Xenografts: what are the advances?

In January, an American patient survived two months after a pig heart transplant. A feat that also raises ethical questions. For Gilles Blancho, president of the Transplantation Society, xenografts are one line of research among others.

Has an animal-to-human organ transplant ever been performed?

Yea ! At the beginning of the 20th century, xenografts showed the feasibility of transplantation, that is, the possibility of connecting an organ through its vessels to the vessels of another individual. We already knew that it was technically possible, but the organs were always rejected by the recipient. For a long time, primate organs were transplanted. A patient lived nine months with a chimpanzee kidney in 1964, and in 1984 an American baby survived 21 days after a baboon heart transplant.

Despite the patient’s death, this debut is considered a success. Because ?

For the first time, the heart of a genetically modified pig has been transplanted into a human, without hyperacute rejection – which occurs within minutes. A success achieved thanks to research: in 2016, baboons that received a pig heart in a heterotopic position (outside the chest: the heart beats but does not pump blood) survived for three years. Two years later, a team from Munich (Germany) transplanted pig hearts in an orthotopic position (inside the abdomen) and the monkeys survived for six months. After these experiments, the operation carried out in January represents a first success. Will it lead to the development of xenografts? I’m not sure.

Why is a transplant, human or animal, rejected by our immune system?

Our body is able to differentiate the non-self from the self thanks to molecules present on the surface of our cells, the antigens (or HLA). The latter form a specific identity marker for each one (only identical twins have the same). The body recognizes the graft as non-self and triggers an immune response, which anti-rejection drugs block. Patients live thirty or forty years with a transplant thanks to lifelong treatments. With xenograft, an incompatibility of molecules is added due to species difference. In fact, we preform natural antibodies directed against genes of mammalian origin. They protect us against zoonoses, but in the case of an animal organ transplant, they cause rejection. By removing the targets of these antibodies, we ensure that the graft is not attacked, at least during the first few weeks.

What genetic changes did the pig’s heart undergo?

The core has been modified in several ways. Three porcine tissue genes against which we have antibodies were invalidated, thanks to genome-editing techniques. A fourth gene was inactivated, the growth hormone receptor. In fact, these pigs grow quickly. And it was necessary to prevent the implanted heart from continuing to grow and being crushed in the rib cage. Finally, six human genes were inserted to help protect the graft, including genes that block antibodies.

Can other organs be transplanted?

Potentially yes, but obstacles remain. Thus, the liver produces many proteins, such as insulin, which circulate in the body and become targets for our antibodies. This type of transplant can be considered in emergency situations, for example, in cases of fulminant hepatitis, when we have a few hours for the transplant. A porcine liver, not implanted in the chest, could compensate for the lack while waiting to find a compatible human liver. On the kidney side, experiments have shown that porcine organs (grafted onto baboons) correctly purify the blood. The lung, in turn, is one of the organs strongly rejected by the body. And the difference in anatomy poses a problem: could this organ function well with a vertical movement while in animals it expands horizontally?

Why was the heart of a pig implanted and not that of a primate, genetically closest to us?

For several years, it was decided to abandon the use of primates due to the proximity of the species and the consequent risk of transmission of endogenous viruses, which could recombine with the human genome. That’s what happened with HIV, which was transmitted from chimpanzees to humans in the mid-20th century. Furthermore, experimental research has shown that pig hearts implanted in the chest of baboons work well.

How to prevent the transmission of swine virus to humans?

It is essential to work with animals raised in animal facilities under aseptic conditions and selected very young to ensure that they have not been in contact with pathogenic flora. Even if the risk is lower than with the primate, retroviruses recorded in the pig genome can recombine with the human genome. Thanks to the CRISPR-CAS 9 technique [qui permet de couper, remplacer, inactiver, modifier un gène, ndlr]a German team managed to invalidate known endogenous retroviral sequences.

These xenotransplants also raise ethical questions…

Do we have the right to intervene in the animal’s genetic heritage and exploit it for treatment? These are fundamental questions. We have used the animal for millennia for food, and the conditions of industrial livestock are not very ethical. Using it for health purposes doesn’t shock me. Furthermore, it is not a question of transforming the pig, of becoming a sorcerer’s apprentice, but of resorting to some individuals of rare lineages, which in fact become biomedicine.

Faced with the scarcity of organs, what hope do these xenografts represent?

Xenotransplants are one line of research among others. For the heart, doctors now have alternatives such as circulatory assistance, a pump attached to a belt that makes it possible to compensate for the organ’s failure. And artificial hearts, despite the technical problems to be solved, represent a solution for the future. It will therefore be necessary to prove that the benefits of a xenograft go beyond what exists. For the kidney or lung, on the other hand – where an artificial organ is much more complicated to manufacture – there is real interest in continuing research on animal organs.

Science is also advancing in the regeneration of bioartificial organs or organs…

Yes, for the latter, it is a matter of starting from an organ, emptying it of its cells and cultivating cells derived from the recipient’s stem cells in it, in order to obtain an immunocompatible organ. In 2016, human hearts taken from the deceased were recellularized with stem cell cells and started beating again (in the laboratory). An animal can become a bioreactor: Japanese scientists are working on animals carrying organs composed of human cells that can be transplanted into patients. Other avenues concern the regeneration of injured organs, using stem cells. This is all still experimental. But it could be that the advancement in stem cell research or regeneration is faster and that xenografts are overwhelmed. There are still many paths to be explored.

Leave a Comment

Your email address will not be published.