Gene drives: Saving agriculture and feeding the masses?

By Charlotte Hutchings

The global population is rapidly expanding and is expected to reach 9 billion by 2050 (Gerland et al., 2014). To feed a population of this size, food production will need to increase by an estimated 60-110% (Pardey et al., 2014; Ray et al., 2013). Unfortunately, 815 million people suffered from undernourishment in 2016 as a result of food insecurity and inequality (FAO et al., 2017). Thus, meeting rising demand and ensuring global food security is, and will continue to be, a major challenge for all societies. 

Given its crucial contribution to our food supply, there is an inevitable pressure on agriculture to increase productivity or else risk widespread poverty. One factor that substantially limits agricultural productivity is the activity of arthropod pests, primarily insects and mites. Arthropod pests are responsible for extensive crop losses due to feeding damage, reproductive activity and transmission of plant viruses (e.g. Yu et al., 2016). However, whilst the need to protect crops is evident, doing so is becoming more challenging as climate change and increased international trade facilitate insect invasions and range expansions (Andrew & Hill, 2017; Tobin et al., 2014). Moreover, the use of conventional chemical pesticides is no longer desirable due to their harmful impact on human health and the environment, as well as the evolution of resistance.

Genetic pest control has become an attractive alternative due to its potential to solve devastating pest infestations without off-target effects or unwanted chemical residues. Recently, gene drives have been proposed as a potential genetic method for controlling agricultural pests. These ‘selfish’ genetic elements achieve a rate of vertical transmission greater than that predicted by Mendelian laws (i.e. >50%). This gives gene drives the novel capacity to spread through a population of sexually reproducing organisms, as long as any associated fitness costs are not too high (Champer et al., 2016). Thus, gene drives could be engineered into target species and used to spread lethal elements or cargo genes with the aim, ultimately, to suppress or modify pest populations.

Several natural sources of gene drive have been described, including transposable elements, chromosomal rearrangements and homing endonuclease genes (Champer et al., 2016). The latter bias their own inheritance though a ‘homing’ mechanism that converts heterozygotes into drive homozygotes. Thus, the drive element encodes a site-specific endonuclease which cleaves a double-stranded break in its target site on the homologous chromosome. Following DNA repair via the homology-directed repair pathway, the drive element is copied into the break site. When such homing occurs in the germline or early embryo, the probability of offspring inheriting the gene drive element is greater than 50% (Burt, 2003). 

Whilst the concept of synthetic gene drive has long been imagined, until recently their application has been limited due to technological challenges and evolutionary instability (Min et al., 2018). However, the rise of CRISPR genome editing has made synthetic gene drives a very real possibility. For example, a CRISPR cassette can be engineered to mimic the activity of a homing endonuclease gene. A gene encoding the Cas9 endonuclease is fused to a guide RNA that specifies the target sequence. Consequently, following Cas9-mediated cleavage and homology-directed repair, the CRISPR cassette, and any genetically linked cargo, will be copied into the homologous chromosome and inherited by the majority of offspring. 

Importantly, it is not the gene drive element itself that is toxic. The ability to control pest populations relies on the effect that gene drives can have on reproduction or survival. For homing-based gene drives this requires the copying process to be targeted such that the element interrupts an essential gene to induce sterility or lethality. Such a drive has been engineered in Anopheles gambiae, the African malaria vector, by targeting haplosufficient female fertility genes. This system achieved transmission rates of up to 99.6% in caged populations and successfully reduced female fertility by 20-fold (Hammond et al., 2016). Ultimately, this reduction in fertility would limit reproductive capacity and lead to a population crash.

Whilst the development of synthetic gene drives continues, we must consider whether agricultural pest control is a realistic application for this biotechnology. Currently, gene drive systems have been engineered in A. gambiae, A. stephensi (the Asian malaria vector), Drosophila melanogaster and Saccharomyces cerevisiae, but no agricultural pest species (Chan et al., 2013; Fasulo et al., 2020; Gantz et al., 2015; Hammond et al., 2016). To expand gene drives beyond model organisms will require an extensive knowledge of target species’ genetics, ecology and biology. Importantly, any target pest will have to (i) undergo sexual reproduction, and (ii) have a relatively short generation time (Min et al., 2018). These two prerequisites are essential for any gene drive to be able to spread through a population in a meaningful timescale. Unfortunately, such requirements mean that gene drives cannot be used to control some of the most damaging agricultural pests, such as aphids, that are asexual.

Nevertheless, scientists have already begun to propose agricultural pest species that could be controlled using gene drives. These include D. suzukii and the red flour beetle (Tribolium castaneum). However, if this biotechnology is to succeed as an agricultural pest control it undoubtably has many more hurdles to cross. In particular, scientists will need to work alongside policy-makers and the public to ensure widespread acceptance following previous controversies surrounding the use of biotechnology crops (Min et al., 2018). 

References:

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Chan, Y., Takeuchi, R., Jarjour, J., Huen, D. S., Stoddard, B. L. & Russell, S. (2013) The design and in vivo evaluation of engineered I-OnuI-based enzymes for HEG gene drive. PLoS ONE. 8, e74254. doi: 10.1371/journal.pone.0074254.

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