The picture is historical. A team of Chinese scientists and Spanish doctor Miguel Ángel Esteban have for the first time succeeded in creating the outline of a human organ in another animal. The experiment, conducted using humanized kidneys in pig embryos, represents a step towards the still distant dream of using other mammals as an inexhaustible source of organs for transplantation. These hybrid organisms — dubbed chimeras after the mythological monster with the head of a lion, the belly of a goat, and the tail of a dragon — still pose daunting ethical dilemmas.
Esteban, born 53 years ago in the Valencian town of Castellón de la Plana, moved to China in 2008. There, the Spaniard and his Chinese colleagues at the Guangzhou Institute of Biomedicine and Health reprogrammed adult human cells to regain their ability to form any organ or tissue in the body. The team introduced these pluripotent human cells into day-old pig embryos that had previously been genetically modified so that they would not develop pig kidneys. Human cells have filled this empty niche and produced a rudimentary kidney, an intermediate stage of the renal system called the mesonephros. These pig-human embryos were carried in sows for up to 28 days, which is about a quarter of the gestation period for this species. Half the cells in his kidneys are human.
The work, led by Chinese scientist Liangxue Lai, follows the path taken by the team led by Spanish researcher Juan Carlos Izpisua, who announced in 2017 the creation of pig-human embryos that contained barely one human cell per 100,000 pigs. These groundbreaking experiments were carried out at the University of Murcia and on two farms in Murcia, after an intense debate by a panel of experts from the Carlos III Institute of Health, which approved the tests despite “the biological risks involved in the creation of pig chimeras”. /human”. The committee stipulated that no animal could reproduce with human cells.
Izpisua praises the new work in which he was not involved. “It goes a step further and shows that cells can organize in space and give rise to organized tissue structures,” says the researcher and director of the San Diego Institute of Science at Altos Laboratories, a new US multinational involved in the extension of life preoccupies man with health. “It has not previously been possible to develop mature humanized organs in pigs, but this study brings us a step closer,” reflects Izpisua. “It’s a big step forward.” About 150,000 organs are transplanted each year worldwide, but in the United States alone, according to official figures, there is a waiting list of 100,000 people and 17 of them die every day.
The team, led by Miguel Ángel Esteban and Liangxue Lai, is now working towards reaching mature kidneys, trying to overcome technical and ethical obstacles. One of the red lines is to prevent human cells from exiting the kidney and integrating into the pig’s brain or gonads, whether they are the testicles or ovaries. “The question is whether it is ethical to allow pigs to be born with mature, humanized kidneys. Everything will depend on the level of contribution (human cells) in other tissues of the pig,” says Esteban. Their study, published Thursday in the journal Cell Stem Cell, shows that “very few” human cells proliferate in the brain and spinal cord of pig embryos. “In order to eliminate any kind of ethical problem, we continue to modify human cells so that they cannot enter the pig’s central nervous system under any circumstances,” affirms the Spanish doctor.
As early as 2020, a team from the University of Minnesota in the USA succeeded in creating human endothelium – the inner layer of blood vessels – in pig embryos. A year later, the same group, led by Mary Garry and Daniel Garry, created 27-day-old pig embryos with humanized muscles. Nephrologist Rafael Matesanz, founder and former director of the National Transplant Organization, emphasizes that this is the first time a human organ has been created in another animal. “It is a conceptually very important and significant step, but it is far from the start of kidney production,” warns the nephrologist.
Matesanz was one of the members of the committee that approved Izpisua’s experiments in Murcia. In his opinion, it is “doubtful” that a trial like the one now being carried out in Guangzhou would be approved in Spain given the possibility that some human cells could colonize the pig embryo’s brain, which has indeed happened. “The big risk is that the cells will go into your central nervous system and create a pig-man. Or that they go to the reproductive system and the same,” he warns. “All of these experiments clearly stem from China, where legislation is much more lax than Spanish or American,” says Matesanz.
The founder of the successful National Transplant Organization believes that “a much more promising avenue” is to produce genetically modified pigs so that their pig organs do not cause rejection in humans. On September 25, 2021, a New York University surgical team successfully transplanted a pig kidney into a brain-dead woman. On January 7, 2022, American David Bennett became the first person to punch a pig’s heart in the chest after surgery at the University of Maryland Medical Center. Bennett died of heart failure two months later, with no apparent symptoms of organ rejection, although the heart was infected with a swine virus.
Spanish chemist Marc Güell is one of the founders of eGenesis, one of the American companies that modifies pig DNA to create pig organs for human transplants. Güell also praises the new results. “It could help to better understand where the current frontiers of interspecies chimerism lie. What else will be necessary?” asks the chemist from the Pompeu Fabra University in Barcelona.
Nephrologist Josep Maria Campistol, director general of the Hospital Clínic de Barcelona, also has an influence on all the doors that pig-human embryos open. “They could be an endless source of organs, with the potential to create specific, personalized human organs for certain patients,” he points out. It would be a way to get replacements from a specific person’s cells. Campistol also relies on regenerative medicine. “I am convinced that in the near future we will be able to regenerate chronically diseased kidneys, livers or hearts, restore their function in whole or in part and avoid transplantation,” says the director general of the clinic.
Campistol was one of the co-authors of Izpisua’s 2017 research showing that human cells can implant in a pig embryo. “Another very important element that we are working on is that you can use these pig models to test the usefulness of different therapy strategies before applying them to human patients,” says the nephrologist. “Obviously there’s still a long way to go, but it’s creating some really incredible expectations.”
