Eradicating malaria with CRISPR gene drives
With CRISPR gene drive technology, we now have the ability to completely eradicate malaria and all other mosquito-borne diseases by introducing non-lethal genetic modifications into mosquito populations that reduce their ability to transmit disease. The total cost of eradicating malaria using CRISPR gene drives likely would be less than 1% of what is currently spent just trying to contain malaria. Efforts to develop and safely test CRISPR gene drives to eradicate mosquito-borne diseases are only just beginning. Faster progress is essential: every day we delay, 2,000 more people will die by our inaction.
Background
CRIPSR/Cas9 technology has now advanced to the point where “search and replace” edits can be made to the genome of nearly all animals, including mosquitoes. More recently, researchers have demonstrated that self-reproducing CRISPR “gene drives” can be introduced into sexually reproducing animal populations. These “gene drives” consist of a CRISPR/Cas9 complex that pinpoints a particular location in the genome, and then introduces a copy of all the DNA required to reproduce additional copies of the same CRISPR/Cas9 gene drive complex. When an animal carrying the gene drive sexually reproduces with a non-carrier animal, the gene drive inherited from the carrier makes the necessary edits to the non-carrier chromosome, such that both chromosomes of nearly all offspring inherit the gene drive, rendering the offspring homozygous. Studies in fruit flies have demonstrated a 97% gene drive propagation rate (vs. 50% for normal Mendelian inheritance).
As a result, any gene drive introduced into a population will rapidly spread throughout the entire population, as long as the gene drive does not reduce the fitness of its offspring by more than 50%.
Gene drives can be used to eradicate mosquito-borne illness
Gene drives can carry any payload of interest, deactivating, changing, or adding any gene of interest. Researchers working to reduce mosquitoes’ ability to transmit disease have identified many such genes of interest. For example, mosquitoes have been genetically engineered to be less able (or unable) to smell and bite humans, and to protect or augment the mosquitoes’ immune systems to better fend off the plasmodium parasite that causes malaria in humans. Such changes make the mosquitoes less fit to survive in the wild, but not sufficiently so to override the effects of the gene drive on propagating the mutations throughout the entire population.
Another approach to mosquito-borne disease control is to genetically engineer mosquitoes to produce only male offspring. This approach is being used in the wild today to dramatically reduce mosquito populations. If implemented inside a gene drive, such an approach has the potential to drive disease-carrying mosquito species to complete extinction if desired. However, such an approach may be less desirable than simply reducing mosquitoes ability to transmit disease, because any mosquitoes that evolved resistance to the gene drive (for example, by a deletion mutation that modifies the gene targeted by the gene drive) would likely be able to avoid extinction and repopulate the ecological niche vacated by the susceptible mosquitoes. It is therefore preferable to focus on introducing mutations that significantly reduce the mosquitoes’ ability to carry disease, while allowing the mosquito populations themselves (and their gene drives) to survive long enough to completely eradicate the targeted diseases.
Safety and efficacy concerns must be quickly addressed
Genetic engineering engenders serious opposition for many reasons. The most legitimate of these concerns focus on the need to empirically test the safety of any self-reproducing change, to ensure that the intervention doesn’t do more harm than good, particularly through any unintended consequences. Such concerns are often supposed to be enforced by regulation, although the genetic modification of wild populations does not fit easily within the regulatory mold of agencies such as the FDA, USDA, and EPA. Regardless, it will be important to address this very valid concern through very careful testing of any proposed intervention. This would likely first involve extensive testing within biosafety level 3 laboratories (engineered to prevent any laboratory organisms from escaping into the environment). Once an intervention has proven effective (and no serious side effects observed) in a BSL3 laboratory setting, the intervention could then be field tested on a remote island with an isolated mosquito population, where effects on native ecosystems could be evaluated. Only once such laboratory and field trials prove satisfactory should any gene drive carrying mosquitoes be introduced into larger populations.
Another important consideration when evaluating the safety and efficacy of any such intervention is the impact of inaction. Currently, mosquito-borne illnesses kill millions of people a year, and cause severe sickness and disability in millions more. When weighing any potential negative effects of a gene drive intervention, we must balance it against the ongoing mass casualties of mosquito-borne illnesses. When presented with the choice between the absolutely certain death of 2,000 people per day and the possibility of slight disturbances to natural ecosystems, the moral calculus clearly favors making sure the intervention will be effective and reasonably safe, but not unnecessarily delaying its introduction even a day longer than absolutely necessary.
Urgent need for rapid action and funding
The same argument underscores the urgency of moving forward with research and implementation of a malaria-curing gene drive. The most effective malarial intervention currently being deployed (insecticide-treated bed nets) by the most effective organizations (such as AMF) spend about $2000-$3000 for each life that they save by distributing bed nets. Given that 750,000 people die every year of malaria alone, that would easily justify spending over $2 billion per year on research, development, and implementation of interventions with a reasonable chance of totally eradicating malaria. By contrast, the total cost of eradicating malaria using CRISPR gene drives would likely be 100x-1000x less than that. (If current institutions fail to act, it’s even possible that the necessary genetic modifications could be performed by a small group of unfunded enthusiasts working in a shared laboratory. However, a properly funded institutional research and development project would be better able to perform the necessary safety and efficacy trials before any modified organisms are released into the wild.)
CRISPR gene drives represent our best chance of eradicating malaria in the short term, because of their ability to self-propagate genetic modifications throughout entire mosquito populations. It is essential, and urgent, that we begin doing everything in our power to do so as quickly as possible. We cannot continue to allow people to die while debating whether to save them. The time for action is now.
