Hanging next to his desk is a banner with renderings of one particular species—Aedes aegypti—in every stage of development, from egg to pupa to fully grown, enlarged to sizes that would even make fans of Jurassic Park blanch. His license plates have a single word on them: AEDES.
“I have been obsessed with mosquitoes for 30 years,” says James, a molecular geneticist at the University of California, Irvine.
There are approximately 3,500 species of mosquito, but James pays attention to just a few, each of which ranks among the deadliest creatures on Earth. They include Anopheles gambiae, which transmits the malaria parasite that kills hundreds of thousands of people each year. For much of his career, however, James has focused on Aedes. Historians believe the mosquito arrived in the New World on slave ships from Africa in the 17th century, bringing with it yellow fever, which has killed millions of people. Today the mosquito also carries dengue fever, which infects as many as 400 million people a year, as well as such increasingly threatening pathogens as chikungunya, West Nile virus, and Zika.
In a widening outbreak that began last year in Brazil, Zika appears to have caused a variety of neurological disorders, including a rare defect called microcephaly, where babies are born with abnormally small heads and underdeveloped brains.
The goal of James’s lab, and of his career, has been to find a way to manipulate mosquito genes so that the insects can no longer spread such diseases. Until recently, it has been a long, lonely, and largely theoretical road. But by combining a revolutionary new technology called CRISPR-Cas9 with a natural system known as a gene drive, theory is rapidly becoming reality.
CRISPR places an entirely new kind of power into human hands. For the first time, scientists can quickly and precisely alter, delete, and rearrange the DNA of nearly any living organism, including us. In the past three years, the technology has transformed biology. Working with animal models, researchers in laboratories around the world have already used CRISPR to correct major genetic flaws, including the mutations responsible for muscular dystrophy, cystic fibrosis, and one form of hepatitis. Recently several teams have deployed CRISPR in an attempt to eliminate HIV from the DNA of human cells. The results have been only partially successful, but many scientists remain convinced that the technology may contribute to a cure for AIDS.
In experiments, scientists have also used CRISPR to rid pigs of the viruses that prevent their organs from being transplanted into humans. Ecologists are exploring ways for the technology to help protect endangered species. Moreover, plant biologists, working with a wide variety of crops, have embarked on efforts to delete genes that attract pests. That way, by relying on biology rather than on chemicals, CRISPR could help reduce our dependence on toxic pesticides.
No scientific discovery of the past century holds more promise—or raises more troubling ethical questions. Most provocatively, if CRISPR were used to edit a human embryo’s germ line—cells that contain genetic material that can be inherited by the next generation—either to correct a genetic flaw or to enhance a desired trait, the change would then pass to that person’s children, and their children, in perpetuity. The full implications of changes that profound are difficult, if not impossible, to foresee.
“This is a remarkable technology, with many great uses. But if you are going to do anything as fateful as rewriting the germ line, you’d better be able to tell me there is a strong reason to do it,” said Eric Lander, who is director of the Broad Institute of Harvard and MIT and who served as leader of the Human Genome Project. “And you’d better be able to say that society made a choice to do this—that unless there’s broad agreement, it is not going to happen.”
“Scientists do not have standing to answer these questions,” Lander told me. “And I am not sure who does.”
CRISPR-Cas9 has two components. The first is an enzyme—Cas9—that functions as a cellular scalpel to cut DNA. (In nature, bacteria use it to sever and disarm the genetic code of invading viruses.) The other consists of an RNA guide that leads the scalpel to the precise nucleotides—the chemical letters of DNA—it has been sent to cut. (Researchers rarely include the term “Cas9” in conversation, or the inelegant terminology that CRISPR stands for: “clustered regularly interspaced short palindromic repeats.”)
The guide’s accuracy is uncanny; scientists can dispatch a synthetic replacement part to any location in a genome made of billions of nucleotides. When it reaches its destination, the Cas9 enzyme snips out the unwanted DNA sequence. To patch the break, the cell inserts the chain of nucleotides that has been delivered in the CRISPR package.
By the time the Zika outbreak in Puerto Rico comes to an end, the U.S. Centers for Disease Control and Prevention estimates that, based on patterns of other mosquito-borne illnesses, at least a quarter of the 3.5 million people in Puerto Rico may contract Zika. That means thousands of pregnant women are likely to become infected.
Currently the only truly effective response to Zika would involve bathing the island in insecticide. James and others say that editing mosquitoes with CRISPR—and using a gene drive to make those changes permanent—offers a far better approach.
Gene drives have the power to override the traditional rules of inheritance. Ordinarily the progeny of any sexually reproductive animal receives one copy of a gene from each parent. Some genes, however, are “selfish”: Evolution has bestowed on them a better than 50 percent chance of being inherited. Theoretically, scientists could combine CRISPR with a gene drive to alter the genetic code of a species by attaching a desired DNA sequence onto such a favored gene before releasing the animals to mate naturally. Together the tools could force almost any genetic trait through a population.
Last year, in a study published in the Proceedings of the National Academy of Sciences, James used CRISPR to engineer a version of Anopheles mosquitoes that makes them incapable of spreading the malaria parasite. “We added a small package of genes that allows the mosquitoes to function as they always have,” he explained. “Except for one slight change.” That change prevents the deadly parasite from being transmitted by the mosquitoes.
“I’d been laboring in obscurity for decades. Not anymore, though—the phone hasn’t stopped ringing for weeks,” James said, nodding at a sheaf of messages on his desk.
Combating the Ae. aegypti mosquito, which carries so many different pathogens, would require a slightly different approach. “What you would need to do,” he told me, “is engineer a gene drive that makes the insects sterile. It doesn’t make sense to build a mosquito resistant to Zika if it could still transmit dengue and other diseases.”
To fight off dengue, James and his colleagues have designed CRISPR packages that could simply delete a natural gene from the wild parent and replace it with a version that would confer sterility in the offspring. If enough of those mosquitoes were released to mate, in a few generations (which typically last just two or three weeks each) entire species would carry the engineered version.
James is acutely aware that releasing a mutation designed to spread quickly through a wild population could have unanticipated consequences that might not be easy to reverse. “There are certainly risks associated with releasing insects that you have edited in a lab,” he said. “But I believe the dangers of not doing it are far greater.”