Ethics of Gene Therapy in the Military: Promise and Potential Problems
Authors: Peter H. Schwartz
Journal: Molecular Therapy (2020)

Recent research on mice has shown that gene therapy can neutralize the effect of certain types of chemical weapons.1Betapudi V. Goswami R. Silayeva L. Doctor D.M. Chilukuri N. Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice.Sci. Transl. Med. 2020; 12: 12Crossref Scopus (4) Google Scholar,2Kaiser J. Genetic modification could protect soldiers from chemical weapons. Science January 23, 2020.2020https://www.sciencemag.org/news/2020/01/genetic-modification-could-protect-soldiers-chemical-weaponsGoogle Scholar This approach may one day protect people, but it also raises worries. Some of these questions stem from it being gene therapy, but most stem from the fact that its key use would be on the battlefield. The most challenging questions involve assessing a therapy that is designed to protect soldiers but could also hurt them. It’s important to begin the discussion by reviewing how dangerous chemical weapons are and why they have been banned by international treaty since the 1960s.3Delfino R.T. Ribeiro T.S. Figueroa-Villar J.D. Organophosphorus compounds as chemical warfare agents: a review.Journal of the Brazilian Chemistry Society. 2009; 20: 407-428Crossref Scopus (198) Google Scholar,4Moshiri M. Darchini-Maragheh E. Balali-Mood M. Advances in toxicology and medical treatment of chemical warfare nerve agents.Daru. 2012; 20: 81Crossref PubMed Scopus (87) Google Scholar The most commonly used nerve agents, such as sarin, tabun, and VX, are organophosphates that inhibit acetylcholinesterase and lead to nerve dysfunction, resulting in the inability to breathe, heart problems, seizures, and death. Chemoprotective clothing and gas masks provide some defense, but they are not perfect. Once a person is exposed, medical treatments have limited efficacy and may not be able to forestall death or brain damage.3Delfino R.T. Ribeiro T.S. Figueroa-Villar J.D. Organophosphorus compounds as chemical warfare agents: a review.Journal of the Brazilian Chemistry Society. 2009; 20: 407-428Crossref Scopus (198) Google Scholar,4Moshiri M. Darchini-Maragheh E. Balali-Mood M. Advances in toxicology and medical treatment of chemical warfare nerve agents.Daru. 2012; 20: 81Crossref PubMed Scopus (87) Google Scholar If an attack is expected, then some medications can be given to reduce or block the effect of nerve agents, though these treatments have limitations too. One approach being tested in animals is to inject an enzyme that quickly breaks down organophosphates.1Betapudi V. Goswami R. Silayeva L. Doctor D.M. Chilukuri N. Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice.Sci. Transl. Med. 2020; 12: 12Crossref Scopus (4) Google Scholar,2Kaiser J. Genetic modification could protect soldiers from chemical weapons. Science January 23, 2020.2020https://www.sciencemag.org/news/2020/01/genetic-modification-could-protect-soldiers-chemical-weaponsGoogle Scholar But these enzymes do not last in the bloodstream very long, so they may need to be given right before a possible attack, perhaps multiple times. The gene therapy approach may solve this problem: scientists injected a gene into mice that was taken up by their liver cells and made the protective enzyme. The study found that the enzyme remained active in the blood for the entire 5-month study and allowed the mice to survive multiple injections of the nerve agents.1Betapudi V. Goswami R. Silayeva L. Doctor D.M. Chilukuri N. Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice.Sci. Transl. Med. 2020; 12: 12Crossref Scopus (4) Google Scholar,2Kaiser J. Genetic modification could protect soldiers from chemical weapons. Science January 23, 2020.2020https://www.sciencemag.org/news/2020/01/genetic-modification-could-protect-soldiers-chemical-weaponsGoogle Scholar The experiment is just “proof of concept,” of course, since much more research would be needed to make the treatment for humans and identify its risks and benefits. But the potential advantages are clear. Despite the international treaty banning their use, chemical warfare is still being used, most recently in Syria. The approach will attract the attention of ethicists in part because it is a possible gene therapy. Of note, though, the approach does not have two features that often raise the most concern about genetics. First, the treatment is somatic therapy, not heritable, so it doesn’t involve changes in the germline or affect the next generation.5Baylis F. Human germline genome editing and broad societal consensus.Nat Hum Behav. 2017; 1: 0103Crossref Scopus (24) Google Scholar Second, it is an intervention countering a physical danger, and thus does not fall in the realm of “enhancement” of the sort that many worry gene therapy will eventually aim at, attempting to make people (or soldiers) smarter, taller, or stronger.6Daniels N. Normal functioning and the treatment-enhancement distinction.Camb. Q. Healthc. Ethics. 2000; 9: 309-322Crossref PubMed Google Scholar,7Greene M. Master Z. Ethical Issues of Using CRISPR Technologies for Research on Military Enhancement.J. Bioeth. Inq. 2018; 15: 327-335Crossref PubMed Scopus (11) Google Scholar While certain enhancements are accepted in current medical practice, such as plastic surgery for appearance or botox for wrinkles, these cosmetic interventions are classified differently than most medical care, for instance not covered by health insurance. When proposed enhancements involve long-term medications or, worse, genetic modification, concerns grow, as can be seen with current programs in military enhancement, such as human-machine interfaces and neuroenhancement.8Giordano J. Neurotechnology in national security and defense: Practical considerations, neuroethical concerns. CRC Press, Boca Raton2014Crossref Google Scholar The proposed gene therapy, in contrast, is more like a vaccine to protect against future illness (in this case caused by nerve agents rather than viruses). The most important concerns about this gene therapy stem from its potential risks, much like for other new therapeutics. While being long-acting is a major point in the approach’s favor, this feature also brings potential dangers: scientists have already pointed out that the synthetic enzyme made by the gene could, by persisting in the blood stream, stimulate an immune response to the naturally occurring form, which is important in cholesterol metabolism.1Betapudi V. Goswami R. Silayeva L. Doctor D.M. Chilukuri N. Gene therapy delivering a paraoxonase 1 variant offers long-term prophylactic protection against nerve agents in mice.Sci. Transl. Med. 2020; 12: 12Crossref Scopus (4) Google Scholar In addition, the fact that the treatment permanently modifies the individual’s genome raises the dangers of other long-term side effects, such as increasing cancer risk, which would be difficult to identify. The short-term benefits, one might hope, would make such long-term dangers acceptable, initially in research projects and then more generally in widespread use, but here things get complicated, in part because of the potential military use. For one thing, it can be difficult to carry out ethical clinical trials in the military, since military personnel may not feel as if they can choose to participate, due to command structure and culture.7Greene M. Master Z. Ethical Issues of Using CRISPR Technologies for Research on Military Enhancement.J. Bioeth. Inq. 2018; 15: 327-335Crossref PubMed Scopus (11) Google Scholar,9Black 3rd, J.L. Genome projects and gene therapy: gateways to next generation biological weapons.Mil. Med. 2003; 168: 864-871Crossref PubMed Scopus (10) Google Scholar Perhaps even more importantly, since the treatment is preventative, it would presumably be used for all soldiers who have a significant risk of being exposed to nerve agents. But will the benefit to the potentially few soldiers who are actually exposed outweigh the risks to the many treated? Questions like this always arise for preventive interventions, such as screening tests: many people are tested and treated, but relatively few benefit. Groups such as the United States Preventive Services Task Force or American Cancer Society make recommendations by tallying up the benefits and risks at the population level. Things are more complicated for a preventive treatment in the military, where the risk to the individual is affected by decisions by superior officers. Sending soldiers into a situation where chemical weapons may be used is slightly easier if the soldiers are at least somewhat protected. For this reason, the availability of the treatment might increase the risk to the individual soldier, on balance, by increasing the chance of their being exposed even as it reduces the harm from exposure. The treatment may thus more directly benefit military efficacy overall rather than individual soldiers. These issues arise for all technological and medical means used to protect or treat soldiers. Think of everything from armored vehicles to the incredible advances in trauma medicine that have saved so many. All these advances are admirable and indispensable, but their availability may lead soldiers to be placed in situations with higher risk. When we start imagining making changes to soldiers’ DNA, changes that will last a lifetime, there are new, higher stakes. Ruling on the ethics of gene therapy in the military, as for other technological advances, depends in part on judgments about how the technology or treatment will be used and for what ends. Even though the potential benefits to our soldiers and military understandably motivates this research, the first widespread uses of gene therapy may be more appropriately tested and implemented outside of the military.