Creating Zika-Proof Mosquitoes Means Rigging Natural Selection

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Of the many great things promised by Crispr gene editing technology, the ability to eliminate illnes by modifying organisms might just top the list. But doing that requires perfecting something called a gene drive. Think of gene drives as a means of supercharging evolution to, say, give an entire population of mosquitoes a gene that kills the Zika virus. The difficulty is, organisms develop resistance to gene drives, much like they eventually outwit pesticides and antibiotics.

Researchers dedicateno small amount of period and thought to creating gene drives that they are able outsmart evolutionbecause the potential payoffs are so great. The lowly mosquito transmits dozens of illness that kill more than a million people every year, making it the deadliest animal in the world. Pesticides, mosquito nets, and medication won’t solve the problem, but gene drives might–provided scientists can construct them less likely to succumb to the genetic mutations that might render them useless.

In a newspaper presented today in Science Advances , Harvard scientists used computational models to test a means of doing just that. The resulting gene can spread to 99 percentage of a population in as few as 10 generations, and persist for more than 200 generations without the mosquitoes( or any other population) developing a resistance. Although the researchers did not test their method by tinkering with real mosquitoes, their modeling createsa blueprint for anyone eager to build a more successful gene drive.

Simply put, a gene drive makes a specific gene spread through a population more rapidly than would happen through naturealone, something geneticists refer to as” super-Mendelian inheritance .” Typically, this entails insertinga bit of DNA into the genome of an organism–say , Aedes aegypti , the primary transmitter of the Zika virus. When the modified, ortransgenic, mosquito mates with a wildmosquito, their offspring carry one one copy of the drive gene immediately opposite its natural counterpart. The drive gene snippings out the normal gene and inserts a copy of itself, doing this over and over and over again until every mosquito carriestwo copies of the drive gene–and therefore, resistance to Zika. Thats the idea, anyway. But because nature is imperfect, mistakes happen. More specifically, mutants happen. The very act ofcutting out the normal gene induces the whole system moresusceptible to mutants. And if enough of them add up over period and across a population, the drive gene can actually becomerecessive.

Noble et al.

To fight back, science must develop a gene that works even if it isn’t perfectly copied, says computational biologist Charleston Noble, the paper’s lead writer. The trick is to decouple the costs of resistance and the cost of the drive.

Nobles team indicates doing this through a technique called recoding that genetic technologist and paper co-author George Church is train. Because of redundancies in genetic code, there are times when you can do things like change a C to a T or a T to an A and still get the same proteins even though the DNA sequence is different. To offer an oversimplified justification, it means you can createa drive that targetsa gene essential to survival or reproduction. If the drive inserts smoothly, great. The gene drive drives on. If it doesn’t insert itself smoothly , no problem. The mosquito dies, or does not reproduce. And, because the new code for the essential gene doesnt precisely match the target it replaced, it won’t get snipped itself.

This kind of approach is definitely the direction the field is going to have to go, says Philipp Messer, a molecular geneticist whose laboratory at Cornell is among the fewtesting gene drives in insects. Whether or not it works experimentally is still an open question. You can rattle off countless reasons why a method that works beautifully in computer modeling might utterly fail in the wild. Only one example–Nobles simulations assumed an infinite number of mosquitoes all equally likely to breed with one another. Here in the real world, oceans and mountain ranges and other natural obstacles might create populations the gene-driven mosquitos can’t or don’treach.

Plus , not all bugs evolve resistance equally. Even within a single species, the differences in individual genomes make it hard to predict how effectively a drive gene will insert itself into a population.” All these models assume there’s one fixed interest rate at which these things originate ,” Messersays.” But that doesn’t seem to be the case .” Right now, Messer islooking at the rate at which resistant mutants occur in a Drosophila gene drive system. That work remains under peer review, but his labis already finding mutation rates much higher than previously reported. That indicates the battle against gene drive resistance is far from over, even with an arsenal that includes tools like Crispr.

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