Gene Driving to Combat Insect-Borne Diseases

sn-mosquitoes

A fascinating analysis by the Bill and Melinda Gates foundation shows that one type of animal kills far more humans than any other, and it’s not sharks, crocodile, cobras, nor even the most obvious candidate, other humans. No, it’s the mosquito.

In particular, it’s the genus Anopheles of mosquitoes, which carries thePlasmodium parasite that causes malaria. But there also are Aedes mosquitos that carry viral diseases, such as dengue fever and humanity’s newest nemesis: the Zika virus.

Alongside a growing awareness of the public health impact of insect-borne diseases, the rise of CRISPR gene editing during the last three years is emblematic of the enormous power that biotechnology is giving humans over the biological elements of nature. If we’re going to intervene in nature in a major way, insect vectors that carry disease are likely to be the first targets.

CRISPR is one of a handful of candidate technologies that can enable gene drive, a concept that has been in biology since the 1970s, but until recently has been largely science fiction. Using a gene drive strategy, biotechnologists could modify virtually any population of organisms that reproduce sexually and with rapid generation times, the prime example being mosquitos, which go through about ten generations per season.

Gene drive feasibility has been proven experimentally and could be applied to a range of projects, from rendering insect pests uninterested in consuming agricultural crops to eliminating insect-borne diseases. The latter application is the focus of this article and could take the form of annihilating selected mosquito populations, or modifying those mosquitos so that they resist infection by disease-causing organisms, have no interest in biting humans, or both.

But, precisely because gene driving is powerful enough to do things on the scale of say eliminating the malaria parasite from an entire continent, it also can worry people and governments. This means that any program implemented to change insects on a massive scale in any geographic area will depend strongly on good communication to people and foreign governments regarding the underlying science and how the whole plan would work. This includes explaining gene drive safety measures as well as the ability to reverse gene drive effects –a possibility that, like gene driving itself, is particularly feasible today because of CRISPR. The issue is immensely technical and at the same time immensely vital, given the gravity of mosquito-related public health issues. It’s a situation that lends itself well to the art of science diplomacy.

What is a gene drive?

Essentially, a gene drive is any phenomenon –natural or human made– that causes a gene to be inherited at a frequency higher than you would expect from Mendelian genetics, genetic drift, founder effects, bottlenecking –all of the forces of evolution that you learn about in basic biology. Molecular genetics emerged in the 1970s and as that happened scientists came across various natural molecular phenomenon that occasionally caused increased inheritance. For instance, if the Mendelian prediction for inheritance is that a father will pass down a particular gene to 50 percent of his children, the newly-discovered phenomena could increase the inheritance to 60 percent, or 70 percent. The fact that this could happen in insects or yeast led scientists to wonder whether humans might devise some artificial means to achieve a gene drive. It was pure science fiction at the time, because there was no such technology to do that, but today there are various candidate gene drive technologies, and CRISPR is the one being discussed most.

Normally, if a rare gene is introduced into a large population, whether human, insect, or other animal, the gene will remain rare. With CRISPR-CAS9 editing systems, however, new sequences can be programmed so that they’re passed down to offspring and then expand from one member of a chromosome pair to the other. This is quite from the familiar Mendenlian mechanism and it’s possible because of the CAS9 sequence. It’s like getting a gene for blue eyes from your father and instead of that gene remaining recessive to the brown-eye gene that you got from your mother the blue-eye gene copies itself and knocks out the brown-eye gene, so your genetype is blue-blue, instead of Brown-blue. Do this with animals that reproduce generations rapidly and within months you can put the new genetic sequences into just about every member of the species within a certain geographic area.

Engineering the germs out of mosquitos

The public has been aware of the feasibility of genetically modified mosquitos for some time. Most recently, the idea has been discussed in connection with a success by British company Oxitec in field tests of GM Aedes mosquitos to fight Zika virus in Brazil. Also, back in 2011, researchers showed that they could modify Anopheles mosquitos genetically to resist plasmodium infection. Neither one of these projects was a gene drive system, however, because the engineered property could not be spread through mosquito populations.

But last November, in the prestigious journal Proceedings of the National Academy of Sciences, a team led by Ethan Bier from the University of California San Diego and Irvine published groundbreaking work demonstrating experimentally how a CRISPR-CAS9-based method called mutagenic chain reaction (MCR) could force gene edits through mosquito populations—in other works perform a gene drive.

“This work suggests that we’re a hop, skip and jump away from actual gene-drive candidates for eventual release,” declared Harvard evolutionary engieneer Kevin Esvelt, whose research has demonstrated CRISPR gene drive approach in yeast and nematode worms.

The technology—and importantly the underlying science showing that it would work on a large scale—is developing rapidly and there are several teams around the planet developing gene systems that virtually could eliminate Plasmodium from Anopheles. This means that we’re facing a crossroads with enormous international implications.

Spreading disease resistance and peace of mind

Importantly, for safety, Esvelt has explained that the researchers in California purposefully did their work using non-native mosquito species that are not native to the United States, namely Anopheles stephensi, which (actually native to India)

“Even if they escaped the lab,” said Esvelt, “there’d be no one to mate with and spread the drive,”

As for why you wouldn’t want to spread the drive to reduce the spread of disease, that’s partly because it’s prudent not to make the experiment bigger than it’s designed to be, but it’s also a diplomacy issue. To convince governments of foreign countries to approve of something as ambitious and powerful as a gene drive, it’s fundamental that researchers have to show they can keep things under control. The first step toward this end is to get scientists together to draft guidelines and safety protocol, and that’s what Bier, his colleagues, and other researchers considering gene drives are advocating currently.

“In an analogy to the famous Asilomar conference concerns held to address concerns raised at the dawn of recombinant DNA technology in the 1970s, perhaps a similar meeting should be convened to discuss how MCR technology should be regulated at both federal and institutional levels to assure that it is employed safely to achieve its full potential to ameliorate the human condition,” Bier suggested in a recently.

Until such guidelines are drafted and researchers around the planet are on the same page, nobody is about to release a gene drive system into the wild. But let’s suppose that two or three years from now, governments are ready to do it, after becoming very confident with the technology and also after public discussions regarding whether it’s wise to manipulate nature. Imagine now, that the government of Brazil, for instance, wants to implement something more aggressive than the recently-tested GM mosquito whose effects would merely reduce mosquito populations, just as spraying would do and thus would not be a permanent solution. Imagine that Brazil wants to move forward with a CRISPR-based gene drive to render Aedes mosquitos immune to invasion by Zika, and Anopheles immune to Plasmodium. The engineered mosquitos are then released into the wild, let’s say in the central Amazon, and then it works; studies of mosquitos are showing decreasing infection with the disease causing agents, but mosquito populations are not shrinking so it appears there will be no ecological harm, and let’s imagine epidemiologists are finding that rates of malaria and Zika are on the decline. But as the new genetic sequences gradually encompass all of the target species in an expanding wave from central Brazil toward the outer regions, let’s imagine that a bordering country, Venezuela for instance, gets nervous. They don’t want their mosquitos contaminated with the engineered sequence. Then what?

That’s a tricky diplomatic situation, but like the gene drive itself, Bier and his colleague and former graduate student Valentino Gantz have proposed an elegant solution. The research is now so advanced that for any CRISPR gene drive, an eraser program also can be engineered. It can be released in the wild and penetrate populations just like the initial gene drive. It would work by sending out only CRISPR sequences similar to the ones sent out in the gene drive, but without the CAS9 sequences that enable the new sequence to expand from one chromosome to its sister chromosome. Any mosquitos infected with the eraser would be protected like those infected with the gene drive program, but now the spread of the gene drive would be shut off. Thus, in our imaginary scenario, you could release the eraser along the Brazil-Venezuela border and create kind of genetic wall between the two countries.

Could an eraser reverse any and all effects of a gene drive? The answer to that is no. All it can do is stop the advance, or reverse the progression of the altered sequences. It cannot reanimate an extinct species, and so if your gene drive disrupts the ecosystem then after a certain point the damage is not reversible. Understanding this depends exquisitely in appreciating the underlying science. There’s really no way around that as we live in world where issues are ever more depending on science technology. But this is why gene drives are an area where science and diplomacy are intimately connected.

Article Credit: Genetic Literacy Project