Editing Evolution

Gene drive is a revolutionary new genetic technology that could help eradicate diseases and save species. But is it risk-free?

No point in the incorporated United States is farther south than Palmyra Atoll, a four-square-mile speck of an island located near the equator about 1,000 miles south of Hawaiʻi. One of the world’s 180,000 tiny islands, Palmyra is home of the Pisonia forest, one of the best remaining examples of a tropical coastal strand forest. It has a rich diversity of birds, wildlife and – until about three years ago – a thriving population of some 30,000 black rats. The rats, which most likely arrived via battleship during World War II, quickly multiplied and preyed on everything from native plant seeds and seedlings to the eggs and chicks of both ground-nesting and tree-nesting birds, to native land crabs. They overran the island in such large numbers that several seabird species, including burrow-nesting shearwaters and petrels, stopped breeding there.

Scientists have already used genedrive to create versions of Anopheles gambiae mosquitoes, which carry the parasite that causes malaria, so that the female mosquitoes can’t produce fertile eggs.

“[Rats] can sink an island into imbalance very quickly,” says Heath Packard, a spokesman for the Santa Cruz-based group Island Conservation. In 2011, Palmyra’s co-owners, the US Fish and Wildlife Service – which manages the atoll as a National Wildlife Refuge – and The Nature Conservancy, partnered with Island Conservation to rid the island of the rats. The coalition treated Palmyra with a highly toxic rodenticide, Brodifacoum, over two years, and in 2013 the island was declared rat-free. Packard estimates that about 90 percent of the world’s 180,000 islands are infested by invasive rodents. Rats have been eradicated from only 400 of them. “Virtually all of them involved the use of rodenticide to do that,” he says, but the method isn’t always foolproof. “You need to make sure every rodent receives a fatal dose. If you leave one pregnant female on the island it will repopulate the island with invasive species in less than a year’s time.”

Island Conservation has long been looking for a way to rid islands of invasive rats and mice without the use of toxic chemicals. Now, it believes it has found one: a new genetic engineering tool called gene drive. By circumventing the traditional rules of genetic inheritance, gene drives can, among other things, cause targeted species to become extinct over the course of a few generations.

Island Conservation has convened an independent ethics panel to explore the potential and pitfalls of using gene drives and is looking for a place to conduct a field trial on either rats or mice. Packard believes the technology offers “an incredible opportunity to protect imperiled species,” like the birds in Pisonia forest.

Decades ago, when Steve Jobs helped launch the personal computer revolution, he said he was democratizing the technology. Today, a new generation of high-tech researchers and entrepreneurs are adapting computer culture to biology, making complex gene technologies available to the masses. But unlike the computer parts freshly assembled in Jobs’s garage, their innovative new products are an attempt to improve upon genetic codes that have been around for 4 billion years.

Synthetic biology, commonly defined as the science of manipulating or editing genomes to engineer new living organisms, is basically genetic engineering 2.0. This rapidly growing biotech field is expected to be worth $38.7 billion by 2020. And right now, gene drives are the most exciting – and most potentially dangerous – new tool in the bio-hacking toolkit.

artwork depicting a double helix and a pair of snips to cut it Gene drives – which have always existed in nature – are mechanisms that promote the
inheritance of a particular gene over others in any sexually reproducing species.

Gene drives – which have always existed in nature – are mechanisms that promote the inheritance of a particular gene over others in any sexually reproducing species.

Normally, an organism has a 50 percent chance of inheriting any given gene from each of its parents. But in the 1940s biologists found that some genes circumvented these traditional rules of genetic inheritance and managed to pass themselves on to a larger number of offspring than normally expected. The genes did this by developing the ability to make multiple copies of themselves in the parent’s genome, which increased their chances of being inherited, and eventually, over several generations, allowed them to spread to all members of a population. Back then, scientists theorized about the possibility of using these “selfish genes” to control disease-carrying insect populations, but nobody knew how to replicate the natural phenomenon. Until now.

The first viable method suggesting how selfish genes could be used came in 2003. Austin Burt, a professor of evolutionary genetics at London’s Imperial College, suggested attaching one of these selfish, self-replicating genes to another gene – the one carrying traits that you actually want to propagate. This piggyback approach would allow the desired gene to circumvent heredity bottlenecks along with the selfish gene. Burt envisioned using this “gene drive” to alter mosquitoes that spread malaria. But his method required a genetic tool that didn’t exist at the time, one that would be able to zero-in accurately on a specific gene and replace it with the modified, selfish and desired gene combo – the so-called “gene drive.”

That fine tool took another nine years to show up. In 2012, researchers developed crispr-Cas9, a high-precision gene-editing tool that could cut and paste nearly any gene into any organism, a scientific breakthrough that opened up a whole new area of biotechnology.

crispr-Cas9 is a naturally-occurring segment of DNA found in bacteria that helps them fight off invasive viruses. (crispr, an acronym for “clustered regularly interspaced short palindromic repeats,” is one part of the bacteria’s immune system which keeps bits of dangerous viruses around so it can recognize and defend against those viruses next time they attack. The other part of the defense mechanism, Cas 9, is an enzyme that acts as a pair of “molecular scissors.” The system also includes two separate kinds of RNA – one that guides Cas9 to a particular location and another that acts as a transactivator, enabling the enzyme to cut out foreign DNA at a specific location in the alien genome so that bits of modified DNA can then be added or removed.)

The slightly modified version of the crispr-Cas9 system that the researchers developed can function as a gene drive in any other life form – from other bacteria to mice to humans. When it’s inserted into a cell, crispr-Cas9 can locate and cut out any specified section of the cell’s dna and replace it with a copy of itself along with the desired gene that’s been tethered to it. This ensures that the desired gene will copy itself in every successive generation so that each future generation would have more offspring with the desired genetic trait, until at some point the entire species would have it. crispr-Cas9 has often been compared to the search-and-replace function in word-processing applications.

The crispr technology was barely two years old when, in July 2014, a research group led by Kevin Esvelt of the Massachusetts Institute of Technology and George Church of Harvard Medical School revealed that they had successfully used gene drives to spread genomic alterations in lab-grown yeast populations that were “typically copied at rates above 99 percent when mated to wild yeast.” Two months later, Valentino Gantz and Ethan Bier, molecular biologists at the University of California, San Diego, demonstrated that gene drives could work with a 97 percent inheritance rate in fruit flies, which are much more complex organisms than single-celled yeast. Then in 2015, two independent research groups, one at the University of California, Irvine and another at Imperial College in London, developed gene-drive modified mosquitoes.

Of course, biologists could edit genomes using enzymes long before the development of crispr. But these methods were expensive, not as precise, and difficult to engineer. crispr, however, has made genome editing so easy, cheap, and widespread in the past few years that, as the tool’s co-creator Jennifer Doudna, a molecular biologist at the University of California, Berkeley, says, “even third-graders” are using it in their science class. (Since scientists working independently at UC Berkeley and MIT/Harvard almost simultaneously invented the crispr editing tool, they are now battling in court over patent rights. Doudna was part of the UC Berkeley team.)

A technology whose basic purpose is to spread genetic mutations creates risks we have never before had to consider.

But third-graders won’t be using gene-drive technology anytime soon; the advance from crispr to crispr-Cas9 is exponential, with its promise of reprogramming not individuals, but entire species, forever. While other crispr-based, DIY genome-editing tool kits are easily accessible – one can order these online for as little as $150 – the crispr-Cas9 gene drive technology is still tightly guarded by the labs across the world that are working with it. So far, no gene drive experiments have ever been conducted outside the laboratory and real world applications, which are fraught with ecological and moral quandaries, are thought to be at least a decade away.

But given that gene drives offer almost magical possibilities to enhance beneficial traits or remove undesired characteristics in living things, Island Conservation isn’t the only organization busy mulling real world applications of the technology. The prospect of eradicating pests and disease vectors without using toxins, or saving an endangered species by making them immune to certain diseases, has captured the imagination of many in the fields of conservation and public health.

According to Harvard’s Wyss Institute for Biologically Inspired Engineering, which was partially responsible for the invention of crispr-based editing tools, gene drives might be able to perform a variety of tasks vital to the well-being of people and the planet. These include the elimination of diseases such as malaria, dengue, yellow fever, West Nile disease, sleeping sickness, Lyme disease, and Zika; the eradication of troublesome invasive species; the alteration of pests that damage crops or carry crop disease, or the enhancement of crops themselves so that they can resist the pests.

Given the health and social benefits it could bring, pressure to use this technique is mounting. But at the same time, real-world application of a technology whose basic purpose is to spread genetic mutations creates risks that we have never before had to consider.

For starters, nearly nothing is known about how the spread of a gene-altered organism will affect ecosystems. Would removing disease-carrying mosquitoes upset ecosystems by depriving birds, bats, frogs, lizards, and other insect-eating critters of a food source? Theoretically at least, even one gene-drive altered organism could eventually affect an entire population. Doesn’t that imply that we run the risk of irrevocably altering a wild species, or even wiping it out, if a lab specimen escapes by accident? And what if a gene drive manages to cross the species barrier and affect non-target insects or animals?

These questions have acquired extra urgency now that gene drives are being used to alter organisms in labs across the world.

Austin Burt and his Target Malaria team at the Imperial College in London have already utilized the technology to create versions of Anopheles gambiae mosquitoes, which carry the parasite that causes malaria, so that the female mosquitoes can’t produce fertile eggs. The Bill and Melinda Gates Foundation, which considers gene drives “necessary” to end malaria, has invested tens of millions of dollars on Target Malaria, which now includes research teams in Italy, Mali, Burkina Faso, and Uganda. At the Massachusetts Institute of Technology, Esvelt and his colleagues are working on editing white-footed mice to make them resistant to the bacteria that causes Lyme disease so that they can’t pass the infection along to ticks or other critters and humans.

chart depicting generations of mosquitoes Click or tap this graphic to view it larger

Meanwhile, the Defense Advanced Research Program Agency (darpa), a branch of the Pentagon, too, has become a major funder of gene drive research. The agency is planning to develop a program it calls “Ecological Niche

-preference Engineering” in which it would utilize genome editing to modify an organism’s preferences for food, temperature, and habitat. The program would also edit the genomes of disease transmitting insects, bio-fouling microorganisms, and crop pests to protect human health, infrastructure, and agriculture. (Gene drives show quick results only in species with short life cycles, like mice and mosquitoes. Because of humans’ relatively long life spans, it would probably take hundreds, if not thousands of years for a gene drive to alter the human genome, rendering it impractical for use on people.)

All these programs are moving ahead at a clip amid a regulatory vacuum. There are currently no agreed-upon national or international regulations or procedures for how gene drives should be developed or used. In the US, it’s not even clear which government agency – the US Food and Drug Administration, the Department of Agriculture, or the Environmental Protection Agency – will have jurisdiction over gene drives. Neither is it clear how international treaties – such as the Cartagena Protocol on Biosafety which governs cross-border movement of genetically engineered organisms – will be honored, given that wild animals don’t exactly recognize international boundaries. As Zach Adelman, a molecular biologist at Virginia Tech University points out: How are we to regulate “something that, by definition, can’t be contained”?

Kevin Esvelt, the MIT scientist who co-authored the 2014 study that was first to offer proof of the gene drive concept, today sounds more like a skeptic than a supporter of the technology. Last year he told Technology Review, an MIT publication, that gene drives are the kind of science experiment that “If you screw up, it affects the whole world.”

Indeed, the possibility of a screw-up has been of deep concern within the scientific community, more so than with any other emerging technology in recent years.

In June 2016, the National Academy of Science released a report, “Gene Drives on the Horizon,” that urges researchers working on gene drives to exercise caution. “The potential for gene drives to spread throughout a population, to persist in the environment, and to cause irreversible effects on organisms and ecosystems calls for a robust method to assess risks,” the report said. Meanwhile, 27 leading scientists, including Esvelt, Bier, and Burt, issued guidelines in Science for working with gene drives in the laboratory. An accidental release of a gene drive, they warned, “could have unpredictable ecological consequences. Just as researchers working with self-propagating pathogens must ensure that these agents do not escape to the outside world, scientists working in the laboratory with gene drive constructs are responsible for keeping them confined.”

An accidental release of gene drive organisms, they fear, would devastate public trust in the technology and jeopardize any chance of it being used for much-needed humanitarian benefits such as the eradication of malaria, which kills more than a half million people every year, most of them children, and sickens 200 million more. Esvelt believes it’s entirely possible that at some time in the future, a gene drive accident will allow transgenic material to spread globally. “It’s not going to be bioterror,” he’s been known to say, “it’s going to be ‘bioerror.’ ”

Keenly aware of this danger, labs experimenting with gene drives use utmost caution. At UC San Diego, for instance, Gantz and Bier’s gene altered fruit flies are kept in three layers of tubes and boxes, and the lab is locked behind five doors with fingerprint security; the Target Malaria lab in Imperial University is sealed by a steel door and the gene-altered mosquitoes are kept in small net-covered cages behind glass walls.

But many experts fear amateur bio-hackers may figure out how to develop gene drives on their desktops before any regulatory frameworks and security protocols are in place. It’s unlikely they will use similar precautions when editing genomes in their kitchens.

artwork depicting a microscope and a mosquito Many experts fear that an accidental release of a gene drive could have unpredictable
ecological consequences. They also worry that amateur bio-hackers may figure out how
to develop gene drives on their desktops before any regulatory frameworks and
security protocols are in place.

While there is no evidence that any amateur biologists have created a gene drive yet, they might be getting close, as demonstrated last October by students at a science fair in Boston. The annual competition of the International Genetically Engineered Machines (iGEM) encourages college students to solve real-world challenges by building genetically engineered biological systems with standard, interchangeable parts. Several thousand students designed, built, and tested their projects over the summer and gathered in Boston to present their work and compete at the annual jamboree. This included a team of students from the University of Minnesota that came perilously close to developing a gene drive. Organizers of the science fair became concerned when the Minnesota students revealed they were working on developing a gene drive that could turn yeast red, as well as reverse the process and return it to its original color.

The project eventually failed because the students lacked enough time and adequate lab equipment to create an actual gene drive in time for the competition, but they came close enough to prove that the technology could be developed outside highly-secure labs. Since then, iGEM has imposed new rules that guide how future submissions must deal with the gene drive mechanism.

Apparently the Federal Bureau of Investigation was on hand to witness the event. Mollie Halpern of the FBI’s Office of Public Affairs says the bureau sent a special agent to the science fair to make sure students understood the risks of synthetic biology. “This outreach effort is one way the FBI will stay ahead of the threat posed by synthetic biology and build partnerships between law enforcement and the scientific community,” Halpern says.

Even key players in the field of synthetic biology like Stewart Brand are offering only conditional support of gene drives. The veteran conservationist and founder of the controversial Long Now Foundation – which is exploring the feasibility of digging up the DNA of extinct animals like the woolly mammoth and bringing them back to life by rebuilding their original genome – sees gene drives as “a great set of new tools for conservation where nothing else does the job.” He says, however, that scientists should not release gene drives into the wild unless they have an “undo button” that would reverse the gene drive if something goes haywire. “If there’s something going on you don’t like, you [should be able to] send another gene drive to repair the first gene drive,” he told EIJ.

Other environmentalists are less sanguine.

“Gene drives are basically a technology that aims for a targeted species to go extinct,” says ecologist and entomologist Dr. Angelika Hilbeck, president of the European Network of Scientists for Social and Environmental Responsibility. “While this may appear to some conservationist professionals to be a ‘good’ thing and a ‘silver bullet’ to handle complicated problems, there are high risks of unintended consequences that could be worse than the problems they are trying to fix.”

Some worry about the technology getting into wrong hands, especially corporations that put profit over public good. Last year, for instance, agri-biotech giant Monsanto purchased a crispr technology license from the Broad Institute, an affiliate of Harvard and MIT. Two other large producers of GMO products, Dow and DuPont, have also bought similar licenses. While the licenses forbid the companies from using crispr in gene drives, many are not convinced it will be enough to keep Monsanto out of the potentially lucrative gene drive business.

In 2016, the NSA listed genome editing as a potential weapon of mass destruction.

Jim Thomas of the Canada-based ETC Group, which monitors the impact of new technologies, says Monsanto has enough financial incentive to find a way around the contracts. “What would it mean if Monsanto decides to change the genetics of all the weed species in North America to suit its business plan of selling [its weedicide] Roundup?” he asks. “It would increase its dominance in the marketplace, and what would that do to agriculture?”

Claire Hope Cummings, the author of Uncertain Peril: Genetic Engineering and the Future of Seeds, says the term “gene drive” does not convey the horrific damage she thinks the technology could do to ecosystems. “Gene drives are ridiculously dangerous and there is nothing to stop them from being deployed and causing real damage,” she says.

Three national security and intelligence gathering agencies of the US government – the FBI, National Security Agency, and the Pentagon – seem to concur with these concerns.

In 2009, the FBI set up a special branch within its Weapons of Mass Destruction Directorate to monitor the biohacker community in order to identify and stop people who might misuse synthetic biology and commit criminal acts. And last year the NSA listed genome editing in its Worldwide Threat Assessment as a potential “Weapon of Mass Destruction and Proliferation.” Potentially, a terrorist outfit, or even a lone actor, could create a handful of mosquitoes or other parasite with a gene for making a toxin, power them with a gene drive, and release them in the open.

The Pentagon’s research arm, darpa, though enthusiastic about the potential benefits of gene drives, has launched a “safe genes” project to deal with what it calls the “potential risks of this rapidly advancing field.” Specifically, darpa is looking into building a “reverse gene drive” – Stewart Brand’s “undo” button.

Renee Wegrzyn, a darpa program manager, says the agency “wants to develop controls for gene editing and derivative technologies to support responsible research and defend against irresponsible actors who might intentionally or accidentally release modified organisms.” The “Safe Genes” project will address “the inherent risks that arise from the rapid democratization of gene editing tools,” she states in an article on darpa’s Safe Genes webpage.

Bioterrorism, however, is more of a theoretical threat right now. As Austin Burt has pointed out in the past, gene drives can work only in sexually reproducing species and scientists understand only a few such organisms at the level of detail needed to engineer a successful gene drive. Bioterrorists, he says, won’t find it easy to adapt the technology for nefarious uses.

While it may indeed be years before animals or plants with gene drives are released into our environments, pressure on governments and international organizations to write rules guiding the development of gene drives is growing.

In September, at the International Union for Conservation of Nature’s World Conservation Congress in Hawaiʻi, member nations called for an assessment of gene drives and related techniques, and their potential impacts on conservation and sustainable use of biological diversity. They also called on nations to refrain from supporting or endorsing gene drive research, including field trials, until the assessment is complete.

However, a December meeting of the UN Convention for Biological Diversity rejected a call for a similar moratorium by more than 170 environmental and other nongovernment organizations.

Scientists like Esvelt, who believe in the potential of gene drives to do good, say that the technology can’t move forward without public acceptance and the only way to achieve that is to open up the research for scrutiny.

A National Academies of Sciences, Engineering, and Medicine report – that was sponsored in part by groups experimenting with gene drives, including the Bill and Melinda Gates Foundation and darpa – stressed as much last year when it said that “public engagement may be as crucial as scientific outcomes in making decisions about whether or not to release a gene-drive modified organism into the environment.”

But some wonder how any regulation or UN-adopted resolutions or any amount of “informed decision-making” could possibly keep the world safe from such a powerful biological tool once it’s let loose in the wild. “There is no governance that will stand in the way of real, widespread, irreversible damage to society and to the natural world,” Cummings says. “Our western educated scientists are politely suggesting we ‘should’ come up with guidelines. Really, you think?”

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