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In 2003, scientists Imperial College London had a slightly eccentric idea. They wanted to deal with mosquitoes increasingly resistant to pesticides that killed half a million people a year by spreading malaria in sub-Saharan Africa. What biologists Austin Burt and Andrea Crisanti proposed was nothing short of hacking the laws of heredity.
By planting a deadly gene in the mosquito's DNA and engineering it so that the change spreads out at each generation faster than nature imagined, they thought they could completely destroy a population with only a few Trojan sceptometers. . This concept of "genetic drive" was decades old, but no one had succeeded in designing one in a laboratory, let alone applying it to a global public health scourge.
Fifteen years and $ 100 million later, scientists at Imperial College have finally succeeded, at least on the first count. Using Crispr, Burt and Crisanti's team eliminated cohorts of mosquito vectors of malaria Anopheles gambiae in as little as seven generations. The results, published today in Nature Biotechnology, represent the first annihilation of a population of animals by genetic means.
"It's a really amazing development," says Omar Akbari, an entomologist at the University of Urvine, who was not related to the study. Akbari's laboratory is working on the genetic mechanisms to make mosquitoes resistant to malaria, largely because an approach to eradication has long been considered impossible. "There is just a tremendous evolutionary pressure on the body to resist."
But by exploiting a critical gene with no flexibility to move spontaneously on the way, the London team has overcome the persistent problem of resistance.
"This is the first time we show that we can, in principle, handle the fate of an entire species," says Crisanti, whose groundbreaking work has been widely supported by the Bill and Melinda Gates Foundation, largest donor in the world. gene drive technologies. Starting in 2011, researchers formally partnered with partner institutions in Burkina Faso, Uganda and Mali to create local insectariums and field sites to test a campaign against malaria in the wild someday . If all goes well, the project supported by Gates, called Target Malaria, could apply for a permit to field test Crispr'd mosquitoes from Imperial College as early as 2024.
More tests must be done first. While the genetic engine worked well in small cages of 20 cubic centimeters with a laboratory strain of Anopheles gambiaethis does not guarantee that it will work in the jungles and savannahs of Africa. To understand how modified mosquitoes will behave in a more realistic environment, the next step is to test them in larger areas, up to fifteen feet in size. This environment (still far from the boundless natural world) can be adapted to mimic the circadian rhythms and atmospheric conditions of the external test sites in Africa that they will use in the future. Mosquitoes are expected to adopt more natural behaviors, such as swarming to find a partner, which was absent in small cages.
In June, Crisanti's laboratory sent a secure box filled with tiny cucumber-shaped black mosquito eggs to a custom-built facility outside Rome, where the next round of trials is already taking place. There, the researchers begin to cross the laboratory strain loaded with gene drive with Anopheles gambiae shipped from test sites in Burkina Faso. Then, they will study how the modification propagates through these more genetically diverse local strains. And they will keep track of the success of these mosquitoes to find partners. To spread their genetic time bomb in a wild population, they must be competitive with wild males. All of this data will be collected to be submitted to regulators whenever Target Malaria is confident of having a product that works.
"At some point, science will be ready," says Delphine Thizy, Mission Manager at Target Malaria. "Then, public acceptance and regulatory frameworks will have to be taken into account."
Genetically modified insects have been introduced into the environment before – British biotechnology Oxitec was the first to use sterile mosquitoes to control Zika in the Americas – but the issue of regulating genetic drives remains open. No country in the world has yet to do it.
"There are unique dimensions to placing us in unknown territory," says Jennifer Kuzma, co-director of North Carolina State University's Genetic Engineering and Society Center. One of the problems is that genetic mechanisms are designed to spread. This makes it virtually impossible to carry out confined field trials, as is the case traditionally for genetically modified crops. "We do not have the opportunity to learn from limited tests that take into account different cultural and geographical landscapes," says Kuzma. "And I do not think we really have to deal with these issues yet."
Target Malaria is fully aware of these limitations. This is why it is not a question of directly testing the genetic drives. They start very cautiously with a much less controversial mosquito. Earlier this month, the government of Burkina Faso authorized Target Malaria scientists to release a strain of Anopheles gambiae genetically modified with a "sterile male mutation". None of the 10,000 male mosquitoes that the group will release into the wild later this year will be able to produce their own offspring.
This sterile strain of mosquitoes was also produced in Crisanti's laboratory and underwent the same caged tests as in Italy before obtaining regulatory approval in Burkina Faso. Although this one-time version does not do much to fight malaria effectively – it would take at least ten times longer to get rid of the environment – Target Malaria hopes it will be an important step to gain the trust of the local communities. And by proving to regulators that they can track their mosquitoes in the wild.
If the sterile male experiences go well, they will move on to something called "X Shredder", a genetically modified mosquito that produces almost entirely male offspring. After a few months, the change will eventually disappear from the population. Therefore, it will still not be an effective strategy for malaria eradication. But this will give more data to regulators before considering a large-scale genetic dynamic that could cross borders and persist in perpetuity.
Crisanti thought it would take them at least three more years to get an eradication engine that works. But with technology going beyond assumptions earlier than anticipated, conversations about the long-term impacts of effective deployment of genetic drives are much more real.
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