Genome Editing and Gene Drive: Hacking Evolution?
Gene drives introduce the most fundamental alterations of organisms, enhancing both potential benefits and potential risks. For example, gene drive enabled by genome editing is being considered as a means to stop the spread of mosquito-borne diseases such as malaria, dengue and Zika. The concept of gene drive was first conceptualized in the 1960’s by an entomologist who hypothesized that mosquito breeding programs could be set up so that male offspring could be favored due to the identification of a male-producing factor that is expressed from the genome of some male mosquitoes. As a result, release of male mosquitoes harboring this male producing factor could shift the sex ratio of the mosquito population so that the number of females was reduced to below the level required for efficient disease transmission (Hammond, 2016; Wieczorek, 2016). It was the advent of genome editing using CRISPR-Cas9 that has offered unprecedented opportunities to reduce mosquito populations (Gurr and You, 2016).
Gene drives work by incorporating a system of biased inheritance so that the ability of a gene or genetic element to pass from parent to offspring through sexual reproduction becomes enhanced. As a result, the presence of this genetic element increases in frequency and spreads from one generation to the next until most or all members of a given wild population representing that species contain the same element. Unlike classical Mendelian inheritance, in which each offspring has a 50% chance of inheriting a specific gene from one of their parents, gene drives dictate that most or all offspring will inherit a particular genetic trait that is under the control of gene drive technology. In the study of genome-edited mosquitoes, for example, genes that confer a recessive female sterility phenotype were disrupted. CRISPR-Cas9 gene drive constructs designed to target and edit each sterility gene and its homologue were inserted into the female sterility gene locus. This approach resulted in a massive increase of sterile females. Population modeling showed that this gene drive could be used to effectively target female reproduction (because only females bite humans) in a mosquito population (Reid and O’Brochochta, 2016). The technology could also be extended to edit mosquitoes so that they are no longer able to transmit infectious diseases (Singer and Frischenecht, 2016).
Gene drive technologies using CRISPR/Cas9 have given humans the potential to eradicate entire species from this planet. Profound ethical concerns are immediately apparent. What are the risks of gene drive with respect to human health and the environment? How will gene-driven suppression of specific species of mosquitoes or other pests alter the Earth’s ecosystem as a whole? How do we as a national or global society decide when and where gene drive technologies are to be used? Who decides? The threat of Zika virus over the past year, for example, in South America and Southern states of the US has instigated a public discussion of the benefits and risks of gene-drive mosquito technologies. The ecological discussion is devilishly complex: the Aedes aegypti mosquito itself is an invasive species alien to the Western Hemisphere, in no real sense natural or critical to ecological integrity.
Gene drive technologies could suppress or eliminate invasive species that threaten biodiversity, or eliminate weeds, and/or even alter pathogens that damage crops or carry diseases. Gene drive technologies could also introduce new traits to existing populations, and could possibly rescue or save endangered plant species – or resurrect extinct ones (vide woolly mammoth project).
For example, in an effort to protect the biodiversity of native plant species in the US, gene drives are being developed to suppress the spread of the non-indigenous spotted knapweed Centaurea maculosa. Originating from Eastern Europe, the spotted knapweed was introduced into the United States in the 1800s. It spread rapidly, damaging ecosystems and causing soil erosion. A gene drive solution could spread throughout the knapweed population, and several approaches could be taken. One of these would entail the suppression of a sex-determination gene, in a fashion analogous to the mosquito gene drive described above, that could lead to an imbalance in plant sex ratio and consequently a population crash (Langin, 2014). Unlike mosquitoes, however, knapweed grows slowly and it is unclear how factors such as rate and distance of pollen spread in the wild would affect the gene drive process (National Academies Press, 2016).
Another example for the use of gene drive in plants would be the elimination of pigweed (Amaranthus palmeri) from agricultural fields. This weed reproduces rapidly and has evolved resistance to glyphosate, one of the most widely used herbicides globally. Using gene drive technology, the glyphosate resistance trait could be reversed in pigweed, making it again susceptible to this widely used herbicide. Alternatively, a suppression drive that creates a biased sex ratio could be created in pigweed, resulting in a population collapse of this species (National Academies Press, 2016).
Not only could genome edited crops be used in conjunction with gene drive to eradicate weeds, they can also be designed to eliminate pests. Gene drive crops could be designed that no longer will act as hosts for insect and microbial (fungal, bacterial and virus) pathogens. As scientists gain a further understanding of what specific proteins are involved in pathogen-host interactions, the employment of gene drive to disrupt these interactions could ensure that future generations of crops will no longer support pathogen growth.
There are some caveats to the use of gene drive. For example, the technology will not work on invasive plant species that do not sexually reproduce or which reproduce very slowly. It is possible too that gene drives may have to be reapplied over time, because plants will undergo natural selection and lose the trait that has been introduced (Callaway 2017). Potential resistance of a few individuals in a given population to gene drive is also a possibility, and could lead to the eventual re-emergence of a population that is impervious to its further usage. On the other hand, gene drives could permanently change entire plant or animal communities within a relatively short period of time, for better or for worse. It is the unforeseen and perhaps irreversible consequence of destabilizing current ecosystems that brings pause to the idea of applying gene drives without a binding social contract with all stake-holders across the globe at the table.