BPC Science Writing Competition 2nd Place: “A Sexy New Way to Fight Malaria”

By Charitha Gowda

Having a boy? Or a girl? The odds are 50:50, right? While that may be true for us, it doesn’t have to be the case for some species that preferentially produce more males than females. It is this naturally-occurring imbalance in the sex ratio that scientists are hoping to exploit as part of new malaria eradication efforts.

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Scientists at Imperial College London are embarking on an innovative strategy to target the Anopheles gambiae, the main mosquito species that transmits human malaria, by taking advantage of a process known as genetic distortion in sex ratio (1). This was originally described in two different genera of mosquitoes, the Aedes and Culex, where approximately five males to every three females were found when examining natural populations of some species (2). Differences in mortality rates between males and females do not appear to drive the imbalance. Instead, researchers have traced the sex ratio distortion to a bias toward the production of male gametes, or sperm.

Such new approaches to prevent or control malaria are sorely needed. Although substantial progress has been made since 2000, there is still much work to be done. With 650,000 deaths due to malaria each year, this disease remains a major threat to over 3 billion people worldwide who are at risk of contracting malaria. Additionally, the mosquitoes responsible for transmitting malaria are rapidly evolving strategies to overcome or become resistant to our current insecticides and mosquito repellants.

What does sex imbalance have to do with malaria control efforts?

For Anopheles gambiae, only the female mosquitoes bite and pass on the malaria parasite to humans. Additionally, it has been long appreciated that female members of a species are critical for determining ongoing propagation of a population. Thus, inducing a male predominance during sexual reproduction has been explored as an approach to suppress or even eliminate insect populations that transmit disease to humans.

In a study published in the journal Nature Communications in 2014, researchers at Imperial College London described how they genetically modified male mosquitoes of Anopheles gambiae to overwhelmingly produce male offspring (1). When the transgenic male mosquitoes were mated with normal, or wild-type, female mosquitoes, up to 95% of the offspring were male. Furthermore, the scientists found that the sex imbalance trait was inheritable, passed on to sons of the transgenic mosquitoes. Most excitingly, when the scientists released the genetically modified mosquitoes into cages with wild-type mosquito populations, the loss of females over time resulted in loss of the entire population within six generations. The hope is that introducing these genetically modified mosquitoes into the wild could ultimately lead to elimination of the Anopheles gambiae species, taking the deadly malaria parasite with it.

How did the researchers do it?

To describe how the sex imbalance occurs naturally, we first have to understand the genetics of sexual reproduction. During sexual reproduction, a male parent cell divides into two sperm, distributing an X chromosome to one and a Y chromosome to the other. The chance coupling of one of these cells with a female gamete or egg, that by definition has an X chromosome, ultimately leads to either a male (XY) or female (XX) offspring. What happens to preferentially select for males in these mosquitoes? Through a molecular process not fully understood yet, it appears that selective breaks occur in the DNA strands of the X chromosome from the male parent cell, thereby leaving only the sperm with the Y chromosome viable and available for mating.

This process was replicated in the transgenic male mosquitoes by taking advantage of several key features of the Anopheles mosquito’s DNA and sexual reproduction process. Researchers identified an enzyme that specifically cut a DNA sequence found on the Anopheles mosquito’s X chromosome and thereby destroys the chromosome. Introducing this enzyme into male mosquitoes led to loss of the sperm carrying the X chromosome during sperm production. However, the enzyme is also found in the surviving Y chromosome-bearing sperm and can go on to destroy the X chromosome from the maternal gamete after mating has occurred. This leads to a premature halting of sexual reproduction. Indeed, prior efforts by researchers to exploit this specific endonuclease were unsuccessful because the transgenic male mosquitoes were sterile. To tackle this challenge, the scientists set out to create a variant of the endonuclease that works during the first part of sexual reproduction – during sperm production – but not after female fertilization. Now, six years later, introducing this endonuclease variant into male mosquitoes resulted in genetically modified males that were not sterile and favored male offspring.

Toward a brave new world…

While the study has garnered a lot of excitement in the global health and malaria research fields, the study’s authors caution that there are big questions to be answered before implementing this plan. Most importantly, the ethical implications of potentially eradicating another species, even that of just one species of mosquito, are difficult to grasp.

There may be unintended consequences as well. Due to the specificity of the genetic modification for Anopheles gambiae, other mosquito species should not be targeted for elimination, unlike what occurs presently with insecticides. However, loss of even one species may invite different, or new, species to inhabit the empty niche.

That the Anopheles mosquitoes could evolve resistance to the genetic modification is another concern, as this has been seen repeatedly with other malaria control programs. However, the targeted DNA sequence is found within an essential, multi-copy gene, which researchers believe makes the rapid development of resistance unlikely.

The study team is already embarking on new experiments to evaluate the safety and efficacy of the genetically modified mosquitoes on a larger scale. Creating tropical ecosystems in large cages, the team hopes to mimic real-world conditions and results. For now, the researchers are pleased to have taken a novel first step towards envisioning a brave new world, potentially one without the scourge of malaria.

REFERENCES:

  1. Galizi R., Doyle, L.A., Menichelli,M., Bernardin, F., Deredec, A., Burt, A. et al. A synthetic sex ratio distortion system for the control of the human malaria mosquito. Nat Commun. 2014;5:3977.
  2. Hickey, W.A., Craig Jr, G.B. Genetic distortion of sex ratio in a mosquito, Aedes Aegypti. Genetics 1966;53(6):1177-1196.
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