Gene drive: Malaria

By Qinyi Wang and Kah Yan Ng

Within the last few decades, significant progress has been made in malaria control efforts worldwide. Despite this, the World Health Organisation recorded 228 million cases in 2018, resulting in 405,000 deaths (WHO.int, 2020) mostly in young children in sub-Saharan Africa (CDC.gov, 2020). The symptoms include fever, headache, muscle aches, and when the disease progresses to the severe stage, severe anemia, respiratory distress, and multi-organ failure are seen frequently (Teem et al., 2019).  

This acute febrile disease is predominantly spread through specific mosquito ‘vectors’ which carry a parasite of the Plasmodium genus (WHO.int, 2020). Researchers have identified 5 species of Plasmodium capable of causing malaria in humans, with P. falciparum being the most life-threatening (Teem et al., 2019). The female Anopheles gambiae mosquito is responsible for high transmission rates in high-risk regions, and their activity is prolonged due to the steady local climate all year round (WHO.int, 2020).  

Current preventative measures are focused on vector control using insecticides, either on mosquito nets or indoor sprays. Anti-malarial drugs have also been utilised, proving effective in disrupting the life cycle of malaria infection (WHO.int, 2020). However, these methods are no longer foolproof. Insecticide and drug resistance have reduced the effectiveness of these traditional methods and highlight the need for new strategies in the global response to malaria.  

In recent years, rapid developments in gene-editing have sparked increased application of these technologies in diseases. A gene drive is a novel approach to malaria vector control. Scientists edit the mosquito genome to force the spread of a genetic modification through a mosquito population at a much higher rate than normal. This can effectively overcome limitations of Mendelian inheritance and bypass natural selection (Scudellari, 2019). 

As only the female Anopheles gambiae mosquito transmits Malaria, some genetic modifications have been designed with the aim of reducing the reproductive capability of its population. This method is an attractive alternative to the use of insecticides, as it can be species-specific and more effective in controlling vector numbers in the long run. Nevertheless, designing the gene drive is not without its challenges (Scudellari, 2019).  

With the latest CRISPR technology, it is important to select a gene that can be targeted for many generations. This can only be done if the gene selected is well conserved – essential for survival that it does not get mutated too much over generations (Scudellari, 2019). In this case, the double-sex gene (Agdsx) has been chosen to bias female infertility by inducing a faulty alternatively spliced female transcript (dsxF) while leaving the alternatively spliced male transcript (dsxM) unaffected (Kyrou et al., 2018).  

The double-sex gene of the wild type allele is targeted using the CRISPR technology to induce homology directed repair using an inserted cassette as the template, disrupting the sequence between intron 4 and exon 5, which is exclusive only to dsxF. According to Kyrou et al. (2018), half the dsxF−/− offspring were normal males while the other half were infertile females with some male morphological features. Two examples of these morphological features that can be observed under the microscope is the absence of male clasper and presence of antennae which resembles that of the male. 

Recently, Simoni et al. (2020) published a paper which introduced a similar gene drive model involving Agdsx which could collapse the mosquito population more rapidly. This model aims to tilt the balance between male and female mosquito numbers to favor the male by inserting the gene for the X-chromosome-shredding I-PpoI nuclease into Agdsx. By doing so, the nuclease will cleave the X chromosome, leaving the Y chromosome intact so that there is a bias towards male offspring. 

Apart from laboratory experiments of the gene drive, caged trials have been carried out to better represent and consider the consequences of altering the ecosystem – taking into consideration of the food chain, mating habits and other ecological factors at hand (Scudellari, 2019). Moving forward, caged trials must be carried out at a larger scale to better represent the real-world environment. Regardless of the model implemented, releasing the caged population into the wild may result in unintended and irreversible damages. It has the power to change the ecosystem as we know it. 

All in all, it will be a groundbreaking scientific achievement should the gene drive work without causing a drastic side effect when implemented. If successful, this theory can be immediately applied to different species of mosquitoes which transmit diseases such as dengue and Zika virus, and eventually applied to other invasive species. 

References: 

CDC.gov. 2020. CDC – Malaria – Malaria Worldwide – Impact Of Malaria. [online] Available at: <https://www.cdc.gov/malaria/malaria_worldwide/impact.html&gt; [Accessed 30 September 2020]. 

KYROU, K., HAMMOND, A.M., GALIZI, R., KRANJC, N., BURT, A., BEAGHTON, A.K., NOLAN, T. and CRISANTI, A., 2018. A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes. Nature biotechnology, 36(11), pp. 1062-1066.

SCUDELLARI, M., 2019. Self-destructing mosquitoes and sterilized rodents: the promise of gene drives. Nature, 571(7764), pp. 160-162. 

SIMONI, A., HAMMOND, A.M., BEAGHTON, A.K., GALIZI, R., TAXIARCHI, C., KYROU, K., MEACCI, D., GRIBBLE, M., MORSELLI, G., BURT, A., NOLAN, T. and CRISANTI, A., 2020. A male-biased sex-distorter gene drive for the human malaria vector Anopheles gambiae. Nature biotechnology, 38(9), pp. 1054-1060. 

TEEM, J.L., AMBALI, A., GLOVER, B., OUEDRAOGO, J., MAKINDE, D. and ROBERTS, A., 2019. Problem formulation for gene drive mosquitoes designed to reduce malaria transmission in Africa: results from four regional consultations 2016–2018. Malaria Journal, 18(1), pp. 347. 

WHO.int. 2020. Fact Sheet About Malaria. [online] Available at: <https://www.who.int/news-room/fact-sheets/detail/malaria&gt; [Accessed 30 September 2020].