BIOMEDICINE
With This Genetic Engineering Technology, There’s No Turning Back

By Antonio Regalado on November 23, 2015.

The students in Anthony James’s basement insectary at the University of California, Irvine, knew they’d broken the laws of evolution when they looked at the mosquitoes’ eyes.

By rights, the bugs, born from fathers with fluorescent red eyes and mothers with normal ones, should have come out only about half red. Instead, as they counted them, first a few and then by the hundreds, they found 99 percent had glowing eyes.

More important than the eye color is that James’s mosquitoes also carry genes that stop the malaria parasite from growing. If these insects were ever released in the wild, their “selfish” genetic cargo would spread inexorably through mosquito populations, and potentially stop the transmission of malaria.

The technology, called a “gene drive,” was built using the gene-editing technology known as CRISPR and is being reported by James, a specialist in mosquito biology, and a half dozen colleagues today in the Proceedings of the National Academy of Sciences.

A functioning gene drive in mosquitoes has been anticipated for more than a decade by public health organizations as a revolutionary novel way to fight malaria. Now that it’s a reality, however, the work raises questions over whether the technology is safe enough to ever be released into the wild.

“This is a major advance because it shows that gene drives will likely be effective in mosquitoes,” says Kevin Esvelt, a gene drive researcher at Harvard University’s Wyss Institute. “Technology is no longer the limitation.”

Starting last summer, Esvelt and other scientists began warning that gene drives were about to jump from theory to reality (see “Protect Society from Our Inventions, Says Genome Editing Scientists”) and needed more attention by regulators and the public. The National Academy of Sciences is studying the science and ethics of the technology and plans to release recommendations next year on “responsible conduct” by scientists and companies.

Gene drives are just the latest example of the fantastic power of CRISPR editing to alter the DNA of living things, which has already set off a debate over the possibility that gene editing could be used to generate designer human babies (see “Engineering the Perfect Baby”). But Henry Greely, a law professor and bioethics specialist at Stanford, says environmental uses are more worrisome than a few modified people. “The possibility of remaking the biosphere is enormously significant, and a lot closer to realization,” he says.

Malaria is caused when a mosquito bite transmits plasmodium, a single-celled parasite. It’s treatable, yet every year, 670,000 people die from malaria, the majority of them young children in sub-Saharan Africa.

James says his mosquitoes are the culmination of decades of mostly obscure, unheralded work by a few insect specialists toward constructing a genetic solution to malaria. It finally became possible this year when scientists in the laboratory of Ethan Bier, a fly biologist at the University of California, San Diego, who is a coauthor of the paper, finally used CRISPR to perfect a molecular “motor” that could allow the anti-malaria genes to spread.

The mosquitoes have two important genetic additions. One is genes that manufacture antibodies whenever a female mosquito has a “blood meal.” Those antibodies bind to the parasite’s surface and halt its development. Yet normally, such an engineered mosquito would pass the genes only to exactly half its offspring, since there’s a 50 percent chance any chunk of DNA would come from its mate. And since the new genes probably don’t help a mosquito much, they’d quickly peter out in the wild.

That’s where CRISPR comes in. In a gene drive, components of the CRISPR system are added such that any normal gene gets edited and the genetic cargo is added to it as well. In James’s lab, practically all the mosquitoes ended up with the genetic addition, a result Esvelt calls “astounding.”
What worries Esvelt is that, in his opinion, the California researchers haven’t used strict enough safety measures. He says locked doors and closed cages aren’t enough. He wants them to install a genetic “reversal drive” so the change can be undone, if necessary. “An accidental release would be a disaster with potentially devastating consequences for public trust in science and especially gene-drive interventions,” he says. “No gene-drive intervention must ever be released without popular support.”

James says the experiment was safe since the mosquitoes are kept behind a series of locked, card-entry doors and because they aren’t native to California. If any escaped, they wouldn’t be able to reproduce.
In fact, the whole point of a gene drive is to release it into the wild, a concept that has long been accepted, at least in theory, by public health organizations including the Gates Foundation. Now that they’re actually possible, however, alarming news headlines have compared the technology to “the next weapon of mass destruction” and even raised the specter of insect terrorism, such as mosquitoes that kill people with a toxin.

Gene-drive terrorism is probably nonsense, at least for now. That’s because even if insect weapons were possible, in practice it’s unlikely a terrorist organization would invest millions in an advanced genetic-engineering program. “I have been thinking quite a bit about bad things you could do with it, and we haven’t come up with anything that would succeed,” says Bier. “There are so many bad things you could do that are easier.”

Instead, Bier and James say they are convinced that engineered mosquitoes should be released as soon as possible, something they hope to do if they can find a community affected by malaria that will agree to it. “Imagine we could design a mosquito that would magically cure cancer,” says Bier. “Well, the fear of getting malaria is the same fear we have of getting cancer. In my opinion the benefits outweigh the risks, and we should move forward as aggressively as we can.”