How to better control or eradicate deadly infections using transgenesis or genome editing technologies?

by Gaetan Burgio

Deadly infectious diseases, such as those transmitted through mosquitoes, are a huge threat to the human population. The rapid pace in the development of transgenesis technologies and genome editing over the last few years have raised many hopes, but also given birth to many fears.

Mosquito borne diseases: threats to human health

Mosquitoes transmit many infections, including malaria, dengue, yellow fever and chikunguna. These mosquito-borne diseases affect millions of people worldwide and are a huge cost burden for populations living in these endemic areas. It is a matter of urgency that new treatments are found to improve the quality of life, and to save lives. Unfortunately there are to date no efficient vaccines or drug treatments available to cure these deadly diseases. Preventive strategies such as bed-nets or insecticides are the mainstay for control and prevention of these diseases. However, insecticide resistance is developing at an alarming pace preventing any hope of controlling or curing these diseases. Recently however, the rapid developments in the genetic technologies such as transgenesis or genome editing have raised hope and confidence in combatting and controlling these diseases.

Mutating mosquitoes: A promising avenue to control these diseases.

Way before the rise of genetic technologies, back in the 1930’s, it was thought that these diseases could be controlled by releasing large numbers males mosquitoes sterilized with high dose irradiation. Native females that mated with sterile males would not produce any viable eggs. The Sterile Insect Technique (SIT) has proven successful in controlling pest such as fruit flies, however the success rate is variable due to the decreased fitness of the sterile males, competition from other males or immigration of pre-mated females.

With the discovery of gene knockout, PiggyBac, transposon mutagenesis, or, more recently RNA interference, the success of SIT technologies has significantly increased. This improvement has led to better disease control due to the prevention of the development of the mosquito larva or due to the exertion of a killing effect against the pathogens. Using various release strategies such as fogging, vehicle release or more recently, sustained release of transgenic male mosquitoes, attempts to control mosquito-borne diseases has had variable success. For instance, a few attempts have been made to control mosquitoes responsible for dengue fever using transgenesis strategies. Insects carrying a dominant lethal mutation (RIDL) were released in large numbers in the field. In one instance, the RIDL strain OX513A, a late acting lethal mutation at pup stage of the larval development, has proven successful in well-defined and small areas endemic for dengue fever in South America. However this strategy is not suitable for a large release of transgenic mosquitoes as it does not fully suppress the population already present and not subject to transgenic alteration.

The rise of genome editing technologies.

Recently, Genome editing technologies such as Zinc-Finger nucleases or Transcription Activator-Like Effector (TALE) have increased the flexibility and ease of generating transgenic mosquitoes. While multiple transgenic strains have been created, none to date have been released in the field. Recently, the CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats) mediated genome editing has considerably facilitated the generation of transgenic mosquitoes by genome manipulation. Recent experiments in flies have pushed the boundaries of the technology to its limits by creating mutations and transmitting almost 100% of the genetic alterations across to the next generation. This ‘chain reaction’ or ‘gene drive’ strategy could be use to rapidly spread mutant genes without having to sequentially release the insects in the field. In a very short period of time, the desired mutation can spread rapidly through the population and become highly prevalent in all the targeted vector population. By targeting the vector, this technique has shown it can lead to the eradication of the disease. This ‘gene drive’ strategy has the promising potential of curing mosquito-borne diseases such dengue, malaria or yellow fever.

Ethical and ecological challenges

The latest technologies of using CRISPR/Cas9 genome editing and, in general, transgenesis strategies in mosquitoes, whether combined or not with the use of the ‘gene drive’ technology, has raised the possibility of the eradication of mosquito-borne diseases. However, there are serious ethical and ecological challenges to consider before adopting these strategies. Firstly, a successful vector control program relies on the fitness of the mutated vectors, the nature of the gene targeted and the vector release protocol. Additionally, sterile males would have to compete with wild males in a genetically diverse mosquito population. Worryingly, as well as PiggyBac transposon mutagenesis, genome-editing strategy creates off-target effects that could spread into the targeted population and to another species and would have the potential to considerably modify the genome of a non-targeted population. Additionally, there is always a risk of the lack of biocontainment and escape from CRISPR/Cas9 edited mosquitoes leading to a ‘chain reaction’ in the wild population. The fast pace in the development of genome editing technologies and ‘gene drive’ shows exciting potential, but the scientific community has also expressed concerns and fears about the rapid adoption of this technology. Discussions between researchers, regulatory agencies, ethicists, philosophers and the public must occur to ensure that the community is well informed of the risks, benefits, and limitations of genome editing and gene drive technologies.