Bioethical Inquiry https://doi.org/10.1007/s11673-018-9865-6 CRITICAL PERSPECTIVES Ethical Issues of Using CRISPR Technologies for Research on Military Enhancement Marsha Greene & Zubin Master Received: 23 August 2017 / Accepted: 7 May 2018 # Journal of Bioethical Inquiry Pty Ltd. 2018 Abstract This paper presents an overview of the key for military institutional review boards and ethical questions of performing gene editing research on policymakers. military service members. The recent technological ad- vance in gene editing capabilities provided by CRISPR/ Keywords CRISPR/Cas 9 . Enhancement . Military. Cas9 and their path towards first-in-human trials has Ethics of research involving humans . Informed consent . reinvigorated the debate on human enhancement for Risk–benefit analysis non-medical purposes. Human performance optimiza- tion has long been a priority of military research in order to close the gap between the advancement of warfare Introduction and the limitations of human actors. In spite of this focus on temporary performance improvement, biomedical The development of the CRISPR/Cas 9 system has enhancement is an extension of these endeavours and revived the debate over gene editing applications in the ethical issues of such research should be considered. many areas including biological research, human health, In this paper, we explore possible applications of and agriculture and food production among others. CRISPR to military human gene editing research and What is discussed less in the literature is the use of how it could be specifically applied towards protection CRISPR/Cas and other gene editing technologies to of service members against biological or chemical enhance humans specifically for military purposes. weapons. We analyse three normative areas including The President’s Council on Bioethics under former risk–benefit analysis, informed consent, and inequality President George W. Bush acknowledged that when of access as it relates to CRISPR applications for mili- performance is a matter of life and death, such as with tary research to help inform and provide considerations soldiers on the battlefield, human enhancement may be more acceptable and indeed allowable (President’s Council for Bioethics 2003). Yet the Council cautioned M. Greene that it may be unwise to allow the warfighter to become Senior Policy Analyst, Peraton, Contracted to the Office of the indistinguishable from his weapon. Nevertheless, as Under Secretary of Defense for Research and Engineering, 4800 Mark Center Drive, Suite 17E08, Alexandria, VA 22350-3600, evidenced by the Defense Advanced Research Projects USA Agency (DARPA) Broad Agency Announcement e-mail: [email protected] (BAA) in 2014, human performance optimization con- tinues to be a major area of research focus (DARPA- Z. Master (*) Biomedical Ethics Research Program, Mayo Clinic, 200 First BAA-14-38). In this call, DARPA solicited proposals to Street SW, Rochester, MN 55905, USA improve warfighter performance, improve bioengineer- e-mail: [email protected] ing safety, and create a biological based manufacturing Bioethical Inquiry platform. The announcement underscores the Depart- gene defects in human embryos (Ma et al. 2017)andis ment’s current focus on temporary optimization mea- considered important in improving assisted repro- sures to include the development of short acting drugs ductive technologies (Simón 2013;Ishii2017). and biologics designed to enhance everything from Research involving human embryo manipulation, wound healing to improvement of a broad range of however, is largely being conducted outside the cognitive abilities. With the emergence of United States due to regulatory restrictions. Sever- CRISPR/Cas technology and the possibility for al of these applications have relevance to Depart- permanent gene enhancements of service members, ment of Defense (DoD) initiatives. the debate over where the ethical line should be Other military applications of CRISPR could involve drawninmilitaryhumanperformanceoptimization directly enhancing human soldiers. Humans remain the requires further consideration. rate-limiting factor in the conduct of war. While In this paper, we focus on the ethics of research using weapons have become increasingly more sophisticated, CRISPR on adult military service members, specifically provisions must be made in modern wargame exercises as it relates to potential exposure to biological agents. to allow the warfighter to sleep, receive nutrition, and This focus is deliberate because warfare is increasingly heal after trauma or injury. Science fiction has conjured becoming asymmetrical with the emergence of guerrilla images of warfighters with super strength, enhanced and insurgent forces. Military operations have shifted to vision, and limited psychosomatic reactions to the hor- counterinsurgency with specific attention regarding how rors of war. CRISPR research in the private sector is also to combat the threat of non-lethal weapons (e.g., trending towards enhancements that could be desirable bioagents). We discuss the governance of research in- for military applications. For example, a study with volving humans in the military and follow with a dis- CRISPR-mediated gene editing of beagle embryos pro- cussion of how CRISPR can be used to protect duced pups with twice the muscle mass having direct warfighters against biological agents. Finally, we per- implications for human research (Zou et al. 2015). Sci- form an ethical analysis of research involving military entists have also isolated genes from other species that personnel specifically on issues of risks–benefit analy- could theoretically be genetically engineered to enhance sis, informed consent, and equality of access and outline humans such as a thermal imaging gene in reptiles several considerations for institutional review boards which may confer the ability to see in low light condi- (IRBs) and policymakers. tions (Gracheva et al. 2010). Even a potential candidate gene for Post-Traumatic Stress Disorder has been de- scribed indicating that it may be possible to one day Military Applications of CRISPR eliminate emotional detachment that warfighters some- times encounter in the aftermath of war (Cornelis et al. CRISPR/Cas9 is a major technological feat with tremen- 2010). Such experimental endeavours are likely to face dous potential to impact the agriculture and health in- major regulatory hurdles if they are ever seriously con- dustries. These tools are currently being used to expedite sidered for development. crop and livestock breeding, engineer new antimicro- More practically, the availability of CRISPR gene bials, and control populations of disease-carrying in- editing is likely to impact both policy and practice in sects (Gao 2018; Nunez and Lu 2017; Hammond et al. warfighter health and performance research. CRISPR 2016). For human health, CRISPR can be used to treat itself could be used to weaponize biological agents and diseases for which gene editing has previously been the military will need to consider how the warfighter considered a therapeutic strategy, including Parkinson’s could be optimized for performance during a hypothet- disease, Alzheimer’s disease, muscular dystrophy, cys- ical attack (Hoehn et al. 2017). Historically, service tic fibrosis, sickle cell disease, hemophilia, autism, HIV, members are often subject to mandatory vaccination and various cancers among other applications (NASEM programs to protect against biological agents while de- 2017). Two first-in-human safety trials have been initi- ployed. However, it may prove difficult to develop ated to study whether CRISPR edited immune cells are effective vaccines for some of these new and emerging more efficient at killing tumour cells in people with biological threats. Initial work aimed at identifying can- terminal cancer (Cyranoski 2016;Reardon2016). didate genes that confers sensitivity to anthrax could lay CRISPR technology has reportedly been used to correct the ground work for these types of studies (Martchenko Bioethical Inquiry et al. 2012). Reduced expression of one such gene, Prior to the Common Rule era, military research capillary morphogenesis gene 2 (CMG 2), correlates involving human subjects was largely accelerated due strongly with lower susceptibility to anthrax. Interest- to the use of poison gas during World War I and the ingly, individuals who are closely related express subsequent development of a chemical warfare defence CMG2 at similar levels which could indicate that sensi- programme. During the time between the two world tivity to these types of bioagents may be heritable traits. wars, it is estimated that approximately 60,000 U.S. If genes such as CMG2 can be validated, the CRISPR service members were experimentally exposed to Mus- system could be exploited in a variety of ways, some of tard gas and Lewistite (Brown 2009). Although the which may not involve gene editing at all. In 2012, a programme ramped down significantly following the team of researchers engineered a Cas9 enzyme that was end of World War II, military scientists continued re- unable to cut DNA (Qi et al. 2013). Essentially, the search and development to seek out more effective CRISPR/Cas9 machinery could be directed to a specific compounds that could act as nerve agents, incapacitat- locus in the genome and used as either a gene promoter ing compounds, and psychoactive agents. An additional or suppressor, a sort of on/off switch for certain genes. 6,720 service members are estimated