Adrian Malloch Science & Environment Life hackers Gene editing is now being used in research around New Zealand, usually to ‘switch off’ genes one by one in order to figure out what they do. Overseas, this technology has started to emerge from the lab—it has the potential to help eradicate pests, save threatened species, even cure diseases—and soon, we’ll have to decide whether gene editing should be permitted more widely in New Zealand. What are the risks? What could we use it for? And how should we decide?

Written by Kate Evans Photographed by Adrian Malloch

Each tomato plant sits in a transparent plastic pottle, its roots in agar, its uppermost leaves pressing against the lid. In a few weeks, the plants will be moved into a greenhouse, but for now, they line the shelves of a small, windowless tissue-culture room in Plant & Food Research’s Palmerston North laboratory.

The plants look like ordinary tomato seedlings, but in some, marked with a pink cross, a tiny genetic change has occurred. Zoom into a single tomato cell and there are its chromosomes, long threads of genes tightly wound together. Zoom in again and each gene is made up of a unique series of nucleotide base pairs. Every feature of each tomato plant is coded in sequences of just two base pairs: adenine-thymine (A-T) and guanine-cytosine (G-C). There are about 900 million base pairs in the tomato genome, forming around 30,000 genes.

In some of these seedlings, a couple of base pairs have been deleted, enough to disable two genes that might be responsible for fruit softening.

The alteration is minute, the implications enormous. These tomato seedlings represent one of the first uses in New Zealand of a new technology for editing genes called CRISPR. Those six letters stand for a mouthful—Clustered Regularly Interspaced Short Palindromic Repeats. The name is a relic from the 1980s, when scientists discovered mysterious repeated sequences of base pairs inside the DNA of bacteria.

It turned out that these sequences were part of the bacteria’s immune system—a kind of search-and-destroy function. When certain bacteria are attacked by a virus, they steal a short piece of the intruder’s DNA and store it within their own genome, marking it with CRISPR—these repeated sections of base pairs.

If the virus attacks again, the bacteria send out a protein called Cas9, loaded up with an RNA copy of the virus DNA. Cas9 acts like a tiny pair of scissors, while the RNA sequence tells it exactly where to cut. When Cas9 encounters a sequence of DNA in the virus that matches its RNA guide, it snips that sequence out, destroying the virus.

In 2012, several teams of scientists showed it was possible to attach any sequence of RNA to Cas9 and the protein would cut a genome at that precise spot—transforming the CRISPR system from a biological curiosity into a powerful editing tool.

“All you need to do is change this short sequence of about 20 nucleotides and you can deliver the ‘scissors’ to wherever you want,” says Peter Fineran from the University of Otago, a CRISPR specialist. “The big hype and potential now is taking what people have learned about the biology and applying it as a technology.”

Other methods of gene editing existed, but CRISPR and Cas9 have made it faster, cheaper, and much more precise.

It’s now possible to make highly targeted changes to DNA, disabling a gene or inserting one into a specific place. (Gene editing differs from what is known as ‘genetic modification’ in its high level of precision, and because gene editing frequently involves making alterations within the DNA of one species, rather than inserting genes from another.)

Gene editing has the potential to improve lab research, create new crop varieties, eradicate pests, wipe out pathogens, manage threatened species, and bring extinct ones back from the dead.

That’s the idea, anyway. The reality is we haven’t done much of this yet—and we’re still in the middle of asking ourselves if we should. New Zealand could be at the forefront of gene editing, or take a principled stance against it.

We have a history of opposition to genetic modification, and some of the strictest laws in the world controlling the use of genetic technologies—in New Zealand, all research involving CRISPR is carried out under a permit and in strict confinement.

But we also have a record of doing radical things for the sake of conservation—and gene editing could help us tackle some of our greatest environmental problems.

What are the opportunities and the risks of gene editing? Is it all or nothing? Could we approve some uses and not others? And, most importantly, how do we decide?

[Chapter Break]

“With molecular biology you’re dealing with tiny volumes of things you can’t see,” says Nick Albert, a scientist at Plant & Food. He sits at a long bench crowded with pipettes, glass bottles of clear liquid, sterile gloves, PCR machines, ring-binders, spray bottles, a large inflatable dinosaur, and a polystyrene box with ‘Nick’s, not yours’ scrawled on it in Vivid.

Albert isn’t in charge of the tomatoes. Rather, his work involves the least controversial application of gene editing—making lab research easier. He’s been switching plant genes off in order to answer the question: What enabled the first plants to survive on land, 470 million years ago?

Albert is an expert in Marchantia, a family of primitive liverworts, the closest living relatives of the first terrestrial plants. He’s investigating a set of compounds called flavonoids, which all plants make. He suspects these evolved as a sort of sunscreen to protect plants from harsh UV rays, thus allowing them to emerge from the ocean.

Using CRISPR, Albert can knock out Marchantia genes one by one, enabling him to figure out exactly what each gene does.

To do that, Albert needs Cas9, as well as the RNA sequence that acts like GPS coordinates, directing the protein where to cut. Already it’s as simple as buying them online. He uses a computer program to create an RNA sequence to match the gene he’s targeting, clicks ‘Buy’, and receives a tube in the mail.

That’s the easy part. The next step is to get the RNA and Cas9 through the plant’s tough cell wall. To do this, he loads the Cas9 and RNA sequence into bacteria, then grows the bacteria and Marchantia together in a culture. The bacteria transfer the instructions for making Cas9 and the RNA sequence into the plant, so that it performs the edit Albert wants inside its own cells.

If it works, the plant will make the Cas9 scissors and the guide RNA all by itself. The protein will search for the target sequence and snip the genome. Then, if the plant doesn’t make a perfect repair, that gene will switch off.

It doesn’t always work. But it works enough of the time that Albert has succeeded in growing Marchantia that can’t make flavonoids, meaning he’s found the gene responsible for producing them. That suggests the answer to his question is yes—these compounds evolved to help plants adapt to life on land.

Gene editing is being used around the world for this purpose: to identify the functions of specific genes, in projects that will never leave the lab.

“It’s just been the most incredible research tool,” says Albert. “It still is time-consuming, but it absolutely changed the way I could do this, and made the answers much more clear-cut.”

Meanwhile, other scientists are working on applications that may, one day, appear more widely.

Plant & Food scientist David Brummell is an expert on fruit softening and has spent the past year trialling the use of gene editing in tomatoes. Not that he’s especially interested in tomatoes. They’re what’s known as a ‘model crop’: they’re easy to manipulate in the lab, and produce fruit after only a few months—unlike, say, an apple tree.

“The rate fruit soften at determines their storage life—so if you’re trying to ship stuff by sea, an extra week can make all the difference,” says Brummell. “You can reach new markets or it can give you the opportunity to change from air freight to sea freight. You don’t want to knock the gene entirely out, though, because you want your fruit to have an appealing texture when you eat it. So we’re knocking out a couple of genes, which may or may not have a dramatic effect—but we won’t really know until it fruits.”

Brummell’s team used CRISPR to target two potential fruit-softening genes, and they think it worked in six of about 30 plants that survived the tissue culture process.

In summer, they’ll have their first fruit, although Brummell may need to breed another generation before the changes are expressed. (Tomatoes, like humans, have two sets of chromosomes—two copies of each gene.)

“We expect them to soften more slowly, and have a different, less-melting texture,” he says.

This experiment is just a proof-of-concept. Brummell’s primary goal is to figure out how to use the CRISPR system.

“We need to understand the technology, know how to use it, and be ready if industry and consumers decide they want this in New Zealand,” he says. “We don’t want to be starting from nothing.”

When it comes to developing new plant varieties, gene editing offers huge advantages: it’s a faster, more precise way of carrying out work that’s already taking place.

Currently, many new cultivars are developed using ‘mutation breeding’, where plants are exposed to chemicals or radiation in order to cause random mutations. Then there’s a long wait for the plants to mature, to see if any useful traits have been produced. Researchers might grow 10,000 plants to find one with the mutation they need.

“If you wanted a new apple or potato variety, you’d need to put 20 years aside for breeding with the old methods,” says Brummell. “With this, we potentially could have something within a year.”

Mutation breeding doesn’t require a permit in New Zealand, but using CRISPR to make a single, deliberate mutation does.

Those regulations need updating, says Brummell. When most people imagine a genetically modified organism (GMO), what comes to mind is something ‘transgenic’—where genes from one species have been inserted into another. But Brummell isn’t producing transgenic tomatoes.

“There is no foreign DNA in the final plant: there is nothing in the plant that couldn’t have happened by nature or plant breeding,” he says.

If Brummell’s experiment works on tomatoes, it could inform work in other crops. Further afield, gene editing could prove a weapon against plant diseases such as rusts or blights—a gene that made plants susceptible to these pathogens could be switched off, for instance, or a gene shown to increase resistance in one tree could be introduced to others.

[Chapter Break]

Regulations around the world are struggling to keep up with gene-editing advances. Many countries, including China, have guidelines but not enforceable laws; in the United States, simple edits that don’t introduce foreign DNA are not considered GMOs, and are not regulated; Canada bases its rules on the potential impact of the new trait, not how it was made, and the European Union is still debating. One thing is certain: developments overseas will force us to make a decision about the use of gene editing sooner rather than later.

“The last thing we want is for the public to feel this is being thrust upon them,” says Albert. “But we actually don’t have very long. Overseas, work is well under way using CRISPR in plants. At some point, a new cultivar will be released that people here might want—maybe black-spot resistant roses or drought resistant pastures.”

It may be that there’s a market advantage for New Zealand to retain its GMO-free identity, even—or perhaps especially—if other countries embrace gene editing in food production.

However, even with strong import regulations, it will be tough to keep gene-edited products out of New Zealand. We would have to rely on other countries to label or declare whether the technology has been used, and there likely won’t be any way to check.

“The thing with CRISPR is if you’ve just changed a single base or two, it’s incredibly difficult to prove that it’s been made by that method,” says Albert. “So fruits and vegetables could be brought into this country which are superior to ours and we’d have no idea whether it was done by regular breeding or using these new technologies.”

[Chapter Break]

Albert and Brummell may be changing only one or two base pairs, causing a tiny mutation which could have occurred naturally—but disrupting the function of a couple of genes is just the beginning of CRISPR’s power.

It’s also possible to use Cas9 to introduce an additional piece of DNA to a cell. When the sequence is cut, the cell repairs the gene using template DNA provided alongside the protein. This opens up all kinds of opportunities: not just deletion, but insertion, or wholesale cutting-and-pasting.

At perhaps the opposite extreme from ‘changing one base pair to make a tomato firmer’ lies ‘bringing an extinct animal back to life’.

Until recently, the notion of bringing back the mammoth, the moa or the dinosaurs was more fantasy than fact. No longer.

Numerous technical, ethical and ecological challenges remain (and forget about dinosaurs—DNA degrades over time, and they’ve been gone too long). But in theory it’s possible to repeatedly edit the genome of an existing species until it resembles that of a recently extinct relative.

Experiments are already under way. At Harvard Medical School, George Church is working on resurrecting the woolly mammoth—or rather, creating a mammoth-like elephant that could reprise the giant herbivore’s critical role in the ecosystem of the Arctic steppe-tundra.

Since 2015, Church’s team has been identifying genes that helped mammoths survive on the steppes—the base pairs that result in long, shaggy hair, or specialised haemoglobin molecules that efficiently transport oxygen at low temperatures—and splicing them into Asian elephant cells using CRISPR. So far, they’ve made 45 mammoth-type changes to the elephant genome, a small fraction of the differences that likely exist between the two species. We haven’t yet sequenced the complete Asian elephant genome, let alone the mammoth one, which needs to be reconstructed from degraded fragments of DNA taken from bones and tusks preserved in the tundra.

[sidebar-1]

Nevertheless, in February 2017, Church said his team was just two years away from creating a hybrid elephant-mammoth embryo. This would involve cloning via ‘nuclear transfer’—taking an elephant egg, removing the nucleus, and inserting an edited nucleus containing mammoth-like DNA. This process is fraught with problems, and is only the first hurdle. The team would then need to incubate it, either in an Asian elephant—raising all kinds of ethical questions—or an artificial womb, which has not yet been invented.

The obstacles are legion, but progress in this field is rapid. There may well come a point—even within the next decade—where de-extinction is technically possible. But presuming we can—should we? Is this something we ought to consider for some of New Zealand’s lost species? It’s a beguiling idea, but moa are likely to be even more difficult than mammoths. The moa genome is far from complete; DNA recovered from moa bones has been degrading for more than 500 years.

The moa’s closest living relative is the turkey-sized South American tinamou (a curious creature in its own right, laying the world’s only known iridescent egg), but the two species diverged 50 million years ago, meaning the tinamou wouldn’t be much help as a guide genome or surrogate mother.

Moreover, there’s a big difference between resurrecting a species in captivity, as a curio, and releasing it into the wild. How would that work?

That’s the question we should be asking first, says conservation biologist Philip Seddon from the University of Otago, an expert in species reintroduction.

“All the proponents of de-extinction are like, ‘And, step seven, release your mammoth!’ It’s a really complicated process, even with species that have only been missing from an area for a decade.”

One of his biggest concerns is the impact de-extinction could have on current conservation funding. Even if the ‘wow’ factor of de-extinction attracted new sponsors to the cause, he says, problems would start once the animals were released into the wild.

“As soon as you release it, you’re saying, ‘Okay, Department of Conservation, here’s a new species for you to manage’. And what do they stop doing in the meantime to do that?”

University of Canterbury philosopher Douglas Campbell has also been pondering the ethics of de-extinction. After examining the arguments for and against, he’s quite enthusiastic about the idea.

“By far the strongest argument for de-extinction is that it’s business as usual for conservation. What is conservation’s ordinary goal? To protect and restore biodiversity. So, all things being equal, and supposing that we can, we should be trying to bring them back.”

Things aren’t equal, of course—and the strongest argument against de-extinction, he says, is that it would come at the expense of saving species that aren’t extinct yet.

“That’s a really good reason for what I’m calling the ‘freeze now and resurrect later’ strategy.”

Campbell advocates waiting a decade or five until gene editing and associated technologies mature, become cheaper, and have been thoroughly tested. After all, the moa and the huia won’t be any more extinct by then.

“In the short term, people are right to dismiss it. But conservation is about long-term thinking—not 10 years, but 100 years, the time spans at which forests grow. It’s on that kind of timescale we should be looking at de-extinction. It’s not just a silly fad.

“This was all science fiction as recently as the early 1990s—but it’s not science fiction any more. It’s all about to get really important.”

There is one thing that we can do now to keep the options open for our grandchildren, says Campbell. We should be cryogenically freezing and storing as much genetic material as possible from threatened species, and from museum specimens of extinct ones.

“The Holocene extinction is under way now, and gathering steam, and there are going to be so many species we won’t be able to save. If we can’t save them, they should be going in the freezer—that white box in the corner of the lab. That’s where we should be chucking everything we can get our hands on.”

“Because otherwise people in the future will look back on us as just being complete idiots—much as we look back at the Victorians and think, ‘They could have easily saved the huia’.”

The freezer strategy could also come in handy for species with low genetic diversity, such as the little spotted kiwi, all 1700 of which are descended from just three birds, and the kākāpō.

Conservation geneticist Helen Taylor from the University of Otago specialises in what happens to the genomes of populations when they get very small, and it’s generally not great: infertility, malformed embryos, trouble hatching.

Gene editing could be a possible solution to this problem, she says. “Museum collections are a really important resource. You could sequence the genome of a bunch of museum kākāpō and ask, ‘Which genetic variants have we lost?’ Then you could splice that back into the kākāpō genome to restore some of that lost diversity.”

This ‘genetic rescue’ is much less problematic for ecosystems, compared with bringing extinct species back to life, says Seddon.

“I think the best application of so-called de-extinction technology is probably for things that haven’t quite gone extinct yet,” he says.

But de-extinction, or even genetic rescue, shouldn’t be our first priority when it comes to the conservation estate. There’s no point in bringing back a lost taonga at great expense only for it to become rat bait. We need to sort out our pest problem first.

And gene editing may be able to help with that, too.

[Chapter Break]

It’s 2040, and DOC is releasing hundreds of female rats on Stewart Island. They’ve all been gene-edited to switch off a gene for male fertility on one of their chromosomes.

Because the gene is recessive, and affects only males, these females are able to breed with local male rats. And because their genomes also contain a ‘gene drive’, all their offspring inherit the edited gene. Their male babies will be infertile; their female babies will pass the gene onto their offspring.

Over a few generations, infertility spreads through the island’s rat population, affecting almost all males. The population crashes. Soon, rats are eradicated from the entire island. No toxins, no traps. Not even any killing.

Gene drives—genetic elements that are more likely to be inherited than a typical gene—occur in many species, and for decades researchers have been trying to find ways to take advantage of them. Now, CRISPR allows a gene-drive system to be inserted into any sexually reproducing species.

Gene drives modify an organism to create the Cas9 protein and RNA template itself, so that it constantly edits its own cells. (In this instance, the RNA sequence would guide Cas9 to a gene necessary for fertility, in order to disable it.)

“It’s a way of distorting the normal rules of probability,” says geneticist Neil Gemmell from the University of Otago. He’s investigating the possibility of using gene drives to help achieve the Predator Free 2050 goal. “When individuals normally have sex, there’s a 50/50 chance of them passing on a particular variant to their offspring. With gene drives, those probabilities alter dramatically, so effectively it’s like playing with a double-headed coin.

“You’re pushing the change through the population rather than letting random probability dictate what’s going to happen.”

That’s the brilliance—and the frightening power—of gene drives. They could be used to alter mosquitos so they no longer spread malaria, dengue, or Zika; to programme pests to leave crops alone, reducing the need for pesticides; or, in New Zealand, to wipe out introduced wasps, rats, stoats and possums.

“It’s happening very fast,” says Gemmell. “I would suspect that in three to five years we will have a genetically engineered ‘gene-drive’ rodent that could at least in theory be used for population control.”

In doing so, what kind of genie would we let out of the bottle?

“One of my concerns initially was, ‘How do you turn this off—how do you limit its spread?’” says Gemmell. “If I can make something that can affect everything, then that’s a plague.”

This prospect has caused considerable alarm. Conservation luminaries Jane Goodall and David Suzuki, who have both campaigned against genetic modification, last year joined a call to ban the use of what they labelled ‘genocidal genes’ in conservation.

But is there such a thing as a ‘safe’ gene drive? One of the scientists involved in inventing the technique thinks so—now, Kevin Esvelt has committed himself to figuring out how to keep gene drives under control.In 2014, just a couple of years after completing his PhD, Esvelt led a team from George Church’s Harvard lab which showed how CRISPR could be used to make gene drives. It was a eureka moment, he says, followed by a terrifying come-down.

“I personally hold myself morally responsible for all the consequences of CRISPR-based gene drives,” he tells me over Skype. “Because I was the one to think of it—and I was the one foolish enough to tell the world that it was possible.

“In an attempt to live up to that, I’m trying to ensure that all potential applications of the technology are developed in an appropriately wise and humble fashion—and historically we don’t have such a good record of doing that.”

Using the “full-power” version of gene drives for conservation probably isn’t wise, he says.

“If it works anywhere near as well as we think and hope, then it’s too effective to be used at all for conservation.”

That’s because it would take only a couple of edited escapees to start spreading the gene drive through a new population. Models suggest that eradicating a species from an area could take up to two years—plenty of time for mistakes to happen.

“If we’re talking rodents, they’re obviously great at stowing away,” says Esvelt.

The prospect of an edited possum making it back to Australia would cause tensions in the trans-Tasman relationship, and even if we tested the technology on rats on a small offshore island, it’s impossible to rule out people popping one in their pocket if they thought it would give them an economic advantage: “The idea that they wouldn’t be deliberately moved around seems positively farcical to me.”

Esvelt is primarily concerned about losing the trust of the public. Gene drives could result in tremendous positive change—as long as foolish uses of the technology don’t turn people against them.

“If someone screws this up with rodents, and it gets spread around the world illegally, my suspicion is it would make it a lot harder for African nations to agree that they want to use it against malaria. And since malaria killed 429,000 people last year and infected over 200 million, that’s not something that I really want on my shoulders.”

There are a number of ways to rein in the power of gene drives, he says. One would be to make them very specific, such as by affecting a gene that’s only present in the target population.

That’ll work only in some circumstances, says Esvelt—there may not always be a suitable gene, or it may not be unique enough to prevent the gene drive spreading to other populations.

Instead, Esvelt is working on an idea he calls a ‘daisy drive’—a gene drive with a time limit. Daisy drives run out and stop after a certain number of generations. They’re made up of a string of elements, connected like a daisy chain. The components of the drive are scattered around the organism’s genome, and each element drives the next, in a linear formation, like the launch of a multi-stage rocket.

Natural selection ensures the daisy-drive components are progressively lost, meaning the drive eventually runs out of ‘fuel’ and disappears.

Esvelt also has an idea for reversing gene drives and restoring original traits to a given population in case of emergency.

[sidebar-2]

None of this has been shown to work. But Esvelt’s team at the Massachusetts Institute of Technology is currently testing the daisy-drive concept on billions of microscopic nematode worms. These are easily grown in containment, and evolve rapidly—100 generations a year—meaning researchers can test how one of these drives might play out in a population over time, and check for unintended genetic consequences.

Esvelt’s team plans to introduce a daisy drive that will make the worms fluorescent but stop after converting 20 per cent of them.

“If anything goes wrong and it keeps on spreading, then it will be very readily detectable because all the worms will start glowing green,” says Esvelt.

If it does work, Esvelt thinks New Zealand should consider using daisy drives in order to reach the goal of Predator Free 2050. He’s motivated partly out of concern for animal welfare—he used to work in an animal shelter—and this technology could reduce the use of poisons and traps.

“If there is a way to help ecosystems without causing rather excruciating agony to a lot of complex mammals, that would be great.”

[Chapter Break]

But would it be worth it? What if the entire idea of messing around with genomes just isn’t right?

In 1968, counter-culture writer Stewart Brand—now a leading proponent of de-extinction—began his book Whole Earth Catalog with the line: “We are as gods and might as well get good at it.”

Humans have already changed the world irrevocably. We’ve moved animal and plant species between continents, and driven others to extinction. We’re filling the atmosphere with greenhouse gases and the oceans with plastic. And since we began domesticating wolves and wheat, we’ve changed the course of evolution, using breeding to alter the genes of species we find useful. Perhaps gene editing is just the latest tool in our management of the Earth.

The idea of playing god, though, doesn’t sit well with many.

Josephine Johnston is an ethicist from Dunedin who has looked closely at this idea. She heads research at the Hastings Center, a bioethics think tank near New York—and though she’s lived in America a long time, she hasn’t lost a vowel of her Kiwi accent.

Concerns about playing god fall into two categories, she says. The first is the idea of hubris—that we are overstepping the bounds of what we understand, risking consequences that we can’t foresee.

“We have a history of thinking we understand things way better than we do. After all, some of those pests ended up in New Zealand because people thought it would be a good idea to introduce them in the first place.”

The second concern involves the feeling that there ought to be limits on how much we alter the world around us: “That it isn’t our job to be constantly trying to change everything, especially permanently. A sense of, ‘How far are we going to take this Master of the Universe thing’?”

Yet these are reasons to proceed with caution, not reject gene editing outright, says Johnston. Like knives, or electricity, or nuclear technology, CRISPR is a tool that can be used for good or ill.

“Some of its uses could be appalling, and then there will be some that will sound really appealing. It’s not going to be all bad or all good, it’s going to be a lot more complicated than that.

“That’s bad news in some ways, because it would be a lot easier if there was a straightforward answer. The hard work now is that we will actually have to think about the particulars of the different possibilities.”

And ‘we’ means ‘all of us’. A number of studies are gauging public opinion about gene editing, especially for eradicating pests. A National Science Challenge project is currently surveying 8000 New Zealanders about their attitudes towards novel pest-control techniques, including gene drives. It’s a world first, says project leader Edy MacDonald from the Department of Conservation.

“People’s values drive their decision-making, not facts and information. So if people don’t feel comfortable with these technologies, we’re interested to find out why.

“Are they against anything artificial, and wouldn’t want to touch it with a 10-foot pole? Or do they care that it’s not applying toxin, and allows animals to live out their natural lives?”

The first stage of the study will be finished by the end of the year.

“It will be more exciting than Christmas for me, the day we get the results back,” says MacDonald. “No one has done this before, and we actually have no idea what the nation is going to think about it.”

A much smaller study by the University of Otago may offer some clues. Helen Taylor asked conservation workers about using gene editing, and 41 per cent said they would rather see a native species go extinct than use gene editing to save it—but 85 per cent were in favour of using gene editing to eradicate pests. That suggests people do make a distinction between different applications, even if the risks are roughly the same.

“There’s definitely a value judgement there for people, an emotional connection to their species, and their response to meddling with that is far different than for stoats and possums,” says Taylor. “You can’t grow a kiwi in the lab—this is the kind of thing that has to be road-tested on invasive species before anyone is even remotely comfortable with introducing it into native species.”

What people think matters. Public acceptance is crucial for the use of these technologies outside the lab, and the social hurdles may turn out to be higher than the technical ones.

“If we do not have societal buy-in for using these things, then why would we spend five or six years of our life developing something that ultimately no one has the appetite to use?” says Neil Gemmell. “I’d rather have an open, ongoing conversation about what we know—and then ask the question, ‘Do we want to pursue this?’”

[sidebar-3]

Scientists have a moral imperative not only to inform the public what they’re doing, but to consult them—especially when it comes to gene drives, says Kevin Esvelt.

“If you deliberately develop an application intended to alter a shared ecosystem behind closed doors, then you are inherently denying people a voice in decisions that will affect them. So what we’re trying to do is invite communities to take a look at the different options available before we do anything at all in the lab.”

Esvelt has been putting this idea into practice on the islands of Nantucket and Martha’s Vineyard on the east coast of the United States. Through public meetings and working groups, he’s speaking with locals about using gene drives to eradicate Lyme disease, which plagues the islands. To do this, he would gene-edit the mice that host the ticks spreading the disease. Now, New Zealand is part of Esvelt’s constituency, too.

“Nowhere else has a public commitment to completely remove invasive species. In effect, by announcing that you want to do this, you’ve announced that you are potential early adopters—and I’m very interested in developing a technology that might help to do the job.”

In September 2017, Esvelt held his first public meeting in Dunedin, and plans to return regularly—to explain what he’s working on, to ask questions, and to listen.

“A large part of going to New Zealand is asking people to help. Because I am not infallible—and people actually living in an environment might know something about how ecological interactions work there, and be able to raise things we might not have thought about.”

It’s all part of Esvelt’s master plan to change how research is done. Science rewards secrecy, but he’s advocating radical transparency.

He thinks scientists should disclose in advance what they’re planning to develop, and allow their competitors and the public to provide feedback. Esvelt’s team shares all its research proposals online—a professional risk, but one he hopes will improve oversight, safety and public support. We can’t afford for people to lose trust in science, he says.

“If you’re not sure what to do when developing a new technology, think back to what Monsanto did in developing genetically modified crops—and do the opposite.”

Many of the scientists spoken to for this story brought up the ‘Monsanto effect’—suspicions about GMOs and the motivations of large corporates—as the biggest barrier to gene editing.

There is a risk that if the development of gene-editing technology races away from our ability to understand, debate, and regulate it, it could inspire the same kind of fear. All the more reason for an open public discussion about what it could all mean—starting with a handful of tiny tomatoes.

“It is really challenging to find a language in which we can share what we’re doing,” says Nick Albert. “But the worst thing we could say is, ‘Trust us, we know what we’re doing’—that would get my back up, too.”

Talking about CRISPR isn’t easy—the biology is complex, the ethics up for debate. But we need to find a way. Gene editing is here, and it could bring great promise, or great peril—or perhaps both. It’s a heavy responsibility, and we have no choice but to confront it.

Watch this space.

Resurrecting the huia The huia would be an ideal candidate for de-extinction, says University of Canterbury philosopher Douglas Campbell. Here’s why. It hasn’t been gone long The last huia died about a century ago. One of the main reasons for the species’ demise was that they were killed in their thousands for museum collections by naturalists such as Walter Buller, who wrote of “watching this beautiful bird and marking his noble bearing… before I shot him”. There are thousands of stuffed and bottled huia in museums around the world, representing a good amount of genetic diversity, and scientists are now working on sequencing its genome. It would be relatively easy Okay, it wouldn’t be easy at all. But there are some things in the huia’s favour. Birds have much smaller genomes than mammals, meaning fewer edits would be required. The huia—one of only five species that made up the Callaeidae family of New Zealand wattlebirds—has two close living relatives, the kōkako and the saddleback, and while birds can’t be cloned (it’s to do with the way their eggs form), there’s an experimental new technique called ‘primordial germ cell transfer’. Primordial germ cells are those that later develop into sperm and egg cells—in birds, they migrate through an embryo’s bloodstream to the gonads about 24 hours after the egg is laid. Scientists might be able to grow saddleback or kōkako germ cells, edit them to resemble a huia, and inject them into a developing egg at just the right time. That wouldn’t have to be a wattlebird egg—it could be a chicken. The chick that emerged from the egg would also be a chicken, carrying inside it the sperm or eggs of the edited huia. When it bred with another such chicken and laid an egg of its own, that shell would be tapped open by the distinctive beak of a huia. They would probably cope in captivity The early stages of any de-extinction project would require captive breeding. Naturalists and Māori recorded that huia were extremely ‘confiding’—friendly and unafraid of humans. “Like fantails on steroids,” says Campbell. Māori sometimes kept huia as pets, and Buller had a pair in a cage in his room, which suggests they would thrive in an aviary setting. And conservationists have years of experience with rearing other wattlebirds. We have somewhere to put them Huia, like kōkako, weren’t capable of sustained flight, meaning they would be easy to contain on offshore island reserves, or fenced sanctuaries. And as Campbell points out, even if one did get out, “it’s hard to imagine a de-extinct huia turning into this crazed killer animal that slaughters people or eats sheep”. They were beautiful Huia were arguably the most charismatic of all New Zealand birds. That’s why they were a favourite of collectors, and why Māori prized them so dearly—their distinctive tail feathers were worn only by those of high rank, and were traded throughout Aotearoa. Yes, we’re biased towards charismatic animals—but that is a good reason to choose them, says Campbell. “They’re the ones that make the forest particularly neat for humans, and to the extent that we find the forest neat, we’re much more inclined to conserve it. “The reason people put effort into predator control in their bits of bush is the buzz they get out of seeing the bird life come back. And huia were amazing birds—the real stars of the New Zealand bush.” Kate Evans + Read sidebar

Should we CRISPR ourselves? Researchers are exploring the possibilities of editing our own genes in two settings. The Cas9 protein could be introduced into a particular body part to edit certain cells—for instance, to the eye, in order to treat macular degeneration, which has already been accomplished in mice. More controversial is what’s called ‘germline editing’—making changes to the genome of a human embryo, which would then be expressed in every cell of the body. This raises the possibility of eradicating inherited genetic diseases, particularly those caused by a mutation within a single gene, such as Huntington’s disease or muscular dystrophy. And it also gives rise to serious ethical concerns, from the fact that embryos can’t give informed consent to the prospect of ‘designer babies’. Still, scientists in China are trialling various gene-editing applications on embryos, and in August, an American team announced it had fixed a genetic defect in human embryos that can cause serious heart problems. Will this happen in New Zealand? Not for at least a decade, and probably longer, says Andrew Shelling, an expert in breast and ovarian cancer and head of the Medical Genetics Group at the University of Auckland. Rather, we’re likely to wait and see what happens in the rest of the world, he says, especially when it comes to germline editing. (All research on embryos is currently prohibited in New Zealand.) Meanwhile, medical researchers around New Zealand are using CRISPR to identify gene function in human cells and animal models. At the University of Auckland, CRISPR is helping scientists to carry out studies on cancer, diabetes, obesity, and Parkinson’s disease. As for editing diseases in a clinical setting, that’s something we’ll have to grapple with over the coming decades. Ethicist Josephine Johnston thinks we’ll end up with something more nuanced than a ban or a free-for-all. “Think about drugs—just because we allow some drugs to be used in medicine, it doesn’t mean we allow all applications of that medication. We hold them to standards of safety and efficacy, we think about how serious the condition is versus how severe the side effects are. It’s a pretty nuanced process, but we do it. I can see something just like that being considered for different types of uses of gene editing in humans.” Kate Evans + Read sidebar