Our Work

Target Malaria is an innovative project aiming to reduce the population of malaria-transmitting mosquitoes in sub-Saharan Africa. By reducing the population of malaria mosquitoes, we aim to reduce the transmission of the disease.

We are focused on reducing the number of female malaria mosquitoes. Only female mosquitoes bite and the number of productive females in a population will usually determine future population size.

We aim to develop a technology that can be complementary to other mosquito control methods and which offers a solution that is long term, cost-effective and sustainable as it tackles the problem at the source. Our technology targets specifically the malaria-transmitting Anopheles mosquitoes and will not affect other types of mosquitoes or insects. A decrease in the number of these specific vectors will lead to fewer cases of malaria, freeing up resources and allowing people in affected areas to live without the burden of disease.

Many small mosquitos in the background Many large mosquitos in the background Blue globe Worldwide, there are over 3,500 species of mosquitos
Many mosquitos in the background 837 of those species are in Africa, with an arrow pointing to Africa Africa continent
Target Malaria’s work specifically targets only 3 species, with arrow pointing to mosquitos Anopheles gambiae, Anopheles coluzzii, Anopheles arabiensis
Mosquitos hoving above the text Arm with a red spot where a mosquito has just bit These 3 closely related species are responsible for most of the malaria transmission in Africa
Targeting these mosquitos can HELP SAVE many of the 395,000 people who die from malaria in Africa every year The vast majority of which are children A long line of boys and girls holding hands and high-fiving

Our Goal

We aim to tackle malaria at the source. Our approach is malaria control by mosquito control. By reducing the population of malaria mosquitoes, we aim to reduce the transmission of the disease. Worldwide there are more than 3,500 species of mosquito, with 837 of them in Africa. Of these, a single cluster of three very closely related species are responsible for most of the malaria transmission – Anopheles gambiae, Anopheles coluzzii and Anopheles arabiensis.

Within this cluster, we are focused on reducing the number of female malaria mosquitoes. Only female mosquitoes bite and are therefore able to transmit malaria when they take a blood meal, and the number of productive females in a population will usually determine future population size.

Currently, we are evaluating a couple of approaches to reduce the number of Anopheles gambiae by creating strains of genetically modified malaria mosquitoes. This work is still at an early stage, but our models indicate that this method has the potential to significantly reduce the numbers of these mosquitoes, and the transmission of malaria, within a socially relevant timeframe. We are taking a step-wise approach working with regulators and communities to ensure acceptance and approval at each step.

How it Works

As a mechanism to reduce the number of female Anopheles gambiae mosquitoes, we are investigating the use of genes that produce enzymes (called nucleases) that cut specific sequences of DNA. The concept for these nucleases is based on Homing Endonuclease Genes (HEGs) which are a class of nuclease genes, found in simple single celled organisms, which are capable of copying themselves from one chromosome to another. In principle there are several types of endonuclease that could be re-programmed to act in a similar way to HEGs and we are testing a wide range of these nucleases.

We are exploring different strategies to use these nucleases to reduce or modify populations of Anopheles mosquitoes. When introduced in the malaria mosquito, they work by identifying and cutting through essential genes targeted by our researchers, such as fertility genes or genes key to pathogen transmission. The interrupted gene will no longer function, and modified mosquitoes will be affected according to the nature and importance of the gene. It is possible that enzyme-based gene drive could also be used to change mosquito populations such that they are no longer able to transmit malaria.

The ultimate goal of all of the strategies is to produce modified malaria mosquitoes that can pass these genes on to a disproportionately high percentage of their offspring, so the modification is spread throughout the specific population relatively quickly and is effectively “self-sustaining”. This makes the reduction of the malaria mosquito vector population relatively cost effective and simple to implement because the mosquitoes themselves do the work. Two of the main areas we are currently focussing on are biasing the sex ratio of mosquito populations and reducing female fertility.

How we create a Gene Drive mechanism
  • Everything living has DNA
  • Genes cause the traits that determine our differences. Individuals have two copies of each gene.
  • We used DNA-cutting enzymes called nucleases to modify mosquito genes in a very precise way. We use these nuclease to make genes drive: by cutting and pasting from one chromosome to another, or by removing a chromosome that determines the sex of the mosquito
  • Genetic traits that work for us: Malaria resistance, unable to fly, produce only males, female infertility.
  • Most genes are inherited half the time
  • Driving genes are always inherited
  • New genes tend to stick around in low numbers
  • Gene drives increase gene spread. With only a few individuals, a driving gene can spread a modification through the target population effectively. This is called Gene Drive.

Everything living has DNA

Genes cause the traits that determine our differences. Individuals have two copies of each gene.

We used DNA-cutting enzymes called nucleases to modify mosquito genes in a very precise way. We use these nuclease to make genes drive:

by cutting and pasting from one chromosome to another

or

by removing a chromosome that determines the sex of the mosquito

Genetic traits that work for us: Malaria resistance, unable to fly, produce only males, female infertility.

Most genes are inherited half the time

Driving genes are always inherited

New genes tend to stick around in low numbers

Gene drives increase gene spread. With only a few individuals, a driving gene can spread a modification through the target population effectively. This is called Gene Drive.

Biasing the Sex Ratio

This strategy relies on altering the sex ratio in malaria mosquito populations to decrease the number of female malaria mosquitoes relative to males. Only female Anopheles gambiae transmit the disease, and a reduction in the number of females limits reproduction and the future population size, therefore reducing the number of vectors for malaria

The approach is based around the sex-determining chromosomes (XY for males, and XX for females) and relies on the fact that female offspring require two functional X chromosomes– one from each parent – in order for female offspring to be produced.

Target Malaria researchers have used nuclease enzymes (image 1) to identify and cut through several key sites on the X chromosome (image 2) in the sperm of male Anopheles gambiae which leads to a fragmentation of this chromosome (image 3). When these males reproduce, they can still pass on a functional Y chromosome to their offspring, but they cannot pass on a functional X chromosome due to its fragmentation (image 4). This results in a bias toward male (XY) offspring.

Work published by our team in June 2014 has shown that we can successfully distort the sex ratio of a laboratory population, as over 95% of the offspring produced by modified Anopheles gambiae were male, with only 5% being female. By comparison, under normal circumstances, researchers would expect a 50:50 split between male and females, meaning that our modification reduces the number of females produced by 10-fold.

Mathematical models indicate that the approach could be highly effective in reducing mosquito numbers. Because the modification is intended to be carried on the Y chromosome, it would also be self-sustaining. The male offspring of modified males would remain fertile and every single one of them would have the sex-distorting nuclease gene on their Y chromosome, allowing them to continue the trend of producing mostly male offspring.

Biasing the Sex Ratio

  • To help reduce the population of malaria mosquitoes, Target Malaria researchers are looking at several strategies. One is focused on biasing the sex ratio. Target Malaria researchers have identified several key sites on the X chromosome that are unique and not present in the Y chromosome.
  • A nuclease gene that produces a nuclease enzyme is placed on the Y chromosome. It recognises the key sites on the X chromosome, cutting through them and leaving the chromosome fragmented. The Y chromosome remains intact.
  • Individuals that inherit an X chromosome from their father are female. Individuals that inherit a Y chromosome from their father are male. Because the males now have fragmented X chromosomes, they can only produce male offsprings. This is called sex biasing.
  • Target Malaria scientists modify male mosquitoes to carry the nuclease gene and then release them into the wild population.
  • During reproduction with a wild female, the modified males can only pass on a functional Y chromosome. This will result in up to 100% male offspring. The male offsprings carry the genetic modification and will pass it on through future matings.
  • Over time, as more modified males mate with wild females, there will be more male mosquitoes in the population and fewer females, leading to a significant reduction in the overall size of the population and the number of mosquitoes able to transmit malaria. Studies have shown that sex-biasing can result in a population in which only 5% of all mosquitoes are females.

Focus on Mosquito Female Fertility

This strategy focuses on using nucleases to knock out genes that are key to fertility in female Anopheles gambiae mosquitoes. The approach could significantly reduce the prevalence of malaria because the number and productivity of females in a population determines future population size, and female Anopheles gambiae are highly effective vectors for the disease.

In order to knock out female fertility genes, the nucleases are designed to identify the specified genes (image 1) and cut through them (image 2). When this stretch of DNA is repaired, the nuclease gene is copied and inserted into the cut site (image 3), interrupting the original gene and preventing it from working properly (image 4).

A female that has one copy of this fertility gene disrupted will be able to reproduce normally, but when both copies within her chromosomes are disrupted, the female cannot produce viable offspring.

We have designed these nucleases so that they are only active in the cells of the mosquito that make the sperm and the eggs. Due to the preferential copying mechanism of these nuclease genes in the sperm and eggs, an individual initially containing only one copy of the gene will transmit it to many more offspring than normal.

As fertility genes are fully disrupted in females that inherit two copies of the nuclease gene, this should lead to an overall reduction in the population.

Reducing Female Fertility

  • Target Malaria scientists introduce a nuclease that disrupts a gene essential for female fertility, causing females to be sterile when both copies of the gene are disrupted. The modified male and female each carry one copy of a chromosome with the nuclease gene and are fertile. The gene must be present on both copies of a female’s chromosomes in order to cause infertility.
  • During the production of eggs and sperm, the gene produces an enzyme that cuts the unmodified chromosome and "homes" into the female fertility gene
  • As the second chromosome repairs itself, it copies the genetic material from the modified chromosome. In the cells that make the eggs and the sperm, both chromosomes now carry the nuclease gene. With both copies of the chromosome carrying the gene, all sperm and eggs will receive a copy of the nuclease and the modification has a 100% chance of being passed to offspring.
  • Male mosquitoes that have been successfully modified in the lab are released into wild populations.
  • When they mate with wild females, they pass on the nuclease gene, resulting in 100% of offspring carrying the nuclease of the gene that causes infertility in females.
  • The offspring of the modified males and wild females each carry one copy of the gene, and will replicate the nuclease homing process during the production of their own eggs and sperm.
  • Over time, the gene will pass to enough members of the mosquito population that males and females who each carry a copy of the gene will mate. When two modified mosquitoes mate, their offspring will receive two copies of the modified chromosome,resulting in infertility in the females.
  • Males who inherit two copies of the gene can still reproduce and pass the nuclease to future generations. As the population of female mosquitoes becomes increasingly infertile, the population of malaria mosquitoes should be reduced.