To the ancient greeks, the chimera was a ferocious creature—part lion, part goat, and part snake. The first chimera that Juan Carlos Izpisua Belmonte ever created, in 1992, was considerably less intimidating: It consisted of an embryonic mouse limb grafted onto the wing of an embryonic chicken.
Belmonte was a young scientist at the time, working in a lab in Heidelberg, Germany. He was transfixed by the mysteries of gene expression—the biological signals that govern how an animal develops—and the pure potential that lurked in embryonic cells. Take any vertebrate: a chicken, a pig, a human. At maturity, they are dramatically different organisms, but they start out nearly identical. Belmonte began to wonder: If a mouse limb could live on a chicken’s wing, what else might be possible? How else might scientists alter the signals that dictate what a creature becomes?
Belmonte’s interest in the malleability of destiny was, on some level, personal. The child of poor, barely educated parents in rural southern Spain, he had been forced to drop out of school for a few years as a young boy to support his family with farmwork. Only as a teenager did he return to the classroom—at which point he promptly set off on a rapid trajectory from philosophy (Nietzsche and Schopenhauer were favorites) to pharmacology to genetics.
By 2012, Belmonte was one of the world’s preeminent biologists, running his own lab at the Salk Institute in La Jolla, California, and another one in his native Spain. Like his colleagues all over the globe, he was pondering how to make use of a powerful new tool in the discipline’s arsenal—the Crispr-Cas9 gene-editing platform. After the first major Crispr papers appeared, Belmonte quickly set his sights on an audacious target. In the US alone, around 100,000 people are on a waiting list for an organ transplant at any given time, and some 8,000 of them die each year for lack of a donor. As Belmonte saw it, Crispr and chimeras could be a solution. He hoped to use the new gene-editing technique to fool the bodies of large livestock into becoming incubators for human hearts, kidneys, livers, and lungs.
Belmonte’s exploratory research started in mice. Using Crispr, he and his team deleted the genes that allowed the animals to grow several organs, including eyes, a heart, or a pancreas. Rather than let these maimed mouse embryos develop on their own, the Salk researchers injected some rat stem cells into the mix. Lo and behold, the rat cells replaced the missing organs, and the animals lived a normal murine lifespan. By 2017, Belmonte and his colleagues had moved onto bigger test subjects. They injected human stem cells into 1,500 ordinary pig embryos, then implanted those embryos into sows. Within about 20 days, some had developed into people-pig chimeras. It was a modest success. The embryos were far more pig than person, with approximately one human cell for every 100,000 porcine cells. But the experiment was nonetheless a major milestone: They were the first chimeric embryos ever created by merging two large, distantly related species.
Much as he did with mice and rats, Belmonte plans to use Crispr to switch off a pig’s propensity to create its own organs, then fill the gap with human cells. But the second step—getting the human cells to take root in pigs at higher rates—has proved devilishly hard. “The mouse-rat efficiency is quite good,” Belmonte says. “Human-pig efficiency is not so high. So that is a problem.” Today, Belmonte’s lab is slogging through an arduous process of trial and error, testing how different animal and human cells interact when combined, in hopes that they can apply what they learn to pig-human chimeras. But even that slog is, by the research standards of just a few years ago, proceeding at lightning speed. With conventional methods, Belmonte says, “it would take hundreds of years. But thanks to Crispr, we can move quickly to many, many genes and modify them.”
If Crispr has helped to supercharge the ambition of Belmonte’s work, it has also sent him careening into some of the thorniest ethical terrain in science. The ancients regarded chimeras as bad omens, and modern Americans have been similarly spooked by them—especially those that blur the line between human and animal. In his 2006 State of the Union address, President George W. Bush ranked the creation of such hybrids as among “the most egregious abuses of medical research.” In 2015, Belmonte learned that he was in the running for a Pioneer Award, one of the National Institutes of Health’s most prestigious and generous grants; then he found out that his application was on hold, he says, because of his chimera work. That same year, the NIH suspended federal funding for any studies that introduce human stem cells into animal embryos, saying it needed time to think through the ethical issues. A year later, the agency announced plans to lift the moratorium and opened the idea to public comment; 22,000 responses flooded in. So far, funding is still on pause. (Belmonte eventually won a Pioneer Award, but still carried out much of his pig research in Spain with private funds.)