Despite the significant benefits synthetic gene drives may provide, an unplanned or poorly managed release of a gene drive modified organism could potentially change the environmental landscape well beyond the site of its introduction.
The introduction of foreign species and their genes into a new environment is not new. With human exploration and travel we have introduced new species into different environments either inadvertently (e.g. within ships’ ballast water) or consciously (e.g. new crops, garden flowers or even animals for sport hunting) for many decades. Many invasive and feral species have become established in Australia, some of which have caused ecological and environmental damage. The introduction of new genes occurs both through new mutations arising in existing populations and though the movement of genes from one population to another. For instance, insecticide resistance genes in Australian insect pests have likely arisen both locally following mutation and been introduced from overseas populations (Umina et al., 2014).
Significant technical and knowledge challenges remain which must be overcome to engineer a successful synthetic gene drive, and these challenges should not be underestimated. The four proof of concept studies published over 2015 have all been in laboratory organisms which are highly uniform and unlike wild populations. The genetic constructs produced in controlled laboratory conditions are unlikely to perform in the same way in natural environments where conditions are much more variable and unpredictable. Additionally in a wild population, a trait which reduces the biological fitness of an organism—for instance a gene drive containing a construct designed to suppress reproduction—will slow down the spread of the gene drive.
The release of a low threshold synthetic gene drive designed to spread genes throughout an entire population demands additional care. The consequences of such releases are potentially widespread, and hence international consideration and consultation may be required. The spread of genes between populations—gene flow—must be understood prior to the release of any synthetic gene drive, but this is particularly important with low threshold drives. The possible transfer of genes between distinct species must also be considered. Gene drives shouldn’t be implemented in species where there is potential for introgression with non-pest native species.
There is the possibility that releases of gene drive modified organisms will lead to unpredicted and undesirable side effects. Past eradication of pest species by conventional means such as baits or sprays have in some instances allowed another problematic pest to flourish as a result of a vacated niche or the withdrawal of predation (Dutcher, 2007). We must consider equivalent problems that might arise from possible future use of gene drive modified organisms.
It is also important, however, to put the hazards presented by gene drive modified organisms into perspective. A 100% effective gene drive can only ever double in frequency with each generation inheriting the drive mechanism. Mosquitoes have an average generation time of three weeks and it would take multiple generations to spread a gene drive to a portion of a local population. By comparison, a viral pandemic would affect national and international populations in a matter of weeks. While there should be caution in regard to the use of synthetic gene drives, there would be time to react if an unintended release or unexpected effect were detected.
The potential of evolution to modify gene drives and the constructs being driven also needs to be carefully considered. Resistance to the gene drive is likely to evolve unless other DNA repair systems that organisms possess can be turned off or multiple, independently acting, drive systems are developed. Before release into the environment, likely evolutionary changes in each genetic construct and their consequences will need to be carefully modelled and evaluated. In addition, untargeted changes in the genome associated with the creation of drives may need to be evaluated.
Hazards pertinent to the applications of synthetic gene drives relating to pathogens, invasive organisms and agricultural applications are discussed in more detail below.
There are several hazards associated with releasing an organism containing a gene drive which results in the extinction of an insect-borne disease. Removing one vector could allow another potentially dangerous species to take its place by competitive- or predator-release processes. Releasing a gene drive modified organism that was only partially successful could also cause a loss of herd immunity in previously exposed populations. Public health would benefit in the short term but possibly not in the longer term, because individuals within the population may become more susceptible to the disease as the vector recovers from the initial suppression.
Ecosystems are highly interlinked systems within which the abundance of each species is governed by the balance of births, deaths, immigration and emigration. Their dynamics are controlled by positive and negative feedback cycles that respond to external forces in ways that are often difficult to predict. Introduced non-native species, if they are successful and flourish, can alter these processes and cause significant changes to the abundance of native species, and the feedback cycles they operate within. Gene drive modified organisms offer the potential to restore impacted ecosystems by suppressing invasive species, potentially to extinction. Modified ecosystems, however, may not return to a previous (desired) state even if the drive is successful. Furthermore, species that have become reliant on the invasive species could suffer as its abundance was reduced, and other harmful species could be released from predation pressure or competitive exclusion, and thereby flourish. Regardless of the cause—be it through a gene drive, attack by an invasive species or habitat loss—extinction of species requires careful and serious consideration.
Gene drive modified organisms may also spread naturally, or through human-mediated dispersal mechanisms, to other regions and other parts of the worlds. A possible consequence of creating a synthetic gene drive aimed at eradicating European carp or rabbits in Australia could be that the drive spreads overseas where these animals have important food, cultural and/or ecological values.
The spread of gene drive modified organisms also poses hazards in agriculture domains. Efforts to improve agriculture in Australia using synthetic gene drives may target problem weeds such as Echinochloa colona, or barnyard grass. This is a damaging weed for Australian farmers but in India the seeds of this grass are used to prepare a dish consumed on festival fasting days. Consequently, if a gene drive modified organism was released to suppress the weed population in Australia it could also affect a food source in other parts of the world. Elimination of a pest species might also create an empty niche that could be filled by other pests, as in the case of redlegged earth mites that show competitive interactions with other species of earth mites.
Significant technical limitations currently exist for gene drives in weeds. Gene drives can only function if double strand DNA breaks are repaired by homologous recombination, but some plants use non-homologous end joining pathways which prevents the use of the current generation of synthetic gene drive constructs.
Another challenge for agriculturally related gene drives is to avoid the development of resistance (Fukuoka et al., 2015). Resistance alleles can prevent a gene drive from spreading in pests and weeds (Champer et al., 2016). Efforts to avoid the development of resistance include stacking traits so that there are multiple defences to target the same pests and weeds. This strategy is already used in GM crop plants with resistance to insects where multiple insecticide genes are stacked together to reduce the likelihood of insects evolving resistance.
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