For the first time, scientists have used a gene drive to destroy a population of mosquitoes in a laboratory.
Genetic engineers at Imperial College London deployed the technique over the past two years, introducing a genetic mutation that spread through the population and eventually sterilized all of the mosquitoes. The group published the results of their work Monday in Nature Biotechnology.
Their success is a huge step in the effort to reduce the spread of malaria. Before now, scientists had struggled to create gene drives that successfully spread through a population of mosquitoes and stopped them from reproducing.
“With this achievement, the major barriers to saving lives are arguably no longer mostly technical, but social and diplomatic,” said Kevin Esvelt, a Massachusetts Institute of Technology professor who studies gene drives and was not involved in this paper.
A success in the laboratory does not necessarily mean that the technology would work in the wild. The lab mosquitoes spent their entire lives in cages about half the size of chest freezers and reproduced differently than they would in the open air.
To test the gene drive, scientists put hundreds of modified and regular mosquitoes into these cages and let them mate. They randomly picked 650 of the eggs laid by the mosquitoes, which they grew into the next generation of bugs. After seven to eleven generations, which took about five to eight months, none of the mosquitoes laid eggs. The gene drive worked.
“It’s a really important breakthrough,” said Zach Adelman, a professor of entomology at Texas A&M, who was not involved in the paper.
Adelman said that the research is so important because it shows that scientists can overcome a problem that had stymied previous attempts to create working gene drives in mosquitoes — resistance.
But much like bacteria develop resistance to antibiotics, so too can laboratory mosquitoes develop resistance to a gene drive. In previous experiments, including work by the same Imperial College team, mosquitoes had small random mutations that immunized them against the gene drive. The mosquitoes passed those protective mutations onto their offspring, blocking the gene drive from spreading the modification that would have destroyed the population.
The Imperial College scientists created a gene drive that did not fall prey to this type of resistance. They ensured that anytime a mosquito had a random, protective mutation, the gene drive would also sterilize that mosquito — ensuring the protective mutation could not spread.
“We have a solution to the functional resistance that arises in gene drives,” said Kyros Kyrou, a Ph.D. student at Imperial College who is the first author on the paper. In the paper, he also acknowledges that there may be other forms of resistance that the team did not find in this trial but that might show up in larger trials.
The next step is to test the gene drive mosquitoes in larger cages, which are the size of a room, that more realistically mimic the environment where the mosquitoes might eventually be released in Africa, said Andrea Crisanti, a professor in the life sciences department at Imperial College, who led the research.
This will allow the researchers to test whether other conditions, such as the temperature and variety of light, would impact the effectiveness of the gene drive, Crisanti said. The large cages also have room for more mosquitoes, so researchers could let all of the offspring develop as opposed to randomly picking eggs.
And the big cages would allow the mosquitoes to reproduce naturally, which they didn’t have space for in the small cages. The males swarm in cylindrical cloud, and the females dart in, looking for a mate.
Larger trials would allow researchers to spot rare mutations that might doom the gene drive that just didn’t show up in the small trial.
“When you get up to 1 million mosquitoes, you’re going to see the things that happen one-in-a-million,” Adelman said.
The cages are maintained by a private company in Terni, Italy, about an hour-and-a-half drive from Rome, Crisanti said. The trials should start by the end of 2018, and data should be available within eight months or a year.
One open question is whether the gene drive could spread between different types of mosquitoes. If scientists release a gene drive in the wild that could eliminate large numbers of mosquitoes, they would want to know which mosquito species would die. And the environmental impact of eliminating multiple mosquito species might be different from eliminating just one.
Normally, when one species of mosquito mates with another species of mosquito, the offspring are sterile, and so cannot pass on any modified genetic material. But that is not always the case.
Anopheles gambiae mosquitoes are extremely closely related to Anopheles coluzzi mosquitoes — the two were actually considered the same species until 2013. And they are also closely related to Anopheles arabiensis mosquitoes.
“The gene drive would be able to cross between [Anopheles gambiae and Anopheles coluzzi],” Kyrou said. He added that, “I would not rule out the possibility of our gene drive’s ability to spread into [Anopheles arabiensis] as well.”
Adelman and Esvelt said more data are needed to see how far the gene drive could spread across different species of mosquitoes in the wild.
As for when the mosquitoes would actually be released into the wild, Crisanti said the decision isn’t up to him.
“That is more a political decision rather than a technical one,” Crisanti said.
His collaborators are already working on that political process. Crisanti is part of the “Target Malaria” project, an international effort funded mostly by the Bill and Melinda Gates Foundation, which has teams in three African countries — Burkina Faso, Mali, and Uganda — that are building the infrastructure to study and potentially releasing gene drive mosquitoes.
So far, the team in Burkina Faso has made the most progress. In August, it received permission from the national government to release a test batch of 10,000 genetically engineered mosquitoes into the wild. Those mosquitos do not have a gene drive, but they serve as a trial run for the real thing.