Can animal organ transplants solve the donor shortage?

They used to be kidneys, but surgeons and cardiologists have succeeded in transplanting the heart of a genetically modified pig into a human for the first time in the United States. Can xenotransplantation be the solution to the human organ shortage? Are there impassable ethical boundaries or limits?

The Spanish Lluís Montoliu, biotechnologist, expert in genetic editing and president of the Ethics Committee of the Higher Council for Scientific Research (CSIC), answers ten questions – scientific and ethical – about the challenges of transplants from animals.

– How is the significance of a news item of these characteristics assessed?

– That a person has survived with a pig’s heart for more than 72 hours is an undeniable success. Xenotransplantation has been investigated since the 90s, and after many years of problems and many tests in animal models, especially in non-human primates (baboons) and after having survived for several years of these animals with genetically modified pig organs, we started to glimpse the first successes in people, for whom it was designed from the beginning, with the woman in clinical death who had a pig kidney transplanted to her leg last September and now with the pig heart xenotransplantation to a man who needed to replace his, very sick. It is a long-awaited milestone, regardless of how many days, weeks, or months this person survives. It will be the first of many other patients to follow. It is a historic advance in transplant medicine.

– Can it be the xenotrasplantes In the future, the definitive solution to the shortage of human organs for transplantation and therefore for many chronic diseases?

– The xenotrasplantación It was never intended as a definitive solution, but rather as a strategy to save time, for patients on waiting lists who do not get the organ they need. Around 30% of people on waiting lists continue to die. With the xenotrasplantación From pig to human organs it is possible to extend the time that patients can wait to receive another organ from a donor. The best transplant of a human heart will always remain the heart of another human.

– Do you think that some ethical considerations can be glimpsed?

– Since the strategy of xenotrasplantación It has been investigated for a long time, there has been time to raise all these debates. It is ethically acceptable to use the organs of an animal to make up for the lack of human organs, since the possible therapeutic benefit (saving the life of a human person) is greater than the damage to the animal, which is sacrificed in order to obtain the organs. It should be noted that pigs generate far fewer ethical problems than non-human primates and are generally more accepted by society.

– They are obviously genetically modified animals to avoid immediate rejection of the organ. Is this such a sophisticated technique that it makes this type of transplant very residual or exceptional? Or a technique that can be replicated with relative ease until its use becomes universal in the future?

– The pig used, generated by the Revivicor company, carries 10 genetic modifications, four inactivated porcine genes and six added human genes. They are therefore transgenic, multi-transgenic pigs. The technology used is the same that was used to create Dolly the sheep, by cloning or nuclear transfer of somatic cells, in 1996. Revivicor is heir to PPL Therapeutics, the Scottish company that was behind the birth of Dolly. They are techniques that have been used for many years. The sophistication is discovering which genes must be inactivated from the porcine genome and which genes must be added from the human genome so that the transgenic pig organs are not recognized as foreign and rejected by the immune system of the transplanted person. That is the challenge, the real problem.

– Do you consider that it is, therefore, a reality that is on the way to becoming a daily clinical practice, as are transplants from humans?

– I don’t know if everyday is still the word we can use. It has taken us almost 30 years to make the first two xenotrasplantes from pig to human. Many more trials will be necessary to turn this still experimental surgical procedure into a treatment. Many combined experiences are necessary (the company, veterinarians, cardiovascular surgeons, etc …) so that these can be reproduced xenotrasplantes in other hospitals. But I am convinced that the number of patients will gradually increase until they acquire all the necessary experience to be able to approve the procedure as an authorized treatment. This xenotransplantation was cleared by the FDA as compassionate use, given that the patient was already medically evicted and just waiting to die.

– Are the risks of a transmission of animal-specific infections ruled out?

– In the 90s, endogenous porcine retroviruses (PERV) were described which, under conditions of cells in culture, in vitro, could infect human cells. But such infection has never been proven in vivo, in animals. PERVs were considered for some time to be a significant barrier to xenotrasplantación and even moratoriums were proposed. In 2017, George Church’s laboratory described pigs lacking PERV, inactivated with CRISPR tools. But it is not these pigs that have been used. Those Church pigs still have to be extensively modified to acquire the 10 modifications that Revivicor incorporates to prevent, regulate or delay rejection.

– Are pigs always the “best” animals for this type of transplant? There’s others? (primates, guinea pigs, etc)

– Both for their ease of breeding, for the large number of animals available, for their physiology, for their metabolism, and for the size of the organs, pigs are the most suitable animals for xenotrasplantes. Primates, which in principle would be genetically closer, nevertheless raise enormous ethical problems (in the European Union it would be illegal to use them for this purpose) and also neither because of organ size nor because of rearing issues and waiting time to reach adult individuals would be adequate. Much less any rodent of much smaller size.

– At the moment the xenotrasplantes they are considered “in-between stations” while the human organ suitable for transplantation arrives. Can it be consolidated as a definitive clinical practice in the future?

– The lack of human organs for transplantation could be solved with different strategies. Xenotransplantation is one of them, and it aims to save time, give more time to patients who would continue to wait to receive a definitive organ. Whether the pig organs can endure and survive long periods of time is something we do not know. We know that in primates, baboons have survived for several years. More experiments are needed and enough time has to pass. The first human heart transplants also died shortly after, and the current ones have a reasonable and long life expectancy. Other strategies would be organoids, 3D-printed organs or chimeras, all of which are much further removed from their clinical applications and still in the basic research phases.

– Genetic editing. Biological engineering. Personalized medicine. Can science and technology open a new social gap, because they are technologies that are only available to a few?

– This I think is one of the main problems and challenges that we face, collected in the fourth principle of bioethics, which is the principle of justice. That the treatments that are developed are available to everyone who needs them, not just to those who can afford it. Naturally the promoter biotechnology companies have their legitimate right to collect money to compensate for the investments made, but these prices must be reasonable and affordable by the national health systems, which can finance these treatments for their citizens.

– Is there a limit? A border that science should never cross?

– Ethically the problems would come when trying to transplant non-metabolic organs, such as the brain. This is probably the current limit, not only scientific and technical, but ethical, transplantation or xenotrasplante of brains, if it ever comes up, it would probably be one of those experiments we shouldn’t do. I do not see any sense in it at the moment and I do see many dangers and potential problems, not only ethical. I think that with the number of people waiting for kidneys, livers, pancreas, hearts, etc … there is enough work, research and clinical practice for the next few years without the need to get into more trouble.