October 26, 2021
V. military interest in crispr
The seemingly unlimited potential of CRISPR editing in humans has not been lost on world leaders. For example, Vladimir Putin – who is kept informed about genetic research by his endocrinologist daughter — in 2017 touted the potential and warned of the dangers of CRISPR at a youth festival (see Fig. 9 and the YouTube video):
“Genetic engineering will undoubtedly open up incredible opportunities in pharmacology, new medicines, altering the human genome if a person suffers from genetic diseases. Alright, that is good. But there is another part to this process. What does it mean? It means that humans acquire the capability to get into the genetic code, which was created by nature, or, as religious people say, by Our Lord. What practical consequences can this entail? It means – we can already imagine it – not so much theoretically, it is already possible to create a person with the desired features. This may be a mathematical genius, this may be an outstanding musician, but this can also be a soldier, an individual who can fight without fear or compassion, mercy or pain. You are aware that humankind may, and most probably will, enter a very complicated and very demanding period of its existence and development.”
Russia does not intend to be a latecomer to this “very complicated and very demanding period.” In September of 2019, the Russian State Duma published on a state procurement website a call for an 8.97 million ruble ($134,500 U.S.) contract to be awarded for study (to be completed by Nov. 30, 2019) of the ethical and religious aspects “of a new generation of assisted reproductive technologies (genome editing, management of metabolism during pregnancy, etc.) in order to create a new type of society based on more advanced legislation.”
But most concerns in the western world today focus not so much on Russia as on the unclear intentions of the Chinese government with respect to human germline genome editing.
Super Soldiers?:
As described in part I of this post, the Chinese government prosecuted and convicted He Jiankui in 2019 for his widely publicized creation of the first human CRISPR babies. Did they make a public show of prosecuting He Jiankui based on real ethical concerns, or rather to cast a veil over their intentions to pursue classified analogous research in order to create a generation of “super soldiers” (see Fig. 10)? The uncertainty about their intentions was highlighted in a 2017 report from the Atlantic Council:
“There is so much gene-editing research being conducted in China it is difficult to pinpoint the primary sources. It is also not easy to discern whether the research in China has civilian, military, or defense applications. The secretive Academy of Military Medical Sciences [AMMS] and the Third Military Medical University are the most likely defense labs. These DARPA-like institutions handle medical studies for the People’s Liberation Army and both are feverishly pumping out CRISPR research… Chinese military scientists are using the technique to produce proteins of human blood called albumin in baby pigs. Military researchers are improving CRISPR gene splicing with their own innovative light-induced editing systems. Other studies focus on improving cancer drug resistance. The Chinese military is also investigating removing Hepatitis-B virus DNA with CRISPR… civilian scientists are speeding through experiments with monkeys and mice. But more worrisome are this year’s Chinese CRISPR breakthroughs in human embryos.”
The latter reference in the above quote is to Chinese research on germline editing in non-viable human embryos. Concerns about potential Chinese military applications were further stoked by a 2019 article in Defense One by Elsa B. Kania (an expert on Chinese defense technology at the Center for a New American Security) and Wilson VornDick (a former U.S. Navy officer and consultant on China matters). Kania and VornDick noted that:
“In 2016, an AMMS doctoral researcher published a dissertation, ‘Research on the Evaluation of Human Performance Enhancement Technology,’ which characterized CRISPR-Cas as one of three primary technologies that might boost troops’ combat effectiveness… contending that the ‘great potential’ of CRISPR-Cas as a ‘military deterrence technology in which China should “grasp the initiative” in development.’… Although the use of CRISPR to edit genes remains novel and nascent, these tools and techniques are rapidly advancing, and what is within the realm of the possible for military applications may continue to shift as well. In the process, the lack of transparency and uncertainty of ethical considerations in China’s research initiatives raise the risks of technological surprise.”
In 2020 Donald Trump’s Director of National Intelligence, John Ratcliffe, pushed concerns still further by publishing an op-ed in the Wall Street Journal, claiming that “China has even conducted human testing on members of the People’s Liberation Army in hope of developing soldiers with biologically enhanced capabilities. There are no ethical boundaries to Beijing’s pursuit of power.” The Chinese government replied by calling Ratcliffe’s claims a “miscellany of lies.” Elsa Kania, one of the co-authors of the Defense One article, has been openly skeptical of Ratcliffe’s claims: “It’s important to understand what the Chinese military is discussing and aspiring to actualize, but also to recognize the distance between those ambitions to the reality of where technology is at this moment. Even though militaries around the world may have quite a lot of interest in the possibility of super soldiers… at the end of the day, what is feasible within science does impose a constraint on any actor that is trying to try to push the frontiers.”
In particular, the human genome is quite complicated. While there are a few rare diseases that arise from mutations in a single human gene – and are thus susceptible to prevention by editing that gene – most characteristics of the human phenotype result from contributions originating in at least several, and sometimes many, genes. Furthermore, most genes serve multiple purposes, and not all of those purposes are yet understood. It is thus not so clear how to do genome editing to increase something like human strength or resistance to pain without risking highly undesirable side-effects. Even in the case of the single-gene mutation that leads to sickle cell anemia, that same mutation also improves human resistance to malaria, which is why it developed by natural selection primarily in Africa.
Christophe Galichet, a senior research scientist at the Francis Crick Institute in London, puts it this way: “It’s wrong to think that one gene will have one effect. If you take a gene, you could have an individual with greater muscles or being able to breathe at high altitude. But maybe further down the line the individual will develop cancer.” And this is true under the false assumption that CRISPR editing is 100% efficient; in fact, it often affects off-target genes as well as the ones intended for modification, introducing yet additional, unpredictable, side-effects.
While acknowledging the difficulties and the risks described in the preceding paragraph, it is also worth noting that researchers working in China’s Key Laboratory of Regenerative Biology at the Guangzhou Institutes of Biomedicine and Health claimed in 2015 to be the first to use genome modification to double the muscle mass of dogs. They did this by using CRISPR-Cas9 to edit 65 beagle embryos to remove myostatin-producing genes that normally limit muscle growth. A male and a female beagle resulting from these embryos, pictured in Fig. 11, are said to have twice the muscle strength of normal beagles and to be considerably stronger and faster. Possible implications for human strength enhancement are clear.
Of course, the U.S. has its own Defense Department-funded CRISPR research program and might have gone there first. For example, a February 2021 BBC article claims that “Some analysts see China’s efforts as a direct response to the US. A 2017 report in the Guardian said that a US military agency was investing tens of millions in genetic extinction technology that could wipe out invasive species, something UN experts warned could have military applications.” That report referred to the Safe Genes program administered by DARPA, and specifically to funding of research on gene drives, which we have described elsewhere on this site.
In 2019, DARPA “announced that it wishes to explore genetically editing soldiers,” although with a focus on enhancing soldier health and resilience and biosecurity. The Safe Genes program manager, Renee Wegrzyn, puts it this way: “We set out to protect against misuse of genome editors, and by virtue of making progress in that mission, we’re also laying the groundwork for safe, predictable, and potentially transformative applications of the technology to preserve the health of service members and support public health more broadly.”
One example of DARPA’s stated goals for genetically enhanced soldiers is the possibility of adapting the CRISPR “on-off” switch described in section IV to build radiation-proof CRISPR soldiers. The symptoms of radiation poisoning result from mutations induced in cells within the blood and the linings of the stomach and esophagus. These cells undergo frequent cell division, passing the radiation-induced mutations along to descendant cells before the body’s genetic damage repair mechanisms can take effect. The ultimate goal of the research group, led by Jonathan Weissman of MIT and Fyodor Urnov of UC Berkeley, is to create a CRISPR-based pill or injection that would boost the expression of genes that produce proteins involved in the genetic repair mechanism, including the protein G-CSF, which stimulates bone marrow to produce white blood cells.
Such a pill or injection could be given to soldiers, first responders or civilians before they enter a region known to have dangerously high radiation levels, or to astronauts before they launch on deep space missions, such as one to Mars. The treatment could possibly work as well in limiting the after-effects of an unanticipated exposure to a nuclear attack or a dirty bomb. But even once the appropriate genes to be targeted are identified by ongoing research, there are still the hurdles involved in finding appropriate delivery mechanisms to target only the appropriate cells and in carrying out clinical trials on human subjects. But DARPA’s hope is that this will provide one important way to enhance the protection of soldiers and citizens. Another one of the stated long-term goals of DARPA’s Safe Genes program is to develop ways to alter the human genome to “protect a soldier on the battlefield from chemical weapons and biological weapons” for which vaccines are not readily available.
Uncertainty about what the timeline might be in other countries to introduce significant military enhancements via CRISPR editing – whether these involve enhancing soldiers’ capabilities or creating new bioweapons – is leading to military and defense spending on CRISPR research in a number of countries. For example: “The French armed forces have been given the go-ahead to start research on developing ‘enhanced soldiers’.” French Defense Minister Florence Parly described the decision as defensive in nature: “But we must face the facts. Not everyone shares our scruples and we must be prepared for whatever the future holds.” For now, the French funding supports research on neural implants “that could ‘improve cerebral capacity’ or help soldiers tell enemy from ally. These could also allow commanders to locate them or read their vital signs from a distance.” But France currently bans research on genetic or eugenic practices.
In 2021 the UK has launched its own equivalent of DARPA, the Advanced Research and Invention Agency (ARIA). While we don’t yet know details of ARIA’s support for genomic editing of soldiers, it is relevant to note that UK defense reviews have highlighted the role of genetic engineering for “defence and national security” and that ARIA was created to not be subject to freedom of information requests, in contrast to DARPA in the U.S. The CRISPR arms race is under way, but is likely to be presented publicly for the foreseeable future as focused on biosecurity and defense.
In a paper discussing ethical issues with the use of CRISPR for military enhancement, Marsha Greene and Zubin Master point out other possibilities for soldier enhancement that are not far removed from the real axis. “Scientists have also isolated genes from other species that could theoretically be genetically engineered to enhance humans such as a thermal imaging gene in reptiles which may confer the ability to see in low light conditions (Gracheva et al. 2010). Even a potential candidate gene for Post-Traumatic Stress Disorder has been described indicating that it may be possible to one day eliminate emotional detachment that warfighters sometimes encounter in the aftermath of war (Cornelis et al. 2010).”
Outside of Putin’s general comments noted above (see Fig. 9), there is little public knowledge about what Russia is investing with regard to genome editing for military purposes. What is clear is that they launched in 2019 the development of “genetic passports” for military personnel, a start on the concept introduced by Putin of such passports for all Russian citizens. Alexander Sergeyev, the head of Russia’s Academy of Sciences, has stated that: “the most important and interesting project considered by representatives of the Russian Academy of Sciences and the Military Academy, is the so-called Genetic Passport of a soldier. The project is far-reaching, scientific, fundamental. Its essence is to find such genetic predispositions among military personnel, which will allow them to be properly oriented according to military specialties.”
In a separate interview, Sergeyev expanded: “The [military] project involves not only the assessment of the physiological state, but also the prediction of human behavior in stressful, critical situations that are associated with the military profession…It is about understanding at the genetic level who is more prone to, for example, to service in the fleet, who may be more prepared to become a paratrooper or a tankman.” Once such genetic passports exist for a population, it would seem an inevitable step to enhance the genetic predispositions further by selective breeding, perhaps augmented by genome editing on the embryos that result from such breeding. This could lead, in the words of military history author Joseph Micallef, to “the creation of a permanent, genetically enhanced military caste, a sort of super Praetorian Guard.”
Enhanced Bioweapons:
Collection of genomic data for a population is of interest not only for a country’s own citizens, but for those of an adversary as well. Micallef again: “China has become one of several countries that is actively looking to gather DNA data from other countries. Shortly after the COVID-19 pandemic broke out in the U.S., BGI Group, a global biotech company based in China, offered to build and help run state-of-the-art COVID-19 testing labs for Washington and five other states. The offer set off alarm bells at the White House, given that BGI had strong links to the Chinese government and military, and led Bill Evanina, a counterintelligence official, to warn that ‘foreign powers can collect, store and exploit biometric information from COVID tests.’”
Genomic data on the population of an adversary offers a strategic advantage in designing genetically engineered bioweapons. According to Micallef: “Knowledge of the DNA profile of a country’s population could lead to the development of disease pathogens specifically targeted to genetic vulnerabilities among its citizens. The U.S. has the advantage of being a very heterogeneous population, so it is less vulnerable to such targeted pathogens than, say, a country like Japan, which has a lot less genetic diversity…First, the gene-mapping and editing capabilities of genomics allow scientists to manipulate a pathogen’s DNA and determine what particular genes control how it expresses itself. This can lead to a better understanding of how to counter its effects and the medicines needed to do so. It also can facilitate the creation of super pathogens.”
In principle, the Biological Weapons Convention of 1975 – signed by 183 countries – bans the development, production, acquisition, transfer, stockpiling or use of biological weapons and toxins. However, in addition to lacking mechanisms for verification and enforcement, the convention has a broad exemption for research related to biodefense. Hence, most military-funded CRISPR-based research is presently described as aimed toward biosecurity. For example, recall that the U.S. Department of Defense advertises its goals in funding CRISPR research this way: “DARPA’s goals for Safe Genes are to mitigate the risks and security concerns related to the accidental or intentional misuse of such technologies and, at the same time, enable the pursuit of novel genetic solutions that support public health and military force protection and readiness.” But as Micallef points out: “The distinction between offensive and defensive bioweapons research is subtle. Even a relatively benign pathogen can become a bioweapon if one party has conferred immunity to its population and an opponent has not.”
The U.S. National Academy of Sciences has put together a framework for assessing the threat posed by potential synthetic bioweapons (see Fig. 12). The panel ranked threats based on their assessments of four basic criteria: usability of the technology; usability as a weapon; requirements of actors; potential for mitigation. They list three possibilities as the ones of most severe concern: the re-creation of known pathogenic viruses; fabrication of biochemicals via in situ synthesis; and making existing bacteria more dangerous. These three concerns are among the simplest applications of genomic editing, especially via CRISPR-Cas9. According to a post by Nicholas Cropper: “Making existing bacteria more dangerous and altering organisms to produce different biochemicals are common lab practices around the world today. Recreating known viruses sounds difficult, but in 2002 scientists successfully recreated the Polio virus from only the publicly available genome and mail-order biomolecules. That experiment was conducted before the discovery of CRISPR-Cas9 and the method has only become easier in the intervening years.” In addition, one must consider the possibility that the genome of recreated viruses could be edited to generate resistance to previously developed vaccines or treatments.
The dangers are only exacerbated by the wide availability of CRISPR-Cas9 tools to biohackers unconstrained by the Biological Weapons Convention. Thus, Cropper concludes: “COVID-19 has proven how ill-equipped America is to deal with novel infectious diseases. The U.S. is currently constructing a facility that will allow the Department of Defense to rapidly develop and produce limited medical countermeasures to a bioweapon, but that’s a baby step compared to what’s needed.”
VI. brave new world?
Contemplation of human germline gene editing, whether for therapeutic or enhancement purposes, raises a host of thorny ethical and regulatory issues. The scientists who have dominated CRISPR research have so far been cautious and responsible with respect to prospects for germline editing in humans. But will leaders who control funding and support for both science and the military, or companies seeking a profitable bioengineering business model, be similarly concerned with ethics and safety and medical necessity? Many prosperous humans would be willing to pay large fees for germline editing to eliminate certain genetic disease susceptibilities from their descendants, and perhaps even for editing to enhance desirable features for future leadership and mating purposes, even if there are still some technical risks.
There is the concern by many that scientists altering the human genome are “playing God.” But given the wide availability and cheapness of CRISPR-Cas9 tools, one must at least pay attention to a question raised by frequently outspoken Nobel Prize winner James Watson: “If scientists don’t play God, who will?” Some might even argue that if humans have evolved naturally to a stage where they have mastered gene-editing and can use that mastery to enhance the survival and possibly the procreativity of their descendants, then applying that knowledge should be considered simply a form of “accelerated” natural selection, replacing random genome mutations with engineering.
On the other hand, it is unlikely that such germline editing would be available to all, so it would not be a case of the entire species undergoing accelerated evolution. The price of such editing and in vitro fertilization procedures would mean that it is the prosperous or the military, or other classes useful to governments, who get “enhanced,” not poor or middle-class citizens. And might germline editing be imposed on poorer children’s embryos, not to enhance, but to dull their characteristics? Might it be used to usher in a new era of eugenics? Could that lead to a government-sponsored “caste” system among humans, akin to that portrayed in Aldous Huxley’s (Fig. 13) 1932 dystopian novel Brave New World, where mass-produced embryos are sorted in a Social Predestination Room and the resulting children are subsequently conditioned to love their assigned lot in life?
Rereading Brave New World in the CRISPR era gives one a renewed sense of Huxley’s prescience. He was writing during the infancy of genetics, decades before the double helix structure of DNA would be revealed, a half-century before a project to map the complete human genome would be conceived. Yet he foresees germline editing, for example, having the Director of Hatcheries and Conditioning anticipate “a germinal mutation” to speed up the physical maturation of humans, especially of Epsilons (the lowest caste), where “we don’t need human intelligence.” But Huxley also recognizes that such medical interventions on individuals are insufficient to create an entire population dedicated to achieve the World State’s bee-colony-inspired goals of “Community, Identity, Stability,” their replacement for the goals of Republics, such as “Liberté, Egalité, Fraternité.”
So in addition to genetic editing to sort embryos into five castes (Alpha—the leadership class, Beta, Gamma, Delta and Epsilon, each with further Plus and Minus side-groupings, see Fig. 14), the World State in Brave New World further relies on technology to generate up to 96 genetically identical lower-caste embryos from a single fertilized egg. The embryos then are subjected to Henry Ford-inspired assembly-line chemical treatments to enhance the desired and suppress the undesired characteristics for the destination caste: “…that is the secret of happiness and virtue – liking what you’ve got to do. All conditioning aims at that: making people like their unescapable social destiny.”
Infants in Brave New World undergo further Pavlovian conditioning to instill the state’s desired likes and dislikes into them. For example, for Deltas: “They’ll grow up with what the psychologists used to call an ‘instinctive’ hatred of books and flowers. Reflexes unalterably conditioned. They’ll be safe from books and botany all their lives.” The children are later subjected to sleep-time subliminal indoctrination intended to develop adults who are both perfectly content with their predetermined place within the strict hierarchy and unquestioningly committed to World State philosophies, such as “Everyone belongs to everyone else” and consumerism in the name of “Our Ford,” to fuel the world economy. “The students nodded, emphatically agreeing with a statement which upwards of sixty-two thousand repetitions in the dark had made them accept, not merely as true, but as axiomatic, self-evident, utterly indisputable.” And that indoctrination is reinforced throughout the citizens’ lives.
The goal is stated succinctly in the novel by Mustapha Mond: “The world’s stable now. People are happy; they get what they want and they never want what they can’t get.” That contentment is supported among adults by encouragement of free sex and pharmacology: the ubiquitous euphoria-inducing drug Soma is described as a form of “Christianity without tears.”
So CRISPR germline gene editing is only a first step along a very long trajectory of technical and social development to reach a brave new world, such as Huxley envisioned it. But then Huxley saw those developments as taking six centuries, after the World State was established with the aid of biological weaponry: “The Russian technique for infecting water supplies was particularly ingenious…Liberalism, of course, was dead of anthrax.” And it is not clear that germline editing would necessarily lead to a state-installed caste system, as opposed to one dictated by access to the marketplace. If one is willing to wait for six centuries to see a caste system of either type established successfully, one could also imagine gene drives used to instill desired enhancements in a small selection of humans, who will then spread those genetically favored traits among all their descendants. Over six centuries one goes through enough human generations that such traits can be spread through a large-population caste, limited in extent through the choice of mates for reproduction that people with the enhanced traits might make.
What such long-term speculations tell us is that regulation of human germline editing is desirable. Apart from the scientific consensus noted in section III, supporting “defining a responsible pathway for clinical use of heritable human genome editing” when it is deemed to be both safe and medically necessary, there is not yet much in the way of international regulatory guidance. In the wake of the He Jiankui “CRISPR babies” announcement, the World Health Organization established a commission (separate from the national academies group mentioned in section III) to look into creating a global regulatory framework for germline editing. But, as Christiane Woopen, chair of the European Group on Ethics in Science and New Technologies (EGE) puts it: “But (with CRISPR technology), it would be good to have [global regulations providing] assurance that no one country will step ahead and create gene edited human embryos for reproduction. But I can’t see this happening yet. At least there is the WHO expert panel developing international governance.”
In the absence of global regulations there is a patchwork of regulatory policies among different countries, summarized in the map in Fig. 15. In the US, Canada, Brazil, most of western Europe, Australia and South Korea, there is national legislation relevant to oversight of human genome editing. But it would be an overstatement to indicate that such legislation outright bans all genome editing with the fundamental aim of human enhancement.
For example, in an article on Genetic Warfare: Super Humans and the Law, Morial Shah summarizes the situation presented by the Oviedo Convention of the European Union. The Convention’s Article 13 “specifies that an intervention ‘seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants.’ Accordingly, it makes clear that EU member states may not lawfully engage in [germline editing or] human enhancement. Nonetheless, since the distinction between therapy and enhancement is open to debate, EU states may enhance their citizens under the guise of therapy. For instance, soldiers or athletes may receive treatment to make them run faster or carry oxygen to better treat ‘fatigue’ or ‘exhaustion.’”
In the U.S. “FDA regulates human genome editing under its existing framework for biological products, which includes gene therapy products. The FDA has authorized a number of gene therapy trials but has not yet approved a gene therapy for market. If one is approved, it will still be subject to the FDA’s ongoing monitoring and, if necessary, restrictions on its use. However, since DARPA’s technology does not count as a product for sale on the market, the FDA’s oversight may not extend to DARPA’s genetic technologies developed for military purposes. Commercial applications of genetic enhancement for athletes or other humans, may however, fall within the scope of the FDA’s authority. That acknowledged, the existing framework leaves much to be desired for a coherent and principled approach to legislation on this topic.”
As indicated in the map above, China and India have not legislation but rather restrictive national guidelines governing germline editing. These were enough to prosecute He Jiankui for his violation of the guidelines in creating the first CRISPR babies. However, just as in the U.S., it is not at all obvious that these guidelines provide meaningful limitations on research aimed at military applications of genome editing. Nor do they rule out research on CRISPR editing of non-viable human embryos, such as was carried out as early as 2015 by a Guangzhou team attempting to edit a gene that causes the blood disorder thalassemia, even though conventional therapies exist for that disease. Besides the above-mentioned countries, the situation in the rest of the world, including Russia, regarding regulation of human genome editing is either unknown or ambiguous.
Ethical quandaries and cultural differences abound in any discussion of potential regulations on gene-editing in humans. Is it even possible to make a clean distinction between therapeutic and enhancement purposes? Can different groups agree about conditions to be considered as genetic disorders for therapeutic treatment? For example, many members of the deaf community protested the use of cochlear implants as a surgical mitigation for deafness because “What may seem to a hearing person as opportunity may be seen by some deaf people as a loss.”
Is it acceptable for a pregnant woman to abort a fetus if genetic testing on the embryo reveals a genetic disorder, such as Down’s syndrome? Is it more acceptable for prospective parents to make use of the currently available in vitro fertilization approach of preimplantation genetic diagnosis? In this technique (see Fig. 16) couples who produce multiple fertilized eggs can choose which one(s) to implant in the womb, discarding the rest, based on their preferences among genetic characteristics of the various embryos. Is germline editing, whether for therapy or enhancement, a radical step beyond this technique already in use? In other words, is human choice among random chromosomal pairings OK, while engineering to impose such preferences in the genome of embryos is not OK?
It may not be the one Huxley envisioned, but we are clearly on the threshold of a brave new world where such questions must be contemplated. And the aggressive funding of CRISPR research by military and defense organizations in various countries may force us to accelerate our learning curve.
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