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.)
John De Vos, director of the Department of Cell and Tissue Engineering at Montpellier University Hospital and Medical School in France, has no trouble envisioning worst-case scenarios involving pig chimeras. If too many human cells make it into a pig’s brain, for instance, the animal could theoretically develop new kinds of awareness and intelligence. (In 2013, scientists in Rochester, New York, injected mice with human brain cells, and the mice turned out smarter than their peers.) “It would be horrible to imagine a form of human consciousness locked in the body of an animal,” De Vos says. What if scientists inadvertently created a pig able to intellectualize its own suffering, one with a sense of moral injustice? Even if you could accept killing a farm animal to harvest its organs—which many animal welfare activists don’t—surely it would be monstrous to kill one with humanlike intelligence to go along with its humanlike pancreas.
Belmonte offers a straightforward solution to this problem: more Crispr. Using gene editing, he says, researchers can prevent a human cell from colonizing the brain of a pig. Similar interventions could keep human DNA from entering the porcine germ line—proliferating into future piglet-people for generations to come—another scenario that has made bioethicists especially squeamish. “In the laboratory,” Belmonte says, “we have technologies that could avoid those ethical concerns.”
A wiry 58-year-old, Belmonte has a dimpled smile, narrow eyes, and a gentle but energetic demeanor. Chimera research is, as it happens, only one major front that his lab is exploring with Crispr. He and his team have also performed a slew of experiments in epigenetic editing—a variation on Crispr that modulates gene expression rather than hack away at the DNA sequence itself. With it, they have reversed the symptoms of diabetes, kidney disease, and muscular dystrophy in mice. For good measure, they’re also trying to rewind the aging process itself.
“He is pushing boundaries on the things we can do nowadays,” says Pablo Juan Ross, a professor in the department of animal science at UC Davis, who has been conducting chimera experiments with pigs and sheep in his own laboratory. Both scientists are keen on proving the value of gene editing and chimeras. With such a dire need for human organs, Ross asks, wouldn’t we rather have technology that can develop them on demand with animals, instead of waiting for the next teenager to die in a car accident?
But while he is eager to show what might be possible, Belmonte is not particularly impatient to see his research leave the laboratory. He opted to destroy his fetal pig chimeras during their first trimester, before they could develop into anything more ethically confounding—despite the fact that in Spain, where they were grown, regulations would have allowed Belmonte to euthanize the animals after bringing them to term. And he is altogether wary of editing genes in people. “We need to know much more before we can use Crispr in a human being,” Belmonte says. “I wouldn’t dare to move it outside of the lab yet.”
The science itself isn’t the only thing that needs to progress. There also has to be a thorough debate about gene editing, Belmonte says; scientists like him must have a strong voice in it, but so should physicians, the public, and the government. De Vos agrees. “Einstein did basic research in physics,” he says. “But it was at a country level that it was decided to apply these findings to bomb Hiroshima—not at the scientist level.”
Still, the clock is ticking on that debate. Belmonte firmly believes that scientists today are on the cusp of curing diseases, reversing aging, and saving lives with homegrown organs. “What we are talking about is not like taking an aspirin,” he says. “It could change our own evolution, our own species.”
A revolution in the culture at large—or at least a reckoning—will lag not far behind, whether we like it or not. “We change our values depending on the facts that are presented to us,” Belmonte adds. “That’s the way societies have evolved.” Given the pace of new developments in biology, we already have a lot of catching up to do.
This article appears in the April issue. Subscribe now.
Let us know what you think about this article. Submit a letter to the editor at [email protected].