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Cut & Paste Conservation

Cut & Paste Conservation

By Emma Marris

Illustration by Jason Holley
We can now replace a gene in any organism for a hundred bucks a pop. We can alter wild species to save them. So should we?

It is the year 2095, and everyone is celebrating the birth of the first black rhinoceros to be born with a horn for almost 70 years. It wasn’t disease that kept the animals hornless for so long. It was an intentional modification introduced in the year 2025 using genetic engineering techniques discovered in 2012. Using these techniques, biologists were able to create genes that would delete the rhino’s horn and spread them through the entire rhino population, thus ending the killing of these endangered animals for wealthy horn collectors in China and Vietnam. Once all the old poachers had hung up their guns for good, a new gene that turned the horns back on was simply released into the population, along with a so-called “gene drive” to make sure it would spread throughout the entire population. And presto-chango, the horns were back.

This story is no pipe dream. “We could do that in a totally seamless fashion, yes, absolutely,” says Kevin Esvelt, a geneticist at the Massachusetts Institute of Technology and an expert on the new technologies. Esvelt worked in one of the two labs that nearly simultaneously discovered a newer, cheaper, and more precise way to genetically engineer plants and animals, called the CRISPR system. He went on to propose and test gene drives that would spread these engineered genes quickly throughout populations. These new tools are so cheap and effective that even those working with the paltry budgets of the average conservation project can suddenly consider using genetic engineering.

In a world where you can cut and paste any gene you want into any spot in an organism’s genome for about a hundred bucks a pop, a whole smorgasbord of possibilities are suddenly on the table. Invasive predators could be eliminated from islands by spreading sterility genes or genes that ensure that all offspring are male. Species that are threatened by disease could be altered to naturally express antibodies to those pathogens from birth. Trees threatened by fungal infections could be made to ooze fungicide from their cells. And perhaps someday, completely new species could be created that would flourish in a warmer, weirder world. But should we alter wild species to save them? Is it right?

American Chestnuts were once the grandest of all trees in Eastern North America. Then, in the first half of the 20th century, a fungus from China raced through the forest, killing virtually all of them. READ MORE Illustration by Jason Holley

These technologies won’t stay in the lab long—they are just too good to resist—so scientists, ethicists, and conservationists are scrambling to tackle the hard questions about the ethics of using advanced genetic engineering techniques. A flurry of papers, meetings, and conversa-tions has begun among the the pipette-wielders, deep-thinkers, and species-savers. Because ultimately, the question boils down to what conservation values. Is biodiversity the ultimate good, regardless of where it comes from or where it appears? Are conservationists saving individuals, species, or genes? Is “naturalness” so core to conservation that making organisms less natural to save them would also make them less valuable? The legacy of CRISPR on conservation may be as much about defining the values of the field as it is about expanding its methods.

Conservationists tend to be—well—conservative. So it is no surprise that there is a lot of skepticism about using CRISPR and gene drives in the field. Many reject the idea on its face. An open letter signed by such conservation legends as primatologist Jane Goodall and activist David Suzuki reads, “Given the obvious dangers of irretrievably releasing genocidal genes into the natural world, and the moral implications of taking such action, we call for a halt to all proposals for the use of gene drive technologies, but especially in conservation.” But Esvelt also hears from the CRISPR-curious. “Many conservationists have been saying, ‘We have been doing this for decades and it is just not working. We should at least take a look,’” he says.

The CRISPR system is based on an immune response that evolved in unicellular organisms to help them identify and destroy invading viruses. Snippets of viral DNA are stored in special spots in the organism’s genome. These spots are marked by the “Clustered Regularly Interspaced Short Palindromic Repeats” of DNA that give the technique its acronym. Enzymes are then loaded with RNA that matches those snippets of viral DNA. When the same kind of virus shows up again, the enzymes use that RNA to find the corresponding snippet in the live DNA and then mercilessly cut it out, crippling the virus.

This defensive system can be tweaked to become a kind of “cut and paste” for genes. Cas9 enzymes (short for CRISPR-associated protein 9) or similar enzymes are loaded with RNA corresponding to the sequence a researcher wants to change, and they do their thing and find the sequence and cut it out. The researcher also adds a “repair template”—the sequence of DNA that encodes the gene they want to insert. The cell’s own repair machinery will use this template as a guide, and voilà: The genome has a new gene.

This system changes one organism. If the alteration is made in just one chromosome, then when the organism mates and reproduces, there is a 50 percent chance the new gene won’t be passed on to the offspring, since each parent contributes only half its chromosomes to its children. Over time, any new gene might get swamped in the population. That’s where the gene drive comes in. If instructions to make all the parts of the CRISPR/enzyme system were added to the organisms’s genome, then it would have the ability to alter the chromosome next to it—cutting out the gene of interest and inserting the new gene. When the organism reproduces, both of its chromosomes would have the altered gene and—crucially—the machinery to edit the gene from the un-engineered parent. So the offspring would also end up with two copies of the altered gene … and so on forever. In essence, the process of genetic engineering that particular gene would be encoded into the genome such that it would become a normal cellular function.

Since the gene drive ensures that the altered gene rapidly spreads through any interbreeding population, many find the prospect of unleashing it unnerving, to say the least. And no one is proposing doing so in the wild anytime soon. “Right now with CRISPR and gene drives, we have the power to do something, but we are not good enough to understand the effects in advance,” says Esvelt. “The system is just too complex. My model is: Start small, and small means no drive system at all, see what happens in the wild, and, if you are happy with those results, scale up a bit.”

Cross That Bridge

If the thought of any genetic engineering of wild plants or animals makes you dubious, you are not alone. But the potential benefits could be enormous. Before any conservation projects get off the ground, the first applications are likely to be in the realm of human health. Indeed, the U.S. Food and Drug Administration is considering an application by a company called Oxitec to test a genetic manipulation of mosquitoes in the Florida Keys after successful trials in the Cayman Islands, Panama, Brazil, and Malaysia. The company’s transgenic male Aedes aegypti mosquitoes mate with wild females; the offspring are programmed to die before adulthood. The company claims up to 90 percent reduction in the test populations—reductions that could presumably also greatly reduce deaths and birth defects due to diseases like dengue, Zika, chikungunya, and yellow fever—diseases that kill tens of thousands of people every year. Since Aedes aegypti make up a small percentage of the diet of their predators—there are lots of kinds of mosquitoes and most predators eat other insects, too—the effect on the ecosystem is predicted to be minimal.

The first conservation applications may well be similar: helping wild animals and plants fight off diseases that threaten them with extinction, from bats battling white-nose fungus to black-footed ferrets perishing of plague.

These potential benefits to humans are part of the reason why Margaret McLean, who serves as director of bioethics and associate director overall at the Markkula Center for Applied Ethics at Santa Clara University, feels the technology should be explored—carefully. Many who have opposed the use of genetic engineering have cited the “precautionary principle,” the idea that actions have to be shown to be largely harmless before they are undertaken, and that the burden of proof is on those wanting to take the potentially harmful action. This ap-proach can lead to paralysis, McLean says. “It is a bit akin to my mother’s admonition when I was learning to drive: You cannot drive across the Golden Gate Bridge until you have driven across the Golden Gate Bridge.”

Instead, McLean likes the concept of “prudent vigilance,” derived from the first report of the Presidential Commission for the Study of Bioethical Issues. For her, this means “acknowledging we don’t know everything we need to know, but we need to move ahead while paying a lot of attention to unintended risks of the path we have chosen.”

The Birds and the Trees

Ronald Sandler, a philosopher at Northeastern University in Boston who has written a book on the ethics of emerging technologies, believes genetic engineering for conservation should be judged “on a case-by-case basis.” Where the genetic techniques are clearly effective, and where they are remediating the primary threat to the species, he thinks they should perhaps be judged acceptable. “The model really is that you are undoing the primary, immediate, human-introduced threat.”

Esvelt agrees, and his favorite example is the case of Rapid ‘Ohi‘a Death, a fungal infection attacking one of the most common native trees in Hawaii. ‘Ohi‘a (Metrosideros polymorpha) are small trees with stiff leaves in geometric rosettes and an exuberant red pom-pom flower. They form the backbone of many Hawaiian ecosystems. Using bacteria as a messenger for the enzymes, RNA guide, and DNA template, the sapwood cells of these iconic trees could be altered to secrete a fungicide that could save whole ecosystems. The modification would not be inherited by the tree’s offspring, so it would be akin to a vaccine. “I think we should do it,” says Esvelt. “Yes, it is unnatural, but the fungus that is killing it is also unnatural. It is our responsibility.”

The company Oxitec has bred its transgenic male mosquitoes with wild females. Offspring are programmed to die before adulthood. Could this reduce deaths and birth defects from disease with minimal impact to the ecosystem? Illustration by Jason Holley

If the intervention works, ‘ohi‘a will presumably also be resistant to other fungi, so the trees may survive in even higher numbers than normal. And this might have effects on the insect species that eat their leaves and even the predators of those insects, like the endangered ‘akeke‘e bird (Loxops caeruleirostris)—of which fewer than 1,000 remain.

Predicting what effects a changed organism may have in complex ecosystems is arguably more challenging than making the genetic changes in the first place, according to Owain Edwards, who leads a research team on environmental biotechnology and genomics at Australia’s Commonwealth Scientific and Industrial Research Organisation (CSIRO). “We have learned from past mistakes to try to predict what could go wrong, but it’s equally hard to predict what happens if it goes right,” Edwards says. “The technology itself is not nearly so much an investment. Most of the investment is going to be in making sure it is going to be a safe and smart thing to do.”

Even a scientifically solid risk assessment may not be enough to convince everybody. Despite a long history—genetically modified organisms (GMOs) have been on our plates since the 1990s—the technology still seems frightening and unproven to many. It is fair to say that opposition to GMOs is fierce and even trendy in certain circles. And this opinion very well might automatically be transferred to any conservation projects employing gene modification. “I think the scientists in conservation could well be as surprised as the scientists in crop breeding were by the backlash,” says Bill Adams, a geographer at University of Cambridge who has written about this issue.

“Those of us who think these technologies have important potential for conservation need to learn from what happened with GMOs and try to avoid those mistakes,” says Kent Redford, a conservation veteran who has been investigating the options presented by high-tech biological tools for the past four years. “We don’t have a chance in conservation in using any of these technologies unless we are really smart about how to talk to people about the potential.”

A scan through the public comments filed to the FDA during the permitting process for the Oxitec mosquito make this very clear. Although many people wrote in to support the experiment, there were also dozens of comments like this one from Richard Pecha: “Is it not bad enough that we are consuming GMO’s...??? NOW you want to release Frankenstein blood suckers into the environment. May God forgive you for wanting to tamper with creation....May you and yours to be the first to be a host for such a monster!” Or this one from Helene Atkins: “Messing with Mother Nature and the Eco system has proven disastrous in the past and we MUST NOT allow this!!!” But for some, the reasons for supporting are clear, as Brian James wrote: “When I compare mosquito elimination to the alternatives of fogging my family, this is a slam dunk. A perfect solution to an otherwise vexing situation.”

Toxic Toads

While the early uses of CRISPR in conservation may be to heal or prevent disease, another promising application is to use the technology to kill—to eradicate non-native species that are threatening native species. Worldwide, more than 700 species are threatened or already extinct thanks at least in part to exotic mammal predators. CRISPR alterations could make these predators infertile. It could be a more humane way to remove them than the current arsenal of traps, guns, and poisons used in such projects. “There simply aren’t any more generations,” geneticist Kevin Esvelt says.

Exotic cane toads were brought to Australia intentionally to control other pests. But their toxic skin makes them a menace to native fauna. What if we used CRISPR to remove the toxin from these Aussie imports? Illustration by Jason Holley

And in Australia, the exotic cane toad—a huge, lumbering brown toad with a slightly menacing expression— poses a threat to native animals that try to eat the toad, then perish from its toxic skin. The toad is threatening such endangered and adorable creatures as the pointy-nosed Northern spotted quoll, a carnivorous marsupial. “What if we could build a drive system that could knock out the toxin?” asks Esvelt. “You are removing their unfair advantage. It is a neat idea.” It is a neat idea, but also a fraught one. If altered cane toads made it back to their native range in South America, the gene drive could remove the toxin there, too, and make the toad vulnerable to extinction itself. “You are going to have to talk to all the South American nations and get their permission,” says Esvelt. “You have to assume that there is some human troll that is going to deliberately move them.” Esvelt also recommends readying a countervailing gene drive that could override or block the first. Toads with this genetic machinery would have to be kept in captivity, ready for instant release if the gene drive makes the hop across the ocean. It sounds elaborate, but Esvelt thinks it might come to pass. “Australians really hate cane toads. They would pay for the monitoring system,” he says.

Interestingly, cane toads were brought to Australia intentionally. They were brought from Hawaii in 1935 to control two sugar cane pests: French’s cane beetle and the greyback cane beetle. No one predicted they would become a menace. But they have, and so they also stand today as an allegory of the hubris of intervening in ecological systems when the consequences may be impossible to predict. Could introducing a gene to stop the cane toad also have unforeseen negative consequences?

Beyond this kind of project lie even more extreme possibilities—from temporarily removing the rhino’s horn to making species more resistant to heat and drought as the climate changes. Some have even proposed “cognitively enhancing” Australian species at risk due to predation from non-native cats and foxes—making them smarter, so they could outwit their evolutionarily new predators.

But Bill Adams, the Cambridge geographer, isn’t so sanguine that scientists would always use the new technologies in the most careful and enlightened ways for the good of all. A self-confessed cynic where this is concerned, he says, “I look at high-tech centralized development with suspicion. I tend to assume that they will be myopic and self-interested and bought out.”

Au Naturel

These kinds of projects begin to fundamentally alter the very species we are trying to save. And this prospect opens up a very large question: What do we mean when we say we want to save the planet? What are we trying to save? Individuals? Species? Genes? Does it matter if you have to alter 5 percent of a species’ genome to keep it around?

Or, as Adams asks: “Is what you are really seeing a leaky bag of genes floating around in the landscape? Or do we want to save the organism we can see and name and the cultural values of it?” In fact, we’ve been altering wild species for thousands of years.

“Even just by putting selective forces on species, we are changing their genetics: by changing their habitat, warming the planet, using pesticides,” says Michelle Marvier ’90, a professor of environmental studies and sciences at Santa Clara. “We are just doing it in a really mindless way.”

Are changes that we make directly, with intention, morally different?

Marvier points out that naturalness—in the sense of being unaltered by humans—is an unspoken value in conservation, along with the more visible values, like diversity and evolution.

And this may be why tinkering with species feels wrong—or at least like a compromise—to many. And it may explain why an even further-out idea—making completely new species on purpose—doesn’t seem like conservation, even though it would increase biodiversity.

“It is going to be a big challenge to the foundational principles of the field,” surmises Marvier.

“Naturally-evolved biodiversity” is the real goal of conservation, according to Ronald Sandler. “It is not biodiversity as such—the value of biodiversity has historically been tied to the source of the diversity.”

Sandler has argued that there is a difference between saving a species “as it is” and altering endangered species. Changing a wild species not only potentially lowers its value by lowering its naturalness, but also opens up a whole new kind of interaction between humans and wild species that needs to be more thoroughly ethically explored. “We start changing intelligences or engineering coral populations to make them resistant to higher temperatures, then we are on the avenue to substantially changing the natural world,” Sandler says. “There is potentially a qualitatively different way of thinking about our relationship with ecological systems. I am not making a value judgement on that right now.”

Esvelt doesn’t rule out the idea of creating new organisms—if not now, then someday far in the future. “Should we make new species to atone for the sixth great mass extinction? It is an open question,” he says. Some of these new species could even be designed for other planets. Meanwhile, Margaret McLean pleads for a bit of pragmatism. “I think we ought to think carefully about genetic engineering and the opportunities it gives us but not let this shiny object draw our attention from some common sense approaches that are available now: mitigate against climate change, protect environments, look at pesticide use, look at the trade-offs that go into the cup of coffee we have in the morning.” The discussions around genetic engineering for conservation are just getting started. They may help conservation define itself for the 21st century. They are questions with long-term consequences, which ask us to peer into an uncertain future and make ethical choices for ourselves, for other species, and for generations yet unborn.

Who’s to say that when the time comes to replace the rhino’s horn that a majority of Earth’s people won’t prefer a sterling silver or glow-in-the-dark horn? The values of future generations aren’t easy to predict.

As these conversations continue, “I would hope that ethicists have a place at the table,” says McLean. “I think that the stakes are of immense proportions and the more multidisciplinary these conversations are, the better the outcome of the conversation.”

Emma Marris is a freelance environmental writer. She lives in Klamath Falls, Oregon.

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