The advent of CRISPR gene editing has enabled the creation of gene drives, a technology that can increase the odds of a certain gene being inherited. While the technology could help us tackle malaria and control invasive species, the scientific community is divided on whether it is ethical.
The possibility of creating gene drives was introduced into the scientific community in 2003 by Austin Burt, a professor at Imperial College London. Burt was studying ‘selfish genes’ that can copy themselves into a specific target DNA sequence. He suggested that these genes, called homing endonucleases, could be used to make the majority of an organism’s offspring inherit a specific gene, instead of only half of it.
“A gene drive is based on a natural phenomenon that occurs in many simple organisms like fungi, yeast, molds… that uses DNA cutting and repair to increase [the gene’s] own frequency over generations,” says Alekos Simoni, a researcher at Imperial College London who works in the development of gene drives as scientific manager of the Italian non-profit Polo GGB.
This technology has a lot of potential. For example, it could be used to decimate populations of malaria-carrying mosquitoes by making the majority of their offspring male. However, there are concerns about the permanent nature of these genetic modifications and whether it could cause irreparable damage to the ecosystem it is used in.
While the concept of artificial gene drives has been entertained since 2003, programming homing endonucleases was a big challenge. It took the advent of CRISPR technology to make creating specific, controllable gene drives a reality.
“The CRISPR revolution came out in 2012, and, all of a sudden, all you needed was a guide RNA that you could order from a company [to] cut the genome pretty much anywhere you wanted,” said Ethan Bier, a professor at the University of California San Diego and expert on gene drive technology.
Do we need gene drives?
Many researchers working on gene drives are trying to combat malaria, which kills more than 400,000 people per year. It is a particular focus of Target Malaria, an international not-for-profit research consortium funded by the Bill & Melinda Gates Foundation.
Researchers are introducing gene drives into malaria-carrying mosquito species to reduce the spread of the disease, either by gradually reducing their ability to breed, or by limiting their ability to pass on the parasite. For example, the research group of Andrea Crisanti, a professor at Imperial College London, successfully created a gene drive in the lab that distorts the sex of the mosquito offspring so that eventually the population is almost completely male and numbers crash.
“We are at a crossroads for malaria control, there’s been great progress in reducing malaria in the last 15 to 20 years. But after many years of malaria decline, for the last two consecutive years this decline stalled and this is largely due to a lack of investment,” says Simoni, who worked with Crisanti’s group in the development of the mosquito gene drive.
“The current methods to control malaria are facing difficulties in terms of insecticide resistance, and there are risks that the malaria parasite will soon become resistant to drugs.”
Simoni and his colleagues believe that targeting malaria using gene drives would be more cost-effective and feasible than traditional interventions such as insecticides. There are more than 3,500 species of mosquitoes in the world, more than 800 of which can be found in Africa alone. Gene drives can target just the species of mosquitoes that transmit malaria — Anopheles gambiae, Anopheles coluzzii and Anopheles arabiensis — which in Africa are responsible for more than 90% of malaria transmission, while leaving other insects and mosquito species untouched.
“The current malaria interventions, which are mainly based on insecticides, have a very wide spectrum of action. So they can target many, many different insects, not just mosquitoes,” emphasizes Simoni.
Another more controversial area where use of gene drives is being considered is to control invasive mammalian species. For example, the GBIRd program aims to use gene drives to eliminate invasive rodent species from islands, where they cause massive ecological damage. Meanwhile, an Australian project has proposed gene drives as a method to control the large population of feral cats that prey on native and endangered local species. And a research group at the University of Edinburgh is looking into whether gene drives could be used to control grey squirrels, which are an invasive species in the UK.
Finally, an overlooked but extremely useful application of gene drive technology is to create model species in the lab. “The big enabling thing of active genetics of this kind of system is that it just holistically creates a different way of approaching crossing organisms and getting traits you want together. And it makes it a lot easier. It’s like superconductor genetics,” said Bier.
What are the risks?
Although gene drives can be found naturally, for example in yeast, we still can’t anticipate the full consequences of introducing them into a wild animal population. Because of this, in June more than 75 environmental and agricultural organizations signed a letter urging the EU Commission to back a moratorium on the use of gene drive technology.
“I think it would be wise, given that so much could go wrong with this, to slow down the process and to take more time to discuss it, then test it indoors, and then see if society wants this,” says Mareike Imken, a campaigner at the German not-for-profit organization Save Our Seeds, one of the signatories to the list.
Gene drives currently fall under the EU GMO directive. At the request of the EU Commission, the European Food Safety Authority is currently carrying out a review of the risks of using gene drives in insects, the results of which are due to be released later this month.
One of the concerns that have been raised about gene drives is that releasing a genetically modified organism could cause long-term disruption in the ecosystem, which could result in unforeseen consequences.
To address this potential issue, Target Malaria is running a study in Ghana to evaluate the role that malaria-carrying Anopheles mosquitoes play in their ecosystem.
“It’s looking at the roles of Anopheles mosquitoes in the ecosystem in terms of the food web, pollination, and the general ecosystem,” explains Simoni. “The preliminary knowledge that we have so far for the role of Anopheles mosquitoes in the ecosystem is that they play a very small role. But we are definitely actively exploring this in more detail.”
Another concern is that a gene drive could get out of control and spread uncontrollably across country borders, which could create additional legal issues.
“People who are in the field recognize that it’s very important to have mitigation strategies in place, in case they become necessary,” notes Bier. Together with colleagues at the University of California San Diego, he has recently developed two methods of preventing gene drives from spreading past a certain point. Over five to ten generations, these methods can either inactivate or remove the gene drive from the mosquitoes’ DNA.
“One should never predicate the use of a gene drive on having designed these recall or neutralization elements,” Bier added. “If you have concerns about the gene drives, then you probably shouldn’t release it.”
In fact, according to Bier, adding these additional elements of control can make the whole system more susceptible to mutations.
An additional problem with gene drives is that the modified animals can develop mutations that neutralize them. “Just like with insecticides, you can expect that the insect will become resistant one way or another,” says Bier. “There are a variety of ways that can happen. One is that the drive itself creates mutations that prevent the drive from going further.”
Simoni’s group is trying to prevent these mutations by placing the gene drive somewhere in the mosquito genome that is unlikely to be susceptible to mutations.
Another option is to create a drive that does not impact the health of the mosquitoes too severely, but instead targets the malaria-causing parasite — something that can help alleviate evolutionary pressure. Anthony James and his team at the University of California, Irvine, have been working on using gene drives to spread malaria resistance genes among mosquito populations.
A possible disadvantage of this approach is that there is a chance that the parasite could evolve in response. Bier admits this is a concern, but thinks it is unlikely to happen in nature.
First of all, an evolutionary arms race between the parasite and mosquito could make the parasite too dangerous to be carried safely by the insect, depriving it of its vector. Additionally, even if the parasites were able to increase their numbers in response, only a limited amount make it to the mosquito’s salivary gland and therefore to humans.
Although they acknowledge that the technology is still at an early stage, many scientists seem confident that gene drives could be an effective way to control mosquito populations. However, they seem less sure about gene drives in mammalian species.
“I think there can be a problem for species that are distributed around the world like the common mouse because it might be difficult to constrain it in an area,” says Simoni. He emphasizes that the risks and benefits for using gene drives need to be assessed on a case-by-case basis.
What does the future hold?
So far, gene drives have been created and studied in the lab. But such a restricted setting may not be an accurate representation of how they would fare in the wild.
It seems that scientists, governments and other interested parties are now in a ‘Catch 22’ situation. With many environmentally focused groups pushing for a moratorium on gene drive research, it is likely that regulations will only become stricter for this technology. But the only way to really test it properly is in a carefully controlled field trial.
“I think they should give our groups the opportunity to test them on something like an island where we can make a very clear evaluation of whether gene drives work in nature at all,” says Bier.
“The next step of arming them and then putting them out into the population to try to suppress malaria? Well, that’s a place where I think people should be careful and think about it very, very carefully.”
The biotech community has been largely silent on the issue of gene drives, and some businesses have decided to focus their efforts on less controversial endeavors, such as infecting mosquitoes with harmless bacteria that reduce their ability to spread disease. One of the most advanced alternatives has been developed by Oxitec, a British company that controls mosquitoes using other genetic engineering technologies that disappear from the wild population within about 10 generations.
“Mostly because the technology is still at quite an early stage, there’s still a lot of work that needs to be done,” says Nathan Rose, Head of Regulatory Science at Oxitec. ”I think we’re going to have to wait and see what happens with the lab development, to see what’s being done in terms of overcoming resistance. And then also seeing how the different countries actually handle this and how they integrate this into their existing regulatory systems.”
“I do think that in the case of malaria, odds are that it will do a lot more good than harm,” says Bier. “But, that’s a decision to be made by public health officials and politicians in consultation, very importantly, with the local people, for whom that decision could make all the difference in the world.”
Simoni believes he and his colleagues at Target Malaria and Imperial College are on the right path. “I think that when we are discussing the use of genetic technology for public health, we need to balance the risk of the technology with the benefits of it. And the benefits for malaria elimination is millions of lives that could be saved.”
However, Imken believes that other methods of targeting diseases like malaria could actually save more lives. “Malaria is caused by the mosquito, yes, but the suffering and the deaths are not caused solely by this pathogen. It’s the social environment, it’s the health system, it is how quickly people can be treated, how healthy they are in general.”
“Our suggestion to this debate would be to look at the problem more holistically and see if we can look at solutions that would benefit other problems as well. For example, putting more money into public health systems… Wouldn’t that be a more stable, less risky, and more beneficial solution, than developing this one technology for this one illness?”
Whether gene drives will end up being used as a tool to control wild populations, or remain a tool to be used in the lab, remains to be seen. It’s a complex issue, with valid points being made both for and against the use of the technology.
“Hopefully the right decision will get made so that a technology that might help people can do that,” says Bier. “Because if the choice is to not use it, that’s a choice too. And if there are negative consequences that come from that choice, then people have to live with the ethical burden of having made that choice as well.”
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