Gene-editing on autopilot: What could go wrong?

The headline in The Economist called the genetic engineering tool known as gene drive “extinction on demand.” The Guardian referred to it as “genetic extinction” technology.

Alarmist?

Perhaps.

Researchers, however, are making progress in unleashing a genetically altered mosquito that could spread its modified genes to all of its mosquito offspring and eventually wipe out an entire local population—maybe even every mosquito of its kind on the planet. Which sounds a bit risky.

But there is a reason that researchers want to take that chance: to eliminate the major vector for malaria—a disease spread by the bite of Anopheles mosquitoes that carry the parasite Plasmodium, which causes red blood cells in its victims to burst open. Malaria can lead to fever, chills, nausea, lung problems, kidney failure, brain damage, and even death. So, eliminating malaria sounds like a great idea; the disease killed about 450,000 people in 2016 alone—mainly children in sub-Saharan Africa.

Consequently, last month, scientists in Italy took that gamble and released mutated mosquitoes into a lab that mimics the hot and humid environments where malaria thrives. (The effort is part of Target Malaria, an international project aiming to eliminate malaria.)

But the genetic engineering process the group used has met with controversy. Researchers say that an animal carrying a gene drive in its genome could spread a modified trait well-beyond targeted populations, potentially having dramatic impacts on ecosystems across the planet. (And targeting is key, because not all species of mosquitoes carry the disease-bearing parasite; out of about 3,000 species of mosquitoes, it seems to be just the Anopheles mosquito group that can harbor Plasmodium.) And activists point to the millions of dollars the US military has invested in gene-drive research as a cause for skepticism about harnessing the technique.

How the risky genetic engineering process works.The CRISPR-based gene drive is a section of genetic code (DNA) that is edited into an organism’s genome. The drive contains a modified gene as well as the code for “guide” RNA (a molecule similar to DNA) that can target genes that researchers seek to modify. The drive also contains the code for a gene-cutting protein called Cas-9, which is used in gene editing. Sexually reproducing organisms receive two copies of a given gene, one from each parent. If one of those copies contains a modified-gene connected to a CRISPR-based gene drive then, during reproduction, the gene drive will cut out the competing version of the gene from the other parent. The cell will then replace the damaged DNA using the modified gene in the gene drive as a template. Voila, the offspring will have only one version of the gene.

This process will repeat itself when the offspring reproduces with future mates, potentially leading to every member of a species containing the gene drive. Inserting a modified gene in a gene drive essentially pairs it with the ability to activate the CRISPR gene-editing process on its own.

So what could go wrong?

Plenty.

Humans have long tried to control invasive species (or ones they plain just didn’t like) by introducing predators or competing species in the environment—often with bad results. Hawaiian sugarcane growers, for instance, brought in mongoose to kill off field rats. Turns out mongoose like to hunt during the day, while rats are, well, nocturnal. The pioneering researcher who helped develop CRISPR-based gene drives, Kevin Esvelt, later came to believe that a trait associated with a gene drive would relentlessly spread across the world.

In a 2017 paper, Esvelt and a co-author wrote about the possibility of using a CRISPR-based gene drive to introduce a gene that affects fertility in rats in New Zealand, where they are an invasive species. Eventually, the authors argued, the trait would spread to rats all over, including in places where they support the ecosystem or are valued. This is because a gene-drive rat would likely be accidentally or intentionally transported somewhere else.

Esvelt, who supports using a CRISPR-based gene drive to eradicate malaria, nonetheless advocates a cautious approach to experiments: “The bottom line is that making a standard, self-propagating CRISPR-based gene drive system is likely equivalent to creating a new, highly invasive species: both will likely spread to any ecosystem in which they are viable, possibly causing ecological change.”

New paper: Our default expectation is that self-propagating #genedrive will invade most populations of the target species around the world. Unless fighting malaria, best not to build one that can spread in the wild. https://t.co/3Yv2xst948 1/4

— Kevin Esvelt (@kesvelt) June 20, 2018

Meanwhile, the US military is a key funder of gene-drive research. The Defense Advanced Research Projects Agency’s Safe Genes program has invested $65 million in gene-editing research, including projects on gene drive. A key focus of the program is to “address potential health and security concerns related to” accidental or intentional misuse of gene-editing technology. Project teams “will work to substantially minimize the risks inherent in such powerful tools,” a press release states.

NPR reports that the Target Malaria team in Terni, Italy, has taken precautions to ensure the modified mosquitoes it is researching don’t escape. Even if they did, they wouldn’t survive in the local climate.

But the ultimate goal is to conduct field tests and release gene-drive mosquitoes into the wild.

That prospect is what worries researchers and activists. Eliminating or introducing an entire species (which is essentially what a gene-drive mosquito would be) can wreak havoc upon the populations of birds and other organisms that feed on it, with similar effects upon the creatures that feed upon the feeders, and so on downstream—often with unexpected results. (Who knew that taking a mere 101 cane toads from Puerto Rico and introducing them to Australia in 1935 would lead to dramatic reductions in the numbers of native species there today?) The study of how ecosystems work by watching how they fall apart—a field known as invasion biology—is still relatively young, but it’s clear that biodiversity is crucial to keeping a system healthy and resilient. An ecosystem is a finely tuned, elegantly constructed machine that needs all its parts to function; anything that removes a piece, or throws in a random monkey wrench, can greatly damage the works.

Consequently, last fall the United Nations brokered a deal to require local consent for wild gene-drive efforts. Such consent could prove incredibly difficult to obtain. In the lead-up to a field test, Target Malaria is conducting research in sub-Saharan Africa to better understand what the implications would be for potentially killing off an entire local population of mosquitoes. The group says its still at an “early stage” in its work.