CRISPR-Cas9 is a genetic engineering tool discovered in 2012. This disruptive innovation is raising hopes in various sectors, particularly in the agri-food industry and in medicine. However, it remains surrounded by many uncertainties, whether ethical, technical or legal. To understand its significance, we must first go over some of the basics of genetics.
Calvin et Hobbes, par Bill Watterson
Every organism, whether plant or animal, contains deoxyribonucleic acid (DNA) molecules in its cells, the coding parts of which are transcribed and translated into proteins with different biological functions. If mutations in the DNA occur, the phenotypic characteristics can be altered. Such mutations occur naturally in all organisms and, when they confer a selective advantage and are also heritable, they are conserved by natural selection: the best adapted individuals have a greater chance of surviving, reproducing and passing on their genetic heritage. It is through this mechanism, theorised by Darwin, that species have evolved and improved to adapt to their environment.
The selection of mutations can also be the result of human activity. Humans have long used the principle of selection in agriculture: by sowing the most successful maize seeds over a period of about 9000 years, humans have succeeded in increasing the size of an ear of corn by a factor of 12 [1]. The slowness of the process is due to the low frequency of occurrence of hereditary mutations conferring a selective advantage. In vitro mutagenesis techniques have made it possible to increase this frequency, but it was above all the discovery of endonucleases and the development of transgenesis techniques in the second half of the 20th century that founded genetic engineering. Endonucleases are enzymes capable of cutting DNA at a specific sequence, called a restriction site. Transgenesis made it possible to create new organisms by directly importing a foreign gene, and thus to produce new characteristics not linked to the occurrence of random mutations. The method was revolutionary, but it remained dependent on the presence and location of the restriction site recognised by the endonuclease. Applications were therefore limited.
In contrast, CRISPR-Cas9 is an endonuclease that can recognise any restriction site because it is guided by a strand of ribonucleic acid (RNA) that can be edited on demand. The technique offers unprecedented flexibility. It allows a mutation to be induced at a specific site and its applications are very broad. It offers new hope in medicine because it will now be easier to modify the expression of genes involved in diseases that are currently difficult to treat [2]. Its applications are also promising in agriculture, since this technique of directed mutagenesis makes it possible to obtain new targeted varieties much more quickly. Some see it as a way of meeting the major ecological challenges of the 21st century, by creating varieties that are naturally resistant to diseases or pests, making the use of pesticides obsolete, or plants that consume little water and are adapted to climate change. These genetic scissors would also make it possible to stabilise first-generation hybrid varieties, whereas farmers are currently forced to buy back their seeds every year [3].
However, these advances are still surrounded by their share of uncertainties. Firstly, from an ethical point of view, the possibilities offered by CRISPR-Cas9 are fuelling fantasies of the posthuman at a time when there is no consensus in international society on the limits that should not be crossed. Shortly after the birth of twins genetically modified using this technique by Chinese doctor He Jiankui, several scientists, including the Frenchwoman Emmanuelle Charpentier, who was involved in the discovery of CRISPR-Cas9, argued in the journal Nature for a moratorium on the genetic modification of germ cells for non-experimental purposes [4]. In contrast, other scientists have reaffirmed their willingness to modify embryos and bring them to term [5]. It is therefore becoming urgent to create an international framework for reflection. On 29 August, the WHO announced the launch of a register to monitor research involving the genetic modification of human embryos [6].
From a technical point of view, the method is not infallible. According to an Inserm study [7], only 40% of cells are correctly modified. In 60% of cases, unwanted mutations may affect the targeted gene. In addition, there is a risk of mutations at off-target sites. Finally, the interactions between genes are not always identified, so that the modification of a gene may have unforeseen consequences on non-target functions [8]. A recent study suggests that twins born in China may have a reduced life expectancy [9]. Already, research groups are working on a more reliable method that would limit unwanted changes [10].
Finally, the legal framework surrounding CRISPR-Cas9 is widely debated. A patent war has created major uncertainties for operators [11]. In the field of health, the bioethics bill currently under discussion aims to “remove the unfounded constraints on research using certain cells, by maintaining a renewed framework adapted to the state of science”.[12]. In particular, it facilitates research on embryonic stem cells, as opposed to research on human embryos, by replacing the current authorisation regime with a regime of declaration to the Biomedicine Agency (Article 14). It also removes the ban on the creation of transgenic embryos (Article 17). Finally, in the agri-food sector, the controversy over the submission of products obtained by CRISPR-Cas9 to the regime of genetically modified organisms (GMOs) is in full swing. On 25 July 2018, the Court of Justice of the European Union upheld the precautionary principle with regard to organisms obtained using new mutagenesis techniques, including CRISPR-Cas 9. It concluded that Directive 2001/18/EC on the deliberate release of GMOs and Article 4§4 of Directive 2002/53/EC on the common catalogue of varieties of agricultural plant species [13]. Thus, products and varieties obtained by CRISPR-Cas 9 should now be subject to the authorisation and monitoring regime for GM products. Since then, several public statements in favour of a more flexible framework for the exploitation of agricultural products obtained by CRISPR-Cas9 have been published or signed by universities, research centres and interest groups [14]. Taking into account the product obtained rather than the method used is a constant in the criticism, because the product obtained by mutagenesis involving CRISPR-Cas9 would not be different from products – not subject to the GMO regime – obtained by natural mutation or classic mutagenesis. But in addition to these substantive questions, it is also the legitimacy of the judge to decide a political, technical and social issue that is being questioned. There is no doubt that the recently elected European Parliament will soon be confronted with these debates.
Chloé Suel
Doctoral student at the University of Paris I Panthéon-Sorbonne.
[1] “Genetically Engineered Crops: Experiences and Prospects”, Académies américaines des sciences, de l’ingénierie et de la médecine, 2016, cité dans le rapport parlementaire “Les enjeux économiques, environnementaux, sanitaires et éthiques des biotechnologies à la lumière des nouvelles pistes de recherche”, OPECST, 14 avril 2017.
[2] E.g. : “Des chercheurs éliminent le virus du Sida chez la souris, une première”, Sciences et Avenir (site web), jeudi 4 juillet 2019.
[3] “Le clonage s’invite chez les plantes cultivées”, Le Figaro, 17 janvier 2019.
[4] “Adopt a moratorium on heritable genome editing”, Nature, 14 mars 2019.
[5] “L’OMS lance un registre mondial sur la recherche en matière de correction sur le génome humain”, communiqué de presse, 29 août 2019.
[6] ibidem.
[7] Grégoire Cullot et coll., “CRISPR-Cas9 genome editing induces megabase-scale chromosomal truncations”, Nature Communications, 8 mars 2019.
[8] “Adopt a moratorium on heritable genime editing”, précité.
[9] Jeremy Luban, “The hidden cost to genetic resistance to HIV-1″, Nature Medicine, 3 juin 2019.
[10] E.g. ”CRISPR-Cas 9 : vers un outil plus sûr pour éditer les génomes”, Inserm (site web), 14 mai 2019, accessible en ligne : https://www.inserm.fr/actualites-et-evenements/actualites/crispr-cas9-vers-outil-plus-sur-pour-editer-genomes.
[11] Nathalie Blanc, ”La propriété intellectuelle et les progrès contemporains de la génétique : le cas des ciseaux génétiques”, Revue juridique personnes et familles, n°7-8, 1er juillet 2019.
[12] Projet de loi relatif à la bioéthique enregistré à la présidence de l’Assemblée nationale le 24 juillet 2019, p. 7, disponible en ligne : http://www.assemblee-nationale.fr/15/pdf/projets/pl2187.pdf.
[13] CJUE, arrêt du 25 juillet 2018, aff. C-528/16, Confédération paysanne E.A.
[14] E.g. : “Open Statement – European scientists urgently reach out to the newly elected European Parliament and European Commission to enable the potential of genome editing for sustainable agriculture and food production“, 25 juillet 2019, disponible en ligne (https://www.ceplas.eu/fileadmin/user_upload/News-2019/Open_statement_EuGH_full.pdf) ; ou encore : ”Directive OGM: des organisations agricoles souhaitent une révision”, AFP Infos Economiques, 10 septembre 2019.
The opinions expressed in this article are those of the authors and do not reflect the position of the Institute.