Esvelt’s motto then, is “Evolution has no moral compass. We do.” At MIT, Esvelt the black sheep wants to develop technology “to continue improving human and environmental well-being” while avoiding traps that could be hazardous to our health. He quotes Charles Darwin: “Man selects for his own good, Nature for that of the being which she tends.”
Esvelt obtained his PhD at Harvard working with chemistry professor David Liu on a suitably grand idea: to fast-forward evolution in a tube to optimize the function of proteins and other biomolecules. If you don’t understand how a protein works well enough to engineer precise alterations, then generate a billion or more variants, test, pull out the ones that work the best, rinse and repeat. Directed evolution was pioneered by Frances Arnold, who won the Nobel Prize for Chemistry in 2018. But it’s a lot of work, Esvelt says, “and I’m a big fan of laziness.”
After six years, Esvelt and Liu developed a system called phage-assisted continuous evolution (PACE).V After hundreds of cycles run over a week, they typically produced the engineered variant they’re looking for.28 Esvelt next joined Church’s lab. But his early PACE experiments failed because other scientists in the lab were growing large cultures of phage, which kept infecting his cells. Esvelt turned to the CRISPR-Cas system simply as a means to fend off phage floating in the air.
In 2013, Esvelt joined Prashant Mali, Luhan Yang, and Church in publishing one of the first demonstrations of CRISPR gene editing in human cells. Next he wondered: What if you could teach the cell to do genome editing on its own so that editing could occur during each successive generation? Could there be genes that do this naturally? One possibility was a microbial homing endonuclease that cuts DNA in highly specific sequences and inserts the corresponding gene into the gap. He found Burt’s paper from 2003, in which he had tried putting I-SceI from yeast into mosquitoes, copying itself using the cell’s natural DNA repair mechanism. “Wow, this guy was a genius,” Esvelt remembers thinking. “He thought of this a decade ago!”
Indeed, Burt’s radical idea to edit mosquitoes was to harness gene drive systems that occur naturally,29 probably originating hundreds of millions of years ago. (The cow genome, for instance, is littered with genetic elements from snakes that spread via a gene drive.) Eradicating a few billion A. gambiae mosquitoes would have little to no impact on the ecology of the region, while hundreds of mosquito species that do not transmit malaria would be unaffected. It took years to perfect, but in 2011, Burt and Andrea Crisanti finally reported a successful gene drive in mosquitoes in the lab.30
Esvelt realized that CRISPR held advantages over endonucleases in constructing a gene drive to eradicate malaria. Prior to the development of CRISPR, nobody had contemplated being able to edit an entire wild species. “The concept was completely absent from science fiction at the time,” Esvelt told me. “Literally, no human ever conceived that we might be able to do this. All of a sudden, boom! It looks like we can.”
Teaming up with mosquito biologists, in 2014 Esvelt published the concept of a CRISPR-based gene drive.31 The idea went like this: encode the CRISPR system for making a mutation along with that alteration in the genome. When the mosquito mates with another insect, the offspring inherit one copy of the edited gene along with the CRISPR system that was used to generate that edit. The offspring thus inherit the machinery to cut and replace the wild-type version of the gene. This ensures that the editing is passed down, skewing the normal 50:50 mendelian ratio of inheritance.
About the same time, a group at the University of California, San Diego, led by Ethan Bier and Valentino Gantz, also developed a CRISPR-based gene drive in fruit flies. Working with Anthony James at UC Irvine, they transplanted their CRISPR system into Anopheles stephensi, responsible for a fraction of malaria cases in India.32 Meanwhile, Burt, Crisanti, Tony Nolan, and colleagues reported similar success in A. gambiae.33
But even as gene drives showed early promise in insectaries, Esvelt worried about the ethical risks of a gene drive potentially running amok and crossing over into other species, as well as the costs of doing nothing. He wrote:
As one of those who introduced CRISPR-based gene drive to the world, I hold myself morally responsible for any and all consequences that emerge from the technology. In my eyes, if something goes wrong that I might have foreseen, that’s on me. If my actions or words inadvertently prevent gene drive from benefiting others, that’s on me. If my failure to act prevents it from saving lives, that’s on me.34
The good news is that a CRISPR gene drive is relatively slow, spreading through generations, and easily detectable. “CRISPR is powerful enough that you cannot really build a gene drive that cannot be targeted with CRISPR, meaning whatever one person does, another person can override,” says Esvelt. What concerns him more is an accidental gene drive release or unauthorized use, hence the push to ensure that this research was done transparently and responsibly. “You might make a gene drive without even realizing it,” he says, which could be introduced into a wild population. A lab accident could devastate the public’s trust in science and governance, setting back gene drives the way the Gelsinger tragedy derailed gene therapy. Moreover, what sort of responsibility does the first community that approves a gene drive test have if subsequent applications go awry?35
Burt leads Target Malaria, a project funded by the Bill and Melinda Gates Foundation. In a basement insectary located somewhat incongruously in South Kensington, thousands of mosquitoes are housed in cubes of white netting in precisely controlled warm and humid conditions. The male flies suck on sugar water, while the females feast on vials of warm blood. Any rogue mosquito that manages to break quarantine by escaping the double steel doors and electronic security—not to mention an electronic mosquito zapper known affectionately as the Executioner—would then face the inhospitable misery of the dank English climate. What works for malaria could similarly be applied to tackling dengue, yellow fever, Lyme disease, and the Zika epidemic.
It’s all very well scheming diagrams and building models about selfish killer genes, but do gene drives work in practice? In 2018, Burt, Crisanti, and Nolan took a giant step in that direction. In their London lair, they crashed caged populations of A. gambiae in fewer than eleven generations.36 The strategy interfered with the insect’s sex chromosomes, reducing the proportion of fertile females in each successive generation until the population reached a dead end. Extrapolating from South Kensington to Burkina Faso, which has the third highest number of malaria deaths behind Nigeria and the Democratic Republic of Congo, the strategy could crash a wild mosquito population in about four years. In San Diego, Omar Akbari’s team has identified another promising target—a gene that when knocked out, prevents female Aedes aegypti mosquitoes, carriers of several viral diseases, from flying. (Males are unaffected.)
Burt says a trial would involve deploying just a few hundred gene-drive mosquitoes in each village. If the social and political concerns can be addressed, Burt reckons that this CRISPR gene drive, coupled with other public health measures such as the use of nets, could eliminate malaria across much of Africa in fifteen years. One low-tech innovation, developed by entomologist (and malaria survivor) Abdoulaye Diabaté, is the Lehmann funnel entry trap, a device that fits to windows and doors from which mosquitoes cannot escape.