Thanks to genetic modification, researchers have been able to identify genes that could reduce the rates of malaria in humans in many ways, such as boosting the ability of anopheles mosquitoes at fighting infection by plasmodium, the parasite that causes malaria in humans. However, these favorable genes must spread to wild mosquito populations in order to reduce malarial infection rates, because wild mosquitoes are the ones that carry and transmit plasmodium. This means that isolating and editing specific genes isn’t the only thing scientists need to do to decrease rates of malaria, and strategies must be devised to integrate modified genes into wild populations.

Homing endonuclease genes (HEGs) are naturally-occurring genes that produce proteins that cut certain pieces of DNA. When the DNA is cut, the cell tries to fix it by copying information from the homologous chromosome, which contains genetic information for the gene that was snipped. This homing strategy can be used to increase the spread of a specific gene, which is desirable for GM traits that lead to the decrease of malaria transmission. Basically what can happen is when a GM and wt mosquito mate without a gene drive, fewer and fewer of their descendants will have the GM trait, because it is mixing with natural populations that don’t carry the GM allele. With a gene drive, though, the HEG drive cuts the wt parent’s DNA in the same place on the chromosome that codes for plasmodium control factor(s). Since the DNA is damaged, the cell copies the alleles from the GM parent, and as a result, both chromosomes code for the GM traits, not just the chromosome from the GM parent.

The main subject of discussion on this website has been improving mosquitoes’ ability to fight off plasmodium infection, but another option that will reduce rate of transmission is reducing vector populations in general; inhibiting the ability of anopheles gambiae mosquitoes to reproduce will decrease the rate of malaria transmission. By altering a recessive gene that is necessary for female fertility, affected a. gambiae mosquitoes won’t be able to reproduce, decreasing the amount of carriers of plasmodium and therefore rates of infection. However, homing must occur before gametes are formed, because otherwise the gene drive would change the other parent’s alleles and the offspring would be homozygous for the GM trait, meaning they would be infertile and unable to spread the gene. Heterozygous mosquitoes can carry and spread the gene without expressing it, therefore not compromising their fertility.

The researchers referenced a fertility index based off of a species of fruit fly to see if they could identify similar genes in a. gambiae, then used CRIPSR or another gene editing tool called TALEN to disable the three fertility genes they found. They also included the fluorescent GFP marker for GM identification, which they use to monitor offspring. The intensity of GFP indicated if the offspring were heterozygous or homozygous recessive, so scientists were able to compare fertility, and found that all the female mosquitoes with two modified genes were sterile, while the mosquitoes with just one GM gene reproduced as normal.

To test the effectiveness of the gene drive, scientists monitored the success of homing, that process in which genes were cut and copied from another chromosome so both sets contained the GM information. In this test, when the natural homologous chromosome was cut and received a copy of the information from the GM chromosome, it also received RFP, which produces a red fluorescent protein that was used for identification. The gene drive was correlated with significant rates of inheritance of the allele marked with RFP, ranging from 94.4-100% when heterozygous GM mosquitoes were crossed with wt mosquitoes.

Researchers also created a population with equal numbers of wt and GM mosquitoes, and found that the percentage of mosquitoes carrying the GM allele rose from 50 to 75.1% over four generations, displaying its affinity to spread through populations.

Evidently, gene drives are powerful tools that enable the application of promising GM traits. Even if a gene was identified that could completely prevent plasmodium infection, it would be useless if it could not be integrated into wild populations, so it’s very exciting to see what methods exist to spread new genes. There are a lot of pieces in the puzzle of genetic engineering, but if they work together effectively, they could save countless lives.

I think the article I covered for this week’s post was by far the one I understood the least. I usually have a hard time processing the information and translating for these posts, but the wording of this particular article was a little over my head. I think I’m just not super familiar with the subject matter yet (teenagers might not be the target demographic for this scientific research paper), and I had to use some separate resources to understand some of the things it was talking about.

In the end, I didn’t use as much of the article as I usually do, but I had already extracted so much information from it, I didn’t want to take away from the parts I deemed most important, which was more about the gene drives and less about the specific genes that coded for fertility, especially as I’m looking more towards changing the immune factors in mosquitoes than eliminating them entirely, because that can have environmental effects. Which I might eventually cover? We shall see! Stay tuned to learn with me!

Hammond, A., Galizi, R., Kyrou, K. et al. A CRISPR-Cas9 gene drive system targeting female reproduction in the malaria mosquito vector Anopheles gambiae. Nat Biotechnol 34, 78–83 (2016). https://doi.org/10.1038/nbt.3439