For my first blog post, I thought I'd bring back one of my favorite topics that I first read about last year. I heard about genetically modified mosquitoes on the news again recently, so I decided to expand and write a lengthy (blog post) but a short essay on this new technology. Enjoy!
Brief points:
- There are several advantages of GMMs over traditional interventions of insecticides, bed nets and SIT.
- Among the various GMM methods, RIDL currently holds the most evidence of effectiveness so far. While RNAi and Wombachia are promising ideas, more studies in the laboratory and field are needed to evaluate its effects to different strains of dengue and possible resistance.
- In addition to considering biological factors, there are also social and economic aspects including cost-effectiveness, community acceptance, and long-term sustainability with capacity building to consider.
- For greater uptake within communities, more accurate information of its advantages and misconceptions should be addressed.
Background
According to WHO, around 50-100 million people are affected
each year from dengue fever, one of the deadliest mosquito-borne diseases,
primarily in tropical and sub-tropical regions1. While many
interventions have been carried out to fight against vector-borne diseases,
they have been ineffective to completely eradicate it. However, today’s
technological advancements have allowed the development of promising innovative
methods, including one that targets the mosquito population with genetic
modifying mechanisms. Scientists have described this new approach as a “quantum
leap” which has the potential to revolutionize, and possibly eradicate, malaria
transmission. The idea of this “mutant mosquito” gained widespread attention
and popularity through a TED talk from Oxitec. Since then, many institutions
particularly in the UK have developed on this idea creating waves in the
scientific community.
Genetic modification (GM) serves as an incredibly useful
tool that has been the subject of unfair and biased criticism2.
Genetically modified mosquitoes (GMM) have several advantages to other
techniques such as SIT (Sterile Insect Technique) and traditional methods of
insecticides and bed nets. And while there are several ways in which to
genetically modify a mosquito, such as the use of RNAi and Wolbachia, the RIDL (release of insects carrying a dominant lethal
gene) technique seems to be the most effective and sustainable GM technique for
the eradication of vector-borne disease. Oxitec, a biotechnology company, has
used the RIDL technique to demonstrate short-term success in the Cayman
Islands, Malaysia, and Brazil2.
The traditional methods
The new approach
To improve upon these challenges, scientists at Oxitec are
utilizing GMM strategies, which may be safer and more effective than SIT4.
One of the most effective GMM techniques is known as RIDL. RIDL, also known as
conditional lethality, modifies male mosquitoes not by irradiation, but by
genetically modifying a mosquito to carry a dominant lethal6. When
this transgene is activated – there are several activation methods - it can
cause lethality in progeny. The most important advantage of RIDL over SIT is
the ability to control the activation of the lethal gene allowing it to be
sex-specific and to time lethality6.
Oxitec has developed
two main activation methods:
(1) The first approach is sex-specific which aims to create flightless female. A construct is
developed to reduce the expression of a female-specific gene that is critical
for flight in pupae. This construct is inserted into the strain of male mosquitoes7.
Once these modified males are released and mate with wild females, the
immediate progeny inherits this dominant female-specific lethal gene, and the
mutation is expressed in a female mosquito progeny7. This results in
F1 females unable to fly to find mates or bite human hosts7. The F1
males, however, remain viable and fertile4. This will decrease the
overall reproductive potential of the wild population5. Instead of
random mutations caused by SIT, males can carry and deliver female-acting
transgenes into the population4.
(2) A second approach of RIDL focuses on stage-specific killing. This allows
scientists to control age of mortality, either in pupae, or in adults, and
targets both males and females4. One way this is achieved is by
inserting mutations so that lethal genes are only expressed in the absence of
tetracycline8. A RIDL transgene is created, which carries the
instructions for the production of a protein called tetracycline transactivator
(tTA), and is inserted into the a strain in Ae.
Aegypti mosquitoes9. This transgene is composed of two proteins,
which allow it to continuously produce even more tTA protein resulting in a
positive feedback loop9. tTA will interefere with the cellular
process causing mosquito larvae to die. However in the presence of
tetracycline, tTA expression can be turned off by binding to tetracycline9.
In other words, scientists can control whether survival of larvae by increasing
or removing tetracycline from the environment. Because these constructs use
either female or stage-specific promoters, they do not affect male fitness or
interfere with other stages of a mosquito’s life4. This helps ensure
stability of the mosquito’s competitiveness in the wild and reduces the
possibility of resistance, which has been a challenge for the SIT method.
Figure 1. Because
I always love drawn out explanations, I outlined the stage-specific killing
method (conditional lethality)d below in a detailed and graphic visualization:
Some other new GM methods gaining traction
RNAi: Using RNAi, scientists hope to improve the mosquito’s own natural immune defense system. This method calls for a genetic construct to be developed that expresses copies of an inverted repeat from a dengue virus 2 (DENV-2) genomic RNA4. Once the virus invades the mosquito, the resulting double stranded RNA forms and triggers an RNAi response degrading the virus and protecting the mosquito4. However, this method was only found effective in laboratory so far.
Wolbachia: The
other GM technology utilizes the natural symbiotic bacteria Wolbachia, which naturally infects other
insects such as Drosophila and
protects them against infection by certain RNA viruses10. The idea
aims to boost a mosquito’s defense system by infecting A.aegypti mosquitos with Wolbachia to prevent dengue infection10.
While this is a promising idea and has been successful in small laboratory
studies, it has several limitations. Research has only tested infection to
protect against DENV-2; its effectiveness against the three other dengue
serotypes has yet to investigated4. On the other hand, the RIDL
method that Oxitec has employed eradicates the entire mosquito species with no
challenges of targeting virus serotypes. Most importantly, the mechanism of how
Wolbachia blocks pathogens is still
unknown4. Without knowing this mechanism, it is difficult to foresee
long-term effects of implementing Wolbachia
in specific mosquito populations and predicting whether they may have adverse
effects, such as if resistance will arise and how we may prevent it.
Challenges ahead for GM technology
The main challenge for any mosquito suppression technique is
sustainability - maintaining
stability of the competitiveness of the mosquito and preventing possible
resistance4. All of the GM techniques including RIDL, have not been
tested long enough yet to ascertain long-term effects. However, RIDL has shown
successful short-term effects thus far. In 2010, male mosquitoes with modified strains
were released in field tests in the Cayman Islands; the results showed a
reduction in A.aegypti population by
80%2. Currently, RIDL technologies have only used single gene
insertions. To avoid the possibility of resistance, future studies can
introduce several conditional lethal systems in a genome8. RIDL future
intervention programs will most likely be used in combination with other
traditional or GM methods to boost effectiveness3.
Misconceptions and advantage
- The most common belief is that scientists are aiming to eradicate all mosquitoes, which would possibly disrupt ecological systems. However, the focus of GMM research is on specific species that transmit disease-causing pathogens to humans, most of which are invasive species in an area in the first place3.
- RIDL has several advantages in safety and in acceptance within a community. If RIDL is successful, the population can anticipate a short-lived presence of the GMM in their community once the mosquito species has been eradicated11. Since only males are released, it may also reduce nuisance biting and the risk of crop damage from egg-laying females11. These mosquitoes can also be manufactured and released locally after training communities allowing for capacity building and empowerment through employment11.
- The RIDL technique allows scientists to control lethality timing by controlling tetracycline release to a mosquito’s diet. This tetracycline requirement produces the conditional lethality aspect of RIDL, which also ensures protection against the accidental release of mosquitoes11
References 1. Sifferlin, A. How Mutant Mosquitoes are Fighting Dengue Fever. Time, 9 November 2012. < http://healthland.time.com/2012/11/09/how-mutant-mosquitoes-are-fighting-dengue-fever>
