For the ancient Greeks, the chimera was an ominous creature - part lion, part goat, and part snake. The first chimera that Juan Carlos Ispisua Belmonte created in 1992 was much less scary: it consisted of a mouse embryonic limb grafted onto the wing of a chicken embryo. At the time, Belmonte was a young scientist working in a laboratory in Heidelberg, Germany. He was fascinated by the mysteries of gene expression - the biological signals that govern animal development - and the sheer potential of embryonic cells.
Take any vertebrate: chicken, pig, human. At maturity, they turn out to be completely different organisms, but they start with almost the same thing. Belmonte began to wonder: if a mouse's foot can take root on a chicken wing, what else could be possible? How else can scientists change the signals that determine what a creature will become?
Is it possible to grow another from one creature?
Belmonte's interest in embryo flexibility was, in a sense, personal. As the child of poor, poorly educated parents in rural southern Spain, he was forced to leave school for several years to support his family by working on a farm. It was only in adolescence that he returned to class - and from that moment he quickly moved from philosophy (Nietzsche and Schopenhauer were his favorites) to pharmacology and genetics.
By 2012, Belmonte had become one of the world's foremost biologists, working in his own laboratory at the Salk Institute in La Jolla, California, and another in his native Spain. Like his colleagues around the world, he pondered how to use a powerful new tool in the discipline's arsenal - the CRISPR-Cas9 gene editing platform. After the first serious work on CRISPR appeared, Belmonte quickly found a goal. In the United States alone, about 100,000 people are on the waiting list for organ transplants at any given time, and about 8,000 of them die each year due to a lack of donors. According to Belmonte, CRISPR and chimeras could be the solution. He hoped to use a new gene-editing technique to turn the bodies of cattle into incubators for human hearts, kidneys, liver and lungs.
The search for Belmonte began with studies in mice. Using CRISPR, he and his team removed genes that allowed animals to grow multiple organs, including the eyes, heart, and pancreas. Rather than allowing these altered mouse embryos to develop on their own, Salk's scientists injected some rat stem cells into the mixture. Then, the rat cells replaced the missing organs and the animals lived a normal mouse life. By 2017, Belmonte and his colleagues had moved on to larger subjects. They injected human stem cells into 1,500 common pig embryos, then implanted these embryos into sows. Within about 20 days, some of them turned into chimeras of man-pigs. It was a modest success. The embryos were more porcine than human: for 100,000 pig cells there was 1 human. But the experiment was successful: these were the first chimeric embryos created by the fusion of two large, distantly related species.
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As with mice and rats, Belmonte plans to use CRISPR to shut off the pig's urge to create its own organs and then fill the gap with human cells. But the second step - getting the human cells to take root in pigs at a faster rate - has proven damn difficult. “The performance of the mouse rats is very good. The efficiency of the pig man is not very high. This is the problem. " Today, Belmonte's lab is undergoing a complex process of trial and error - scientists test how various cells of animals and humans interact with each other, in the hope of applying the findings to the chimeras of pigs and humans. But even this painstaking process, according to scientists, is very fast by the standards of previous years. With traditional methods, they would have taken "hundreds of years."But thanks to CRISPR, we can very quickly collect many genes and modify them.
If CRISPR helped Belmonte in his ambitions, he also sent him to one of the thorniest ethical fields of science. Ancient people viewed chimeras as a bad omen, and modern humans view them the same way - especially when the line between human and animal is blurring. In his 2006 address, US President George W. Bush called the creation of such hybrids one of the "most egregious abuses in medical research." In 2015, Belmonte learned that he was nominated for the Pioneer Award, one of the National Institutes of Health's most prestigious and generous grants. Then it turned out that work on this line was suspended - because of his work with chimeras. In the same year, the NIH suspended federal funding for any research into the implantation of human stem cells into animal embryos.citing the need to reflect on ethical issues. A year later, the moratorium was promised to be canceled, but so far there is no funding. Belmonte eventually won the Pioneer Award, but he did most of his experiments with pigs in Spain at his own expense.
John de Vaux, director of the Department of Cell and Tissue Engineering at Montpellier University Hospital in France, easily presents worst-case scenarios involving pig chimeras. For example, if too many human cells enter the pig's brain, then the animal could theoretically develop new types of consciousness and intelligence. (In 2013, scientists from Rochester, New York, injected mice with human brain cells - and the mice were smarter than their peers.) “It would be horrible to imagine a form of human consciousness trapped in the body of an animal,” says de Vaux. What if scientists inadvertently created a pig that could make sense of its own suffering with a sense of moral injustice? Even if you could kill an animal to harvest its organs, which many animal welfare activists would disagree, no doubtit would be monstrous to kill a creature with a humanoid intellect in order to take away its pancreas.
Belmonte offers a direct solution to this problem: more CRISPR is needed. Using gene editing, he said, scientists could prevent human cells from colonizing pig brains. Such interventions can prevent human DNA from entering the pig germ line so that it is not passed on to future human piglets. This is another scenario that makes bioethics frown. “There are technologies in the laboratory that could help us avoid these ethical issues,” Belmonte says.
Chimera research is just one of the big lines of research in the laboratory of 58-year-old Belmonte using CRISPR. He and his team are also conducting many experiments in epigenetic editing, a variation of CRISPR that modulates gene expression rather than breaking the DNA sequence itself. Thanks to this, the symptoms of diabetes, kidney disease and muscular dystrophy in mice are completely reversed. We can say that scientists are trying to overcome aging itself.
“He is pushing the boundaries of what we are currently capable of,” says Pablo Juan Ross, professor in the Department of Zoology at the University of California, Davis, who is experimenting with chimeras on pigs and sheep in his own laboratory. Both scientists are interested in proving the value of gene editing and chimera creation. Ross is betting that we cannot give up technology that will allow us to grow organs in animals without waiting for another teenager to die in a car accident.
But Belmonte is in no hurry, despite his own impatience. He decided to destroy the first fetuses of embryonic chimeric pigs during the first trimester, without waiting for them to develop into something more ethically complex - despite the fact that in Spain, where they were raised, the rules would allow Belmonte to kill animals at any time. And he's wary of gene editing in humans. “We need to learn a lot more before using CRISPR in humans,” he says. "I would not dare to take him outside the laboratory yet."
Progress should be not only in science. There must also be a thorough debate about gene editing - and there must be a voice not only among scientists, but also among doctors, the public and government. De Vaux agrees: “Einstein did fundamental research in physics. But at the national level, it was decided to apply these results to the bombing of Hiroshima - not at the level of scientists."
Belmonte firmly believes that scientists today are on the verge of curing disease, reversing aging and saving lives with grown organs. It can change our own evolution, our own species.
Do you agree with him?
Ilya Khel