies only within part of Europe, is not exactly confidence inspiring. 2 It is also not clear that old regional/geo-political rivalries will not re-emerge in the heritable, or non-heritable, human genome editing context. Moreover, this may not be confined to monogenic disorders, but cases of therapy vs. enhancement, or other cosmetic treatments, as suggested by the plans of the Ukrainian clinic. The international legislative-regulatory route is far from the finish line, but it should not be abandoned. However, the question of whether other horses should enter the race must also be considered.

A Novel Form of Technology Governance

Legislation to allow governments or international bodies to constrain performance of gene-editing, is not the only way to regulate genome editing. Innovations in the field of patents are giving rise to new forms of (potential) ethical guidance and regulation in gene-editing. The original CRISPR-Cas9 patents were taken out by two groups: the University of California, Berkeley and University of Vienna group of Jennifer Doudna and Emmanuelle Charpentier regarding its use in general, and the MIT/Harvard/Broad Institute group of Feng Zhang regarding its use on eukaryotes in particular, including plants and animals ( Feeney et al., 2018 ). These two groups, and various sub-groups, are issuing licences for CRISPR-Cas9 to various researchers, institutions, and companies across the globe. These licences are crucial as CRISPR is a tool that is fundamental to many areas of research and applications in humans, non-human animals, plants and microorganisms. 3 The technique is used in—and essential to—a vast amount of gene-editing research and many of the patents on this technique are thereby foundational—without licences from the patent holders much work using CRISPR-Cas9 is open to litigation. 4 Accordingly, this puts the patent holders in a significant position of power and control over CRISPR’s uses; a control that can be exerted via the constraints attached to the licences. In addition to the usual patent-related stipulations regarding payment of royalties and exclusivity or non-exclusivity, terms ostensibly based on ethical considerations are emerging in some of the CRISPR-Cas9 licences.

Guerrini et al. (2017) have noted the rise of “ethical licensing” where companies use their patent control over CRISPR techniques to require or forbid certain practices. This is done by having ethical constraints built into their licensing agreements. For instance, Broad’s CRISPR-Cas9 licences forbid the technique from being used in the editing of tobacco plants, with gene drives or for creating “terminator” seeds for agriculture ( Broad Institute, 2017 ). Its licensing practices also forbids its use in human germline modification. All this, even though the local law may otherwise sanction it, or not prohibit it. Similarly, Kevin Esvelt’s (2018a) work on gene drives is focussed on balancing such an environmentally controversial technology by seeking wide community involvement, given the likely impact for all community members. Gene drives (where genetic alterations are spread through a population with increased rates of inheritance) are a good illustration of the future generations concerns in the case of human heritable genome editing. Examples of uses of gene drives include those in mosquitoes, fruit flies, and mice that are CRISPR’d to cause “desirable” changes to spread through a population at higher-than-normal rates of inheritance, in order to control the spread of disease or simply to control the animal population itself. This can have significant potential for widespread, and unanticipated, harms. In the spirit of ethical licensing, Esvelt sees the mobilisation of patent law to be faster than governmental bureaucracy and truly international in its reach (2018a: 30). Esvelt’s advocacy of gene drive technology developed as non-profit, with the particular goal of preventing the profit motive from interfering with public trust, can be promoted with such a leveraging of intellectual property ( Esvelt, 2018b ).

On the face of it, ethical licensing is a potentially welcome initiative. In terms of regulation, rather than having nothing until we have a sufficient consensus, we have a smaller and faster form of ethical decision-making. Moreover, it is the scientists, institutions, and companies at the centre of the CRISPR-Cas9 discovery who are the patent holders. It could be argued that they are ideally placed to better appreciate the potential of their technology, as well as its possible positive and negative uses and, consequently, to devise better, more balanced regulations. There are at least four advantages that can be identified.

• Epistemic—politicians and policy makers are seldom scientific experts, and require numerous civil servants, and other advisors, to support their day-to-day work. They are also susceptible to lobbying and competing and conflicting pressures—e.g., technological safety versus economic benefits. While this does not suggest that those who invent or discover such technological innovations are immune to such conflicting pressures, there may be a better chance that they are better placed to make informed decisions regarding what is possible, realistic, genuinely dangerous, and also better able to balance such competing priorities.

• Speed—Regulation of technology can be slow at the best of times. In cases where a technology is controversial and novel, it can require the input of multiple stakeholders, rival interests, and mutually incompatible groups. The policymakers may include many such incompatible groups making compromise and deal-making an even slower process. Furthermore, the bureaucratic system in place will need to adopt the new policy and enact it, also taking time. On the other hand, control via the terms placed in patent licences can be—relatively speaking—almost immediate.

• Flexibility—This is an advantage similar to speed but still distinct in its own right. Moving at speed in terms of regulation and legislation can be one thing, but it may not include the ability to change course just as speedily if required. When new discoveries are made, or new information arises about an existing patented invention/discovery, there is no slow lag time for revising future licences when one is the patent holder. Even with existing licences, these might contain clauses permitting the patentee to modify the licence terms if new risks or benefits appear.

• Global reach/court enforcement—the traditional international regulatory landscape outlined above does not have any means of global enforcement, nor any firm picture of how one might operate. The only international example is the Oviedo Convention, which cannot even gain ratification from all the counties within the Council of Europe. By contrast, the patent landscape is court-enforced and well-established internationally.

Nevertheless, this route seems problematic for, at least, three important reasons, and unless these are addressed, it is not clear if this route is a real improvement on the longer, slower traditional regulatory route.

Lack of Democratic Legitimacy/Procedural Justice

Firstly, and importantly, ethical licensing lacks the democratic legitimacy and broader consensus that underlies traditional systems of regulation. Of particular concern is the level of power that private governance approaches, such as ethical licensing, can concentrate in the hands of individuals who are not accountable to anyone, besides shareholders. In Feeney et al. (2018) , one concern over patenting foundational technologies, such as CRISPR, was the power it afforded a small group to set the agenda for future research. Perhaps with noble intentions, the “ethical licensing” approach of Broad-Editas is a form of privatised morality—without discussion, debate, public involvement and democratic accountability—that forecloses ethical decision-making on a technology with a wide societal impact. Hilgartner (2018) highlights democratic choice and accountability as crucial in such cases which “shape the technological and social orders that govern our lives”. This, as Hilgartner notes, is a form of configuration power that is also evident in Esvelt’s proposal. While ethical licensing may be welcomed by some, such proposals—and the agenda-setting power they can have—makes “patent policy a matter of profound political importance” ( Hilgartner, 2018 ). The 2013 U.S. Supreme Court ruling that human genes cannot be patented, invalidated key patent claims by Myriad Genetics on both the BRCA1 and BRCA2 genes. Prior to this, Myriad had effectively used its patent control to stop competitors from offering wider and cheaper clinical testing for determining cancer risk—doubtlessly resulting in late diagnosis, illness, unnecessary surgery and death. As Hilgartner notes, despite the ending of its monopoly, Myriad had already amassed an extensive and valuable database on BRCA variants, beyond what its new competitors had access to and therefore “Myriad’s configuration power partially outlived the patents that originally bestowed it”. Similarly, de Graeff et al. (2018) note, that while it is praiseworthy that Editas aims to pursue a socially responsible licensing approach, “leaving the determination of what is “socially responsible” to the sole discretion of the patentee, ethical licensing through private governance raises procedural justice concerns”. One response would be to reform the patent system (so far as possible in the non-ideal context) to reduce the level of exclusivity that patents can grant ( Feeney et al., 2018 ; Feeney, 2019 ). This would constrain the potential for nefarious forms of agenda-setting or configuration power, while—to a greater extent—aligning itself with the socially positive goals of those involved in ethical licensing.

Voluntariness, Wider/Global Coordination and Sustainability/Stability Challenges

Secondly, there is the issue of wider coordination difficulties and likely disagreements between different private actors. This problem is centred on the voluntariness involved in the ethical licensing approach. Nor is the voluntary nature of ethical licensing something that can be easily circumvented—it is a defining characteristic of this approach. In the context of germline editing concerns trumping their current benefits, Guerrini et al. (2017) notes that:

[i]n such instances, the social benefits associated with voluntarily engaging in ethical licensing will spill over beyond those who merely comply with such licenses. These spillover effects may include, for example, increased faith in scientific self-regulation and participation in research. Voluntarily restricting applications can also generate goodwill among the licensing parties and promote institutional leadership that might translate to new, collaborative partnerships (23).

As advocates of virtue ethics will no doubt agree, legal compulsion alone cannot work as effectively without the cultivation of norms and motivations of people to want to comply with such legal requirements, without necessarily having to do so ( Fives, 2013 ). However, while Arneson (2003) sees the potential of informal social norms over the “costly machinery of legal compulsion,” the problem is that norms tend “to sprout up like weeds” (2003: 145). Private governance priorities, if any, will depend on the individual patent holders and there is no reason to assume that all will follow the ethical licensing route or, even if they do, adopt the same scope of ethical licence restrictions. As outlined elsewhere ( Feeney et al., 2018 ), much of the potential application of the currently dominant genome editing technique is built upon a common “foundational” technique of CRISPR-Cas9. This foundational technique is subject to the disputed, overlapping control of two groups (Doudna and Charpentier on one side over its application over DNA, tout court; Zhang on the other over its application on eukaryotic DNA (e.g. plant or animal DNA) and their respective patent claims ( Feeney et al., 2018 ). This now infamous patent dispute has been held up as a pivotal example of how commercial interests can damage scientific collaborations ( Sherkow, 2016 ). Even where “ethical licensing” has been seen to arise with actors in this dispute, there are issues over how long such ethical standpoints last—particularly for a wider group of people, over time in a private arena where profitability, for instance, is an alternative and competing value. As with many other areas, there is also the problematic issue of self-regulation by the patent holders over their own research and commercial activities (e.g. such as when cases of conflict of interest arise). While Contreras (2018) suggests that the option of voluntary solutions is being overly dismissed, the case of Myriad/BRCA alone highlights that any voluntary approach cannot be relied upon ( Hilgartner 2018 ; Feeney, 2019 ).

Potential Motivational Effects/Problems.

In addition to the aforementioned concerns, there is an additional, less obvious issue that can problematise such a reliance on the ethical motivations arising in the private sphere. The sustainability of such voluntary non-profit (“other-regarding”) motivations in a for-profit (incentive-based) environment cannot be assumed. To illustrate, one can review the trend of patent control since the onset of modern genetic interventions, particularly in the USA. The revolutionary developments in recombinant DNA technology by Herbert W. Boyer and Stanley N. Cohen were of significant commercial potential and, patented by Stanford University, generated a sizable source of university funding ( Cook-Deegan and Heaney, 2010 ). However, profit was not the primary goal of the Cohen-Boyer patents, and their licensing decisions largely reflected public service ideals, preventing public harm, and increasing revenue for educational and research purposes ( Feldman et al., 2007 , 1798). Nevertheless, in the intervening years—which included the Bayh-Dole Act (1980) —Peter Lee notes that through “a long (and still ongoing) process of norm contestation, academic culture has become much more receptive to exclusive rights and the commercial exploitation of scientific knowledge” ( Lee, 2013 , 36). This issue is also something that may face similar ethical proposals in the leveraging of private sector motivations for a social or a public good. Norms can indeed sprout up like weeds, but how the local ecology is maintained may well influence the type of weed that is prevalent. This is concerned with the potential interplay between incentives and public-spirited motivations that can be seen with their attempted mutual accommodation in the wider Rawlsian literature. 5 One key complexity that non-ideal theory recognises lies in stronger feasibility constraints than an ideal-theoretical approach to justice would acknowledge—such as what Rawls might consider “unreasonable levels of self-interest” ( Farrelly, 2007 ; Farrelly, 2016 ). In economic theory, Homo oeconomicus is a term used to describe a view of persons as self-interested, rational utility maximisers. While real people (e.g. “pro ethical licensing” members of Broad) may not resemble this image, giving insufficient regard to what “reasonably” self-interested people are like in reality could render unworkable an overly ideal scheme of justice no matter how desirable it might otherwise be ( Brennan and Pettit, 2005 ). While rejecting such an image of purely self-interested people as economists portray, devising institutional arrangements that are not sufficiently economically incentive-compatible is problematic for workable and stable institutions of (genomic) justice ( Brennan and Pettit, 2005 ). People are not knavish and a principle that requires incentives as though we were would be too extreme. Nevertheless, we are not always motivated to an ideal level in order to comply with, or excel upon, socially just institutions (at least not all the time) nor, in so far as we do, could we simply be assumed to continuously do so over time and in all circumstances within which we find ourselves in the normal course of our lives. So far, nothing here seems particularly controversial. It only seems to suggest that the motivations of CRISPR patent-holders (who engage in ethical licensing) may not realistically be assumed to be purely other-motivated, or altruistic, but that they are also in it for commercial profitability, as well as other forms of incentives (such as winning a Nobel Prize).

However, insofar as such feasibility constraints are taken as limitations on what is realistic in terms of social justice, these limitations themselves must be subjected to critical scrutiny. What is feasible depends greatly on the balance between self-interested and other-interested motivations and, consequently, such feasibility constraints not only form the parameters of what can be done, they are also the consequences of what is done. The concern, akin to that of Titmuss (1971) regarding blood donation, is that this use of incentives would lead to a “crowding out” of social (or other-regarding) preferences, which, while arguably productive in pursuing social justice goals in the short term, would undermine such goals in the longer term. 6 As noted above, the ongoing process of academic norm contestation and movement toward commercial interests, that Lee suggests (2013), may also be a symptom of such “crowding out” dynamics. It may be the case that sometimes the gain from more economic incentives more than compensates for the loss in social preferences. In any case, it seems that the momentum in the context of new gene-editing technologies, such as CRISPR-Cas9, is increasingly toward the ethos of the private sphere, and away from the ethos of (purer) scientific collaboration ( Sherkow, 2016 ). The concern is that this may increasingly “crowd-out” social (other-regarding) preferences and undermine the motivational structure conducive to the potential of “ethical licensing” as a sustainable alternative to the traditional forms of regulation.

Overall, while we note some immediately apparent advantages to the ethical licensing approach (i.e. epistemic, speed, flexibility, global reach, and court enforced), it is not clear that these outweigh the potential problems in terms of lack of democratic legitimacy and procedural justice, problems in maintaining voluntariness, wider/global coordination, and sustainability/stability, particularly with the potential for adverse motivational effects/problems over time. If they do, some response will be needed to address these challenges.

Patents in the Public Sphere?

Some of these concerns seem potentially to be addressed by another emerging patent-based approach. Parthasarathy (2018) proposes government-driven regulation using the patent system, which, she argues, has more transparency and legitimacy than the ethical licensing approach. Rather than ethical licensing by private actors, Parthasarathy is seeking a more formal, comprehensive and government-administered regulation using the patent system. Citing the EU’s 1998 Directive on the legal protection of biotechnological inventions, as well as other historical examples of government run patent control, a key model was highlighted by the US Congress’ use of the patent system to control the development and commercialisation of atomic weapons in the 1940s. Some relevant technologies would be patentable, some subject to compulsory licences if in the public interest and some excluded from patenting entirely (e.g. atomic weapons). This would be managed by an advisory committee for gene-editing patents—including (in the US case at hand) members of EPA, health sector, commercial sector and others, in conjunction with members from the US Patent Office. This advisory committee would guide this government-driven approach in terms of deciding when to exert control over gene editing patents. There seem to be some apparent advantages with this approach (over traditional regulation and over the ethical licensing approach above—speed and stability being central, as well as increased democratic legitimacy, at least via this committee). However, problems also arise—such as a “half-way house” of global democratic legitimacy that may not be legitimate enough whilst still compromising the speed of decision-making under the ethical licensing approach. The problem here is that this addition to traditional regulation does not seem to improve things from mere reliance on that same traditional regulation itself. The problem of achieving agreement in terms of the ethical, legal and societal implications of such technologies or applications of technologies; in terms of devising the appropriate level of fostering or restriction of such technologies, or parts of such technologies, will be present in this approach, albeit focussed on the aforementioned advisory committee. If the decision-making process is still easier in the committee, the membership of this committee will become the new area of contention. If this is all avoided, by the top-down arrangement of such a committee (whether by government or state body) then there is an issue of a lack of democratic accountability, oversight, and engagement. Whether or not genome editing of humans is to be welcomed, the assessment will entail the same challenges as existing democratically legitimated approaches to creating regulation. If this is short-circuited in some way, then that very democratic legitimacy may be damaged. Given the profound societal impact that can be anticipated, and the strong emotions and reactions that it can provoke, the wider acceptance of this technology could be damaged by the sense that it “slips in by the back door”. This route also loses the dynamic aspects of the ‘private ethical licensing” route—it may require wider levels of compromise, or consensus, that one or a few patent owners can swiftly sidestep, albeit with even greater loss to democratic legitimacy and oversight, as well as the concerns over motivations outlined above.

An International Patent-Based Approach: TRIPS and the WTO

Even with its various problems—speed being the key one - the legislative and regulatory route remains an important, if not the most important, approach in responsible governance of new technologies. One important concern is whether a focus on some patent-based alternative lessens the urgency for, or interferes with, the more robust, regulatory/legislative approach. Adopting either the private governance model or Parthasarathy’s alternative does not seem to be an adequate alternative in this regard. This does not rule out various mixed approaches which may strike viable balances ( Guerrini et al., 2017 ; Sherkow, 2017 ). In fairness, Parthasarathy (2018) does not see her suggestion as a comprehensive alternative to traditional regulation but argues that it should be part of a comprehensive approach. Whatever the combination involved in such a mixed approach, there is no reason to be confined to using the current patent environment as the default framework. In Feeney et al. (2018) , we advanced a number of proposals for relatively realistic, yet substantial, reform of the patent-based environment limiting the ability of the patentee to exclude others from performing work with the patent invention, including restrictions on the technological field in which rights may be exercised and on the types of activity which can be constrained and, importantly, a restriction on the period for which the patentee can impose exclusivity in the first place (44–46). Whatever the various suggestions for realistic reforms of the existing patent landscape may be, the key point is that such reforms may be needed if there is to be a sustainable inclusion of patent-based approaches that will contribute to the traditional regulatory options whilst as the same time, not interfering with this same objective, for instance, by increasing the power of biotechnological companies.

With gene editing, we see two dominant concerns—safety and justice in access. As regards safety, this has two aspects: safety of society as a whole; and, for human editing, safety of the edited individual and her offspring. Safety, with gene editing, has an international dimension since the edited species are at least potentially mobile—they can cross borders, bringing risk to countries beyond those where the gene editing occurs unless export is only of dead or sterile organisms. For fish, birds, pollen, seeds, and many small animals, it may be impossible to prevent border crossing, and for humans the lessons of medical tourism show us that preventing border crossing by edited humans may likewise be impossible. Thus, while, from an international point of view, it may be acceptable to allow countries to make their own decisions regarding gene editing of species which can be prevented from crossing borders alive, for many species we do not have this luxury. Thus, enforceable international regulation seems to be essential, and patent-related governance should be seen only as a, albeit necessary, stop-gap measure.

Ethical licensing, unless mandated by law, can only be an inadequate partial solution as a result of its voluntary nature. Ad hoc national restrictions on patentability, even though these might include constraints on local and international licensing, suffer from the slowness of bureaucracy and the voluntariness of ethical licensing (e.g. a company may choose not to patent in countries with such ad hoc constraints). Nonetheless, even ad hoc patentability constraints would add to the currently inadequate patchwork of international governance.

Revision of TRIPS and of the mandate of the WTO, however, does offer the opportunity to introduce constraints on patentees on a near-global scale without the delays fundamental to international regulation of the performance of gene editing, constraints that could at the same time address the question of justice of access. Thus, a revised TRIPS might allow signatory members to adopt measures proposed ad hoc by a majority of a WTO ethics advisory committee while still allowing other signatory members to avoid imposing such constraints on their national patents. With enough signatory members adopting constraints extending to the activities of patentees and their licensees in other countries, patentees might well be forced to accept constraints globally. 7

Thus, should such a WTO ethics committee recommend X then any country might require that patents should not be granted in their country unless the patentee agrees to X globally and requires its licensees to do the same. X might include not using the technology in a particular way or the granting of non-exclusive licences to the technology available to all in that country, group of countries, or anywhere. Local enforceability of any patent might also be linked to compliance with any future WTO ethics committee recommendation adopted by the country in question. A patentee would then be required to choose between continuing with its existing practices or maintaining local patent enforceability. The patentee could then wait until the need to enforce its patent locally arose before changing its practices.

To deal with “rogue” actors in “rogue” countries, the WTO recommendation might include requiring patentees to grant third parties royalty-free licences not to operate under a patent in a “rogue” country but to sue the “rogue” actors in that country. Thus if Broad were to have a patent in Ukraine, such a licensee might be appointed to sue the “rogue” clinic at its own cost. Of course, any proposal or regulatory approach—patent-based or otherwise—will unlikely eliminate all forms of rogue actors or rogue actions. However, the addition of our proposal to the range of regulatory instruments available should further decrease the room for such actors to successfully operate. 8

In this paper, we argue that gene editing requires regulation and that this ideally would involve enforceable international legislation. However, we accept that the road to such legislation is long and that even after acceptance it would lack adequate flexibility. We consider the ethical licensing approach to be commendable and that it should be encouraged; however, it is insufficient. Parthasarathy’s ad hoc national modification of patent laws is likewise commendable but insufficient. We argue instead for an amendment of TRIPS and the equipping of the WTO with an ethics advisory committee whose majority recommendations can be adopted (or not) by individual WTO signatory countries.

Data Availability Statement

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

Author Contributions

OF conceived of the paper and wrote the first draft of the manuscript. JC and SS added crucial sections to the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

We acknowledge support by Open Access Publishing Fund of University of Tübingen. OF work is supported by the Hans Gottschalk-Stiftung.

Conflict of Interest

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

Publisher’s Note

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

Acknowledgments

Many thanks to Gardar Árnason for reviewing the final draft and also to the two reviewers for their helpful comments. OF presented an earlier version of this paper at the International Conference Transformative Technologies: Legal and Ethical Challenges of the 21st Century, Banja Luka, Bosnia and Herzegovina. (February 7–8, 2020) and wishes to thank both organisers (especially Igor Milinković) and participants who positively contributed to the current work.

1 The limited revisions include clarifications “on the terms “preventive, diagnostic and therapeutic” and to avoid misinterpretation of the applicability of this provision to “research”. Council of Europe news page: Genome editing technologies: some clarifications but no revision of the Oviedo Convention, June 7, 2021: https://www.coe.int/en/web/human-rights-rule-of-law/-/genome-editing-technologies-some-clarifications-but-no-revision-of-the-oviedo-convention [accessed 22.08.21]. It seems highly implausible to suggest that these few revisions address all the significant advances, and associated ethical and legal implications, over the last decades.

2 We are not here giving any indications regarding the acceptability, or not, of the Oviedo Convention itself; rather we are highlighting that (good or bad) it is still the only show in town with regulatory bite, insofar as it is ratified.

3 We avoid here the many complications that the patent dispute has entailed for those institutions or researchers seeking licences. For more on this, see Feeney et al. 2018 .

4 Basic, non-profit, pure academic research may be exempt from paying royalties or even needing a licence at all. However, even amongst such groups, a fear of litigation is present.

5 Although John Rawls famously stands accused of being too ideal, he does note that any proposal or theory regarding justice must take due account of the “strains of commitment” where people should only be expected to act according to reasonable social rules, including accommodating a reasonable level of self-interest.

6 Benabou and Tirole (2006) note evidence that suggests that the provision of economic rewards and punishments to people in order to foster prosocial behaviour sometimes has a perverse effect of reducing the total contribution those people have been previously providing. They note that a crowding out of “intrinsic motivation” by extrinsic incentives has been observed in a variety of cases. Indeed, provisional evidence even suggests that explicit incentives diminish activity in distinct regions of the brain associated with social preferences ( Bowles and Polanía Reyes, 2009 ). See also Michael Sandel’s chapter on “How markets crowd out morals” in Sandel (2012) : 93–130.

7 Each technology that would be put to such a committee would inevitably raise major lobbying/self-interest concerns in some countries and therefore we suspect that such a committee would have to have delegates from each country or group of countries, eg. grouped according to their level of economic development, geographic location, or population size. Inevitably, these will be political appointees, perhaps supported by a secretariat provided by WTO. Of course, there will be difficulties and challenges here—and with any proposal that seeks to revise TRIPS—we do not attempt to address such issues here.

8 It is worth noting how our proposal should respond to some concerns recently raised by Justine Pila in two papers offering alternative proposals for the regulation of the patenting and licensing of emerging technologies ( Pila 2020a ; Pila 2020b ). In the first paper, Pila argues that the approach of the European Patent Office (EPO) to the interpretation of the morality clause [Article 53(a)] of the European Patent Convention) is “incoherent, unduly restrictive and blind to the regulatory challenges presented by emerging technologies” and that the risk assessment of that clause “necessitates an epistemic and deliberative process aimed at recognizing and confronting the uncertain consequences of new technologies and their implications for society.” ( Pila, 2020a ), 535-6. To do this, she argues, the EPO and the domestic patent offices should introduce a version of the risk assessment model proposed in a brief prepared by the University of the West of England in 2017 for the European Commission and create a “morality and public policy triage system” within those patent offices, i.e. implicitly a system operated by the patent offices themselves. In the later paper, Pila goes on to propose the extension of the “fair, reasonable, and non-discriminatory” (FRAND) licensing system currently operated on a voluntary basis by industry-based standard-setting organizations. Recognising the danger of a voluntary system operated by industry itself, Pila acknowledges that such an extension of the FRAND system should be compulsory for some technologies and that some other means would have to be found for identifying the patents to which such a FRAND-like system would be applied. For medicines, she implicitly identifies the WHO as a possible candidate. ( Pila, 2020b ), 15-8.

Arneson, R. J. (2003). Equality, Coercion, Culture and Social Norms. Polit. Philos. Econ. 2 (2), 139–163. doi:10.1177/1470594X03002002001

CrossRef Full Text | Google Scholar

Bayh-Dole Act (1980). The Bayh–Dole Act or Patent and Trademark Law Amendments Act . (Pub. L. 96-517, December 12, 1980).

Baylis, F. (2019). Altered Inheritance: CRISPR and the Ethics of Human Genome Editing . Cambridge, Mass: Harvard University Press .

Baylis, F., DarnovskyHasson, M. K., and Krahn, K. T. M. (2020). Human Germ Line and Heritable Genome Editing: The Global Policy Landscape. CRISPR J. 3, 365–377. , No. 5. doi:10.1089/crispr.2020.0082

PubMed Abstract | CrossRef Full Text | Google Scholar

Bénabou, R., and Tirole, J. (2006). Incentives and Prosocial Behavior. Am. Econ. Rev. 96 (5), 1652–1678. doi:10.1257/aer.96.5.1652

Bowles, S., and Polania-Reyes, S. (2009). Economic Incentives and Social Preferences: A Preference-Based Lucas Critique of Public Policy . July 1, 2009). CESifo Working Paper Series No. 2734. Available at SSRN: https://ssrn.com/abstract=1443865 .

Brennan, G., and Pettit, P. (2005). The economy of esteem . Oxford: Oxford University Press .

Broad Institute (2017). Information about licensing CRISPR genome editing systems. Available at: https://www.broadinstitute.org/partnerships/office-strategic-alliances-and-partnering/information-about-licensing-crispr-genome-edi .

Google Scholar

Contreras, J. L. (2018). Is CRISPR Different? Considering Exclusivity for ResearchTools, Therapeutics, and Everything In Between. Am. J. Bioeth. 18 (12), 59–61. doi:10.1080/15265161.2018.1531166

Cook-Deegan, R., and Heaney, C. (2010). Patents in Genomics and Human Genetics. Annu. Rev. Genom. Hum. Genet. 11, 383–425. doi:10.1146/annurev-genom-082509-141811

Cyranoski, D., and Ledford, H. (2018). Genome-edited baby claim provokes international outcry. Nature 563, 607–608. doi:10.1038/d41586-018-07545-0

Cyranoski, D. (2020). What CRISPR-baby prison sentences mean for research. Nature 577, 154–155. doi:10.1038/d41586-020-00001-y

de Graeff, N., Dijkman, L. E., Jongsma, K. R., and Bredenoord, A. L. (2018). Fair governance of biotechnology: Patents, private governance, and procedural justice. Am. J. Bioeth. 18 (12), 57–59. doi:10.1080/15265161.2018.1531176

Esvelt, K. M. (2018a). “Rules for sculpting ecosystems: Gene drives and responsive science,” in Gene editing, law, and the environment . Editor I. Braverman (New York: Routledge ), 21–37.

Esvelt, K. M. (2018b). ‘Gene drive should be a nonprofit technology’ STAT . Available at: https://www.statnews.com/2018/11/27/gene-drive-should-be-nonprofit-technology/ .

Farrelly, C. (2016). Biologically Modified Justice . UK: Blackwell .

Farrelly, C. (2007). Justice in Ideal Theory: A Refutation. Polit. Stud. 55, 844–864. doi:10.1111/j.1467-9248.2007.00656.x

Feeney, O., Cockbain, J., Morrison, M., Diependaele, L., Van Assche, K., and Sterckx, S. (2018). Patenting foundational technologies: Lessons from CRISPR and other core biotechnologies. Am. J. Bioeth. 18 (12), 36–48. doi:10.1080/15265161.2018.1531160

Feeney, O. (2019). Editing the Gene Editing Debate: Reassessing the Normative Discussions on Emerging Genetic Technologies. Nanoethics 13 (3), 233–243. doi:10.1007/s11569-019-00352-5

Feldman, M. P., Colaianni, A., and Liu, C. (2007). “Lessons from the Commercialization of the Cohen-Boyer patents: The Stanford University Licensing Program,” in Intellectual Property Management in Health and Agricultural Innovation: A Handbook of Best Practices . Editors A. Krattiger, R.T. Mahoney, and L. Nelsen (Oxford, UKUSA: MIHR and DavisPIPRA ).

Fives, A. (2013). Political Reason Morality and the Public Sphere . London: Palgrave Macmillan . doi:10.1057/9781137291622

CrossRef Full Text

Gaj, T., Gersbach, C. A., and Barbas, C. F. (2013). ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 31 (7), 397–405. doi:10.1016/j.tibtech.2013.04.004

Guerrini, C. J., Curnutte, M. A., Sherkow, J. S., and Scott, C. T. (2017). The rise of the ethical license. Nat. Biotechnol. 35, 22–24. doi:10.1038/nbt.3756

Hall, S. S. (2010). Revolution Postponed. Sci. Am. 303 (4), 60–67. doi:10.1038/scientificamerican1010-60

Hilgartner, S. (2018). Foundational technologies and accountability. Am. J. Bioeth. 18 (12), 63–65. doi:10.1080/15265161.2018.1531163

Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., and Charpentier, E. (2012). A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337 (6096), 816–821. doi:10.1126/science.1225829

Knoepfler, P. (2021). Ukraine clinic plans to sell CRISPR enhancements: hair color, skin, & breast size. The Niche [blog post] https://ipscell.com/2021/04/ukraine-clinic-to-sell-crispr-genetic-enhancements-hair-color-skin-breast-size/ (last accessed 06 25, 21).

Kravchenko, S. (2019). Future of Genetically Modified Babies May Lie in Putin's Hands. Bloomberg . Available at: https://www.bloomberg.com/news/articles/2019-09-29/future-of-genetically-modified-babies-may-lie-in-putin-s-hands (last accessed: 06 25, 2021)

Lee, P. (2013). Patents and the University. Duke L. J. 63 (1), 1–87.

Li, H., Yang, Y., Hong, W., Huang, M., Wu, M., and Zhao, X. (2020). Applications of genome editing technology in the targeted therapy of human diseases: mechanisms, advances and prospects. Sig Transduct Target. Ther. 5, 1. doi:10.1038/s41392-019-0089-y

Nordberg, A., Minssen, T., Feeney, O., Miguel Beriain, I., Galvagni, L., and Wartiovaara, K. (2020). Regulating germline editing in assisted reproductive technology: An EU cross‐disciplinary perspective. Bioethics 34 (1), 16–32. doi:10.1111/bioe.12705

Parthasarathy, S. (2018). Use the patent system to regulate gene editing. Nature 562, 486–488. doi:10.1038/d41586-018-07108-3 https://www.nature.com/articles/d41586-018-07108-3

Pila, J. (2020a). Adapting the ordre public and morality exclusion of European patent law to accommodate emerging technologies. Nat. Biotechnol. 38, 555–557. doi:10.1038/s41587-020-0504-5

Pila, J. (2020b). ‘Reflections on a post-pandemic European patent system’ European Intellectual Property Review forthcoming. Available at https://ssrn.com/abstract=3627384 (last accessed August 12, 2021).

Ranisch, R., and Ehni, H. J. (2020). Fading red lines? Bioethics of germline genome editing. Bioethics 34 (1January 2020), 3–6. doi:10.1111/bioe.12709

Sandel, M. (2012). What money can’t buy: The Moral Limits of Markets . New York: Farrar, Straus and Giroux .

Schroeder, D., Chatfield, K., Singh, M., Chennells, R., and Herissone-Kelly, P. (2019). Equitable Research Partnerships: A Global Code of Conduct to Counter Ethics Dumping (Cham: Springer Briefs in Research and Innovation GovernanceSpringer ). doi:10.1007/978-3-030-15745-6

Sherkow, J. S. (2016). CRISPR: Pursuit of profit poisons collaboration. Nature 532, 172–173. doi:10.1038/532172a

Sherkow, J. S. (2017). Patent protection for CRISPR: An ELSI review. J. L. Biosciences 4 (3), 565–576. doi:10.1093/jlb/lsx036

Titmuss, Richard. (1971). The Gift Relationship: From Human Blood to Social Policy . New York: Pantheon Books .

WHO (2021). “Expert Advisory Committee on Developing Global Standards for Governance and Oversight of Human Genome Editing,” in Human genome editing: a framework for governance (Geneva: World Health Organization ). Licence: CC BY-NC-SA 3.0 IGO.

Keywords: genome editing, CRISPR, ethical licensing, patents, governance, TRIPS

Citation: Feeney O, Cockbain J and Sterckx S (2021) Ethics, Patents and Genome Editing: A Critical Assessment of Three Options of Technology Governance. Front. Polit. Sci. 3:731505. doi: 10.3389/fpos.2021.731505

Received: 27 June 2021; Accepted: 07 September 2021; Published: 21 September 2021.

Reviewed by:

Copyright © 2021 Feeney, Cockbain and Sterckx. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Oliver Feeney, [email protected]

This article is part of the Research Topic

Regulation and Governance of Gene Editing Technologies (CRISPR, etc.)

The Law, Science, and Policy of Genome Editing

Paul Enríquez Online Symposium: Paul Enríquez’s Rewriting Nature: The Future of Genome Editing and How to Bridge the Gap Between Law and Science 102 B.U. L. Rev. Online 42 (2022) PDF | Back to Symposium

Introduction

Genome editing is the most significant breakthrough of our generation. Rewriting Nature [1] explores the intersection of science, law, and policy as it relates to this powerful technology. Since the manuscript went to press, genome-editing developments have continued apace. Researchers have reported encouraging results from the first clinical trials to treat β-thalassemia and Sickle-Cell Disease, [2] the first wheat-crop variety that is resistant to a crippling fungal disease and features no growth or yield deficits, [3] and proof-of-concept data establishing the therapeutic effects of the first clinical trial involving the injection of a therapy directly into the bloodstream of patients suffering from a genetic, neurological disease. [4] Chinese regulators promulgated rules to approve gene-edited crops. [5] These and other developments are testament to the expansive reach and promise of genome editing. Rewriting Nature showcases the technology’s power to transform what we eat, how we provide healthcare, how we confront the challenges of global climate change, who we are as human beings, and more.

One of my goals in writing the book was to help spur robust dialogue and debate about the future of genome editing and the synergistic roles that law, science and public policy can play in promoting or hindering specific uses of the technology. I am grateful to the Boston University Law Review for organizing this symposium on Rewriting Nature and bringing together an extraordinary group of gifted scholars, academics, entrepreneurs, and thinkers, including several members of the National Academy of Sciences, as well as scientists and lawyers to engage in diverse discussions of my book. I am indebted to Professors Rodolphe Barrangou, Naomi Cahn, Dana Carroll, Glenn Cohen, John Conley, Katherine Drabiak, Michele Bratcher Goodwin, Fred Gould, Henry Greely, Gary Marchant, Kevin Outterson, Christopher Robertson, Jacob Sherkow, Sonia Suter, and Allison Whelan for reading the book and contributing their thoughtful insights—during the live event, in print, or both. I am truly honored and humbled by the generous praise they bestow on my work and the collective caliber of insight they bring to the discussion. It is my honor and privilege to share this platform with so many accomplished people who have inspired and taught me a great deal through their work. I am encouraged by the consonance on a vast range of ideas among participants but even more so by the disagreement, as it presents opportunities for engagement and progress. My Essay, thus, focuses on the hard questions and challenges that spring from our disagreements, which allowed me to clarify, refine, and expand on ideas presented in Rewriting Nature and to articulate new ones that point towards future work.

• On Defining Genome Editing

Professor Sherkow’s thoughtful contribution focuses on Chapter 3 of Rewriting Nature , which lays the interpretive and normative groundwork for a working definition of the term “genome editing.” [6] He is skeptical that such a definition is necessary and observes that “the law is quite able to muddle along without a clear definition of a particular thing.” [7]

I concur with the sentiment that definitions can sometimes engender more problems than solutions in some legal contexts, particularly when they are “riddled with vagueness, ambiguity, and incompleteness.” [8] Rewriting Nature explores several of the inherent limitations concerning the use of specific terminology, which may (1) render the meaning of words “malleable” and capable of “evolv[ing] over time and cultures”; (2) be overbroad, so as to make the meaning of words “inherently ambiguous” and difficult to apply uniformly; and (3) trigger the collapse of a definition’s relevance and application to unforeseen circumstances under the weight of undue “stringency” and “rigidity.” [9] I caution at the outset that “no definition is perfect” and recognize that “[n]o one-size-fits-all definition” will ever apply perfectly in every situation. [10]

To support his thesis, Sherkow analogizes the term “genome editing” to the words “family” and “sale.” [11] He notes that “no one seems to be particularly confused” about the meaning of those words in different legal contexts and, therefore, argues that the law is able to “muddle along” without definitions. [12] But Sherkow’s proposition brings to light a fundamental distinction that attenuates the analogy’s scope and application in the legal realm. The terms “family” and “sale” are precisely the type of words that courts are well equipped to construe and interpret based on ordinary meaning and other canons of statutory construction, as well as principles of legislative intent. While judges are unlikely to be fazed by the meaning of the word “sale” in the context of tax, real estate, and commercial laws, [13] there is an inherent challenge for judges, who may fairly be presumed to lack scientific training and to be unfamiliar with a given complex, emerging technology, to construe or infer plain meaning from a scientific term such as genome editing.

The likelihood of confusion over the meaning of such a technical concept is substantial. Without the guiding light of a clear and robust definition grounded in science, judges may follow whatever rules of construction they deem fit or turn to less reliable sources such as general-use dictionaries—which often lack accuracy, specificity, and clarity—in search of an “ordinary” meaning for a specialized concept. [14] This is highly problematic for the reasons I outline in Rewriting Nature . Furthermore, if legal disputes ensue, litigants may introduce evidence of the meaning of genome editing that serves their specific purposes. This opens the door for select “stakeholders to inject self-serving, arbitrary, and subjective interpretations” about the meaning of genome editing. [15]

Courts, of course, are not obligated to follow reference sources, such as dictionaries, and may wholly ignore expert testimony that they deem irrelevant to the inquiry presented. Judicial discretion in these domains contributes to the phenomenon in which courts render interpretations and meanings that eschew scientific evidence. Such occurrences are neither speculative nor hypothetical.

In Nix v. Hedden , [16] the U.S. Supreme Court acknowledged that from the perspective of botany—the scientific discipline that concerns the study of plants—a tomato falls within the definition of “fruit,” a term that refers to the “ripened ovary of a plant and its contents,” including the seeds. [17] Notwithstanding its botanical classification as a fruit, the Court held that a tomato is a vegetable, as a matter of law, because people (1) grow them in gardens among other vegetables and (2) serve them cooked or raw during dinner but not alongside dessert—the way they generally serve fruits. [18] The Court afforded no deference to the scientific meaning of a disputed term and instead relied on the so-called common knowledge of the people at the time to dictate the meaning of fruit. It is not hard to fathom, in light of Nix and similar cases, why scientists and advocates of science-based law and policy are often dismayed when courts ignore relevant scientific evidence and offer jejune legal reasoning as the basis to decide cases with vast repercussions in many areas of society. [19] Absent guidance about the meaning of a scientific concept such as genome editing, courts may churn out a litany of arbitrary decisions featuring broad interpretations and meanings that cannot be reconciled with the particular subtleties and technical context of a given case.

Next, I wish to address Sherkow’s—and, to some extent, Professor Greely’s—comments regarding “universal definitions” [20] that may “fit[ ] all situations.” [21] Sherkow, for instance, grafts a “universality” sine qua non onto my proposed definition of genome editing. But my sense is that he misreads my normative claims. Rewriting Nature features no such universality requirement.

The thrust of my argument is that, due to the increasing reach of the technology across a wide range of disciplines, “[c]ongruity and uniformity on genome-editing terminology [are] sorely needed at this point in time.” [22] Congruity (contextual harmony) [23] and uniformity (consistent treatment) [24] under the law—namely, the harmonious and consistent application of the term—are thus the principal focus of my definitional prescription. Rewriting Nature says nothing about a need for universality (an all-inclusive concept without limit or exception existing under all conditions) [25] in defining genome editing.

Congruity and uniformity breed predictability , which is a quality that the law ought to promote even if outcomes lead to some degree of variation in a given context of a legal dispute. A court may construe or interpret the word “family” liberally to encompass parents, children, siblings, grandparents, cousins, and in-laws and their relatives for purposes of one law regulating family gatherings, but narrowly to refer only to the parent-child relationship for purposes of determining an individual’s qualification as a dependent under a tax law. Such context-dependent degrees of variation, however, would not vitiate the benefits of a robust definition that, for example, anchors “family” to a common denominator that excludes, say, friends and co-workers from the family unit, regardless of the express contextual statutory intent of a specific law or regulation. [26] The definition of “family” may not be universal, but the term can still be uniformly applied to encompass individuals related by blood or marriage in different contexts.

In any event, it is worth reiterating that the book “advocates for the adoption of a (more) uniform definition of genome editing primarily aimed at building a science-based, legal and policy framework to address current and future predicaments within the ambit of genome-editing technologies” and rejects the universal adoption of a rigid, one-size-fits-all definition of genome editing. [27] The definitional prescription concerns efforts to disseminate accurate, science-based information, so as to (1) promote efficient and effective channels of interdisciplinary communication, (2) engage in fruitful discussions grounded on a common understanding of genome editing, and (3) prevent the spread of vagueness, ambiguity, indefiniteness, and confusion in future discussions about genome-editing technologies.

Despite the inherent limitations on specific terminology enumerated in Rewriting Nature , I conclude that such limitations may be largely allayed and overcome by subjecting the proposed definition to rigorous scrutiny and debate. It is true that no one definition may apply perfectly in every situation, but we cannot let the perfect be the enemy of the good. There is value in formulating a robust, science-based definition of genome editing at this early juncture of technological development. Just so, there is no principled reason to avoid subjecting the definition to additional scrutiny as time goes by and the technology continues to develop.

It may be that one option is for the law to “muddle along” without a genome-editing definition for some time. But is it prudent to merely muddle along aimlessly without strategy as courts, policymakers, and society navigate the intersection of law, science, and policy of genome editing? Or would the preferable choice be to confront a complex, foreseeable problem with the benefit of time and widespread input from scientists, interdisciplinary experts, stakeholders, and the public? My sense is that we ought to collectively strive, as a society, to undertake important and difficult dialogues that will promote civic engagement and respectful conversations about science and technology. Sherkow’s and Greely’s thoughtful critiques allowed me an opportunity to clarify some of the things I said and did not say in Rewriting Nature , for which I am grateful.

• Germline Genome Editing and the Constitution

Turning the page on the discussion pertaining to definitions, a number of contributors offered unique perspectives about Rewriting Nature ’s take on germline genome editing (“GGE”) and the Constitution. Professors Suter and Cahn, for example, are skeptical that a subcategory of GGE may potentially give rise to a fundamental right protected by the Constitution. [28] They argue that the “Rehnquist conception of fundamental liberty interests,” which encompasses “[a] rigid and literalist conception of our history and tradition,” excludes forms of assisted reproductive technology (“ART”) such as GGE. [29]

Suter and Cahn refer to the Supreme Court’s two-prong approach articulated in Washington v. Glucksberg , [30] in which the Court concocted a standard to determine whether a fundamental right exists in the Constitution. [31] Under Glucksberg , the asserted right must (1) be “objectively, ‘deeply rooted in this Nation’s history and tradition’” and (2) include a “‘careful description’ of the asserted fundamental liberty interest.” [32] To the extent that the Court may apply a narrow interpretation of Glucksberg as controlling the inquiry of whether a select use of GGE constitutes a cognizable fundamental right under the Constitution today , [33] I am inclined to concur with Suter and Cahn’s analysis because modern GGE constitutes “a nascent biotechnology” not yet proven safe and effective, for which “no deeply rooted history exists.” [34] Rewriting Nature recognizes that contingency.

My analysis and conclusion on this topic, however, ultimately diverge from Suter and Cahn’s perspective because of the structural constitutional jurisprudence erected after Glucksberg . Most notably, my thesis recognizes that Lawrence v. Texas [35] and Obergefell v. Hodges [36] jointly abrogate Glucksberg ’s approach to determining fundamental rights and indeed abandoned the type of rigid application that Suter and Cahn invoke in their analysis. Lawrence , for example, clarified that “[h]istory and tradition are the starting point but not in all cases the ending point of the substantive due process inquiry.” [37] Obergefell subsequently qualified Glucksberg ’s specific breed of substantive due process. Obergefell noted that the definition of rights “in a most circumscribed manner, with central reference to specific historical practices, . . . may have been appropriate for the asserted right” of physician-assisted suicide in Glucksberg but is not the approach the Court has “used in discussing other fundamental rights, including marriage and intimacy.” [38] The Court explained that certain fundamental rights protected by the Constitution “come not from ancient sources alone. They rise, too, from a better informed understanding of how constitutional imperatives define a liberty that remains urgent in our own era.” [39]

Obergefell ’s reasoning thus expressly distinguished the nature of the right under review. On one hand, the Court endorsed Glucksberg ’s narrow holding, which ascribed more weight to historical practices and tradition when striking a purported right of physician-assisted suicide—a right involving, at its core, the termination of life . Conversely, the Court went out of its way to explain that a narrow reading of Glucksberg —one centered exclusively on such reference to historical practices—was not the appropriate analytical framework with which to examine other rights involving marriage and intimacy, which stem from broad protected liberties that are associated with the family-unit sphere and procreation rights.

This nuanced distinction involving fundamental rights—namely, whether the judiciary has implicitly been distinguishing rights associated with the termination of life versus advancement of liberty and autonomy in the procreation and family-unit contexts—is significant for purposes of discussing whether a cognizable right to select uses of GGE may exist under the Constitution. A fundamental right involving parental autonomy to make healthcare decisions and use GGE to rescue one’s child from death and suffering at the hands of congenital disease would be the polar opposite of the asserted right to terminate one’s life that Glucksberg rejected.

The post- Glucksberg line of precedents informs the distinctions that Rewriting Nature draws between a putative right related to specific uses of GGE and the breed of substantive due process articulated in the privacy realm, which includes Roe v. Wade [40] and its progeny. For instance, Roe protects a woman’s constitutional right to terminate her pregnancy. [41] The Court has restricted such a right in recent decades by incorporating an “undue burden” standard into its jurisprudence. [42] My collective reading of these precedents suggests that at least some members of the Court in recent decades have tacitly applied a heightened version of legal scrutiny—perhaps something akin to the strict-scrutiny standard that exclusively applies to government action impinging fundamental rights—in private substantive-due-process cases involving the termination of life, regardless of whether the circumstances arise at an embryonic stage or the point of imminent death. This would explain why cases like United States v. Rutherford [43] and Abigail Alliance for Better Access to Developmental Drugs v. Von Eschenbach [44] have failed to crystallize certain rights for terminally ill patients. Rewriting Nature hints at this distinction, but I am indebted to Suter and Cahn’s thoughtful essay for prompting me to more clearly articulate this point here.

Elucidation of the heightened standard applicable in termination-of-life cases, as well as the legal treatment afforded to them under the current substantive-due-process framework, further buttress my proposition that Roe and its progeny are largely inapplicable to the GGE context discussed herein. After all, “clinical interventions to cure or ameliorate disease in an embryo—with the intent to save a child from premature death—are at the opposite end of what abortion achieves.” [45] The parents who seek GGE want to rescue their offspring from imminent death caused by harmful genetic mutations, whereas the parents who seek an abortion do not wish to bring the embryo to term. Framing the issue in this context may determine what breed of substantive due process presumably applies to the facts of a given case.

Suter and Cahn’s resistance to my proposed theory discerning among discrete subtypes of substantive due process may explain why they argue that substantive-due-process rights are “on shaky ground” and worry that “[i]f Roe falls,” so too might “other fundamental rights, such as same-sex marriage.” [46] Perhaps Suter and Cahn are right. But I am less convinced than they may be in this regard.

The GGE fundamental-right arguments I advance in Rewriting Nature are largely independent of Roe ’s specific brand of privacy-based substantive due process. Several sections of the book note, for example, that a cognizable right that protects select uses of GGE may encompass a right “in its comprehensive sense” [47] and flow from jurisprudence related to “procreative, parental autonomy, and— to some extent —privacy rights.” [48] The analytical thrust of my proposed framework could, therefore, outlast a potential demise of Roe ’s viability as a constitutional precedent.

On this point, like Suter and Cahn, I too point to comments by Justices of the Supreme Court, who have previously expressed a willingness to overrule certain substantive-due-process precedents. [49] But I would go a step further and discern the specific “species” or subtype of substantive due process inherent in each commentary. To my knowledge, even the most “conservative” jurists have not expressed an appetite for outright overruling procreation-based and parental-autonomy substantive-due-process holdings directly predicated upon Meyer v. Nebraska , [50] Pierce v. Society of Sisters , [51] and Skinner v. Oklahoma [52] —all precedents that, at this point, are very long in the tooth. It is hard to fathom that most, if not nearly all, of the Justices appointed to the Court in recent decades would, for example, uphold a statute impinging on the parental autonomy to decide whether to send children to parochial schools. In a similar vein, when viewed through the termination-of-life prism—rather than the one-size-fits-all, substantive-due-process lens—it seems plausible but, overall, less probable that a panel of Justices would open the door to the States’ annulling some subset of more than 500,000 same-sex marriages. [53]

My argument here stems from the observation that even some individuals who outright reject Roe , Lawrence , and Obergefell would effectively make a substantive distinction between the rights of gay and lesbian couples to marry under Loving and the rights of women to terminate a pregnancy under Roe . Because the former implicates a right within the family-unit sphere (in closer proximity to parental-autonomy precedents) and the latter involves what some may frame as the termination of life (in line with Roe ), the two would presumably share different fates if a particular branch of the doctrine of substantive-due-process tree falls; one branch may fall while others hold up, so long as the tree still stands.

Lastly, Suter and Cahn astutely comment on the evolving composition of the Supreme Court and surmise that “it is highly improbable, at a moment when substantive due process interests seem especially vulnerable, that the Court would recognize a fundamental procreative interest in [ART] and especially to genetically manipulate one’s offspring in a manner that could be heritable to future generations.” [54] I wish to counter this proposition by making two brief points.

First, Suter and Cahn frame the issue as one involving a fundamental right “to genetically manipulate one’s offspring.” [55] The ultimate framing of an issue presented for judicial review plays a pivotal role in the outcome of a given case. In Rewriting Nature , I draw parallels to the questions presented in Glucksberg , Bowers v. Hardwick , [56] and Lawrence to posit that the answer to whether parents have a cognizable right to select uses of GGE under the Constitution would vary under a series of hypothetical statements. [57] Suter and Cahn’s framing mirrors one of those statements, which presumably carries a negative connotation: Is there a right to “genetically modify offspring”?

Parents would better serve their interests by framing the question as one associated with a right to rescue offspring from, in some cases, an imminent death; or more broadly, to make child-healthcare decisions to prevent impending life-threatening disease or death. Again, these questions can evoke the sort of nuanced, substantive-due-process subtype distinctions I discuss in this Essay. More importantly, they play a role in elucidating whether the right in question involves an entirely novel fundamental right (genetic modification) or represents a mere extension of already-existing fundamental rights rooted in parental autonomy and procreation (making child-healthcare decisions).

Second, with regard to the argument that the proposed fundamental right associated with GGE is unlikely to materialize at this moment due to an “increasingly conservative” Supreme Court, admittedly I have no idea what the Court may do in a case that raises the GGE constitutional question under discussion. Nor have I the slightest idea as to the composition of the Court ten or twenty years from now. Above all, we must remember that the GGE constitutional questions raised in the book are on the distant horizon. Rewriting Nature is forward-looking and seeks to explore these issues early on so that we have ample time to contemplate the benefits and potential downsides associated with uses of the technology.

In the end, I think Suter and Cahn make an excellent point that ought not to be overlooked, which is that these issues do not arise in a vacuum of science, law, and policy. Rewriting Nature acknowledges that the composition of the Court at a particular point in time would be an important factor to consider. [58] Perhaps I am too sanguine, but part of me generally resists the urge to think of these issues along political lines. I will offer one last comment on this point.

The current COVID-19 pandemic has led to an increase in the political polarization of vaccine mandates. The Court has been called on to resolve disputes about such mandates. [59] Regardless of how each Justice has come down in favor or against a vaccine mandate in a given context, all Justices are nevertheless fully vaccinated. [60] They have availed themselves of a scientific breakthrough—a messenger ribonucleic acid (“mRNA”)-based vaccine—to protect their lives. So too have most representatives in Congress, regardless of political affiliation. The point is that many of these issues, including vaccinations, can certainly be political and become politicized. But it does not have to be so. Judges are human, after all. They have surprised legal experts by voting in unexpected ways in myriad cases—Kennedy in Lawrence , [61] O’Connor in Grutter v. Bollinger , [62] Gorsuch in Bostock v. Clayton County , [63] Roberts in NFIB v. Sebelius , [64] to name a few—and will continue to do so.

Regardless of political association, I am confident that judges are unified in protecting the lives of children. My hope is that precedent, science, as well as tempered, science-based law and policy—not politics—will be the driving forces that shape the future of GGE. I have no principled reason to believe that, at some point in the future, judges would summarily dismiss the pleas of desperate parents and haphazardly oppose a safe and effective treatment that can spare the life of a child because they are bound to blindly follow a particular constitutional ideology. My sincere hope is that by the time that future comes, Rewriting Nature will have at least contributed to jumpstarting relevant science-based discussions about those future issues surrounding genome editing.

III.   Countering Skepticism of Scientific Progress

Professor Drabiak offers a different critique of my proposed approach to GGE. She is doubtful that GGE will ever be safe and effective. Based on a presumption of “unknown factors” associated with GGE, she argues that parents lack the authority to make decisions that can “substantially limit [a] child’s life path.” [65] She further argues for a “right to an open future,” which would limit parental authority to consent to GGE medical interventions or, in the alternative, a “right to genomic integrity” that would forbid carrying out “intentional germline modifications.” [66]

Drabiak’s essay offers a provocative viewpoint that induced me—and probably other symposium participants—to think about GGE from another angle. It is clear, however, that we approach law and science differently.

From my perspective as a scientist, the most unexpected of her arguments is perhaps the assertion that GGE “will never be safe and effective.” [67] The “never-will” proposition in this regard deals in absolutes and is laden with the type of “value judgment” [68] that she ascribes to the scientific community when it points to incremental advances in basic research as the basis for its optimism about a given technology. Optimism, however, is clearly distinguishable from hype. The former is grounded on promising results from empirical research, which spotlight areas of improvement and future research directions. The latter is unsupported by evidence, replete with deceptive simplicity, [69] and prone to manipulation by parties with ulterior motives.

The principle underlying the never-will assertion further concerns me because it implies an unwillingness to consider new evidence that may disprove a given hypothesis. That is antithetical to the scientific method and would all but foreclose an open dialogue about the potential benefits and harms of developing and using any nascent technology. As Professor Barrangou articulated, science and technology are here to help humanity solve big problems that call for big solutions. [70] Averring that GGE will never be “safe and effective” would be akin to claims that interoceanic aviation would never have been safe, or even possible, because the 1903 Wright Flyer covered a ground distance of 120 feet. [71] The same holds true about the once-nascent technology that brought us the mRNA vaccines against SARS-CoV-2, the virus that causes COVID-19. And let’s not forget in vitro fertilization (“IVF”), which since 1978 has led to the birth of more than eight million babies. [72]

Safety and efficacy are relative terms. GGE is no different than other therapeutic contexts in that regard. The U.S. Food and Drug Administration’s (“FDA”) determination that a drug is safe, for example, does not indicate a complete absence of risk or potential harm. Safety means that the therapeutic “benefits of the drug outweigh the risks.” [73]

Adherence to a “never-will” principle would have precluded virtually every modern-era, technological advance in telecommunications, space travel, human medicine, transportation, and more. We should not be skeptical of robust scientific evidence. Scientists, however, must ground their optimism about a given technology firmly in scientific facts to avoid misinterpretation of scientific progress. On that point, Rewriting Nature warns that GGE is “not yet ready for primetime” [74] and that any experiments in the human germline at this time would be “premature” and pose risks not outweighed by potential benefits. [75] Ultimately, we must not lose sight of the fact that GGE is a promising, nascent biotechnology that will continue to develop and improve in years to come.

Still, my most substantive disagreement with Drabiak concerns her discussion of the rights to “an open future” and “genomic integrity.” [76] The rights are tentative and lack specificity; they appear to enshrine an ideal but are rife with obstacles that would preclude their application in the law. The rights also leave me wondering about their source of origin, presumptive limits, constituent elements, how they would be implemented, what mechanisms of enforcement would be available, and how they would interact with other related rights. The language associated with the framing of these rights leads me to assume, perhaps incorrectly, that they derive from human-rights treaties. Accordingly, I wonder about the kinds of obstacles Drabiak foresees in efforts to incorporate them into domestic law, and whether they would be self-executing.

I further question what it means to have an amorphous right that protects “genomic integrity.” Drabiak explains that the right “preclude[s] intentional germline modifications.” [77] But does this mean the right suggests that a purported sanctity (inviolability) of the human germline must be protected? If so, does it follow that we have a duty to maintain the integrity of genomic loci that trigger human disease and death? I am not persuaded that the integrity of a genome featuring a deleterious mutation that causes, for example, Tay-Sachs disease or Cystic Fibrosis is worthy of protection under a fundamental right.

If we equate this presumed germline-integrity argument with a right to bodily integrity, how should we reconcile said right against the constitutionally recognized principle of parental autonomy to make decisions on behalf of children, including granting or withholding consent for medical care? Suppose a toddler with a severe form of aortic stenosis, a congenital heart defect that may lead to congestive heart failure, needs a heart transplant. Assuming the parents opt in favor of the surgery, would that decision render them infringers of the child’s right to bodily integrity? The likely answer under the law of parental autonomy to direct offspring medical-care decisions is no. It is therefore hard to reconcile this concept against a right to “germline integrity” solely because the treatment is molecular in nature and occurs at an embryonic stage. I admit I do not quite understand the logic dictating that at some point in the future, if and when the technology is safe and effective, preventing offspring death and suffering with the use of GGE constitutes an “infringe[ment] upon the dignity and rights of the future child.” [78]

The right to an “open future” is similarly ambiguous. Revisiting the aortic-stenosis hypothetical above, under Drabiak’s proposal, parents who choose the heart-transplant procedure would likely violate the child’s rights because a heart transplant carries significant risks, including death, and is not ever completely safe and effective. The parents could not consent to the transplant because it constitutes an intervention that may “substantially limit their child’s life path.” [79] But would not parents also violate the “open-future” right if they do nothing and allow congestive heart failure itself to limit the child’s life path?

Medical-care decisions of this sort are deeply personal. At a minimum, however, a safe and effective medical intervention performed at the molecular level, which cures or protects a child from serious illness or death, cannot ipso facto violate any children’s rights. As Rewriting Nature notes, implied consent is logically embedded in the parental autonomy to make medical-care decisions regarding the use of therapeutic GGE intervention. [80] Surely, the child whose corrected germline once bore a deleterious mutation that causes Tay-Sachs disease would not grow up wishing her parents did nothing to spare her from a life-threatening disease, death, and suffering.

• On the Nexus of Genome Editing and Administrative Law

Professor Greely’s creative and forward-looking essay contributes a wealth of perspectives, ranging from human genome editing and art to law and regulation, and constitutes a resource for a myriad of future paper topics. [81] I wish to tackle two brief points warranting clarification—one about the regulation of crops in this Section and another about GGE in the concluding Section.

Greely, Professor Gould, and I agree that a regulatory system for crops should focus on the product at issue, rather than the process by which it was created. [82] I also agree that regulation should be commensurate with the degree of risk inherent in each product derived from genome editing. Greely’s view that my “basic position is that if no meaningful differences exist between non-regulated and regulated crops, neither should be regulated,” [83] however, oversimplifies my stance about the future regulatory scheme for genome-edited crops.

A significant portion of my analysis and recommendations about the regulation of crops in Rewriting Nature are guided by the Chapter 7 hypothetical embodiment, which contemplates the making of a fungus-resistant banana crop using recombinant DNA-free genome editing that features a single-point mutation in a receptor protein. [84] Based on the specific facts concerning that embodiment, a mutant crop that has zero foreign DNA and is—but for the single-residue substitution—genetically identical to its naturally occurring counterpart should not be subject to onerous regulations applicable to crops derived from older genetic-engineering techniques. [85] My regulatory prescription for the deregulation of such crops devoid of foreign DNA, therefore, extends exclusively to that fact pattern. The choice to cabin a regulatory analysis to that embodiment was deliberate, so as to allow substantive and nuanced discussion of regulation of that crop. I did not expand on the many other possible types of gene-edited crops due to space constraints and other factors. But Rewriting Nature alludes that a different regulatory scheme would be applicable to crops featuring other types of genetic modifications. [86] And I have further discussed some of these distinctions in greater detail in previous works. [87] To make clear, I neither advocate nor endorse a simplistic one-size-fits-all approach to the regulation of crops.

Suter and Cahn, for their part, embrace much of Rewriting Nature ’s proposed GGE regulatory framework. They also strengthen my arguments by placing them “in the context of other potential regulatory structures.” [88] I embrace their feedback in full as it provides additional support for a robust GGE regulatory framework based on science, ethics, and the free market. I only wish to focus briefly on their suggestion that, because the FDA does not specialize in reproductive technologies, it may be useful to look to other administrative agencies such as the UK Human Fertilisation and Embryology Authority, the UK regulatory agency for fertility treatment and research. Although many before us have proposed the creation of a new agency in the United States to oversee matters of reproductive technology, Suter and Cahn’s essay persuades me to contemplate this matter further in future works. The idea is provocative and interests me because it calls for a “metanationalist” [89] approach to ART regulation. Certainly, it would be beneficial to inspect and study comparative international law to address the issue of future GGE regulation, which has become a “global problem” in the wake of the 2018 birth of the first gene-edited babies in China. [90]

Additional Perspectives and Future Directions

This final Section addresses miscellaneous commentary, reflects on the progress made, and contemplates perspectives about the future of genome editing.

Although Greely endorses my approach to GGE, he contends I make an important error by “dismiss[ing] preimplantation genetic diagnosis” (“PGD”) as an alternative to GGE intervention. [91] To be clear, I do not advance the proposition that PGD is an unsuitable alternative for GGE in some contexts. Nor do I mean to imply that certain heterozygous couples who might potentially carry a faulty allele cannot successfully avail themselves of PGD to conceive a healthy child. [92] To the contrary, both GGE and PGD are methods that could, and likely will, be used side-by-side. My comments about the limitations of PGD relate mostly to homozygous parents—namely, couples in which each parent carries an allele with deleterious genetic mutations that guarantee the onset of genetic disease in their offspring—and concern the practicability of using PGD to help such couples conceive healthy children.

For this category of homozygous parents carrying a faulty allele, GGE is virtually the only way to conceive an otherwise healthy, biologically related child. [93] That is because every fertilized embryo available for implantation features the faulty alleles (because each parent carries a copy of said allele). No amount of PGD in that scenario would allow the parents to screen among embryos for one without the faulty alleles. For them, PGD is not a viable alternative to conceive healthy offspring. This contrasts with the case of a heterozygous couple who could, in theory, screen for embryos without faulty alleles. The problem is that the heterozygous couple would potentially need to produce and screen many embryos, which can be expensive and lead to otherwise “good” embryos being discarded. In that sense, GGE would benefit even the heterozygous parents because they would potentially need to produce fewer embryos. After performing GGE, they could then screen a subset of embryos prior to implantation.

Professor Carroll participated in the 1975 Asilomar Conference on Recombinant DNA and the recent International Summits on Human Genome Editing in 2015 and 2018 and, thus, brings a wealth of experience to the discussion. His essay reflects a thoughtful and measured approach to human GGE. While he agrees with my general GGE approach, he notes that it is difficult for him to understand why I might leave a door open for potential GGE cosmetic modifications but, at the same time, foreclose editing the human germline to modify some disabilities. [94]

Carroll refers to the proposed four-tiered, normative framework in Chapter 11, which distinguishes among permissible and impermissible uses of GGE technologies. [95] My response to Carroll’s question embarks from the recognition of a special history of irrational discrimination against some minority groups on the basis of race, gender, sexual orientation, specific disabilities, and other protected categories under the law. [96] Such past discrimination strongly counsels against sanctioning GGE to modify traits associated with protected groups, regardless of whether the modifications are technologically feasible. Unlike certain therapeutic GGE interventions for which evidence exists to establish safety and efficacy in the near future, cosmetic uses of GGE are not technologically feasible at this time and raise fewer concerns about unlawful discrimination against protected classes.

Consider a set of parents seeking to perform GGE to edit an embryo’s race and eye color. Rewriting Nature explains that there is no constitutional justification to modify an embryo’s race because the law already prohibits racial discrimination. [97] Having green eyes, however, is not associated with a protected class under the law. GGE aimed at eye-color modifications may give rise to ethical, access, and other equitable considerations but, so long as the technology is safe and effective to use, such interventions may warrant a less restrictive approach because (1) they are distant in the future and (2) do not raise serious concerns of insidious discrimination. The nature of the GGE intervention sought should, therefore, dictate whether a specific GGE use ought to be banned or regulated. Rewriting Nature proposes a framework to assist in making those important distinctions among GGE subtypes. The framework is flexible. In the disability realm, for example, it counsels against modifying traits related to certain protected disabilities such as deafness, while recognizing that GGE associated with disabilities closely linked to therapeutic conditions (such as diabetes and congenital cardiovascular disease) may be permissible. [98]

This brings me to Professors Goodwin and Whelan’s contribution, which fits neatly within a growing body of law and social-science literature focused on the intersection of genetics, clinical ethics, and social equality. [99] I welcome and embrace their essay in full and am delighted to see that it fills an important gap in the conversation. I devote some space in Rewriting Nature to issues of social inequality, inequity, and institutional discrimination, but I do not explore topics of fairness, cost, and access to genome-editing technologies with any sufficient depth. The advent of genome editing and its application to myriad facets of society raise an alarming potential to exacerbate healthcare disparities between privileged and nonprivileged communities. Goodwin and Whelan forecast that the incidence of some diseases among “wealthy, largely White, populations will decrease, while those in historically marginalized or vulnerable populations will remain unchanged or even worsen.” [100] Sadly, I agree. But I am encouraged by the work being done by scholars, community leaders, and regulators to build networks and support the institutional infrastructure that will ameliorate social inequality as healthcare-related technologies continue to develop.

Lastly, I want to acknowledge the significant contributions of Professors Barrangou, Cohen, Conley, Gould, and Marchant. [101] Gould and Barrangou—as did Greely—sagaciously noted the importance of focusing on nonhuman uses of genome editing, which can arguably exert a greater impact on society in the long run. Gould’s discussion about “omics” technologies and the increased use of artificial intelligence and data science in crop breeding added context to Rewriting Nature ’s push to adopt science-based regulatory frameworks that focus on products, rather than the processes through which they are derived. Barrangou provided compelling arguments for deploying genome-editing tools to modify trees and forests, which could help ameliorate the impacts of the global climate-change crisis. Conley and Marchant added a much-needed soft-law perspective to the conversation and put the spotlight on the development of new informal mechanisms of international governance for emerging technologies. Finally, Cohen focused his perspicacious remarks on the nexus of normativity and the theory of a jurisprudence of scientific empiricism, which Rewriting Nature introduces as a theoretical structural framework to address questions of science in law. There is much to share about that theory, its underlying mechanisms, and methodology in future work.

My deepest thanks to the Boston University Law Review for making this symposium possible and to all participants, whose superb insights elevated the quality of the discourse. Conversations such as these are precisely what is needed to close the gap between law and science and pave the road ahead for genome-editing technologies. I look forward to many engaging and lively discussions in years to come.

[1] Paul Enríquez, Rewriting Nature: The Future of Genome Editing and How to Bridge the Gap Between Law and Science (2021).

[2] Haydar Frangoul, David Altshuler, M. Domenica Cappellini, Yi-Shan Chen, Jennifer Domm, Brenda K. Eustace, Juergen Foell, Josu de la Fuente, Stephan Grupp, Rupert Handgretinger, Tony W. Ho & Antonis Kattamis, Andrew Kernytsky, Julie Lekstrom-Himes, Amanda M. Li, Franco Locatelli, Markus Y. Mapara, Mariane de Montalembert, Damiano Rondelli, Akshay Sharma, Sujit Sheth, Sandeep Soni, Martin H. Steinberg, Donna Wall, Angela Yen, Selim Corbacioglu, CRISPR-Cas9 Gene Editing for Sickle Cell Disease and β -Thalassemia , 384 N. Eng. J. Med. 252, 258-59 (2021).

[3] Shengnan Li, Dexing Lin, Yunwei Zhang, Min Deng, Yongxing Chen, Bin Lv, Boshu Li, Yuan Lei, Yanpeng Wang, Long Zhao, Yueting Liang, Jinxing Liu, Kunling Chen, Zhiyong Liu, Jun Xiao, Jin-Long Qiu & Caixia Gao, Genome-Edited Powdery Mildew Resistance in Wheat Without Growth Penalties , 602 Nature 455, 460 (2022).

[4] Julian D. Gillmore, Ed Gane, Jorg Taubel, Justin Kao, Marianna Fontana, Michael L. Maitland, Jessica Seitzer, Daniel O’Connell, Kathryn R. Walsh, Kristy Wood, Jonathan Phillips, Yuanxin Xu, Adam Amaral, Adam P. Boyd, Jeffrey E. Cehelsky, Mark D. McKee, Andrew Schiermeier, Olivier Harari, Andrew Murphy, Christos A. Kyrasous, Brian Zambrowicz, Randy Soltys, David E. Gustein, John Leonard, Laura Sepp-Lorenzino & David Lebwohl, CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis , 385 N. Eng. J. Med. 493, 499-501 (2021).

[5] Dominique Patton, China to Allow Gene-Edited Crops in Push for Food Security , Reuters (Jan. 25, 2022, 3:41 PM), https://www.reuters.com/world/china/china-drafts-new-rules-allow-gene-edited-crops-2022-01-25/.

[6] See Jacob S. Sherkow, Writing Definitions in Rewriting Nature : Lessons from FDA Law , 102 B.U. L. Rev. Online 22, 22-23 (2022).

[7] Id. at 23.

[8] Enríquez, supra note 1, at 83.

[9] Id. at 74-75.

[10] Id. at 74, 89.

[11] Sherkow, supra note 6, at 23.

[12] See id. at 23.

[14] See Enríquez, supra note 1, at 83-91 (describing the problems associated with overreliance on dictionaries as sources of ordinary meaning while noting the ambiguity and lack of clarity of dictionary definitions of genome editing).

[15] Id. at 91.

[16] 149 U.S. 304 (1893).

[17] Id. at 307; see also Enríquez, supra note 1, at 87-89 (discussing Nix ).

[18] Nix , 149 U.S. at 307.

[19] Despite Nix ’s holding, the botanical definition of a fruit remains unchanged nearly one hundred and thirty years later. But so too does the legal treatment of tomatoes as vegetables under U.S. trade law remain unchanged. See Harmonized Tarif Schedule of the United States Revision 2 (2022), USITC Pub. 5293, § 2, ch. 7 (Feb. 2022), https://hts.usitc.gov/current [https://perma.cc/UXJ3-FR7Y].

[20] See Sherkow, supra note 6, at 24, 25, 28.

[21] Henry T. Greely, Rewriting (Non-Human) Nature , 102 B.U. L. Rev. Online 16, 18 (2022).

[22] Enríquez, supra note 1, at 73.

[23] See Congruous , Merriam-Webster, https://www.merriam-webster.com/dictionary /congruous [https://perma.cc/48PL-GFJE] (last visited Mar. 9, 2022) (defining the term as “being in agreement, harmony, or correspondence”; “conforming to the circumstances or requirements of a situation; appropriate”; and “marked or enhanced by harmonious agreement among constituent elements”).

[24] See Uniform , Merriam-Webster, https://www.merriam-webster.com/dictionary /uniform [https://perma.cc/K3XN-H86T] (last visited Mar. 9, 2022) (defining the term, in relevant part, as being “consistent in conduct or opinion,” such as in the “ uniform interpretation of laws”).

[25] See Universal , Merriam-Webster, https://www.merriam-webster.com/dictionary /universal [https://perma.cc/P3D4-3ZGD] (last visited Mar. 9, 2022) (defining the term as “including or covering all or a whole collectively or distributively without limit or exception”; “present or occurring everywhere”; and “existent or operative everywhere or under all conditions”).

[26] For purposes of this Essay, we need not engage in an exercise of defining the term family. Suffice it to note that, unlike “family,” the term genome editing lacks an “ordinary” meaning.

[27] E.g. , Enríquez, supra note 1, at 73, 75, 89.

[28] See Sonia M. Suter & Naomi R. Cahn, Regulating Technology as We Rewrite Nature , 102 B.U. L. Rev. Online 29, 30 (2022).

[29] Id. at 31.

[30] 521 U.S. 702 (1997).

[31] Id. at 720-21.

[33] It is, however, quite unlikely that the Court would grant certiorari to address that question today.

[34] Enríquez, supra note 1, at 337.

[35] 539 U.S. 558 (2003).

[36] 576 U.S. 644 (2015).

[37] Lawrence , 539 U.S. at 572 (quoting Sacramento v. Lewis, 523 U.S. 833, 857 (1998) (Kennedy, J., concurring)).

[38] Obergefell , 576 U.S. at 671.

[39] Id. at 671-72.

[40] 410 U.S. 113 (1973).

[41] Id. at 154 (“[T]he right of personal privacy includes the abortion decision.”).

[42] See, e.g. , Planned Parenthood of Se. Pa. v. Casey, 505 U.S. 833, 876 (1992) (plurality opinion) (“[T]he undue burden standard is the appropriate means of reconciling the State’s interest with the woman’s constitutionally protected liberty.”).

[43] 442 U.S. 544, 559 (1979) (holding that the FDA can preclude terminally ill cancer patients from obtaining a drug not recognized as “safe and effective”).

[44] 495 F.3d 695, 713 (D.C. Cir. 2007) (holding that there is no such right of access to experimental drugs that have not been proven safe and effective).

[45] Enríquez, supra note 1, at 346 (emphasis added).

[46] Suter & Cahn, supra note 28, at 32.

[47] Obergefell v. Hodges, 576 U.S. 644, 671 (2015).

[48] See, e.g. , Enríquez, supra note 1, at 331, 337, 338 (emphasis added).

[49] See, e.g. , id. at 353 n.76; Suter & Cahn, supra note 28, at 32 n.24.

[50] 262 U.S. 390 (1923).

[51] 268 U.S. 510 (1925).

[52] 316 U.S. 535 (1942). Skinner held that the right to procreate was both a fundamental right and liberty protected under the Constitution. See id. at 541. Thus, while the Court’s majority struck down the Oklahoma sterilization statute under equal-protection grounds, it also hinted at the application of substantive due process. The concurring opinions expressly invoked due process. See id. at 544-45 (Stone, C.J., concurring); id. at 546 (Jackson, J., concurring). In any event, Justices have recognized that the right to procreate under Skinner provides support to other rights protected under substantive due process. See, e.g. , Obergefell , 576 U.S. at 674-75 (linking the right to procreate to the later-recognized right to marry); id. at 691 (Roberts, C.J., dissenting) (same).

[53] A recent May 2020 study reported there were an estimated 513,000 married, same-sex couples in the United States. See Christy Mallory & Brad Sears, The Economic Impact of Marriage Equality Five Years After Obergefell v. Hodges, UCLA Sch. of L. Williams Inst. (May 2020), https://williamsinstitute.law.ucla.edu/publications/econ-impact-obergefell-5-years/ [https://perma.cc/JN7K-ZG9P].

[54] Suter & Cahn, supra note 28, at 32.

[56] 478 U.S. 186 (1986).

[57] See Enríquez, supra note 1, at 347.

[58] See id. at 353 n.76.

[59] See Biden v. Missouri, 142 S. Ct. 647 (2022); Nat’l Fed’n of Indep. Bus. v. Dep’t of Lab., Occupational Safety & Health Admin., 142 S. Ct. 661 (2022).

[60] Jessica Gresko & Mark Sherman, High Court Confirms Justices Have Received COVID-19 Booster , AP News (Jan. 4, 2022), https://apnews.com/article/coronavirus-pandemic-joe-biden-us-supreme-court-health-centers-for-disease-control-and-prevention-85207706b48cc76147a17d7a476fd9c6.

[61] 539 U.S. 558 (2003).

[62] 539 U.S. 306 (2003).

[63] 140 S. Ct. 1731 (2020).

[64] 567 U.S. 519 (2012).

[65] Katherine Drabiak, Framing Germline Modifications of Human Embryos , 102 B.U. L. Rev. Online 7, 15 (2022).

[67] Id. at 12 (citing George J. Annas, Lori B. Andrews & Rosario M. Isasi, Protecting the Endangered Human: Toward an International Treaty Prohibiting Cloning and Inheritable Alterations , 28 Am. J.L. & Med. 151, 154-78 (2002) (“[M]any believe that . . . inheritable genetic alternations at the embryo level will never be safe because they will always be inherently unpredictable in their effects on the children and their offspring.”)).

[68] Id. at 7, 10, 14.

[69] See Enríquez, supra note 1, at 386 n.72.

[70] Rodolphe Barrangou, Boston University Law Review Online Virtual Discussion on Rewriting Nature (Nov. 5, 2021).

[71] 1903 Wright Flyer , Smithsonian Nat’l Air & Space Museum, https://airandspace.si.edu/collection-objects/1903-wright-flyer/nasm_A19610048000 (last visited Mar. 11, 2022).

[72] Bart CJM Fauser, Towards the Global Coverage of a Unified Registry of IVF Outcomes , 38 Reproductive Biomedicine Online 133, 133 (2019).

[73] 21 U.S.C. § 355-1(a)(1).

[74] Enríquez, supra note 1, at 161, 337. See also Paul Enríquez, Genome Editing and the Jurisprudence of Scientific Empiricism , 19 Vand. J. Ent. & Tech. L. 603, 666 (2017).

[75] Enríquez, supra note 1, at 276.

[76] Drabiak, supra note 65, at 15 & n.47 (referencing Dena S. Davis’s theory of a right to an open future).

[77] Id. at 15.

[80] Enríquez, supra note 1, at 368.

[81] See generally Greely, supra note 21.

[82] See, e.g. , Enríquez, supra note 1, at 256.

[83] Greely, supra note 21, at 20.

[84] See Enríquez, supra note 1, at 252-53.

[86] See, e.g. , id. at 254-56.

[87] See, e.g. , Paul Enríquez, CRISPR GMOs , 18 N.C. J.L. & Tech. 432, 538 n.536 (2017).

[88] Suter & Cahn, supra note 28, at 33.

[89] Paul Enríquez, Deconstructing Transnationalism: Conceptualizing Metanationalism as a Putative Model of Evolving Jurisprudence , 43 Vand. J. Transnat’l L. 1265, 1269, 1303-10 (2010).

[90] See Paul Enríquez, Editing Humanity: On the Precise Manipulation of DNA in Human Embryos , 97 N.C. L. Rev. 1147, 1152-53 (2019).

[91] Greely, supra note 21, at 17.

[92] In this context, I use “faulty allele” to refer to an allele that features a genetic mutation associated with the onset of a genetic disorder or disease.

[93] See Enríquez, supra note 1, at 364. I suppose one alternative would be to perform GGE on each of the parental gametes, rather than on the fertilized embryo. But that is beyond the scope of the subject of GGE in human embryos contemplated in that section.

[94] Dana Carroll, Rewriting Nature: The Case of Heritable Human Genome Editing , 102 B.U. L. Rev. Online 1, 6 (2022).

[95] Enríquez, supra note 1, at 360-78.

[96] See id. at 368.

[98] See id. at 370-71.

[99] See, e.g. , Laura Hercher & Anya E.R. Prince, Gene Therapy’s Field of Dreams: If You Build It, Will We Pay? , 97 N.C. L. Rev. 1463 (2019).

[100] Allison M. Whelan & Michele Goodwin, Will the Past Be Prologue? Race, Equality, and Human Genetics , 102 B.U. L. Rev. Online 37, 39 (2022).

[101] Boston University Law Review Online Virtual Discussion on Rewriting Nature (Nov. 5, 2021).

Share this:

• Share on Facebook (Opens in new window)
• Click to share on Twitter (Opens in new window)
• Click to share on Reddit (Opens in new window)
• Click to share on LinkedIn (Opens in new window)
• Click to share on Pocket (Opens in new window)

Suggestions or feedback?

MIT News | Massachusetts Institute of Technology

• Machine learning
• Social justice
• Black holes
• Classes and programs

Departments

• Aeronautics and Astronautics
• Brain and Cognitive Sciences
• Architecture
• Political Science
• Mechanical Engineering

Centers, Labs, & Programs

• Abdul Latif Jameel Poverty Action Lab (J-PAL)
• Picower Institute for Learning and Memory
• Lincoln Laboratory
• School of Architecture + Planning
• School of Engineering
• School of Humanities, Arts, and Social Sciences
• Sloan School of Management
• School of Science
• MIT Schwarzman College of Computing

Scientists develop a rapid gene-editing screen to find effects of cancer mutations

Press contact :, media download.

*Terms of Use:

Images for download on the MIT News office website are made available to non-commercial entities, press and the general public under a Creative Commons Attribution Non-Commercial No Derivatives license . You may not alter the images provided, other than to crop them to size. A credit line must be used when reproducing images; if one is not provided below, credit the images to "MIT."

Previous image Next image

Tumors can carry mutations in hundreds of different genes, and each of those genes may be mutated in different ways — some mutations simply replace one DNA nucleotide with another, while others insert or delete larger sections of DNA.

Until now, there has been no way to quickly and easily screen each of those mutations in their natural setting to see what role they may play in the development, progression, and treatment response of a tumor. Using a variant of CRISPR genome-editing known as prime editing, MIT researchers have now come up with a way to screen those mutations much more easily.

The researchers demonstrated their technique by screening cells with more than 1,000 different mutations of the tumor suppressor gene p53, all of which have been seen in cancer patients. This method, which is easier and faster than any existing approach, and edits the genome rather than introducing an artificial version of the mutant gene, revealed that some p53 mutations are more harmful than previously thought.

This technique could also be applied to many other cancer genes, the researchers say, and could eventually be used for precision medicine, to determine how an individual patient’s tumor will respond to a particular treatment.

“In one experiment, you can generate thousands of genotypes that are seen in cancer patients, and immediately test whether one or more of those genotypes are sensitive or resistant to any type of therapy that you’re interested in using,” says Francisco Sanchez-Rivera, an MIT assistant professor of biology, a member of the Koch Institute for Integrative Cancer Research, and the senior author of the study.

MIT graduate student Samuel Gould is the lead author of the paper , which appears today in Nature Biotechnology .

Editing cells

The new technique builds on research that Sanchez-Rivera began 10 years ago as an MIT graduate student. At that time, working with Tyler Jacks, the David H. Koch Professor of Biology, and then-postdoc Thales Papagiannakopoulos, Sanchez-Rivera developed a way to use CRISPR genome-editing to introduce into mice genetic mutations linked to lung cancer.

In that study, the researchers showed that they could delete genes that are often lost in lung tumor cells, and the resulting tumors were similar to naturally arising tumors with those mutations. However, this technique did not allow for the creation of point mutations (substitutions of one nucleotide for another) or insertions.

“While some cancer patients have deletions in certain genes, the vast majority of mutations that cancer patients have in their tumors also include point mutations or small insertions,” Sanchez-Rivera says.

Since then, David Liu, a professor in the Harvard University Department of Chemistry and Chemical Biology and a core institute member of the Broad Institute, has developed new CRISPR-based genome editing technologies that can generate additional types of mutations more easily. With base editing, developed in 2016, researchers can engineer point mutations, but not all possible point mutations. In 2019, Liu, who is also an author of the Nature Biotechnology study, developed a technique called prime editing, which enables any kind of point mutation to be introduced, as well as insertions and deletions.

“Prime editing in theory solves one of the major challenges with earlier forms of CRISPR-based editing, which is that it allows you to engineer virtually any type of mutation,” Sanchez-Rivera says.

When they began working on this project, Sanchez-Rivera and Gould calculated that if performed successfully, prime editing could be used to generate more than 99 percent of all small mutations seen in cancer patients.

However, to achieve that, they needed to find a way to optimize the editing efficiency of the CRISPR-based system. The prime editing guide RNAs (pegRNAs) used to direct CRISPR enzymes to cut the genome in certain spots have varying levels of efficiency, which leads to “noise” in the data from pegRNAs that simply aren’t generating the correct target mutation. The MIT team devised a way to reduce that noise by using synthetic target sites to help them calculate how efficiently each guide RNA that they tested was working.

“We can design multiple prime-editing guide RNAs with different design properties, and then we get an empirical measurement of how efficient each of those pegRNAs is. It tells us what percentage of the time each pegRNA is actually introducing the correct edit,” Gould says.

Analyzing mutations

The researchers demonstrated their technique using p53, a gene that is mutated in more than half of all cancer patients. From a dataset that includes sequencing information from more than 40,000 patients, the researchers identified more than 1,000 different mutations that can occur in p53.

“We wanted to focus on p53 because it’s the most commonly mutated gene in human cancers, but only the most frequent variants in p53 have really been deeply studied. There are many variants in p53 that remain understudied,” Gould says.

Using their new method, the researchers introduced p53 mutations in human lung adenocarcinoma cells, then measured the survival rates of these cells, allowing them to determine each mutation’s effect on cell fitness.

Among their findings, they showed that some p53 mutations promoted cell growth more than had been previously thought. These mutations, which prevent the p53 protein from forming a tetramer — an assembly of four p53 proteins — had been studied before, using a technique that involves inserting artificial copies of a mutated p53 gene into a cell.

Those studies found that these mutations did not confer any survival advantage to cancer cells. However, when the MIT team introduced those same mutations using the new prime editing technique, they found that the mutation prevented the tetramer from forming, allowing the cells to survive. Based on the studies done using overexpression of artificial p53 DNA, those mutations would have been classified as benign, while the new work shows that under more natural circumstances, they are not.

“This is a case where you could only observe these variant-induced phenotypes if you're engineering the variants in their natural context and not with these more artificial systems,” Gould says. “This is just one example, but it speaks to a broader principle that we’re going to be able to access novel biology using these new genome-editing technologies.”

Because it is difficult to reactivate tumor suppressor genes, there are few drugs that target p53, but the researchers now plan to investigate mutations found in other cancer-linked genes, in hopes of discovering potential cancer therapies that could target those mutations. They also hope that the technique could one day enable personalized approaches to treating tumors.

“With the advent of sequencing technologies in the clinic, we'll be able to use this genetic information to tailor therapies for patients suffering from tumors that have a defined genetic makeup,” Sanchez-Rivera says. “This approach based on prime editing has the potential to change everything.”

The research was funded, in part, by the National Institute of General Medical Sciences, an MIT School of Science Fellowship in Cancer Research, a Howard Hughes Medical Institute Hanna Gray Fellowship, the V Foundation for Cancer Research, a National Cancer Institute Cancer Center Support Grant, the Ludwig Center at MIT, the Koch Institute Frontier Research Program via the Casey and Family Foundation Cancer Research Fund, Upstage Lung Cancer, and the Michael (1957) and Inara Erdei Cancer Research Fund, and the MIT Research Support Committee.

Share this news article on:

Related links.

• Francisco Sanchez-Rivera
• Koch Institute
• Department of Biology

Related Topics

• Broad Institute

Related Articles

Gene-editing technique could speed up study of cancer mutations

Fast modeling of cancer mutations

Previous item Next item

More MIT News

Newly discovered Earth-sized planet may lack an atmosphere

Read full story →

Robotic “SuperLimbs” could help moonwalkers recover from falls

3 Questions: Technology roadmapping in teaching and industry

Five MIT faculty elected to the National Academy of Sciences for 2024

Professor Emeritus Jerome Connor, pioneer in structural mechanics, dies at 91

MIT’s Master of Applied Science in Data, Economics, and Design of Policy program adds a public policy track

• More news on MIT News homepage →

Massachusetts Institute of Technology 77 Massachusetts Avenue, Cambridge, MA, USA

• Map (opens in new window)
• Events (opens in new window)
• People (opens in new window)
• Careers (opens in new window)
• Accessibility
• Social Media Hub
• MIT on Facebook
• MIT on YouTube
• MIT on Instagram

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Published: 02 December 2015

Genome editing: 4 big questions

• Will Tauxe 1  

Nature volume  528 ,  page S17 ( 2015 ) Cite this article

24k Accesses

7 Citations

41 Altmetric

Metrics details

• Biological techniques
• Drug discovery
• Epigenetics

Despite the popularity of genome-editing techniques, researchers are still grappling with the known unknowns of the technologies. Here are four of their most pressing questions.

1. How much can we reduce the off-target effects of genome editing?

Why it matters  Unintentional edits can occur where a similar or identical target DNA sequence appears elsewhere in the genome. These off-target edits can frustrate the use of genome editing as a lab tool, and may cause side effects if the technique is used as a therapy.

What we know  The frequency of off-target effects varies among the three genome-editing technologies. TALENs produce the fewest off-target edits because they use a longer stretch of target DNA than ZFNs or CRISPR–Cas9 (see page S4 ).

Next steps  The specificity of CRISPR–Cas9 can be increased by adjusting the guide RNA, which leads Cas9 to its target, and Cas9's structure. Bioinformatics can predict where off-target effects are most likely to occur and evaluate their consequences.

2. Which diseases are suitable targets for genome editing?

Why it matters  The more diseases that can be addressed through genome editing, the greater the technology's potential to relieve the disease burden.

What we know  Genome editing has had some success in combating HIV in people with the infection (see page S8 ), providing hope for those with other non-inherited diseases. Encouraging results have also been seen in models of certain monogenic diseases (see page S10 ).

Next steps  To expand the range of diseases amenable to genome editing, researchers need better ways to deliver the technology to the right cells. CRISPR–Cas9 is too large to fit inside the vector adeno-associated virus. CRISPR systems in different bacteria may offer smaller alternatives.

3. Can the phenotypic effects of genome editing be accurately predicted?

Why it matters  For gene editing to be successful, researchers need to be able to determine the effect that making small changes to DNA, or to its packaging, has on the chemical components and physical properties of cells.

What we know  Several approved drugs (that do not edit the genome) treat conditions such as epilepsy and cancer by causing chemical modifications to DNA that do not change the order of its bases, or by altering DNA's packaging. But no one knows which of the alterations lead to these outcomes.

Next steps  Researchers have modified genome-editing tools to make epigenetic changes. By investigating the changes caused by precise edits, they hope to gain a better understanding of the role of epigenetics in gene expression, and hence phenotype.

4. Should we edit the human germ line?

Why it matters  Making heritable edits has the potential to prevent diseases from being passed down the generations. But 'permanent' changes are risky if we do not have a full understanding of human gene expression. There is also the potential for misuse.

What we know  Edits to the genomes of non-viable human embryos have established proof-of-principle, although there is a high failure rate. If viable embryos are edited, implanting them and bringing them to term is just a short step away.

Next steps  Scientists need to engage with governments and invite informed public discussion to draw up rigorous guidelines that govern research and clinical procedure. Systems must then be put in place to ensure that these guidelines are followed.

Author information

Authors and affiliations.

Will Tauxe is a science writer in Atlanta, Georgia.,

You can also search for this author in PubMed   Google Scholar

Related links

Related links in nature research.

CRISPR-Cas9 genome editing

Rights and permissions

Reprints and permissions

About this article

Cite this article.

Tauxe, W. Genome editing: 4 big questions. Nature 528 , S17 (2015). https://doi.org/10.1038/528S17a

Download citation

Published : 02 December 2015

Issue Date : 03 December 2015

DOI : https://doi.org/10.1038/528S17a

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Ethics and genomic editing using the crispr-cas9 technique: challenges and conflicts.

• David Lorenzo
• Montse Esquerda
• Grup Investigació en Bioética

NanoEthics (2022)

Tailoring non-viral delivery vehicles for transporting genome-editing tools

Science China Materials (2017)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

• Skip to main content
• Keyboard shortcuts for audio player

• Your Health
• Treatments & Tests
• Health Inc.
• Public Health

Experts weigh medical advances in gene-editing with ethical dilemmas

Biophysicist He Jiankui addressed the last international summit on human genome editing in Hong Kong in 2018. His experiments in altering the genetic makeup of human embryos was widely condemned by scientists and ethicists at the time, and still casts a long shadow over this week's summit in London. Anthony Wallace/AFP via Getty Images hide caption

Biophysicist He Jiankui addressed the last international summit on human genome editing in Hong Kong in 2018. His experiments in altering the genetic makeup of human embryos was widely condemned by scientists and ethicists at the time, and still casts a long shadow over this week's summit in London.

Hundreds of scientists, doctors, bioethicists, patients, and others started gathering in London Monday for the Third International Summit on Human Genome Editing . The summit this week will debate and possibly issue recommendations about the thorny issues raised by powerful new gene-editing technologies.

The last time the world's scientists gathered to debate the pros and cons of gene-editing — in Hong Kong in late 2018 — He Jiankui, a biophysicist and researcher at Southern University of Science and Technology in Shenzhen, China, shocked his audience with a bombshell announcement . He had created the first gene-edited babies, he told the crowd — twin girls born from embryos he had modified using the gene-editing technique CRISPR.

He, who had trained at Rice University and Stanford, said he did it in hopes of protecting the girls from getting infected with the virus that causes AIDS . (The girls' father was HIV-positive.) But his announcement was immediately condemned as irresponsible human experimentation. Far too little research had been done, critics said, to know if altering the genetics of embryos in this way was safe . He ultimately was sentenced by a Chinese court to three years in prison for violating medical regulations.

In the more than four years since He's stunning announcement, scientists have continued to hone their gene-editing powers.

"A lot has happened over the last five years. It's been a busy period," says Robin Lovell-Badge from the Francis Crick Institute in London, who led the committee convening the new summit.

Doctors have made advances using CRISPR to try to treat or better understand many diseases, including devastating disorders like sickle cell disease , and conditions like heart disease and cancer that are even more common and influenced by genetics.

Jennifer Doudna, a biochemist at the University of California, Berkeley and one of the pioneers in the discovery and use of CRISPR, speaking with reporters at the scientific summit in Hong Kong in 2018. Despite exciting advances, genome-editing still faces technical and ethical challenges, she says. Isaac Lawrence/AFP via Getty Images hide caption

Jennifer Doudna, a biochemist at the University of California, Berkeley and one of the pioneers in the discovery and use of CRISPR, speaking with reporters at the scientific summit in Hong Kong in 2018. Despite exciting advances, genome-editing still faces technical and ethical challenges, she says.

In recent years, scientists have produced new evidence about the risks and possible shortcomings of gene-editing , while also developing more sophisticated techniques that could be safer and more precise.

"We're at an exciting moment for sure with genome-editing," says Jennifer Doudna at the University of California, Berkeley, who helped discover CRISPR. "At the same time, we certainly have challenges."

"We could help a lot of people"

One big remaining challenge and ethical question is whether scientists should ever again try to make gene-edited babies by modifying the DNA in human sperm, eggs or embryos. Such techniques, if successful could help families that have been plagued by devastating genetic disorders.

"There are more than 10,000 single genetic mutations that collectively affect probably hundreds of million of people around the world," says Shoukhrat Mitalipov , a biologist at the Oregon Health and Science University in Portland who's been trying to find ways to safely gene-edit human embryos. "We could help a lot of people."

Shots - Health News

A year in, 1st patient to get gene editing for sickle cell disease is thriving.

But the fear is a mistake could create new genetic diseases that could then be passed down for generations. Some scientists are also concerned about opening a slippery slope to "designer babies" — children whose parents try to pick and choose their traits.

"If we were to allow parents to genetically modify their children, we would be creating new groups of people who are different from each other biologically and some would have been modified in ways that are supposed to enhance them," says Marcy Darnovsky heads the Center for Genetics and Society in San Francisco. "And they would be — unfortunately I think — considered an enhanced race — a better group of people. And I think that could really just super-charge the inequities we already have in our world."

The debate among many scientists seems to have shifted to how to edit a genome safely

Despite those concerns, some critics say the debate over the last five years has shifted from whether a prohibition on inheritable genetic modifications should ever be lifted to what technical hurdles need to be overcome to do it safely — and which diseases doctors might try to eradicate.

As evidence of that, the critics point to the fact that the subject of genetically modifying embryos, sperm or eggs to engineer modifications that would then be passed along to every subsequent generation is the focus of only one of three days of this summit — the first such conference since the CRISPR babies were announced.

"This is quite an ironic outcome," says Sheila Jasanoff is a professor of science and technology studies at Harvard's Kennedy School of Government.

New U.S. Experiments Aim To Create Gene-Edited Human Embryos

"Instead of rejuvenating the calls to say: 'We should be much more careful,' " Jasanoff says, "it was as if the whole scientific community heaved a kind of sigh of relief and said: 'Well, look, of course there are limits. This guy has transgressed the limits. He's clearly outside the limits. And therefore everything else is now open for grabs. And therefore the problem before us now is to make sure that we lay out the guidelines and the rules.'"

Ben Hurlbut , a bioethicist at Arizona State University, agrees.

"There was a time when this was considered taboo," he says. "But since the last summit, there's been a shift from asking the question of 'whether' to asking the question of 'how.' "

It was too easy to scapegoat He, some ethicists say

Hurlbut and others also say scientists have failed to fully come to terms with the high-pressure environment of biomedical research that they say encouraged He to do what he did.

"It just feels easier to condemn He and say all bad resides in his person and he should be ostracized forever as we proceed apace. Not reckoning with what happened and why fosters a certain thoughtlessness, and I would say recklessness," Hurlbut says.

2 Chinese Babies With Edited Genes May Face Higher Risk Of Premature Death

A Russian Biologist Wants To Create More Gene-Edited Babies

That lack of reckoning with what happened could be dangerous, critics say. It could, they fear, encourage others to try make more gene-edited babies, at a time when the public may never have been more skeptical about scientific experts.

"We have seen in recent years a sense that the experts have taken on too big a role and that they have tried to run roughshod over our our day-to day-lives," says Hank Greely , a longtime Stanford University bioethicist. But whether or not inheritable genetic modifications should be allowed is "ultimately a decision for societies and not a decision for science."

A new lab in Beijing

Meanwhile, He Jiankui appears to be trying to rehabilitate himself after serving his three-year prison sentence. He's set up a new lab in Beijing, is promising to develop new gene-therapies for diseases like muscular dystrophy, is giving scientific presentations , and is trying to raise money.

He's not expected to join the London summit this week, and is no longer talking about creating more gene-edited babies. Still, his activities are raising alarm in the scientific and bioethics communities. He declined NPR's request for an interview. But in a recently published interview with The Guardian the only regret he mentioned was in moving too fast.

"I'm concerned," Lovell-Badge says. "I'm surprised that that he's being allowed to practice science again. It just scares me."

Others agree.

"What he did was atrocious," says Dr. Kiran Musunuru , a professor of medicine at the University of Pennsylvania. "He shouldn't be allowed anywhere near a patient again. He's proven himself to be utterly unqualified."

Lovell-Badge and other organizers of the summit dispute criticisms that scientists are assuming gene-edited babies are inevitable and that the agenda for this week's conference short-changes a debate about the ethical and societal landmines that remain in this field of study.

Gene Therapy Shows Promise For Hemophilia, But Could Be Most Expensive U.S. Drug Ever

Summit leaders say they'll dedicate the last day of the meeting to genetic modifications that can be passed down through generations; panel participants will feature scientists as well as a broad array of watchdog groups, patient advocates, bioethicists, sociologists and others.

Conference organizers say they have good reasons for focusing the first two-thirds of the meeting on the use of gene-editing to treat people who have already been born.

"The summit is a chance to really hear about what's happening in the field that has the greatest potential for improving human health," says R. Alta Charo, a professor emerta of law and bioethics from the University of Wisconsin, who helped organize the summit.

Questions of equity have moved center stage

But those current treatments raise their own ethical concerns — including questions of equity. Will the the current and coming gene therapies be widely available, given how expensive and technologically complicated they can be to create and administer?

Goats and Soda

Why astronomical drug prices are bad for health — and profits.

"We're not moving away from the conversation around heritable genome editing, but we are trying to shift some of that focus," says Francoise Baylis , a bioethicist who recently retired from Dalhousie University in Canada and helped plan the meeting. "Really important in this context is the issue of cost, because we have been seeing gene-therapies come onto the market with million-dollar price tags. That's not going to be available to the average person."

The availability of gene-therapy treatments in lower-income countries must be a focus of concern, Baylis says.

"We're going to be asking questions about where are the people who are most likely to be benefit," she says, "and are they going to have access?"

• genome editing
• gene-editing

• Featured News
• Artificial Intelligence
• Bioprocessing
• Drug Discovery
• Genome Editing
• Infectious Diseases
• Translational Medicine
• Browse Issues
• Learning Labs
• eBooks/Perspectives
• GEN Biotechnology
• Re:Gen Open
• New Products
• Conference Calendar
• Get GEN Magazine
• Get GEN eNewsletters

Epigenome Editing Toolkit Elucidates Gene Regulation Mechanisms

A molecular model showing three of the main epigenetic modifications of DNA (orange) and histones (dark blue) [JUAN GAERTNER/SCIENCE PHOTO LIBRARY].

Genes are regulated by complex interactions involving transcription factors, DNA regulatory regions, and epigenetic modifications which alter chromatin structure. Modifications to chromatin regulate important biological processes including development and response to environmental signals. Scientists from the European Molecular Biology Laboratory (EMBL) have developed what they describe as a modular epigenome editing platform that uses CRISPR-Cas9 technology to program epigenetic modifications at any location in the genome. Details of their work are published in Nature Genetics in a paper titled, “ Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications .”

According to its developers, the CRISPR-based system can program nine biologically important chromatin marks at any desired region in the genome. The scientists also designed a reporter system that allowed them to measure changes in gene expression at the single-cell level, and to understand how changes in the DNA sequence influence the impact of each chromatic mark. 

“Our modular epigenetic editing toolkit constitutes a new experimental approach to dissect the reciprocal relationships between the genome and epigenome,” said Jamie Hackett, PhD, group leader at EMBL Rome and senior author on the paper. “The system could be used in the future to more precisely understand the importance of epigenomic changes in influencing gene activity during development and in human disease. On the other hand, the technology also unlocks the ability to program desired gene expression levels in a highly tunable manner. This is an exciting avenue for precision health applications and may prove useful in disease settings.”

Scientists have studied the effects of specific chromatin marks on gene regulation by mapping their distribution in the genomes of healthy and diseased cells, and combining the data with gene expression and the known effects of perturbing specific genes. However, the causal relationship between chromatin marks and gene regulation is difficult to determine. Using CRISPR, the researchers could alter specific DNA locations and dissect the cause-and-consequence relationships between the chromatin marks and their biological effects.

With their epigenome editing system, the scientists identified interesting roles for chromatin marks like H3K4me3. They observed that it increases transcription by itself if artificially added to specific DNA locations. “This was an extremely exciting and unexpected result that went against all our expectations,” said Cristina Policarpi, PhD, a postdoc in the Hackett group and lead scientist of the study. “Our data point toward a complex regulatory network, in which multiple governing factors interact to modulate the levels of gene expression in a given cell. These factors include the pre-existing structure of the chromatin, the underlying DNA sequence, and the location in the genome.” 

For their next steps, the researchers plan to confirm and expand upon their conclusions by targeting genes across different cell types. They’ll also explore how chromatin marks influence transcription across diverse genes and downstream mechanisms. Lastly, the team is exploring avenues for commercializing their technology through a start-up.

Successful Step Made toward Synthetic Genomes

Oxford biomedica to obtain $250k to support gene therapy for stargardt....

• Introduction to Genomics
• Educational Resources
• Policy Issues in Genomics
• The Human Genome Project
• Funding Opportunities
• Funded Programs & Projects
• Division and Program Directors
• Scientific Program Analysts
• Contact by Research Area
• News & Events
• Research Areas
• Research investigators
• Research Projects
• Clinical Research
• Data Tools & Resources
• Genomics & Medicine
• Family Health History
• For Patients & Families
• For Health Professionals
• Jobs at NHGRI
• Training at NHGRI
• Funding for Research Training
• Professional Development Programs
• NHGRI Culture
• Social Media
• Broadcast Media
• Image Gallery
• Press Resources
• Organization
• NHGRI Director
• Mission & Vision
• Policies & Guidance
• Institute Advisors
• Strategic Vision
• Leadership Initiatives
• Diversity, Equity, and Inclusion
• Partner with NHGRI
• Staff Search

What are the Ethical Concerns of Genome Editing?

Most of the ethical discussions related to genome editing center around human germline because editing changes made in the germline would be passed down to future generations.

The debate about genome editing is not a new one but has regained attention following the discovery that CRISPR has the potential to make such editing more accurate and even "easy" in comparison to older technologies.

Bioethicists and researchers generally believe that human genome editing for reproductive purposes should not be attempted at this time, but that studies that would make  gene therapy  safe and effective should continue. 1 , 2  Most stakeholders agree that it is important to have continuing public deliberation and debate to allow the public to decide whether or not germline editing should be permissible. As of 2014, there were about 40 countries that discouraged or banned research on germline editing, including 15 nations in Western Europe, because of ethical and safety concerns. 3  There is also an international effort led by the US, UK, and China to harmonize regulation of the application of genome editing technologies. This effort officially launched in December 2015 with the  International Summit on Human Gene Editing  in Washington, DC. For more information on this summit, see  What's happening right now?

NHGRI uses the term "genome editing" to describe techniques used to modify DNA in the genome. Other groups also use the term "gene editing." In general, these terms are used interchangeably.

Ethical Considerations

Due to the possibility of off-target effects (edits in the wrong place) and mosaicism (when some cells carry the edit but others do not), safety is of primary concern. Researchers and ethicists who have written and spoken about genome editing, such as those present at the  International Summit on Human Gene Editing,  generally agree that until germline genome editing is deemed safe through research, it should not be used for clinical reproductive purposes; the risk cannot be justified by the potential benefit. Some researchers argue that there may never be a time when genome editing in embryos will offer a benefit greater than that of existing technologies, such as  preimplantation genetic diagnosis (PGD)  and  in-vitro fertilization (IVF) . 4

However, scientists and bioethicists acknowledge that in some cases, germline editing can address needs not met by PGD. This includes when both prospective parents are  homozygous  for a disease-causing variant (they both have two copies of the variant, so all of their children would be expected to have the disease); cases of polygenic disorders, which are influenced by more than one gene; and for families who object to some elements of the PGD process. 5 , 6

Some researchers and bioethicists are concerned that any genome editing, even for therapeutic uses, will start us on a slippery slope to using it for non-therapeutic and  enhancement  purposes, which many view as controversial. Others argue that genome editing, once proved safe and effective, should be allowed to cure genetic disease (and indeed, that it is a moral imperative). 6  They believe that concerns about enhancement should be managed through policy and regulation.

Lastly, commenters on the issue are concerned that the use of genome editing for reproductive purposes will be regulated differently inside and outside of the U.S., leading to uses considered objectionable to the American public. These arguments cite the largely self-regulated environments of the reproductive clinics that offer PGD and IVF 7 , 8  and the existing differences in regulations among different countries. 9

Informed Consent

Some people worry that it is impossible to obtain informed consent for germline therapy because the patients affected by the edits are the embryo and future generations. The counterargument is that parents already make many decisions that affect their future children, including similarly complicated decisions such as PGD with IVF. Researchers and bioethicists also worry about the possibility of obtaining truly informed consent from prospective parents as long as the risks of germline therapy are unknown. 10

Justice and Equity

As with many new technologies, there is concern that genome editing will only be accessible to the wealthy and will increase existing disparities in access to health care and other interventions. Some worry that taken to its extreme, germline editing could create classes of individuals defined by the quality of their engineered genome.

Genome-Editing Research Involving Embryos

Many people have moral and religious objections to the use of human embryos for research. Federal funds cannot be used for any research that creates or destroys embryos. In addition, NIH does not fund any use of gene editing in human embryos. (See:  U.S. and NIH regulations and perspective )

While NIH will not fund gene editing in human embryos at this time, many bioethical and research groups believe that research using gene editing in embryos is important for myriad reasons, including to address scientific questions about human biology, as long as it is not used for reproductive purposes at this time. 11 , 12  Some countries have already allowed genome-editing research on nonviable embryos (those that could not result in a live birth), and others have approved genome-editing research studies with viable embryos. 13 , 14  In general, research that is conducted in embryos could use viable or nonviable embryos leftover from IVF, or embryos created expressly for research. Each case has its own moral considerations.

[1] National Academies of Sciences, E., Medicine,. (2017). Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press.

[2] The Hinxton Group. (2015). Statement on Genome Editing Technologies and Human Germline Genetic Modification. Retrieved from http://www.hinxtongroup.org/Hinxton2015_Statement.pdf

[3] Araki, M., & Ishii, T. (2014). International regulatory landscape and integration of corrective genome editing into in vitro fertilization. Reprod Biol Endocrinol, 12, 108. doi:10.1186/1477-7827-12-108

[4] Lanphier, E., Urnov, F., Haecker, S. E., Werner, M., & Smolenski, J. (2015). Don't edit the human germ line. Nature News, 519(7544), 410. doi:10.1038/519410a

[5] Hampton, T. (2016). Ethical and Societal Questions Loom Large as Gene Editing Moves Closer to the Clinic. JAMA, 315(6), 546-548. doi:10.1001/jama.2015.19150

[6] Savulescu, J., Pugh, J., Douglas, T., & Gyngell, C. (2015). The moral imperative to continue gene editing research on human embryos. Protein Cell, 6(7), 476-479. doi:10.1007/s13238-015-0184-y

[7] Ishii, T. (2017). Germ line genome editing in clinics: the approaches, objectives and global society. Brief Funct Genomics, 16(1), 46-56. doi:10.1093/bfgp/elv053

[8] Park, A. (2016). UK Approves First Studies Using New Gene Editing Technique. Time Health.

[9] Araki, M., & Ishii, T. (2014). International regulatory landscape and integration of corrective genome editing into in vitro fertilization. Reprod Biol Endocrinol, 12, 108. doi:10.1186/1477-7827-12-108

[10] Lanphier, E., Urnov, F., Haecker, S. E., Werner, M., & Smolenski, J. (2015). Don't edit the human germ line. Nature News, 519(7544), 410. doi:doi:10.1038/519410a

[11] The Hinxton Group. (2015). Statement on Genome Editing Technologies and Human Germline Genetic Modification. Retrieved from http://www.hinxtongroup.org/Hinxton2015_Statement.pdf

[12] National Academies of Sciences, E., Medicine,. (2017). Human Genome Editing: Science, Ethics, and Governance. Washington, DC: The National Academies Press.

[13] Callaway, E. (2016). UK scientists gain licence to edit genes in human embryos. Nature News, 530(7588), 18. doi:doi:10.1038/nature.2016.19270

[14] Cyranoski, D., & Reardon, S. (2017). Chinese scientists genetically modify human embryos. Nature News. doi:doi:10.1038/nature.2015.17378

Last updated: August 3, 2017

An epigenome editing toolkit to dissect the mechanisms of gene regulation

Understanding how genes are regulated at the molecular level is a central challenge in modern biology. This complex mechanism is mainly driven by the interaction between proteins called transcription factors, DNA regulatory regions, and epigenetic modifications -- chemical alterations that change chromatin structure. The set of epigenetic modifications of a cell's genome is referred to as the epigenome.

In a study just published in Nature Genetics , scientists from the Hackett Group at EMBL Rome have developed a modular epigenome editing platform -- a system to program epigenetic modifications at any location in the genome. The system allows scientists to study the impact of each chromatin modification on transcription, the mechanism by which genes are copied into mRNA to drive protein synthesis.

Chromatin modifications are thought to contribute to the regulation of key biological processes such as development, response to environmental signals, and disease.

To understand the effects of specific chromatin marks on gene regulation, previous studies have mapped their distribution in the genomes of healthy and diseased cell types. By combining this data with gene expression analysis and the known effects of perturbing specific genes, scientists have ascribed functions to such chromatin marks.

However, the causal relationship between chromatin marks and gene regulation has proved difficult to determine. The challenge lies in dissecting the individual contributions of the many complex factors involved in such regulation -- chromatin marks, transcription factors, and regulatory DNA sequences.

Scientists from the Hackett Group developed a modular epigenome editing system to precisely program nine biologically important chromatin marks at any desired region in the genome. The system is based on CRISPR -- a widely used genome editing technology that allows researchers to make alterations in specific DNA locations with high precision and accuracy.

Such precise perturbations enabled them to carefully dissect cause-and-consequence relationships between chromatin marks and their biological effects. The scientists also designed and employed a 'reporter system', which allowed them to measure changes in gene expression at single-cell level and to understand how changes in the DNA sequence influence the impact of each chromatin mark. Their results reveal the causal roles of a range of important chromatin marks in gene regulation.

For example, the researchers found a new role for H3K4me3, a chromatin mark that was previously believed to be a result of transcription. They observed that H3K4me3 can actually increase transcription by itself if artificially added to specific DNA locations. "This was an extremely exciting and unexpected result that went against all our expectations," said Cristina Policarpi, postdoc in the Hackett Group and leading scientist of the study. "Our data point towards a complex regulatory network, in which multiple governing factors interact to modulate the levels of gene expression in a given cell. These factors include the pre-existing structure of the chromatin, the underlying DNA sequence, and the location in the genome."

Hackett and colleagues are currently exploring avenues to leverage this technology through a promising start-up venture. The next step will be to confirm and expand these conclusions by targeting genes across different cell types and at scale. How chromatin marks influence transcription across the diversity of genes and downstream mechanisms, also remains to be clarified.

"Our modular epigenetic editing toolkit constitutes a new experimental approach to dissect the reciprocal relationships between the genome and epigenome," said Jamie Hackett, Group Leader at EMBL Rome. "The system could be used in the future to more precisely understand the importance of epigenomic changes in influencing gene activity during development and in human disease. On the other hand, the technology also unlocks the ability to program desired gene expression levels in a highly tunable manner. This is an exciting avenue for precision health applications and may prove useful in disease settings."

• Epigenetics
• Human Biology
• Epigenetics Research
• Biotechnology
• Biochemistry
• Organic Chemistry
• Microarrays
• Personalized medicine
• Biological psychiatry
• Engineering
• Gene therapy
• U.S. Navy Marine Mammal Program

Story Source:

Materials provided by European Molecular Biology Laboratory . Note: Content may be edited for style and length.

Journal Reference :

• Cristina Policarpi, Marzia Munafò, Stylianos Tsagkris, Valentina Carlini, Jamie A. Hackett. Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications . Nature Genetics , 2024; DOI: 10.1038/s41588-024-01706-w

Cite This Page :

Explore More

• Nature's 3D Printer: Bristle Worms
• Giant ' Cotton Candy' Planet
• A Young Whale's Journey
• No Inner Voice Linked to Poorer Verbal Memory
• Bird Flu A(H5N1) Transmitted from Cow to Human
• Universe's Oldest Stars in Our Galactic Backyard
• Polygenic Embryo Screening for IVF: Opinions
• VR With Cinematoghraphics More Engaging
• 2023 Was the Hottest Summer in 2000 Years
• Fastest Rate of CO2 Rise Over Last 50,000 Years

Trending Topics

Strange & offbeat.