Self-limiting

In the second phase of our project, we will study a self-limiting male bias strain. This consists of modified males which are fertile but produce predominantly male offspring. We have produced a self-limiting male bias mosquito strain by using a nuclease gene that, when activated during sperm production, fragments the X chromosome of the sperm, resulting in a mosquito that mainly has Y-bearing sperm and thus produces predominantly male offspring.

This phase is very similar to one of our final technologies but without a gene drive. This means that the modification is passed on only for a certain number of generations. This is possible by inserting the nuclease gene into a mosquito’s autosome. An autosome is any chromosome that is not a sex chromosome. Anopheles gambiae mosquitoes have two pairs of autosomes and one pair of sex chromosomes. Each autosome in a pair is inherited 50% of the time and will be inherited by 50% of the offspring.

The purpose of this phase is to better inform the development pathway of our final technologies and to strengthen and widen our stakeholder engagement using a self-limiting fertile male modified mosquito, that will decline in number at each generation.

What’s a self-limiting male bias mosquito?

Target Malaria researchers have inserted the nuclease gene into a mosquito autosome. An autosome is any chromosome that is not a sex chromosome. They contain information about other mosquito characteristics. Malaria mosquitoes have 2 pairs of autosomes and 1 pair of sex chromosomes.
  • Target Malaria researchers have developed male mosquitoes carrying a modification that causes them to produce more male than female offspring, biasing the sex ratio of the mosquito population. The modification is passed on to offspring for only a limited number of generations and thus is ‘self-limiting’.
  • Modified Male
  • Number of modified mosquitos decreases over time when the gene modification is 'self-limiting'
  • Like the sterile male mosquitoes, the self-limiting male mosquitoes carry a nuclease gene producing a nuclease enzyme that recognises unique sites on the X chromosome, cuts through them, and leaves the X chromosome fragmented and non-functional.
  • Nuclease Gene being 'cut' into the chromosome.
  • In the self-limiting mosquitoes the nuclease gene is activated during sperm production but has been modified so that it does not fragment the X chromosome in the egg upon fertilisation.
  • Illustration Modified Male and Wild Female Chromosome Gene Fragmentation
  • Illustration Modified Male and Wild Female Chromosome Gene Fragmentation
  • Instead, it only fragments the X chromosome in the sperm. As a result, the self-limiting male mosquitoes produce predominantly  male offspring.
  • Target Malaria researchers have inserted the nuclease gene into a mosquito autosome. An autosome is any chromosome that is not a sex chromosome. They contain information about other mosquito characteristics. Malaria mosquitoes have 2 pairs of autosomes and 1 pair of sex chromosomes.
  • Autosomes vs Sex Chromosomes
  • Each autosome in a pair is inherited by 50% of the offspring. As the modification is located on a single autosome, it will be inherited by 50% of the offspring. Sometimes female offspring will inherit the modification.
  • Modified Male and Wild Female Inheritance Tree
  • Female mosquitoes that inherit the modification produce offspring with an unbiased sex ratio. 50% of their offspring will inherit the modification. Of these offspring, males inheriting the modification will produce offspring with a male bias.
  • Modified Female and Wild Male Inheritance Tree
  • When there are significantly more males than females in the mosquito population, female offspring will have more breeding opportunities than male offspring. Modified males that produce predominantly  male offspring are therefore at a competitive disadvantage and so the modification will be selected out of the population over time.
  • Male Population vs Female Population over time; Modified males decrease, wild males and wild females increase
  • The purpose of this phase is to better inform the development of our technology, and strengthen our stakeholder engagement using a self-limiting fertile modified mosquito strain, that will decline in number at each generation.
  • Illustration of a Target Malaria researcher educating three others.
  • Our next step is to develop self-sustaining mosquitoes with a gene drive that is able to effectively spread the modification through a wild population.
  • Male Population vs Female Population over time; Modified males increase, wild males and wild females decrease.

Our development pathway

Progress on the self-limiting male bias is promising, however it is still under development. The development pathway for the self-limiting male bias mosquito would be very similar to the pathway of the sterile male. We first develop our modified strain under contained laboratory conditions in London (discovery), then we assess the modified strain (strain characterisation studies) and gather the necessary data to submit a regulatory dossier to the relevant authority of the country of the partner institution we are working with. The regulatory dossier then goes through a thorough review, this is done by the relevant national authorities of that country and will then inform Target Malaria of its decision. If the decision is positive, then the project moves on to import its strain to the partner institution’s contained laboratory where it will be studied further. These studies will gather the necessary data to submit a dossier to the regulatory authority of the country to ask for a permit to conduct a small-scale release study. The authorities that grants the permission are the regulatory and national authorities of the country.

The results of our second phase will help inform the further development of our mosquito reduction technologies.

Stakeholder engagement

Throughout each phase, we carry out stakeholder engagement activities, to ensure that communities participating or directly affected by the research can make an informed decision about project activities and that these decisions are recorded. Our engagement goes beyond what is required by law because we see engagement as a process that helps us improve our research

The activities we carry out for the self-limiting male bias strain will be similar to the ones described for PHASE 1. The phased approach allows us to build knowledge and understanding with the communities around the insectaries and in the field sites, so the engagement for this second phase will be a continuation of the engagement for the first phase.

Go to Phase 3

Self Sustaining