Why a pig’s heart and not a monkey’s? What are the ethical dilemmas of xenotransplantation? Top photo: A moment of the first successful transplant of a pig heart into an adult human with end-stage heart disease. University of Maryland Medical Center
A team of researchers and cardiovascular surgeons from the University of Maryland School of Medicine (USA) have just announced to the world that they have successfully performed the first xenotransplantation of the heart from a pig to a human being.
The patient, David Bennett , 57, had a severely damaged heart, in addition to other pathologies and comorbidities that made him ineligible to receive a new, compatible heart from another person. The risks and novelty of the treatment were explained to him and he freely consented, agreeing to undergo a first experimental transplant of a non-human animal heart, from a genetically modified pig.
A few days have passed and the heart is still beating normally in the patient’s chest and no signs of rejection have appeared. In short, this first xenotransplantation, long awaited in the scientific and medical community for many years, is already a success, however long this first patient survives, and we have to recognize it as such.
It is a very important advance that we hope will continue in successive xenotransplantations that can be carried out from now on.
HISTORY OF XENOTRANSPLANTATION
They were revitalized more than 30 years ago , in the early 1990s . Since then, many researchers have been interested in finding a way to avoid the sudden rejection that would occur when trying to place an organ from an animal inside the body of a different species, followed by rejection in the medium and long term.
Many xenotransplantation experiments have already been carried out, mainly from pigs to baboons. I have spent the same 30 years explaining in my classes the possible benefits of xenotransplantation and the medical use of transgenic animals, genetically modified pigs so that their organs could be used in human transplants. It seemed like a great idea, primate survival records were piling up, from several months to around three years in some cases.
The University of Maryland team was one of those that had reported the longest survival time of baboons after being transplanted with pig organs. But we were still missing the icing that culminated the whole process. The definitive experiment was still missing: inserting an organ from these transgenic pigs into a person’s body and ensuring that the xenotransplanted organ continued to function normally.
This is what has been achieved now.
XENOTRANSPLANTATION IS FASHIONABLE
We must remember that in September 2021 we learned about another pioneering xenotransplantation experiment, carried out in a New York clinic on a brain-dead patient, declared clinically dead, who had a kidney transplanted from one of these transgenic pigs into her leg. . This was connected to his blood circulation, and it was found that the feared rejection did not occur and that the organ worked and produced urine.
This experiment, of short duration (the surgeons finished the experiment at 54 hours, after the first critical 48 hours had passed, after verifying the absence of rejection), was a first step. The relatives of the woman, already clinically deceased, had to consent on her behalf.
This advance is completed with a xenotransplantation carried out on a living person, who was also able to consent by himself after receiving information about the experimental procedure to which he was going to be subjected.
WHY PIGS AND NOT PRIMATES?
Pigs are animals whose organs are similar in size to human organs. For this reason, in addition to having very similar physiology and metabolism (pigs and humans are more alike than we are willing to admit), because they are easy to breed and because they do not raise as many ethical problems as the use of non-human primates, pigs are the animal species of choice for xenotransplantation. They have been that way since the proposal was launched in the 1990s .
Although genetically speaking primates would be closer to humans than pigs, the truth is that breeding primates is much more difficult, expensive and requires much more time. Their organs are generally not the size of those of people and their use raises enormous ethical dilemmas in society , in addition to their use in animal experimentation being very limited or prohibited in the European Union, by Directive 2010/63/EU .
The heart used in this first xenotransplantation is derived from a transgenic pig with multiple genetic modifications. Up to ten of these genetic alterations have been included in this animal to prevent or limit the rejection of the transplanted animal organ that would occur without them.
In this pig, there are four inactivated porcine genes and six human genes added to its genome. Among the eliminated genes, two important ones stand out: one aimed at eliminating the protein that adds specific sugars to cell membrane proteins, protein and sugars that we humans do not have (there are three of these similar genes, which must be inactivated) .
In this way, the pig cells are more similar to human cells and our immune system accepts them as its own and does not immediately reject them as foreign.
The other gene is the one that encodes the growth hormone receptor , which has also been inactivated to prevent the pig’s heart from continuing to grow in the patient’s chest to a size that could become a problem, due to lack of space in the heart. the chest cavity. This was one of the problems that arose in pig-to-baboon xenotransplantation and that, thanks to these initial experiments in animals, could be solved.
The growth hormone gene can also be inactivated in pigs to obtain smaller animals whose hearts do not have space problems in the thorax of primates and humans.
A STORY THAT BEGINS WITH DOLLY THE SHEEP
We do not have exact information on the altered genes or the technologies used. It is likely that this collection of ten alterations includes the nine genetic modifications already successfully tested in experiments with baboons .
We also do not know if gene-editing CRISPR technology has been used in the generation of these pigs to inactivate any of these genes. This is likely to be the case, although many of these mutations in the pig were generated years ago by pre-gene-editing procedures, and it is equally possible that CRISPR was not used .
What we do know is that the technology that has made it possible to generate these transgenic pigs is cloning. The same one we discovered when we met Dolly the sheep , the first mammal cloned from adult cells. Dolly was born in 1996 and was discovered by the world in February 1997, 25 years ago, when her description was published in the journal Nature .
Cloning technology, technically, or “somatic cell nuclear transfer” (SCNT), allows the reconstruction of unicellular animal embryos, previously emptied of their genetic material, with the nucleus of cells in culture. The resulting animals are obtained by cloning and, in addition, transgenic. This is the current usual technique for the generation of transgenic pigs and, without a doubt, it is the technique used to generate the ones used for these first xenotransplantations to humans.
Dolly the sheep was born in 1996 in collaboration with the company PPL Therapeutics, which disappeared in 2003. From its dismantling came another, Revivicor, which continued to apply the same technology to generate transgenic pigs by cloning, until in 2011 it was acquired by the pharmaceutical company United Therapeutics , which produced the transgenic pigs from which the kidney used in New York in September and the heart used in Baltimore this January 2022 were harvested. There is an imaginary line connecting Dolly to patient David Bennett.
WHY DO WE NEED XENOTRANSPLANTATION?
The goal of xenotransplantation is not for animal organs to remain in the human body indefinitely. Despite the fact that the organs come from genetically modified pigs, it is still necessary to constantly administer immunosuppressive drugs to the transplanted people. This is already the case with human organs from other immunocompatible people, and it is even more so when they come from another species.
In this experiment, xenotransplantation was combined with a new immunosuppressive drug . The aim was to avoid any rejection that would end the useful life of the transplanted organ and would require a new transplant to avoid the death of the patient. The objective of xenotransplantation is that these patients can buy time so that they can remain on the waiting lists until they can receive the human organ that, now, can serve them for the rest of their lives.
Unfortunately, patients on waiting lists continue to die, as the organ they need to survive does not reach them in time. According to the data , in the US, some 6,000 patients on the waiting list die each year without being able to receive a transplant.
In Europe and in Spain, a country traditionally a leader in donations and transplants, these figures are lower, but they continue to range between 15 and 30% mortality on waiting lists, depending on the organs, according to the conclusions made by the European project EUDONORGAN . These are the patients to whom these xenotransplantation procedures would be mainly intended.
RISKS OF XENOTRANSPLANTATION
At the end of the 1990s , studies carried out in vitro by putting pig and human cells in contact in culture showed that it was possible to detect infections by porcine endogenous retroviruses (PERV), present in the pig genome, in human cells.
Taking into account that a xenotransplanted person will have to live with a significant immunosuppression regimen, it did not seem like the best scenario.
Many questions were raised about the risk of these viruses jumping the species barrier and causing undetermined harm in transplant patients. For some years these findings caused a halt in xenotransplantation research and a moratorium was produced .
After the initial potential danger, it was soon found that the transmission of these PERV retroviruses in vivo was not detected in experiments in which pig organs remained for long months inside the body of non-human primates.
However, the potential danger, at least in theory, existed. And, for this reason, in 2017 George Church’s laboratory obtained pigs in which the more than 60 retrovirus insertions in their genome had been inactivated using CRISPR gene editing tools, pigs that would be free of PERV and could be used with greater safety in xenotransplantation, but pigs to which it would be necessary to add the whole string of genetic modifications necessary to prevent rejection by the human immune system.
The Spanish researcher Marc Güell, currently at UPF , participated in this 2017 work, and in the previous ones by the same team . Pigs used by Revivicor certainly do not have this inactivation of PERV, but experimental evidence does not seem to show that these infections can occur in vivo .
The real risk of xenotransplantation remains rejection, which can be precipitated at any time. This also happens in human-to-human organ transplants, and then a new transplant can only be scheduled to replace the organ that has begun to be attacked by the recipient’s immune system until it is completely non-functional.
For this reason, investigations of all the genetic modifications that need to be included and of the drugs or medications that can be used to reduce this rejection continue to be the main workhorse in the field of xenotransplantation.
As for the ethical dilemmas that these experiments raise , there are those who think (the animal groups) that this utilitarian approach to animals, which we would use to provide us with replacement organs to replace our damaged organs, is not ethically justified .
From my point of view, if I use the tools provided by ethics to elucidate, on the one hand, the potential benefit of being able to save a human life, and on the other, the sacrifice of an animal whose life is ended to access its organs to be transplanted to the patient who needs it, I still consider that the experiment would be ethically justified, since the potential benefits would far outweigh the damage caused.
It must be remembered that in countries like ours the number of pigs intended for consumption and fattening is close to that of the general population . More millions of pigs are slaughtered annually than people live in Spain, pigs that we use for our food.
In the case of xenotransplantation, it is a very small group of animals that have only been produced to obtain these organs whose destination is xenotransplantation.
The real ethical problem of xenotransplantation is the accessibility of these sophisticated and advanced technologies for patients who need it. The fourth principle of bioethics tells us about justice, and reminds us that all the treatments that we can propose or develop must be accessible to everyone who needs them. Not just those who can afford it.
The cost of these procedures is one of the main ethical barriers that will have to be overcome to ensure that these complicated techniques, which require the collaboration of multiple teams of veterinarians, researchers and doctors, can be disseminated, universalized and, hopefully, sooner rather than later , be within reach and available to anyone who may need them.
I think it is important to end by highlighting that we are celebrating. The scientific and medical success of this team from the University of Maryland is to be applauded. After more than 30 years of basic and preclinical research, a person survives with a pig heart replacing his damaged one. This is what is relevant.
Xenotransplantation is not only back . They have come to stay. Now we hope that clinical trials will be established in which a significant number of patients can be enrolled in order to be able to evaluate, with greater clarity, the safety and efficacy of xenotransplantation. Another stage begins. And it will be even more exciting.
A version of this article was published on the author’s blog.