April 2016, updated August 2016, August 2018

A recent outbreak of the Zika virus in the Americas has brought mosquitoes buzzing onto the front pages of newspapers. With a bite, infected mosquitoes can transmit Zika to humans. While most adults will experience only mild symptoms from the virus, the results can be devastating for a fetus carried by an infected mother. Evidence suggests that the Zika virus is likely responsible for a surge of birth defects in Brazil, and nearby countries are on high alert as the virus spreads. Of course, Zika is in the news now, but mosquito-borne diseases are nothing new. Malaria, in particular, threatens human health on an even wider scale than Zika. The malaria protozoan kills hundreds of thousands each year despite our efforts to snuff it out. Campaigns to fight malaria have tackled the problem on many fronts — treating the disease with new drugs, helping people protect themselves from insect bites, and reducing mosquito populations. With advances in genetic technology, scientists are investigating a new approach: genetically engineering mosquitoes to resist the malaria parasite. In fact, in 2012, researchers showed that mosquitoes engineered to carry two different malaria resistance genes, could not transmit the disease at all! But in order to actually combat malaria with this exciting discovery, we’d need to figure out how to get the resistance genes to spread through mosquito populations…

Where's the evolution?

The spread of malaria resistance genes through a mosquito population is fundamentally a question of microevolution — a change in gene frequency from one generation to the next. Scientists have been trying to figure out how to cause mosquito populations to evolve over the course of generations such that mosquitoes carrying the engineered resistance genes would become more and more frequent, and normal, malaria-carrying mosquitoes would become less frequent. When populations evolve via natural selection, a gene spreads because it has a selective advantage, that is, because it gives a boost to the survival or reproduction of individuals carrying that gene. But because malaria doesn’t seem to harm mosquitoes infected with it, a gene to resist malaria (while a boon for human survival), has no benefit at all for mosquitoes. So natural selection would not, by itself cause the resistance genes to spread.

When a gene does no particular harm or particular good, as seems to be the case for malaria resistance genes in relation to mosquitoes, evolutionary theory tells us what is likely to happen to the frequency of that gene in the short term: it will stay about the same. This happens because of basic Mendelian inheritance — the idea that genes are inherited as discrete units and that we pass the genes that we inherit on to our offspring in an unbiased way. It works like this: Humans, mosquitoes, and many other organisms carry two copies of each gene. If an individual carrying one mutant version of a gene and one normal version breeds with an individual that carries two normal versions, on average only half of their offspring will carry the mutant gene version. In this way, over time, the frequency of the mutant gene stays about the same — and if it starts off as a rare gene, it remains a rare gene. This is a big hurdle for researchers trying to shape evolution through genetic engineering. In order to have an impact on a population, scientists would have to produce a large number of engineered individuals.

Now, new research suggests a way to get over that hurdle: a process called gene drive, which biases inheritance so that certain genes are passed along more frequently than others. A few months ago, biologists announced that they’d successfully applied this idea to malaria resistance in mosquitoes. The process relies on a mechanism that converts a heterozygote (an individual carrying one copy of a particular gene version) into a homozygote (an individual carrying two copies of that gene version). The scientists injected a specially engineered piece of DNA made up of a suite of genes into mosquito embryos. This DNA contained the two genes for malaria resistance, as well as a gene that acts as molecular scissors by producing a DNA-cutting protein. Inside the mosquito cell, this new stretch of DNA inserts itself into one mosquito chromosome at a particular location. When that section of the chromosome is expressed or activated, it produces both the proteins that help the mosquito resist malaria as well as a protein that cuts the corresponding (i.e., homologous) chromosome at the exact same location that the new DNA was inserted. When the cell repairs break, the cellular machinery automatically uses the corresponding chromosome (the one carrying the engineered DNA) as a template, so the resistance genes, as well as the DNA-cutting mechanism, are copied to the second chromosome. And when that cell divides as the embryo grows into an adult mosquito, the chromosomes carrying the engineered DNA are copied along with the rest of the genome.

With this so-called “super-Mendelian” inheritance, genes that do no particular harm or good can easily spread through populations. This is because when one of these genetically engineered mosquitoes mates with a wild mosquito (which carries no malaria resistance genes), all of the offspring (not just half) will carry the resistance genes. And theoretically, we’d expect those offspring to go off, mate with other wild, susceptible mosquitoes, and produce all resistant offspring as well. When researchers tested this idea in the lab, they found that the biased spread of the resistance genes occurred quite efficiently for several generations. If such a system could be successfully deployed in areas where malaria transmission is common, it could cause infection rates to drop precipitously over time — mosquito generation by mosquito generation.

Of course, we are not yet ready to attack malaria with super-Mendelian mozzies. The recently developed technique seems to eventually break down in lineages descended from genetically modified females — though scientists are working to fix this problem. Further research will also be needed to make sure that the system is effective where it matters: in the field. And importantly, scientists must investigate the potential risks of attempting this sort of intervention on a large scale. After all, at its heart, a gene drive system is designed to change the course of a species’ evolution forever. Unleashing these new genes is a bit like releasing a new species into the wild. In the past, invasive species and biological control agents have sometimes had disastrous consequences for local ecosystems, so scientists want to be confident that releasing genetically engineered mosquitoes will not cause a ripple of negative effects. Genetically driving evolution to our desired end represents a tantalizing strategy for combating insect-borne diseases like malaria and Zika virus without use of drugs or pesticides — but since we can’t control the genetic genie in this bottle once she is out, scientists are erring on the side of caution and keeping the modified mosquitoes in the lab until we have more information about the long term consequences of this strategy.