Healthy control methods for vector-borne diseases
The role of mosquitoes in the spread of disease was first recognised around the late 1800s and early 1900s. This gradual discovery sparked organised efforts to control mosquito populations. Methods have developed over time, incorporating physical, chemical, and, more recently, genetic control methods.
Dengue, malaria, Zika, chikungunya, and yellow fever are some of the most common and potentially serious illnesses transmitted via mosquito bites. According to the World Health Organisation (WHO), vector-borne diseases account for more than 17% of all infectious diseases and cause more than 700,000 deaths a year. Climate change could exacerbate the problem by influencing the size and spread of mosquito populations.
Since their introduction, insecticides have led the charge in the control of mosquitoes, leading to dramatic reductions in mortality and morbidity over the last 20 years. But insecticides come at a cost, risking damage to non-target species, biodiversity and vital ecosystems. Mosquito species have also adapted and gained resistance to insecticides, decreasing effectiveness.
Genetic control of mosquitoes is one of several new promising tools, enabling recent developments such as inducing sterility in male mosquitoes.
Researchers now consider the most effective tactic for mosquito control is combining several tools to suit the needs of individual locations or circumstances.
An innovative approach
Between 1997 to 2008 Professor Luke Alphey led a group at the University of Oxford studying the application of genetic engineering to insect pests. It was aided by the Biotechnology and Biological Sciences Research Council (BBSRC), Medical Research Council (MRC) and Wellcome Trust funding. The group of genetic scientists developed a revolutionary idea, applying their fundamental research method to mosquito control.
Professor Alphey expands:
Radiation sterilised insects have been used for decades to reduce population numbers. However, radiation can do a lot of damage to insects. We want female mosquitoes to breed with the sterile males, the sterile males must stay fit and healthy to attract those females.
It occurred to me that the molecular genetics methods I was using for fundamental research could be used to control a range of insects, including mosquitoes. Having had this one applicable idea, I followed it, leading me to places I didn’t expect!
Finding effective forms of intervention with minimal negative impacts has become the central ambition of mosquito control. Professor Alphey’s genetic engineering method produced sterile male mosquito strains without any damaging impacts on the insects or the wider environment.
Professor Alphey’s team and collaborators were the first scientists to use genetically modified insects for pest control, and Professor Alphey is a leading figure in the sector.
His work led to a series of patents around transgenic mosquito technology and has continued to be a leading voice, giving government advice and evidence on genetically modified insects.
Watch our Climate Change Bites: How disease-spreading bugs will impact our health and food security seminar, where Professor Luke Alphey sits on the panel.
The benefits of genetic methods of control
Any form of mosquito control needs to lead to lower transmission rates of mosquito-borne diseases. One key advantage of this kind of genetic control is that the sterile males actively seek out female mosquitoes in places which may be inaccessible to insecticide sprays.
Greater reliance on chemical-free mosquito control methods reduces insecticide use and helps protect precious habitats and biodiversity. This will especially benefit parts of the world where ecosystems are already under severe threat due to climate change, land use and other challenges.
Professor Alphey targeted the mosquito species Aedes aegypti, a key vector of dengue.
According to WHO, this flu-like illness:
- results in 40,000 deaths each year
- poses a growing problem in many parts of the world, with an estimated 96 million symptomatic cases a year
Professor Alphey adds:
We did a whole load of things that had never been done before, such as making functional strains of a range of pest insects with chosen properties. We also went out into the field to release them, achieving regulatory and community support.
The results were impressive. Mosquito populations in areas targeted by trials typically fell by over 90%.
Commercialising the science
Mathematical modelling was employed to explore possible approaches and potential impacts fast and efficiently. The results highlighted huge potential for real-world application.
Professor Alphey highlighted:
I’m a geneticist but not naturally an entrepreneur. However, I was committed to seeing what we could do. We needed to license the idea to a company, but the more innovative your idea is, the more difficult this is to do.
Our idea didn’t look like anything else on the market at the time. I didn’t want to drop it, so I did it myself and, with help from others, founded Oxitec.
BBSRC funding enabled industry-academia partnerships and early-stage innovative research, which contributed to the foundation of Oxitec in 2002 by Professor Luke Alphey, Dr David Kelly and Dr David Brooks.
Other funding included:
- Oxford University Innovation
- Innovate UK
- Wellcome Trust
- Bill and Melinda Gates Foundation
- European Commission
Successful first trials
Within a few years, the company was spearheading the world’s first-ever field trials involving the release of genetically modified (GM) mosquitoes in collaboration with the Cayman Islands Mosquito Research and Control Unit. This had followed an earlier release, also led by Oxitec in collaboration with the US Department of Agriculture in Arizona, of GM pink bollworms, which was the first ever GM insect release.
As the first project to develop and field trial GM insects, new regulations had to be put in place, or old ones adapted, nationally and internationally. This included the Special Programme for Research and Training in Tropical Diseases (TDR) guidance framework for testing GM mosquitoes. In 2014, the National Biosafety Committee in Brazil gave technical approval for the commercial release of Oxitec’s GM mosquito strain. This makes Brazil the first country to approve an unconstrained release of GM mosquitoes.
Targeting locations in Brazil, the Cayman Islands, and elsewhere, the trials proved hugely successful. Reductions in the target mosquito population of over 90% were observed relative to nearby untreated areas. The researchers estimated that the decrease in numbers would be sufficient to prevent epidemic transmission of dengue, though the sites were too small for actual epidemiological studies.
Professor Alphey explains:
We aimed to establish precedents and create confidence in a new approach to mosquito control. No one had really considered the release of large numbers of genetically modified insects before.
We set out to revolutionise people’s thinking. With the help of BBSRC and others, that’s exactly what we achieved.
Professor Alphey won:
- BBSRC’s 2014 Innovator of the Year award
- 2014 Entomological Society of America award for Creativity and Innovation in Entomology
- 2008 World Economic Forum Technology Pioneer award
Along with BBSRC backing his research had received, these early awards were pivotal to Oxitec cementing the scientific credibility essential to attracting partners and investors. In 2015, a US biotech company acquired Oxitec for US$160 million.
Recent Oxitec developments
Professor Alphey spent just over a decade as Research Director at Oxitec, after which Oxitec continued to develop and trial GM mosquitos. This included further successful trials for the original mosquito strain in Brazil after 2015 and the development of a new strain, which has been successfully trialled between 2018 and 2020.
In 2021, it announced the commercial launch of its Friendly™ Aedes aegypti solution in Brazil. These are male mosquitoes whose offspring do not survive until adulthood. The company has also extended its capabilities to other pests. The Bill and Melinda Gates Foundation awarded a grant in 2018 to help develop Oxitec’s Friendly™ technology for malaria control.
The establishment of Oxitec, now home to over 50 employees, and its continued success has delivered high-value, knowledge-intensive, sustainable jobs. More widely, the advances achieved in GM mosquitoes have helped stimulate a potentially fast-growing new market in gene-based pest control, generating further opportunities for economic growth.
Moving back to the fundamentals
Professor Alphey moved to the Pirbright Institute in 2014. His research focuses on ‘genetic pest management’, which is the introduction of heritable traits into a wild pest population through breeding. Introducing sterile male mosquitoes is an example of this, but there are other methods, such as using gene editing or bacterial infection to reduce breeding ability or pathogen transmission capability.
Professor Alphey highlighted:
To some extent, my job with Oxitec was done. The necessary science was complete.
So, I moved back to an earlier stage of work at the Pirbright Institute while the company continues to do very well. Public funded research, such as research at Pirbright, is better suited for exploratory work, with sustained long-term funding and more emphasis on increasing human knowledge and realised economic, social and environmental impacts, rather than specific commercial products.
His current work involves ‘gene drives’, genetic systems that can spread themselves through a population, thereby achieving desired effects with smaller and less frequent releases than sterile male approaches. In particular, he focuses on versions that might offer more flexibility, such as ‘local gene drives’, which only affect a smaller target population. This allows users to target specific locations and ensures that the drive is self-limiting, with no risk of affecting an entire species or other genetically similar species.
Professor Alphey says:
There’s a trade-off between release numbers, persistence, invasiveness, and reversibility. The current method of using sterile males is extremely reversible.
If we had more persistent methods, then frequent releases wouldn’t be needed. The aim is to produce a suite of gene-based tools that communities can select from to match their particular circumstances.
Forwards thinking for the future
In August 2022, Professor Alphey moved his team to the University of York, where he will continue his research.
The ability to genetically target a specific species posing a specific health threat in a specific location would be an invaluable addition to the mosquito control arsenal. If Professor Alphey’s current work is successful, the implementation of local gene drives involving genome modification would give users the flexibility needed to tailor releases to specific needs.
By covering more insect species and a wider range of diseases, such measures will aid human, animal, and crop health, boosting prosperity and living standards worldwide.
Professor Alphey says:
Genetically modified mosquitoes have been out in the field for well over 10 years now, and that’s built a platform for upcoming and more sophisticated approaches.
Without that experience, I do not think the more complex gene drives, which have the potential to do great things for disease prevention, could be implemented in the field.
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