This is an excerpt of a Briefing Paper by Third World Network published in June 2022

Introduction

The governance and regulation of advancing life and agricultural sciences is lagging behind technical innovations and our evolving understanding of the science underpinning genetic engineering technologies. Such technologies, mainly in the form of transgenic techniques, were first commercialized nearly three decades ago, though few traits have reached the market. With advances in science and technology, the field is attempting to explore new genetic engineering techniques that can expand the scope, applicability and depth of intervention.

New genetic engineering techniques, however, are evolving beyond the current scope of legal definitions, risk governance and consent mechanisms, with interventions increasingly moving towards ecosystem-wide projects for crop, human health and climate or biodiversity conservation interventions (Greiter et al., 2022; Heinemann, 2019; Sirinathsinghji, 2019). Such advances at the technical level are raising novel biosafety risks that urgently warrant updated assessment methodologies and regulations to address significant biosafety knowledge gaps and increasing levels of uncertainty about how these technologies will impact biodiversity and human health.

Moreover, thorough scrutiny of their potential limitations to alleviate the societal problems they are purported to address, and which existing living modified organisms (LMOs) have not been able to combat, is also needed. Indeed, many of the original concerns raised about LMO commercialization have been borne out, including efficacy problems and unintended agronomic and ecological effects resulting in repeated crop failures and economic damage, particularly for smallholder farmers (for example, see ENSSER, 2021; Kranthi & Stone, 2020; Luna & Dowd-Uribe, 2020; Wilson, 2021). While new technologies are being developed to address the problems that first-generation LMOs failed to solve, proponents are again hyping up the potential benefits and making blanket claims about safety.

In this context, it is imperative that horizon scanning and technology assessment are fully operationalized to protect biodiversity and human health from the new genetic engineering technologies, including synthetic biology, that are yet to be fully understood, and currently difficult, if not impossible, to control, reverse or recall from the environment following release.

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Gene drive technologies

Gene drive technologies are a form of genetic engineering designed to skew inheritance of the engineered trait such that most, if not all, offspring will inherit the trait, with the aim of rapidly “driving” it through a population. Various applications have been proposed, with the most advanced and promoted being gene drive mosquitoes that aim to reduce vector-borne disease burden, such as malaria or dengue fever. The Target Malaria project aims to use gene drives to eliminate mosquito populations (population suppression) by spreading infertility or gender-bias traits, while other projects aim to alter transmission (population modification) of disease pathogens to humans. Agricultural applications such as the elimination of pests, as well as conservation applications such as the elimination of invasive species, are also envisaged (CSS et al., 2019).

Various molecular mechanisms are being deployed to achieve the driving characteristic, the most common being the use of genome editing technologies such as CRISPR systems. These are incorporated into the gene drive organism in order to carry out genetic engineering “live” inside wild organisms, “cutting and
pasting” transgenic DNA at each generation for perpetuity. Described as transferring the laboratory to the field (Simon et al., 2018), rather than the genetic engineering being performed in the laboratory where, in theory, it can be assessed for biosafety concerns, the continuing engineering process means that any
unintended effect cannot be ruled out prior to release.

Unintended effects at the molecular level have been widely documented with genome editing techniques such as those deployed for gene drives. These include on-target and off-target effects, novel protein production and cellular impacts (e.g., see Agapito-Tenfen et al., 2018; Biswas et al., 2020; Brunner et al., 2019; GeneWatch UK, 2021; Ihry et al., 2018; Kawall, 2019; Norris et al., 2020; Ono et al., 2019; Skryabin et al., 2020; Tuladhar et al., 2019), with next-generation effects (Zhang et al., 2018). These unintended effects may continue to occur or accumulate following release, and spread with unknown consequences with regard to their interaction with the environment, pathogens or humans who may be exposed to gene drive organisms and any pathogen within them. The evolutionary impacts of such nextgeneration effects are completely unknown, and raise novel challenges to risk assessment methodologies, as concluded by the Cartagena Protocol on Biosafety’s Ad Hoc Technical Expert Group (AHTEG) on Risk Assessment and Risk Management (AHTEG, 2020).

Unlike existing LMOs, gene drives are designed to spread and persist. The ecological consequences of this are unknown, for example any potential impacts on the target organism’s wider food webs, or non-target organisms that are connected via gene flow to the target organism itself. Ecological effects may take decades to become visible, and are notoriously difficult to study. Using gene drives to remove invasive species can have unexpected detrimental effects if functional roles within ecosystems have been embedded (Lim & Traavik, 2007; Sirinathsinghji, 2020). Such interventions also introduce the risk that they may spread to the target organism within its native range, with potentially serious ecological harm.

Discussions around disease applications have also not given sufficient consideration to potential negative impacts on disease epidemiology. How any unintended or intended effect may impact on disease transmission is unknown and difficult to assess prior to release (Beisel & Boëte, 2013; Sirinathsinghji, 2020). For example, how the modifications may alter disease transmission, or pathogenicity of the target (or non-target) pathogen, particularly with population modification drives that will exert pressure on the pathogens to evolve around the modified trait. Most crucially, such risks, as partially acknowledged by developers (James et al., 2020), cannot be comprehensively assessed in the lab. Moreover, the capacity for vectors to transmit disease is mediated by wider environmental factors, e.g., bacterial symbionts in mosquitoes. How the genetic engineering process impacts on these factors is highly uncertain. Further, whether gene drives will positively impact disease epidemiology, even if they are capable of reducing mosquito numbers, is still questionable.

Finally, gene drives are currently irreversible, and there are no existing strategies to recall, reverse or mitigate a gene drive release. While there are proposals to release mitigating drive systems in response to a gene drive going awry, these only add uncertainty and complexity, with research recently demonstrating unintended genetic effects with some techniques in laboratory flies (Xu et al., 2020). How different genetic elements interact once multiple systems are released into the environment, with continued development of novel gene drive systems, adds yet more uncertainty and complexity that warrant horizon scanning to continually monitor such developments. New developments are also taking place in bacterial systems with applications for addressing antibiotic resistance and bacterial infections, by taking advantage of the natural processes of horizontal gene transfer in bacteria. These developments have thus far garnered little attention but require further monitoring.

Technology assessment that incorporates not only biosafety, but also suitability, ethical and political considerations, is needed. Issues around consent, particularly in obtaining the free, prior and informed consent of potentially affected IPLCs, are critical and part of the broader discussions around gene drives. Social, political and commercial determinants of disease need to be taken into account when weighing up potential costs and benefits of gene drive applications. A narrow focus on vector control may risk marginalizing key health determinants such as strengthening healthcare systems, access to treatments, poverty alleviation and wider sanitation interventions, which should be incorporated into the technology assessment discussions.

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Conclusion

Genetic engineering technologies and their applications are rapidly evolving. They are, however, being framed by proponents as safe, necessary or even as falling outside of LMO definitions, in various attempts to avoid the scrutiny required to protect against potential risks to biodiversity. Emerging techniques such as genome editing that are being applied to crops, gene drive technologies, genetically engineered viruses, HEGAAs and more, pose a plethora of risks and unintended effects, which are already notably acknowledged in biomedical fields (Burgio & Teboul, 2020; Ledford, 2020; National Academy of Medicine (U.S.) et al., 2020).

Nonetheless, proponents are intending to release these technologies into the environment, with explicit intent to increase the scale and levels of intervention beyond agroecosystems, directly into wild species and ecosystems. Reduction of genetic diversity, even at the level of a single gene, can impact food webs and ecosystems, such that even without unintended effects of the genetic engineering process itself, the impacts of altering genes in open settings are unpredictable, with potential adverse effects (Barbour et al.,2022). Genetic changes by human activity can bypass the processes of evolution for their establishment and spread in nature (Heinemann et al., 2021), raising new levels of uncertainty and risk. Moreover, this will occur in the context of fundamental knowledge gaps around how such interventions will interact with complex, wild ecosystems.

Gene drives, RNAi and genetically engineered viruses are just a few examples of some technologies on the horizon or already reaching markets. More applications, including of synthetic biology, and new genetic technologies are in the pipeline.

It is imperative that there is:

1. horizon scanning so that regulators and policy makers can keep abreast of the science, have information relevant for risk assessment and risk management, and thus be adequately prepared for whatever technologies are approaching; and
2. technology assessment so that these new technologies can be robustly assessed, not just for their environmental and human health impacts, but also for their social, cultural and ethical implications. The CBD, as the near-universal legally binding treaty governing biodiversity, must therefore include and operationalize horizon scanning and technology assessment, including in its post-2020 Global Biodiversity Framework.