Author: Lauren Wilburn Edited by: Inês Barreiros, Ruth Sang Jones
The Bill and Melinda Gates foundation has recently donated over $75 million to fund gene drive mosquito research by Target Malaria , a consortium that aims to develop technology for malaria control. The first planned release of gene drive mosquitoes is set to happen over the next two years in Burkina Faso, West Africa.
But what exactly is gene drive, why do we need it and what are the wider implications of the technology?
Malaria: the disease and current situation
Malaria is a parasitic disease spread by the bite of the female Anopheles mosquito. Malaria can present as a range of symptoms including, mild fever, muscle pains (which can progress to severe malaria where the patient can experience severe anaemia and bleeding), renal failure, neurological disorders and death. In 2017, there were an estimated 219 million cases and 435,000 deaths attributed to malaria (1). Over 91% of these cases occurred in the Africa region, and children under the age of 5 were at the highest risk of contracting severe malaria. Fortunately, due to interventions such as insecticide-treated bed nets, indoor spraying of insecticides and improved medical infrastructure, from 2010-2017 malaria deaths were reduced by an estimated 28% (1).
However, these control efforts may be severely jeopardised due to the rapid emergence of resistance to all insecticide classes and the most effective anti-malarial drugs (2, 3). Currently, there are only five classes of insecticides approved for public health use. In areas such as West Africa, there are multi-resistant mosquitoes which show resistance to all insecticide classes (4).
Therefore, if the World Health Organisation (WHO) is to meet its goal of reducing global malaria by 90% by 2030, novel and effective strategies for malaria control must be identified (5). One such proposed strategy is gene drive mosquitoes.
Gene drive technology
“So, what exactly is gene drive technology?”
Gene drive is a system that increases the likelihood of a sexually reproducing organism passing a set of genes on to the next generation, even if those genes negatively impact the organism’s health. In terms of mosquito control this could be a gene that could reduce the capacity of successful mating or shift the bias towards male mosquito offspring. These genes, which go against traditional Mendelian inheritance, are known as ‘selfish genes’ as they are over represented in the next generation and persist in a population, regardless of the hosts fitness (6).
The CRISPR-cas9 genome editing tool has revolutionized the genetic modification field. It has now become easier and more efficient and sustainable to generate genetically modified organisms. Scientists have begun to introduce genetic modifications, under genetic-drive mechanisms. One such study introduced a gene, which conferred sterility in females with two copies, that was under genetic drive to Anopheles mosquitoes in a caged environment (7). Within 7-11 generations, the gene was present in 100% of the colony, which led to reductions in egg numbers until the eventual collapse of the colony.
Other than crashing a mosquito population, other methods to reduce malaria burden have been proposed. These include altering the blood feeding habits of mosquitoes, replacing the population with mosquitoes that are resistant to infection or suppressing the population in other ways such as reducing the flight ability of the mosquito.
There have been some pilot studies that aim to suppress the Aedes mosquito, which transmits disease such as Zika and Dengue. These mosquitoes are genetically modified but the modifications are only passed on to half of the offspring (the males) and do not persist permanently. Therefore, repeated release of over 40,000 males must occur regularly. These pilot studies are headed by British based company, Oxitec. In the Cayman Islands, Brazil and Panama, male Aedes, which do not bite hosts so do not transmit disease, were released. These mosquitoes, trademarked Friendly™ Mosquitoes, carry a self-limiting gene that reduces the survival capacity of their female offspring. Males are released in large numbers and mate with wild females. Their female offspring do not survive till adulthood therefore do not mate, do not blood feed and cannot spread infection.
Gene drive mosquitoes have yet to be released in the wild. The first release of Gene drive mosquitoes is planned for Burkina Faso, West Africa at some point in the next two years. As Burkina Faso shows extremely high levels of multi-insecticide resistance, gene drive mosquitoes are hoped to significantly reduce mortality in the area.
Concerns regarding gene drive technology?
“But why are people concerned about gene drive?”
Although gene drive could be used to wipe out diseases that devastate millions each year, there are a number of concerns regarding the technology. Some issues raised include:
What will be the impact on the ecosystem?
Who is funding this technology?
What other purposes would this be used for?
Will it actually work?
The effect upon the ecosystem
The effect on the wider ecosystem is perhaps one of the strongest criticisms of gene-drive. There has been strong opposition from groups such as Friends of the Earth and ETC that have called for an outright or temporary ban on the use of gene drives.
As gene drive is a completely novel technology it is hard to predict what the wider implications will be. However, researchers are not taking this risk lightly. Studies modeling the potential outcomes of mosquito introduction in specific areas or ecological risk assessments can be used to predict the effect of the mosquitoes upon the wider ecosystem (8). There are also methods that aim to control the spread of a gene, one of which is Daisy-chain technology (9). Daisy-chain is essentially a method of teaching DNA to count how many generations to which it has it has been passed. This could limit the effectiveness of the gene drive over time,therefore keeping the impact of the gene drive local.
Although efforts are in place to determine what the wider implications of gene drive technology could be on the environment, it is clear that more research needs to be conducted on this matter.
Who is funding this technology?
There have been questions about the intended use of the technology outside of vector control. Namely, the applications of gene drive mosquitoes in bioterrorism. Military organizations such as the DARPA, the US defense and research agency have funded gene drive research.
DARPA is aiming to develop a method of reversing genetic engineering. If CRISPR-cas9 is the ‘cut’ and ‘paste’, DARPA hopes to develop the ‘undo’. They state this is primarily due to concerns regarding biosafety and security. However, groups such as the ETC are extremely skeptical about the underlying intensions of the $65 million donated by DARPA.
In addition, there is wider concern about what will happen with the technology and the general trustworthiness of scientists and genetically modified technologies.
This could be because the ethical boundaries regarding CRISPR-cas9 are being blurred. For example, recent headlines regarding chinese biophysicist Professor He Jiankui and the CRISPR-Cas9 edited babies caused controversy regarding the technology. Although Juankui defended his decision regarding the edited babies, it led to widespread condemnation from the scientific community. Many believe it was reckless, unethical and may lead to a public distrust of the technology. There is also the rise of Biohacking, led by individuals such as biophysicist Dr Josiah Zayner, that provides DIY kits to genetically engineer animals at home. Some say the technology is promoting citizen science and advancing science whilst others worry about the unregulated use of the technology.
These concerns clearly point to the need for more discussion and clear policy surrounding the use of gene drive. It also highlights the science versus public divide that has become more prominent in recent years.
Government and policy
Although further research into the science behind this technology needs to be carried out, the next steps need to be taken by the government on policy and social impact.
It is important to discuss the use of the CRISPR-cas9 genome editing tool particularly in the gene drive technology. As gene drive is a predominantly western technology that would be implemented in African and Asian countries, impacted communities need to be informed, involved and lead the control efforts.
The prospect of completely banning gene drive trials was addressed at a 2018 UN discussion regarding biodiversity. Over 200 representatives agreed that gene drive applications should be reviewed on a case-by-case basis and local communities should be consulted. This open-to-interpretation consensus was seen as a victory by both sides of the argument. In addition, the WHO and the Programme for Research and Training in Tropical Diseases (TDR) released the ‘Guidance framework for testing of genetically modified mosquitoes’. However a more updated revision of this framework that encompasses new technologies would be beneficial.
Currently, organisations such as New Partnership for African Development , a pan-African consortium that addresses Africa’s development goals, are being consulted by Target Malaria scientists about gene drives. However, it should be noted that only three out of the 13 partner institutions that make up Target Malaria are representatives from Africa and currently there are no representatives from Asia.
Gene drives could have the potential to make a significant impact on reducing the malaria burden. However, it is not going to be that simple. Malaria is a complex disease that needs an equally complex method of control and treatment. There is ongoing need to research insecticides for public health use, anti-malarial and novel vector control methods.
With the advance of scientific technology, we must strike a balance between using science for the ‘good’ and preventing ethical disasters. Debates regarding new technologies that include representation from multiple countries, with multiple disciplines must be encouraged. By doing that, hopefully malaria will soon no longer be one of the diseases African parents fear.
1. World Health Organization. World malaria report 2018. https://www.who.int/malaria/publications/world-malaria-report-2018/en/
2. Dondorp AM, Nosten F, Yi P, Das D, Phyo AP, Tarning J, et al. Artemisinin resistance in Plasmodium falciparum malaria. New England Journal of Medicine. 2009;361(5):455-67. doi: 10.1056/NEJMoa0808859
3. Alout H, Roche B, Dabiré RK, Cohuet A. Consequences of insecticide resistance on malaria transmission. PLoS pathogens. 2017;13(9):e1006499. https://doi.org/10.1371/journal.ppat.1006499
4. World Health Organization. Global report on insecticide resistance in malaria vectors: 2010–2016. 2018. who.int/malaria/publications/atoz/9789241514057/en/
5. Organization WH, UNICEF. Global vector control response 2017-2030. Geneva; 2017. Contract No.: Box 1. https://www.who.int/vector-control/publications/global-control-response/en/
6. Leftwich PT, Edgington MP, Harvey-Samuel T, Paladino LZC, Norman VC, Alphey L. Recent advances in threshold-dependent gene drives for mosquitoes. Biochemical Society Transactions. 2018;46(5):1203-12. doi: 10.1042/BST20180076
7. Kyrou K, Hammond AM, Galizi R, Kranjc N, Burt A, Beaghton AK, et al. A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes. Nature biotechnology. 2018;36(11):1062. https://doi.org/10.1038/nbt.4245
8. Eckhoff PA, Wenger EA, Godfray HCJ, Burt A. Impact of mosquito gene drive on malaria elimination in a computational model with explicit spatial and temporal dynamics. Proceedings of the National Academy of Sciences. 2017;114(2):E255-E64. https://doi.org/10.1073/pnas.1611064114
9. Noble C, Min J, Olejarz J, Buchthal J, Chavez A, Smidler AL, et al. Daisy-chain gene drives for the alteration of local populations. BioRxiv. 2016:057307. https://doi.org/10.1073/pnas.1716358116