Brief for GSDR – 2016 Update CRISPR/Cas9 - gene-editing technology takes off Friedrich Soltau, United Nations Department of Economic and Social Affairs* Introduction Issues for scientific debate Recent years have seen rapid progress in the The CRISPR technology involves the application area of biotechnology and the life sciences, of a defence mechanism developed by driven by factors such as the sharply falling bacterial; cells against viral invaders. In very cost of DNA sequencing and the wider simplified terms, what makes it useful is that it application of computational approaches. In allows researchers to precisely target a particular, it is a very new gene-editing location on the DNA of a cell, make a “cut”, and technology called CRISPR 1 that has caused then insert a custom-designed DNA sequence. excitement among researchers with its Or, alternatively, “cut” and thus delete the potential applications in biotechnology and targeted genetic sequence, say a gene medicine. The development of a rapid, reliable, encoding an undesirable trait associated with and cost-effective technology for editing the an illness. Unlike previous gene editing genomes of living plants, animals and humans technologies, it is easy to use, in that the holds out great promise. However, the new various elements can be quickly and reliably technology – especially the possibility of assembled, without a process of tinkering and editing the genome so that changes are passed trial and error. The process of gene-editing has down, so-called germline editing – raises essentially moved from being a very ethical and safety concerns (Ledford, 2015a). specialized, custom-designed approach, to a Reports that scientists had used CRISPR to powerful, reliable tool at the disposal of a wide engineer human embryos (albeit ones unable range of scientists. to result in live births) have added urgency to Like any new technology, there are different the ethical debate about the use of the technology (Cyranoski & Reardon, 2015). views about its application. Among the Safety concerns include the risk that the applications that have been raised is the use of CRISPR to propagate so-called gene drives to technique may cause unintended and potentially risky edits, or that lack of adequate eliminate diseases such as malaria, by controls may lead to the escape of edited influencing the capacity of the mosquito vector organisms capable of disrupting ecosystems to transmit the disease, or improving crops varieties (Je Wook Woo et al, 2015). In human and harming biodiversity (Ledford, 2015a). medicine, the CRISP could be used for a range The very rapid adoption of the technology, and of purposes, including improving the function its relative simplicity, adds urgency to of genes, carrying out screening for new discussions around how and when it should be targets for therapeutics, and direct used, as well as the need for monitoring and therapeutics, i.e. gene therapy (Charpentier, oversight. 2015). 1 Outside the realm of human medicine, CRISPR CRISPR stands for “clustered, regularly inter- spaced palindromic repeats”. It often referred to as is poised to accelerate efforts to use CRISPR/Cas9, with Cas9 being the enzyme that biotechnology to create plants and animals cleaves (cuts) the DNA strand. 1 * The views and opinions expressed are the author’s and do not represent those of the Secretariat of the United Nations. Online publication or dissemination does not imply endorsement by the United Nations. with desirable traits. CRISPR has also made deleterious effects, one would also need to possible the realization of a “gene drives”, consider other, protective effects (Lander, which works by installing the gene-editing 2015). machinery in a living thing so that it will spread specific DNA every time an organism In addition, from an ethical standpoint, there is reproduces (Gantz & Bier, 2015). This has it the consideration that the since the people possible, for instance, to engineer in the who would be affected by germline gene laboratory mosquitoes that resist malaria and therapy are not yet born, they are not in a spread this trait to their progeny (James et al, position to decide whether to have the 2015). A recent overview paper by leading treatment (NHI, 2016). Considerations such as this, together with appeal to some of genetic authorities in the field states that gene drives have the potential to prevent the spread of enhancement (“designer babies”), underpin disease, improve agriculture by addressing the call to secure through the United Nations a pesticide and herbicide resistance in insects complete ban on germline editing for and weeds, and help manage invasive species reproductive purposes (Haker, 2015). (Esvelt et al, 2014). The authors caution, The argument has been made that there is no however, that “the possibility of unwanted pressing need for making heritable ecological effects and near-certainty of spread modifications to the human germline (Lander, across political borders demand careful 2015). First, diseases caused by a single errant assessment of each potential application.” gene are actually rare, and germline gene It is important to distinguish the kinds of editing is not applicable to common diseases like cancer or diabetes where the hereditary human gene therapy that can be carried out with CRISPR. One involves targeting the component is caused by many different genes, therapy to body cells such as bone marrow or in conjunction with environmental factors. Second, in most cases pre-implantation genetic blood cells, so-called somatic cells. Importantly, any changes made using this kind testing can be used during IVF to detect the of gene therapy cannot be passed on to a egg cells carrying the disease-related gene. An person’s children. A second form of gene opposing view disputes the safety concerns therapy can targets egg and sperm cells, so- related to “off-target” edits, pointing out that called germline cells. Changes made to CRISPR is very accurate (Church, 2015) and germline cells – deletions or insertions – would becoming more so (Ledford, 2015b). It is also be passed on to future generations (NHI, argued that genetic diseases where prenatal 2016). While such as therapy could, for diagnosis would be of no assistance – e.g. instance potentially free future generations in where one parent has two dominant copies of a family from a particular genetic disorder, a disease-related gene – are more common there is also the risk of long-term side effects than otherwise thought (Church, 2015). that are not yet known. Thus it ought to be A statement released by the Organizing considered that the human genome reflects Committee of the International Summit on our evolution, and that there may be as yet Human Genome Editing, held in December unknown reasons why favourable, protective 2015, stated that germline editing in a clinical genes are not more common (Lander, 2015). setting should not proceed unless concerns Related to this, is the question of pleiotropy – a regarding safety and effectiveness have been single gene may have multiple effects. Thus in resolved, and there is broad social consensus deleting a gene a gene on grounds of its about the appropriateness of the use in this 2 setting (NAS, 2015). The scientists concluded seeking to modify the human genome may only that: “At present, these criteria have not been be undertaken for preventive, diagnostic or met for any proposed clinical use: the safety therapeutic purposes and only if its aim is not issues have not yet been adequately explored; to introduce any modification in the genome of the cases of most compelling benefit are any descendants”. The Convention, which has limited; and many nations have legislative or been ratified by 29 European countries regulatory bans on germline modification” (Council of Europe, 2016), effectively prohibits (NAS, 2015). However, they added the clinical germline interventions and limits the use of use of germline editing ought to be revisited at somatic gene therapy (Adorno, 2005). regular intervals, recognizing that scientific Among the applications that have been knowledge advances and as societal views suggested somatic cells - where changes are evolved. not transmitted to following generations – are The Summit was notable in being organized by sickle cell disease, haemophilia, and cystic the U.S. National Academy of Sciences, the U.K. fibrosis (Porteus, 2015). While risks and Royal Academy, and the Chinese Academy of benefits need to be weighed, such clinical Sciences, thus spanning key domains of activity applications can be evaluated within existing in the life sciences. In addition, the gathering and evolving regulatory frameworks for gene consciously featured participants outside the therapy (NAS, 2015). It also needs to be natural sciences, in order to address ethical, recognized that many of the most important institutional and regulatory dimensions of the consequences of CRISPR are not the ones issue. grabbing the headlines, but rather fact that the technology makes many experiments easier to The statement recognized that basic and carry out, thus facilitating basic research on clinical research will continue, including with diseases such as cancer and autism (Regalado, human germline cells, but that where in the 2015). Another promising area of development “process of research, early human embryos or is the production of non-human organ donors. germline cells undergo gene editing, the Scientists reported that they were able to use modified cells should