Grow human organs in pigs. What can go wrong?

For the ancient Greeks, the chimera was an ominous creature.- partly lion, partly goat and partly snake. The first chimera that Juan Carlos Ispisua Belmonte created in 1992 was significantly less terrible: it consisted of a fetal limb of a mouse grafted onto a chicken embryo wing. At that time, Belmonte was a young scientist working in a laboratory in Heidelberg, Germany. He was fascinated by the secrets of gene expression — the biological signals that control the development of the animal — and the pure potential of the embryonic cells.

Take any vertebrate: chicken, pig, man. In maturity, they turn out to be completely different organisms, but they start practically from the same thing. Belmonte began to wonder: if a mouse's foot could 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, insome sense personal. As a child of poor, poorly educated parents in rural areas in southern Spain, he was forced to drop out of school for several years in order to support his family while working on a farm. And only in adolescence, he returned to the classroom - and from that moment quickly moved from philosophy (Nietzsche and Schopenhauer were loved) to pharmacology and genetics.

By 2012, Belmonte became one of the outstandingworld biologists, working in their own laboratory at the Salk Institute in La Jolie, California, and another in their native Spain. Like his colleagues around the world, he pondered how to use a new powerful tool in the arsenal of this discipline - the CRISPR-Cas9 gene editing platform. After the appearance of the first serious works on CRISPR, Belmonte quickly found a goal. In the United States alone, about 100,000 people are in line for organ transplantation at any particular time, and about 8,000 of them die each year due to the lack of donors. According to Belmonte, CRISPR and chimeras may be the solution. He hoped to use a new gene editing technique to transform cattle bodies into incubators for human hearts, kidneys, liver and lungs.

The search for Belmonte began with research on mice. Using CRISPR, he and his team removed the genes that allowed animals to grow several organs, including the eyes, heart, and pancreas. Instead of allowing these altered mouse embryos to grow on their own, Salk scientists introduced 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 switched to larger subjects. They injected human stem cells with 1500 embryos of ordinary pigs, then implanted these embryos into sows. Within about 20 days, some of them turned into human pigs chimeras. It was a modest success. The embryos were more pig than human: there were 1 human per 100,000 pig cells. But the experiment was successful: these were the first chimeric embryos created by merging two large, distantly related species.

As with mice and rats, Belmonteplans to use CRISPR to turn off the pig's desire to create its own organs, and then fill the gap with human cells. But the second step — getting human cells to take root in pigs at a higher speed — turned out to be pretty darn hard. “The effectiveness of the mouse rats is very good. The effectiveness of human pigs is not particularly high. This is the problem. ” Today, a complicated trial and error process is conducted in the Belmonte laboratory - scientists test how different animal and human cells interact with each other, in the hope of applying the information to the chimeras of pigs and humans. But even this painstaking process, according to scientists, is very fast by the standards of previous years. Using traditional methods, they would need "hundreds of years." But thanks to CRISPR, we can very quickly assemble many genes and modify them.

If CRISPR helped Belmonte in his ambitions, healso sent it to one of the most thorny ethical areas of science. Ancient people considered chimeras to be a bad omen, and modern people treat them the same way - especially when the boundary between humans and animals is blurred. 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 applying for the Pioneer Award, one of the most prestigious and generous grants of the National Institute of Health. Then it turned out that the 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 insertion of human stem cells into animal embryos, citing the need to think about ethical issues. A year later, the moratorium was promised to be canceled, but so far there is no funding. Belmonte eventually received the Pioneer Award, but he conducted most of the experiments with pigs in Spain at his own expense.

John de Vaux, director of the cell andtissue engineering at the University Hospital of Montpellier in France, easily presents the worst-case scenarios involving pig chimeras. For example, if too many human cells get into the brain of a pig, 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 mice were smarter than their peers). “It would be terrible to imagine a form of human consciousness locked in the body of an animal,” says de Vaux. What if scientists inadvertently create a pig that can comprehend their own suffering, with a sense of moral injustice? Even if you could kill an animal to retrieve its organs, which many animal protection activists would not agree with, it would certainly be monstrous to kill a creature with human-like intellect in order to take away its pancreas.

Belmonte offers a direct solution to this problem: need more CRISPR. Using gene editing, he says, scientists will be able to prevent colonization of the pig's brain with human cells. Such interventions can prevent human DNA from penetrating the germ line of the pig - so that it does not pass on to future piglets. This is another scenario that makes bioethics frowning. “There are technologies in the lab that could help us avoid these ethical issues,” says Belmonte.

Chimera studies are just one of the largestdirections that are being developed in the laboratory of 58-year-old Belmonte using CRISPR. He and his team are also conducting many experiments on epigenetic editing — a variation of CRISPR that modulates gene expression, rather than hacking the DNA sequence itself. Because of this, the symptoms of diabetes, kidney disease and muscular dystrophy in mice are completely addressed. We can say that scientists are trying to overcome the very aging.

“He is pushing the boundaries of what we canpresent, ”says Pablo Juan Ross, a professor of zoology at the University of California, Davis, who experiments with chimeras on pigs and sheep in his own laboratory. Both scientists are interested in proving the value of editing genes and creating chimeras. Ross relies on the fact that we can not abandon the technologies that will allow us to grow organs in animals, not waiting for another teenager to die in a car accident.

But Belmonte is in no hurry, despite his ownimpatience. He decided to destroy the first fetal chimeric pigs during the first trimester, not waiting for them to develop into something more ethically complex - despite the fact that in Spain, where they were raised, the rules would have allowed Belmonte to kill animals at any time. And he is careful about editing genes in humans. “We need to learn much more before using CRISPR in public,” he says. "I would not dare to bring it out of the laboratory."

Progress must be not only in science. There should also be a detailed debate on gene editing - and not only scientists, but also doctors, the public and the government should have a voice. De Vaux agrees: “Einstein conducted fundamental research in the field of physics. But at the country level, it was decided to apply these results to bombing Hiroshima - not at the level of scientists. ”

Belmonte is adamant that today scientistsare on the verge of curing disease, reversing aging and saving lives with grown organs. This can change our own evolution, our own appearance.

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