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.”