CRISPR Gene Drives Equivalent to Creating a New, Highly Invasive Species

THIRD WORLD NETWORK BIOSAFETY INFORMATION SERVICE

Dear Friends and Colleagues

CRISPR Gene Drives Equivalent to Creating a New, Highly Invasive Species

In 2013, scientists discovered a new way to precisely edit genes through a technology called CRISPR. Kevin M. Esvelt and colleagues at Harvard University in 2014 suggested that CRISPR could be used to save endangered wildlife from extinction by implanting a fertility-reducing gene in invasive animals, using a so-called gene drive. The theory was that when the genetically altered animals were released back into the wild, the fertility-reducing gene would spread through the population, eradicating the pests (Item 1).

But now, three years later, Dr. Esvelt regrets championing the notion. He said his original paper made a compelling case for all of the potential benefits of gene drive without spelling out the risks and challenges clearly; “I badly misled many conservationists who are desperately in need of hope,” (Item 2). Esvelt and others published two papers to this effect on 16 November 2017, on bioRxiv (Item 3) and PLoS (Item 4).

They created a detailed mathematical model describing what happens following the release of CRISPR-altered organisms. And they discovered an unacceptable risk: Altered genes might spread to places where the species isn’t invasive at all, but a well-established part of the ecosystem. The model revealed that a gene drive would be remarkably aggressive. It would take relatively few engineered organisms to spread a new gene through much of a population. According to Esvelt, “[Modified organisms] probably can’t be safely tested in the field because they’re likely to spread to most populations of the target species throughout the world."

The PLoS paper, co-authored with New Zealand geneticist Neil Gemmell, warns that releasing a standard gene-drive is “likely equivalent to creating a new, highly invasive species.” Even experimenting in a contained lab could be dangerous. For example, if an engineered lab mouse escaped and that lab was in the vicinity of other mice it might breed with, the gene drive could spread accidentally.

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Item 1

‘GENE DRIVES’ ARE TOO RISKY FOR FIELD TRIALS, SCIENTISTS SAY

Carl Zimmer
New York Times
16 Nov 2017
https://www.nytimes.com/2017/11/16/science/gene-drives-crispr.html

The short-tailed weasel, or stoat, decimated native bird populations after it was introduced to New Zealand. Altering the genes of invasive animals might save threatened species, scientists said, but could also have devastating consequences. 

In 2013, scientists discovered a new way to precisely edit genes — technology called Crispr that raised all sorts of enticing possibilities. Scientists wondered if it might be used to fix hereditary diseases, for example, or to develop new crops.

One of the more intriguing ideas came from Kevin M. Esvelt and his colleagues at Harvard University: Crispr, they suggested, could be used to save endangered wildlife from extinction by implanting a fertility-reducing gene in invasive animals — a so-called gene drive.

When the genetically altered animals were released back into the wild, the fertility-reducing gene would spread through the population, eradicating the pests.

The idea appealed to conservation biologists who had spent decades fighting a losing battle against exotic species. Some labs began running preliminary experiments. But now, three years later, Dr. Esvelt wishes he hadn’t broached the idea.

“I feel like I’ve blown it,” Dr. Esvelt, now an assistant professor at M.I.T., said in an interview. Championing the notion was “an embarrassing mistake.”

His regret arises from a study that he and his colleagues published on Thursday on the preprint bioRxiv server.

They created a detailed mathematical model describing what happens following the release of Crispr-altered organisms. And they discovered an unacceptable risk: Altered genes might spread to places where the species isn’t invasive at all, but a well-established part of the ecosystem.

Dr. Esvelt, who also is a co-author of a commentary on the study’s implications in the journal PLOS Biology, and his colleagues still think it’s worth investigating gene drives to save threatened species. But researchers will have to invent safer forms of the technology first.

Dr. Esvelt and other researchers have also been investigating the possibility of using gene drives to eradicate diseases. The most advanced of these projects seeks to wipe out malaria-carrying mosquitoes. These projects are still viable but, Dr. Esvelt warned, scientists now must be mindful of just how powerful gene drives may become.

“It’s an important contribution,” said John M. Marshall, a mathematical biologist at the University of California, Berkeley, said of the new research. “A study like this is the beginning of a formal analysis we need.”

Crispr makes it possible to build molecules that can find a particular sequence of DNA inside a cell. The molecules then snip out the sequence, allowing it to be replaced by a different one.

The technique might make it possible to introduce not just a gene engineered to reduce fertility in, say, an invasive weasel, but also the genes for the Crispr molecules themselves. Then the weasel would gene-edit itself.

Weasels inheriting just one copy of the low-fertility gene would end up with two copies, which they’d pass down to offspring. Soon the whole population of invasive weasels would be producing fewer young, until eventually the population collapsed.

Researchers at the University of California, San Diego, showed that the idea could really work by spreading a gene in fruit flies reared in the lab. Soon afterward, Dr. Esvelt’s own team showed that the process could make certain genes more common in yeast.

The National Academy of Sciences released a report on gene drives in 2016. While experts recognized a number of potential risks, they endorsed more research — possibly including “highly controlled field trials.”

So what exactly would happen if a gene drive were set loose in the wild? Dr. Esvelt collaborated with Charleston Noble, a graduate student at Harvard, and other colleagues to make an informed guess.

The researchers created a detailed mathematical model that took into account how often Crispr fails to do its job and how often mutations arise that protect a target gene from editing, among many other factors.

The model revealed that a gene drive would be remarkably aggressive. It would take relatively few engineered organisms to spread a new gene through much of a population. “It only takes a handful,” said Dr. Esvelt.

That aggressiveness might be good for eradicating an invasive weasel that couldn’t be stopped by poison baits or hunting. But if a few engineered weasels managed to escape the local environment — or were intentionally taken somewhere else — they could easily spread the gene drive throughout the weasel’s native habitat.

That may well mean that experiments in the real world are just too risky right now.

“The very idea of a field trial is that it’s a trial that’s confined to an area,” Dr. Esvelt said. “Our model indicates that this is not the case.”

“The kind of gene drive that is invasive and self-propagating is in many ways the equivalent of an invasive species,” he added.

But safer forms of the technology might be able to attack species where they’re invasive and not harm them elsewhere. In his own lab, Dr. Esvelt is investigating a gene drive that can self-destruct after several generations.

Other researchers are trying to build gene drives that are tailored to invasive populations on islands but can’t harm mainland relatives.

“I would buy into that,” said James P. Collins, an evolutionary ecologist at Arizona State University and co-chairman of the N.A.S. committee on gene drives. “Universal gene drives do have the downsides that these guys talk about.”

But when it comes to attempts to wipe out malaria, Dr. Esvelt draws a different conclusion from his data.

While self-limiting gene drives might be easier to control, they may be too weak to affect vast mosquito populations. It might well be necessary to deploy a quickly spreading gene drive.

Dr. Esvelt’s study suggests that if one nation decided to release such genetically engineered mosquitoes, neighboring countries quickly would become part of the experiment — whether they liked it or not.

International negotiations might be required before such genetically modified mosquitoes were set loose. “That’s not a question for scientists to answer on their own,” said Jason A. Delborne, a social scientist at North Carolina State University and a member of the N.A.S. gene drive committee.

Kristen V. Brown
Gizmodo
16 Nov 2017
https://gizmodo.com/genetically-engineering-the-natural-world-it-turns-out-1820493131

For the native species of New Zealand, European settlement was particularly cruel. The country has no endemic land predators, so many of its birds evolved without the typical avian aptitude for flight. Then came Western settlers, and along with them rats, mice, opossums, stoats, cats, and the occasional misbehaving dog. For these invaders, New Zealand’s flightless birds were a veritable feast. Numbers dwindled. Despite conservation efforts, the country still loses about 20 of its namesake kiwi birds every week.

Then, in 2014, a young Harvard scientist published a paper that caught the attention of conservationists around the world, New Zealand included. Using the genetic engineering technique CRISPR, he suggested that scientists could create something called a gene drive to override natural selection’s typical 50-50 mix. Among other things, this technique might be used to engineer invasive pests to breed themselves out of existence. No kiwi-killing stoats. Presto.

Earlier this year, typically GMO-wary New Zealand signaled it was interested in giving gene drives a whirl. Now, a pair of papers published Thursday suggest there’s just one potentially significant hitch: Gene drives do not appear to be safe to use for conservation—at least not yet.

The problem, it turns out, is that gene drives might actually work a little too well.

“Our models show that standard drive systems are highly invasive,” Kevin Esvelt, the synthetic biologist who published the original CRISPR gene drive paper back in 2014, told Gizmodo.

Gene drives thwart natural selection by creating a “selfish gene” that gets passed down to offspring with more consistency than the rules of inheritance typically allow, eventually—in theory—spreading through an entire population. If New Zealand decided to use a gene drive to rid itself of rats, for example, it’s possible that those genetically altered rats would eventually make their way to other unintended locations, either by stowing away on ships like they did to get to New Zealand in the first place or by other humans not-so-keen on their own rat populations purposefully moving them.

“[Modified organisms] probably can’t be safely tested in the field because they’re likely to spread to most populations of the target species throughout the world,” Esvelt said.

As you might imagine, genetically altering the world’s entire rat population might wind up being a pretty big problem.

The notion of using genetic engineering to thwart natural selection was first proposed in 2003, but it was with the advent of CRISPR and Esvelt’s 2014 paper that the prospect of gene drives seemed within the realm of possibility.

The 2014 paper inspired a rush of enthusiasm and fear within the broader public, and spurred a heated debate within the scientific community about whether it would really work. Ever since first putting the idea out there, Esvelt has worked hard to warn the world just how dangerous it might be. He occupies a weird space: a scientist at the forefront of genetic engineering who is also probably the foremost critic of technology he creates.

Esvelt, who now has his own lab at MIT, said that the pair of papers published Thursday—one in PLoS, the other as a preprint on bioRxiv—amount to a “mea culpa” of sorts.

He said his original paper made a compelling case for all of the potential benefits of gene drives—conservation! eradicating disease!—without spelling out the risks and challenges clearly.

New Zealand is not the first place to get excited about gene drives for conservation. In Hawaii, for one, the idea has been floated as a solution to the disease-carrying mosquitoes that threaten native bird populations. Last year, the United Nations Convention on Biodiversity rejected calls for a global moratorium on gene drives, concluding that the potential benefits are too great to not proceed with “carefully controlled field trials.” A report from the National Academies of Sciences gave a cautious go-ahead to gene drives as well.

“I badly misled many conservationists who are desperately in need of hope,” Esvelt said. “My mistake was in miserably failing to communicate clearly.”

Some recent research has suggested that wild populations will naturally develop resistance to lab-engineered modifications before a gene drive really has a chance to work its magic. In one 2015 study, researchers reported a CRISPR gene drive had allowed an infertility mutation in female mosquitoes to be passed on to all offspring, but as the mutation increased in frequency over several generations, resistance to the gene drive also emerged, making it unlikely for the mosquitoes to invade wild populations. But Esvelt has floated potential ways around this problem, such as inserting the gene drive gene at several important places in a species’ genome so that it’s unlikely to develop resistance. Even with an inefficient gene drive though, the bioRxiv paper suggests a model in which a small number of altered species could spread to unintended populations.

“This is part of an ongoing conversation about the balances of risk and benefits of gene drive technology,” said Jason Delborne, a scientist who works on gene drives at North Carolina State University who was not involved in the recent work. “These new papers signal that we should be even more cautious about gene drive technology.”

The PLoS paper, an opinion piece co-authored with New Zealand geneticist Neil Gemmell, warns that releasing a standard gene-drive is “likely equivalent to creating a new, highly invasive species.” In other words: It could be very, very bad.

“There are these natural mutations that will cause gene drive to stop working, that’s true. But the reason we’re concerned is people are already figuring out solutions to those natural mutations,” Gemmell said. “If you do that, then how do you stop it?”

Even experimenting in a contained lab could be dangerous. For example, if an engineered lab mouse escaped and that lab was in the vicinity of other mice it might breed with, the gene drive could spread accidentally. (An exception to all this, Esvelt said, might be engineering malaria-resistant mosquitoes, which most of the world might agree to even if there was a potential for the engineered mosquitoes to spread globally.)

“As it stands, there’s still a very large gap in understanding between gene drives in the lab and gene drives in the field, and of course field trials are complicated by substantial ethical and political issues,” Gabriel Zentner, a scientist at Indiana University, told Gizmodo. “The article states that ‘now is the time to be bold in our caution,’ and I tend to agree.”

None of this means anyone is giving up hope on using gene drives as a tool for conservation. It’s just that excitement over the technology got a little ahead of the technology itself.

Esvelt and other scientists are working on developing systems that could limit the spread of a gene drive. One potential solution, proposed by Esvelt, creates limits to the number of generations that inherit an engineered trait. Another being developed by a group called the Genetic Biocontrol of Invasive Rodent’s Partnership seeks to find and target genetic sequences unique to a desired population so that the gene could not spread beyond it.

The hope is that these new papers move more scientists to focus efforts on designing localized or self-limiting drives that might one day actually have real-world applications, rather than experiment with standard drives that might be too dangerous to ever deploy.

“I think some of my colleagues think we just shot them in the foot. We’re still excited about what gene drive has to offer,” Gemmell said. “But the tools we have right now are not optimal. We need something you can turn on and off or has a finite life.”

In New Zealand, the gene drive is being considered as part of a bold plan announced in 2015 by the New Zealand government to eradicate all wild predators by 2050. Gemmell is part of the team of scientists exploring the use of the technology in New Zealand, and he said the early research can still proceed as planned, alongside work to develop a safer gene drive. There is currently no concrete plan to deploy a drive. Early stage research alone is likely to take years.

But, the PLoS paper points out, if any gene drive is ever to be deployed at all, transparent conversations about gene drive technology and its potential consequences need to happen with the public now.

In New Zealand, at least, that work has already begun. Predator-Free 2050, a company funded by the New Zealand government, has begun to fund social research into gene drives. The first results were published this week, finding that 32 percent of the 8,000 New Zealanders surveyed were comfortable gene drives, while 18 percent felt they should never be used, and 50 percent were undecided.

Item 3

CURRENT CRISPR GENE DRIVE SYSTEMS ARE LIKELY TO BE HIGHLY INVASIVE IN WILD POPULATIONS

Charleston Noble, Ben Adlam, George M. Church, Kevin M. Esvelt, Martin A. Nowak
BioRxiv
doi: https://doi.org/10.1101/219022
16 Nov 2017
https://www.biorxiv.org/content/early/2017/11/16/219022

   Abstract

Abstract

Interest in developing gene drive systems to control invasive species is growing, with New Zealand reportedly considering the nascent technology as a way to locally eliminate the mammalian pests that threaten its unique flora and fauna. If gene drives successfully eradicated these invasive populations, many would rejoice, but what are the possible consequences? Here, we explore the risk of accidental spread posed by self-propagating gene drive technologies, highlight new gene drive designs that might achieve better outcomes, and explain why we need open and international discussions concerning a technology that could have global ramifications.