Gene Drives Could Fight Malaria and Other Global Killers but Might Have Unintended Consequences

Every year more than 600,000 people die from mosquito-transmitted malaria, most of them children under age five. Some insects that are disease vectors, such as mosquitoes, are currently expanding their range around the world, bringing new threats. Genetic engineering can fix this by permanently altering insect genes through what is known as a gene drive.

This technology allows a chosen set of genes to alter an animal’s biology in some way, such as making them produce sterile offspring. The inability to reproduce then sweeps through a population, upending the laws of inheritance. The genes copy themselves exponentially from generation to generation, rapidly coming to dominate the whole population. Potentially, their careful use might save millions of lives by making mosquitoes unable to transmit malaria or by eliminating the insects entirely. The possibility of a definitive solution to major infectious diseases makes a compelling case for a such a techno fix.

Still, you do not need to be a Luddite or a technothriller writer to imagine how this could all go horribly wrong. Ecology is complicated, and delicate ecosystem balances could be profoundly disrupted. Poorly designed gene drives might even jump to closely related animals that, for example, do not carry disease, creating a disastrous cascade.

Austin Burt of Imperial College London dreamed up gene drives in 2003. He imagined a system in which a gene produces a DNA-cutting enzyme (an endonuclease) that precisely targets the chromosomal location of the gene that encodes it. Such systems are found naturally in fungi but not in animals.

When an individual carrying two copies of such a gene mates with another that has none, all the offspring initially have just one copy of the gene on the chromosome inherited from the gene-drive parent. But soon after fertilization, the nuclease cuts the DNA sequence on the other chromosome from the parent that did not carry the gene at the precise location of the gene drive. The cell then uses the intact chromosome to reconstruct the gap in the DNA sequence of the other chromosome.

Where there was only one copy of the gene, there are now two in every offspring. The same thing will happen in the next generation and the next; the gene’s frequency in the population will grow exponentially.

Burt then realized that by hitching one of these endonuclease genes to a gene that induced sterility or made a mosquito immune to the malaria parasite, it would theoretically be possible to drive that trait into the population, killing off mosquitoes entirely or making them no longer malaria vectors. Success would have massive consequences for human health. But the challenge was how to introduce the endonuclease gene and its associated genetic payload to a spot in the genome where it would work safely without inadvertently affecting other aspects of the animal’s physiology.

Following the advent of CRISPR-based gene editing in 2013, this dream became a reality. And in 2015 researchers at the University of California, San Diego, created a lab-based gene drive in the innocuous vinegar flies?Drosophila that simply made all the flies’ eyes turn yellow. They said they had built “a mutagenic chain reaction.” In other words, they had made what might be considered a “genetic atom bomb.” If one of these things were released into the wild, there would be no way of stopping it.

Researchers around the world soon developed gene drives in mosquitoes. In the laboratory, large populations of mosquitoes disappeared in less than a year thanks to the gene drive. No technical obstacle exists to the release of such a genetic bomb, in insects at least. Immense problems persist in creating gene drives in mammals (for the moment, none exist) because of the way their cells respond to breaks in DNA at different points in the life of a cell. A naturally occurring genetic element, which shows some of the behavior of a gene drive, has recently been harnessed in mice, but it has still not been proved to change the DNA of a whole population. Because of these technical difficulties, it may be impossible to use this technology, say, to wipe out invasive rodents.

In response to the potential ecological threat of gene drives, the U.S. National Academies of Sciences, Engineering, and Medicine set up a committee to study the question, with the support of the main agency funding gene drive research, the Defense Advanced Research Projects Agency (DARPA). This agency, part of the Department of Defense, is intensely interested in the technology’s potential as a security threat. After a review of both the possible advantages and the immense uncertainties as to what might happen were a gene drive to spread in the wild, the conclusion of the committee’s 2016 report was unequivocal: “There is insufficient evidence available at this time to support the release of gene-drive modified organisms into the environment.”

This statement did not assuage all concerns. Gene drive pioneer Kevin Esvelt of the Massachusetts Institute of Technology predicted that, by 2030, there would be a lab leak or some other incident involving gene drives. “It’s not going to be bioterror, it’s going to be bioerror,” he said in 2016. Regulatory safeguards and public involvement had to be built in from the outset of contemplating use of the technology, he has argued.

The immediate question at hand for bioethicists and regulatory authorities is whether gene drives should ever be released from the lab. The main international framework relating to gene drives is the United Nations Convention on Biological Diversity. Of all U.N. member states, only the U.S. has not signed the convention, nor is it likely to. Stanford University researchers, including Francis Fukuyama, have called for the creation of a gene drive regulatory body along the lines of a standard-setting body such as the International Civil Aviation Organization (ICAO). But the ICAO was set up in 1947, when countries had an appetite for international regulation. Regulating gene drives will require profound political change around the world and in particular in the U.S.

Gene drive opponents, concerned about potential ecological damage and suspicious of DARPA and other funders, have called for a moratorium on research. Research nonetheless continues, but it is generally agreed that environmental risk assessments and the active involvement of affected communities are required before any release might be considered. Because of the potential consequences on their environment, people need to give what is called free, prior, informed consent.

Active efforts are underway to test what might happen if gene drives are allowed into the wild. In 2021 Imperial College London researchers funded by Target Malaria, a not-for-profit research consortium itself funded by the Bill & Melinda Gates Foundation, identified eight major ecological effects of gene drives, which could manifest themselves through 46 pathways. Among the potential problems they explored were the possibility that the gene drive could spread to valued nontarget species, leading a decline in their density or in the health of ecosystem services to which they contribute. There is also the risk that the gene drive could produce unexpected genetic alterations to the target species, such as making it able to tolerate a broader range of environmental conditions, leading to the spread of the disease-spreading insect, instead of its elimination. Each possibility would need to be tested in the field before any decision could be made about deploying the genetically altered insects, even with local community support.

Getting community consent has turned out to be quite difficult. With the approval of the Burkina Faso government, Target Malaria released non-gene-drive mosquitoes that had been sterilized and dusted with fluorescent powder in July 2019 to see how far they traveled and therefore the potential risk of gene drive mosquitoes spreading outside of the locality. The local language has no word for “gene,” so terms had to be invented by the researchers.?They also used theater to explain the project, ensuring that illiteracy would not be a barrier to understanding and decision-making.

Nevertheless, the gulf in knowledge left some villagers feeling impotent. “They tell us they are going to eradicate malaria, but because we aren’t scientists, we believe them, but we still have questions about future risks,” one farmer told Le Monde in 2019. And as one woman was quoted as saying in another Le Monde article in 2018, “In any case, we won’t have any say in it, it’s the men who make all the decisions here.”

While giving local communities a veto is essential, gene drives challenge our notions of what “local” is because insects do not respect frontiers. As Kevin Esvelt has put it, “a release anywhere, is likely a release everywhere.”

The people of a malaria-ridden village might want to be rid of mosquitoes and be prepared to do anything to save their children’s lives. But it is not clear that they should have the right to decide for the rest of the region, country, continent or even planet. That is why some kind of international oversight body with the power of regulation, such as the ICAO, is essential.

Maybe there is nothing to worry about; none of the insects currently being targeted is the sole food source for any other animal. But the malaria mosquito?Anopheles gambiae?is eaten by scores of different species. If even some of them go just slightly hungry, unforeseen ecological problems could arise as predators assuage their hunger by turning their attention more to other prey species, destabilizing delicate ecological balances.

Caution about any rush to embrace gene drives may also be in store because simpler, less radical solutions may be at hand. The WHO approved a malaria vaccine in late 2021, and more than a million African children have received one or more dose in a pilot study.

The aims of gene drive researchers are precise, localized in time and space, and laudably humanitarian. No one is planning to inflict massive biocide like Thanos in the Marvel Avengers films. We need to ensure that gene drives are subject to the most intense scrutiny and international regulation before any deployment, or the cure might turn out to be worse than the disease.

This is an opinion and analysis article, and the views expressed by the author or authors are not necessarily those of?Scientific American.