Gene-Editing: Where Do We Draw the Line?

By Lucas Tan

Since the discovery of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) in 2012, scientists and pharmaceuticals have invested countless hours and billions into developing ground-breaking gene-editing technologies due to CRISPR’s simplicity, affordability, and efficiency [1-2]. The potential benefits of gene-editing through CRISPR range from treating genetic diseases like sickle cell disease1 and Duchenne muscular dystrophy2, to increasing the yield and hastening the process of crop growth [3-6]. James J. Lee, a researcher at the University of Minnesota, also claim that, in principle, scientists could utilise CRISPR to significantly boost the expected intelligence of an embryo [7]. For the first time in history, Homo sapiens —instead of natural selection —possess the ability to influence the biological fate of living things on Earth. As with any disruptive technology, it is of paramount importance for us to explore the ethical boundaries of CRISPR. Should genetic enhancements such as increasing the intelligence of individuals be allowed? What constitutes genetic enhancements? Where do we draw the line? This article seeks to present existing applications of CRISPR and explore a variety of — but by no means all — ethical concerns regarding gene-editing.

Figure 1: How CRISPR/Cas9 Works adapted from [28].

Before debating the ethics of gene-editing, it would do well for one to understand how CRISPR works. One of the most popular methods scientists use to perform genetic editing is through CRISPR/Cas9. Cas9, a CRISPR-associated protein, is an endonuclease that forms base pairs with DNA target sequences. It accomplishes this by utilising a guide sequence within an RNA duplex, trans-activating crispr RNA (tracrRNA):crispr RNA (crRNA). This enables Cas9 to introduce a site-specific double-strand break in the DNA. Researchers then engineer the dual tracrRNA:crRNA as a single guide RNA (sgRNA) that possesses two critical characteristics: a duplex RNA structure at the 3’ side that binds to Cas9 and a sequence at the 5’ side that determines the DNA target site through base-pairing with the DNA. This allows Cas9 to target any DNA sequence of interest by changing the guide sequence of the sgRNA programme [8]. Figure 1 is a brief illustration of the process of gene-editing with CRISPR/Cas9.

Genetic congenital abnormalities and disorders are present in 2-5% of births [9], a staggering statistic. Harnessing the power of gene-editing will provide a whole host of benefits. CRISPR gene-editing has already displayed fantastic potential in areas like therapeutics and agriculture. In 2019, D. Alapati et al. accurately timed in utero intra-amniotic administration of CRISPR/Cas9 elements—for monogenic lung disease — to an embryonic mouse model through a CRISPR fluorescent reporter system, allowing specific and targeted gene-editing in fetal lungs. Through the process mentioned above, the mouse model, which possessed the human SP gene SFTPCI73T mutations, had enhanced life expectancy by 22.8% and development of lungs, along with decreased pulmonary pathogenesis [10]. More recently, C. K. W. Lim et al. [11] demonstrated that CRISPR possesses the potential to treat Amyotrophic lateral sclerosis (ALS) — remember the ice bucket challenge? Mouse models displayed a significantly decreased rate of muscular atrophy, improved neuromuscular function, and prolonged life expectancy after in vivo base editing [11]. There are also currently multiple ongoing registered clinical trials that utilise CRISPR. One such clinical trial aims to assess the efficacy and safety of genetically engineered, neoantigen-specific Tumour Infiltrating Lymphocytes (TIL), where scientists utilised CRISPR gene-editing to inhibit the intracellular immune checkpoint CISH, for the treatment of gastrointestinal (GI) cancer [12]. Another clinical trial aims to assess the safety and efficacy of allogeneic T cells that were modified ex vivo through CRISPR/Cas9 gene-editing components in CTX130 CD70-directed T-cell immunotherapy, to treat T cell lymphoma [13]. When it comes to agriculture, the benefits of CRISPR are plenty as well. Examples of existing applications of CRISPR/Cas9 in crops include targeting the gene PL or ALC to increase the shelf life of tomatoes and genetic modifications to obtain disease- and virus-resistant plants [14-16]. While CRISPR possesses a host of benefits, it does have its limitations. For example, an optimal CRISPR/Cas tool must attach and/or break a specified target without producing additional off-targets as by-products in complicated genomes [9]. Nevertheless, research work is already underway to enhance the effectiveness and safety of CRISPR technology. In addition to technical limitations, there are multiple ethical considerations to make.

Those most enthusiastic about genetic enhancements call themselves transhumanists. These people believe that we should transcend the blind and arduous process of evolutionary selection since we now possess the ability to control our biological fate [17]. Some, like Nick Bostrom, criticises that idea, claiming that changing our nature will cause us to lose our human dignity [18]. With the development of rapidly advancing gene-editing technologies, proponents of gene-editing claim that if we do not embrace the full potential of genetic engineering, we are denying many individuals of a ‘normal’ life, and such an act would be considered ethically wrong. Individuals may consider genetic engineering as ‘playing God’ in various cultures. Others may believe in staying ‘natural,’ yet with all the processed foods with additives, pesticides, and other chemicals that most of the population consumes daily, what is considered ‘natural’? It is possible that gene-editing may eventually become commonplace. Would there then be a stigma associated with not having undergone gene-editing? Could gene edits eventually be associated with certain levels of prestige within society?

Some futurists predict that gene-editing technologies will eventually allow individuals to enhance themselves or handpick traits that they want their children to possess. Many around the world would love physical characteristics like a lower body fat percentage or increased intelligence. It is theoretically possible to intervene with the aesthetics of height, hair colour, eye colour, and perhaps, even the more subtle aspects of appearance and even intelligence [7, 19]. While technologies that can create ‘designer’ babies are not available yet, they could soon become a reality. A thought-provoking conundrum to contemplate is that when it comes to traits like intelligence, the distinction between genetic enhancements and gene therapy is blurred [17]. While increasing an individual’s intelligence quotient from 120 to 140 would be considered an enhancement, would raising an individual’s intelligence quotient from 90 to 110 be considered therapy or an enhancement? Ultimately, it depends on our distinctions of normality versus abnormality and health versus disease [20]. In a time when self-image and body consciousness is becoming increasingly widespread due to the influence of social media, many—especially the wealthy—will not see any ethical issues with genetic enhancements for aesthetic purposes. Parents want the best for their children. Should they be offered the opportunity to enhance their children genetically, would parents stop at ‘gifting’ their children an above-average height or increased intelligence, or will there be a never-ending list of enhancements they want? Such a scenario begs a fundamental question: should aesthetic genetic enhancements be allowed, or should we focus solely on gene-editing applications—like therapeutics and agriculture—that bring about societal benefits? Various parties such as policymakers, businessmen, clinicians, and academics need to agree on what constitutes appropriate gene-editing applications in our society.

Figure 2: Somatic Gene Editing Vs. Germline Gene Editing adapted from [29].

Aesthetic genetic enhancements raise several concerns. There is a possibility that such enhancements will only benefit the affluent due to cost and accessibility issues, leading to a greater social inequality gap as the rich will get increasingly competent and possess physically ideal traits. Meanwhile, the less fortunate will drift further away from what is considered the new norm. In addition, the approval of aesthetic enhancements could lead to a less diverse society, which may cause us to end up in an environment with less edge, inspiration, and creativity. One thought experiment described by Walter Isaacson to tackle this problem describes two terms: an absolute good and a positional good. Enhanced resistance to common viruses, for example, is an absolute good. On the other hand, enhanced facial features is a positional good [21]. The distinction? Resistance to a virus benefits society, while enhanced facial features give the recipient a positional advantage. Absolute goods such as treating genetic diseases and enhancing resistance to common viruses could lead to happier and healthier individuals. This could translate to increased economic productivity, reduced healthcare expenditure — governments could spend more on other sectors like education — and the possibility of greater equality due to the potential elimination of the biological determinant of health outcomes.

Another grey area that regulators and researchers frequently tread on is the question of somatic gene-editing (SGE) versus germline gene-editing (GGE). SGE only affects the treated patient and specific types of cells. On the other hand, GGE affects all the cells in an organism, including sperm and eggs; hence edited traits are passed onto future generations. Figure 2 illustrates the differences between SGE and GGE. In 2018, a gene-editing researcher at the Southern University of Science and Technology in Shenzhen, China, He Jiankui, implanted edited embryos in a woman. Through CRISPR/Cas9, he disabled the gene, CCR5, that encodes a protein that allows human immunodeficiency virus (HIV) to enter a cell [22]. Recently, the BBC published an article mentioning that Lulu and Nana, the first gene-edited babies to be born, may not actually possess resistance to HIV due to multiple problems with He’s methods [23]. The full extent of the consequences of gene-edited babies are still unknown, and He is currently serving a three-year sentence in prison for violating medical regulations [24]. Proponents of GGE cite several benefits. Companies and scientists could utilise GGE to avoid passing on single-gene disorders like cystic fibrosis (CF) — a congenital genetic lung disease that can lead to respiratory and digestive system complications and a shortened life expectancy — especially in cases where two carriers of the gene for CF hope to have a child together. This is because there is a 25% chance that the child of two CF gene carriers will develop CF. Only approximately 19% of women undergoing IVF produce one viable embryo [25]. In such a situation, in vitro fertilisation (IVF) will not provide any tangible benefit, and GGE would prove more beneficial in preventing CF. In addition, IVF is also unable to select against polygenic diseases such as diabetes and coronary artery disease [26]. GGE could be a powerful tool in the fight against such diseases in the future. On the other end of the spectrum, those opposed to GGE have made multiple arguments, including the safety of individuals who had undergone GGE, the possibility of negative consequences for future generations, whether we are infringing upon the consent and autonomy of future generations, and the fact that we could also utilise GGE for heritable enhancements [25]. As described above, genetic enhancements may not be ideal in our current society due to certain disparities and ethical barriers that may arise, but how society will receive such technological changes in the future is yet to be seen.

To conclude, gene-editing — although incredibly beneficial in numerous ways — brings about a barrage of questions and concerns from governments, academics, and the public alike. There is still a long list of moral and ethical questions that policymakers and researchers — among other significant players — need to discuss and come to a consensus on over the coming decades. One thing is sure: it is imperative for us to ensure equitable access to gene therapies. Everyone should possess an equal opportunity to be in good health, a state of complete social, mental, and physical wellbeing and not merely infirmity or the absence of disease as defined by the World Health Organisation [27]. Prematurely introducing gene therapies without proper regulation, planning and funding could exacerbate existing health inequities, driving increasing differences between ethnic groups and social classes. How society evolves with the advent of gene-editing and where to draw the line between what is permissible and banned — from genetic therapy to genetic enhancements and GGE — is wholly up to us. With the discovery of CRISPR, we possess greater power than ever before, and with great power comes great responsibility.

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