A pig heart was transplanted in the United States in a patient with severe heart disease for whom there was no therapeutic alternative. It was the first time a pig-to-human heart transplant was successful.

Since the end of the last century, transplant science has sought alternatives to human organ transplant, exploring the possibility of using genetically modified animal organs. Another step in this race is the experiments of Spanish scientist Juan Carlos Izpisua, aimed at the creation of human-animal hybrids or chimeras from which organs (like kidneys or hearts) could be harvested for use in human medicine. The first stage of these experiments essentially consisted of injecting human embryonic stem cells into mouse embryos in order to generate quasi-human organs in the mice, with the eventual aim that they could be used for transplantation in human medicine, experiments that were published in the journal Nature. Thereafter, new experiments by Izpisua succeeded in modifying pig embryos and, later, primates, inoculating them with genetically modified human stem cells to obtain “humanized” animal organs that can be transplanted into humans.

As already mentioned in a Report published on the Bioethics Observatory website by bioethicists Aznar and Tudela, these experiments raise objective bioethical issues, which, in short, center around the following: a) stem cells from human embryos were used in some of these experiments; b) the possibility that the human cells implanted the animal would be unable to colonize organs other than the one they are intended to produce was not fully controlled; c) the possibility that such colonization could even reach the human brain or reproductive organs, which would add a further bioethical difficulty; d) the threat to the conceptual, social and moral boundaries that distinguish human beings from other creatures; and d) biosecurity and animal welfare issues.

A new horizon

Now, however, a new horizon is opening up in the field of transplantation, namely to transplant genetically modified animal organs directly into the patient requiring the transplant and not a human-animal organ produced for that purpose.

These xenotransplants, as they are called, have been studied for decades. The main problem with this line of research is the difficulty in controlling the recipient’s immune rejection, especially when the transplanted organ belongs to another animal species. In this regard, on September 25, 2021 a genetically modified pig kidney was transplanted with relative success into a brain-dead woman, functioning correctly for 54 hours. The transplant was described by nephrologist Rafael Matesanz, founder of the Spanish National Transplant Organization, as a “fascinating experience because, at least in the short term, the genetic modification introduced has made it possible to overcome the interspecies barrier, something that has been pursued for decades”. Nevertheless it continues to pose some bioethical issues as Matesanz says, since “offering a pig kidney to a person is clearly substandard”. Moreover, it should also be considered that authorization to carry out the trial was not given by the transplant patient, but by her family, considering that she — a donor and friend of people with kidney failure undergoing dialysis — would have loved to participate in the trial

pig-to-human transplant

Credit: University of Maryland School of Medicine

Recently, news has emerged of a new xenotransplant carried out at the Faculty of Medicine at the University of Maryland (USA). On this occasion, a pig heart was transplanted, also with relative success, in a patient with severe heart disease for whom there was no therapeutic alternative. The intervention was authorized as compassionate use, i.e. when sufficient evidence of safety and efficacy is not available, but there is no alternative to try to save the patient’s life. This transplant was possible only after the animal from which the heart came was genetically modified, altering 10 genes; three of these were related to immune rejection by the recipient, one of them limits overgrowth of the organ itself and six more genes, of human origin, were introduced into the animal, also in order to lessen the expected immune rejection. Thus, they have shown for the first time that a genetically modified animal heart can function in a patient without immediate rejection by the recipient. On this occasion, consent for the surgery was granted by the patient himself, who was informed of the risks of the operation as it was still an experimental technique.

The initial idea of genetically modifying animals, particularly pigs, came from the geneticist George Church and his collaborator Luhan Yang, lab team leader of what is known as Synthetic Biology at Harvard University. In 2017, Church and Yang co-founded the startup eGenesis, in order to genetically modify pigs using the CRISPR genome editing technique to prevent the xenotransplanted organs from these animals being rejected by the human recipient. The modification was carried out in pig embryos, and in different studies, up to 60 different genes were modified, more than in any other type of application of CRISPR technology carried out previously.

For this project, Church and Yang used a line of “immortal” pig kidney cells, chosen for their ability to survive and divide indefinitely in the laboratory.

Credit: University of Maryland School of Medicine

To make virus-free pigs (PERV), they needed to start with genetically normal cells straight from a living pig. Then, in collaboration with Danish and Chinese researchers, the eGenesis team applied the CRISPR system  to cells derived from the connective tissue of fetal pigs. These cells proved to be more fragile when they were subjected to CRISPR editing: once edited, they failed to grow normally, possibly because damage to their DNA caused them to stop dividing or self-destruct, said Yang. But by exposing the cells to a chemical cocktail that promoted growth and repressed a key growth-suppressing gene, the team increased the portion of PERV-free cells in cell cultures to 100%.

To produce piglets, the researchers used a standard cloning technique: they inserted the DNA-containing nuclei of these edited cells into egg cells taken from the ovaries of pigs at a Chinese slaughterhouse. They allowed each egg to develop into an embryo and implanted it in the uterus of a surrogate mother (see more). Once in the adult phase, the resulting pigs would be used for xenotransplantation.

Progress continues in the race to find solutions to the lack of organs for transplantation and these techniques could help to solve this problem, albeit not in the near future due to the many difficulties involved in both interspecies immune rejection and the functionality of very different organs in some cases, such as the kidney.

Bioethical assessment

In addition to the risks already stated regarding the impossibility of controlling the proliferation of human cells in animal organisms, such as occurs in the production of hybrids, the most recent xenotransplantation experiments present no more ethical difficulty than the safety of the procedure, its longer-term viability and the side effects that could derive from the use of genetically modified organs and tissues from animal species, with the possible risk of zoonosis caused by transmission of animal viruses to the human recipient. The unknowns are many and only prudent experimentation, with proper assessment of the risks and consequences of these processes, will pave the way to a real breakthrough in the field of transplant medicine.

So far, all the transplantation trials of genetically modified organs have been done with animal models in monkeys at Massachusetts General Hospital by surgeon James Marckmann. Above all, however, the major risk to be taken into account in its application to man, in addition to the ethical considerations mentioned above, is that of safety in the sense of preventing the transmission of animal viruses to human recipients.

                   

Julio Tudela                                        Nicolás Jouve

Bioethics Observatory                       Professor Emeritus of Genetics

Institute of Life Sciences                   Department of Biomedicine and Biotechnology

Catholic University of Valencia          University of Alcala

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