In light of the first authorised pig-to-human heart transplant earlier this year we explore the history of xenotransplants, consider the ethical issues of using animals to provide organs, discuss the difficulties of making ethical judgments without enough data or information, and make the case for progressing scientific alternatives over xenotransplantation as a solution to providing organs for future transplants.

Organ transplantation is by nature a controversial subject and has raised ethical concerns for centuries. The use of animals to provide organs for people has compounded this by creating more ethical, scientific, and general questions around viability, feasibility, and necessity. In a world where it is not yet possible to grow replacement organs in a lab, and historical animal research has evidently contributed to the advancement of modern transplant techniques, the continuing pursuit of xenotransplants as a possible solution creates an uncomfortable ethical dilemma.

Here we look at the history of transplants and xenotransplants, and discuss some of the ethical considerations researchers, doctors and patients have faced along the way. We consider the available information on the numbers and welfare of the animals being used today, the alternative opportunities provided by modern science, and argue the case for more transparency across all animal research to help us to be more informed, including the decision-makers burdened with these important ethical dilemmas.

A brief history of heart transplants and xenotransplants

The word ‘xenotransplantation’ comes from the Greek word ‘xenos’ for foreign or strange, meaning to transplant or transfuse live cells, tissue or organs from one species into another. In modern medical science this involves the transplant of tissue obtained from an animal into a human patient. Whilst it has only recently been making headlines, xenotransplantation has been around for centuries; back in the 1600s French Doctor, Jean-Batiste Denys performed blood transfusions from sheep and cows to patients, (1) initially with some success, likely due to the small amounts of blood used. However as further patients died it was soon banned due to the dangers. In the 19th century skin grafts were carried out between various animal species and people. Despite reported successes in historical literature it is most likely none of the grafts became permanent. (1) In 1838 the first corneal transplant from pig to human was carried out, more than 50 years before the first human-to-human corneal transplant was attempted. Again, whilst some corneal transplants were reported as being carried out successfully, the majority were reported to have been rejected within a month. (2)

Our knowledge of the immune system has grown significantly over this time, and we now understand that human-to-human transplants fail for many reasons, but the major one is genetic differences between patient and donor, causing a patient’s immune system to attack the ‘foreign’ tissue. Today this is overcome by using modern technology to ‘match’ the proteins on a donor and recipient as closely as possible, combined with the use of immunosuppressant drugs that modify the recipient’s immune system to help prevent organ rejection. As you can imagine with bigger differences between species and a lack of immunosuppressant drugs these early xenotransplant attempts were doomed to failure.
After further scientific developments in techniques for connecting blood vessels, the first successful human-to-human organ transplant was carried out in 1954 by Joseph E. Murray, who transplanted a kidney between two identical twins in Boston. He had previously studied and trialled the procedure on dogs. Murray also carried out the first successful transplant from a deceased donor in 1962 opening the door for consented organ donation after death. (3)

In the 1960s Keith Reemtsma, a Professor of Surgery at Tulane University, Louisiana, driven by the difficulty of obtaining living kidney donors and failure with deceased donors, explored non-human sources for kidney transplants. This was a time when kidney dialysis was unavailable and immunosuppressant drugs very basic. He believed that organs from a closely related species, such as a chimpanzee, could function in a human body. (1) In total Reemtsma carried out 13 chimpanzee-to-human kidney transplants, while most transplant recipients died after surgery, one lady lived for nine months post-transplant . The University subsequently discontinued their renal xenotransplant work when dialysis facilities were introduced, and human organs became available. (1,4)

The first heart transplant was carried out on a dog in 1905 at the University of Chicago. (5) Heart transplant experimentation using dogs continued into the 1950s with the aim of recovering heart function after the operation. By 1953 full heart and lung transplants were carried out on dogs resulting in six hours survival post-operation, increasing to 250 days survival by 1965. In 1964 Dr Hardy performed the first human heart transplant. It was supposed to be a human-to-human transplant, but due to ethical issues around the timing of death of the human donor, a chimpanzee was used instead and the procedure was a xenotransplant. The recipient died after one hour. (5) The first human-to-human heart transplant occurred in 1964 and resulted in the patient surviving 18 days; a month later the surgeon’s second patient survived for nearly two years. (6) By the end of 1968, 102 transplants had been carried out in 17 different countries. However, with many patients surviving for only a short period of time after the transplant, the number of heart transplants carried out tailed off across the world during the 1970s. (5, 6) The UK’s first ‘successful’ heart transplant was carried out in 1979 at Papworth Hospital on Keith Castle who lived for over five years after the procedure. (6) During the 1980s, with increased knowledge and better immunosuppressants, survival rates increased again. In 1984 baby Fae was the first infant to receive a non-human heart when she was implanted with a tiny baboon heart. She survived for 20 days. (6)

When considering advances in heart transplant methods we should note that mechanical hearts have also been developed and optimised over the past half a century. They are often used to bridge the gap for patients waiting for a suitable heart donor but are still not considered a practical long-term option today. The pioneering procedures for these devices were again carried out in dogs.

Also worth a mention for comparison is the practice of using pig heart valves in heart valve replacement surgery, which has been happening for many decades successfully. Pig heart valves are a common and accepted option alongside human donor valves and mechanical heart valves. Each has its own benefits. The pigs (and cows) used in this process however have been produced for meat and were not genetically modified or specifically bred for the harvesting of organs. (7)

 

Modern Xenotransplant Advances

In October 2020 a paper published in the scientific journal ‘Circulation’ reviewed progress in addressing barriers to the successful xenotransplantation of pig hearts into primates, assuming the same issues would occur with transplants into humans. (8) Advances included the development of GA (genetically altered) pigs that lack specific carbohydrates known to be targeted by the human and primate immune systems, increasing likelihood of organ rejection. (8) The U.S Food and Drug Administration (FDA) approved the first line of this type of genetically modified pig for both consumption (to address certain red meat allergies) and therapeutic use in December 2020. (9) Other genetic modifications that have been made to pigs for the purpose of xenotransplants, include changing proteins in the pig blood vessels to a human version to address issues with unwanted blood clotting. (10) Whilst routinely used immunosuppressants are not effective at preventing rejection of pig organs in xenotransplantation, the 2020 review also discusses advances in drugs that can now help prevent xenotransplant rejection. (10) The lead author of the review, Richard Pierson, suggested at the time that the first humans could receive transplanted pig hearts by the end of 2021. (8) As it turns out he was only out by a week.

Xenotransplantation hit the headlines on the 7th of January 2022 when David Bennett, a 57-year-old man, received a genetically modified pig’s heart in an experimental surgical procedure in the United States after receiving special dispensation to carry out the procedure by the FDA. The procedure was widely reported in the press as a ‘success’ when David was up and talking in the weeks following the surgery. He sadly died two months later. Whilst this may not be considered a ‘success,’ as with many scientific advances, it could still be viewed us progress.

Ethical dilemmas

We all have an ethical compass shaped by our knowledge, beliefs, and experiences which impacts how we see, utilise, and interact with animals in our everyday lives. This informs our views on the use of animals in farming, keeping pets and the use of animals in medical research, including the use of animals to develop new procedures such as transplants.

Organ transplants from the start have raised ethical dilemmas. Back in the 1950s Joseph Murray reportedly spoke to researchers, legal experts, and religious leaders prior to carrying out that first successful kidney transplant operation. He was worried about the ethics of the surgery and the potential for healthy donors to be coerced into donating organs or opening the door to organ markets. (3) Many of us will also have strong feelings about the historical use of dogs to perfect transplant procedures before using them on patients. Whilst modern research methods provide new avenues for perfecting surgical techniques without animals today, the number of lives saved over the past 70 years with these transplant techniques has to be acknowledged. In 2021 26.7 million people opted to remain on the NHS Organ Donor Register, giving permission for their organs to be available for transplants to help save lives after they have gone. (11)

Today there is still a desperate need for healthy organs. There are currently 6,128 people waiting for a transplant in the UK. Between April 2020 and 2021, 159 heart transplants were carried out in the UK, plus two heart and lung transplants, with 310 people on the waiting list at the end of that time period for a heart transplant and 12 more for heart and lungs. (12) The NHS have recently said that the waiting list for heart transplants has increased by 85% in the last decade. (13) In the US, on average 17 people die each day waiting for an organ transplant and every nine minutes another person is added to the transplant waiting list. At the end of 2020, 1,707 people in America were still waiting for a heart. (1,4,5)

At this point having heard how many animals (and people) lost their lives in the development of modern transplant procedures, let’s consider the overlap between medical and veterinary science. Surgical procedures carried out during the historical development of modern transplants were undoubtedly for the benefit of mankind, yet as the techniques advanced, there is likely to be some overlap with the progression of veterinary science. Whilst the availability and cost of organ donors for pet organ transplants may limit the number of procedures carried out, kidney transplants are now an option for dogs with renal failure. The Humanimal Trust is a charitable organisation promoting the concept of ‘one medicine’ and opportunities for medical and veterinary progress to be used for the benefit of all species. (15) This is an interesting concept as most animal studies are approved and carried out for the purpose of medical research and safety testing, far less specifically for veterinary medicine. The use of animal research in medical science and veterinary science is therefore another interesting ethical dichotomy to consider, whilst the ethics of providing veterinary care for our pets raises more dilemmas around responsibility, cost, potential suffering, and euthanasia.

The recent xenotransplant operation was described as ‘ground-breaking’ and opinions at the time varied on whether xenotransplantation would become a common solution to the organ shortage crisis or not. A spokesperson for NHS Blood and Transplant in the UK said in a statement: “We have been watching this particular field of research for many years. However, there is still some way to go before transplants of this kind become an everyday reality.” (16)

Several organisations called out the xenotransplant as unethical and risky, for the obvious risk of rejection from the unproven technique, the reliance on experimental immunosuppressant drugs, the waste of resources and the suffering of the animals used in the development of the GA pigs and those used to provide the organs.(17, 18, 19)

FRAME agrees that the continued reliance on animal research for predicting human responses, researching human disease or sourcing organs and tissue for patients is scientifically flawed. We strongly believe that answers lie elsewhere in the continued development of in vitro methods that grow human tissue to study disease and ultimately grow human organs in the lab. We are already concerned about the number of animals being genetically modified to contain human genes, the number of animals needed to create and maintain these ‘humanised’ lines , the actual and potential wasted life on failed procedures and breeding processes, as well as the potential for planned and unplanned suffering in these processes. (18) From a scientific perspective the benefits of humanising animals for medical research are often limited due to physiological, immunological and metabolic differences between species, and resources would be better placed focusing on the development and progression of human-relevant solutions. Despite the reported ten genetic modifications on the pig used to provide the heart for Mr Bennett, the procedure ultimately failed, likely due to organ rejection, although this is unconfirmed. It is also likely there are yet more differences to take into consideration to avoid acute rejection due to species differences in the basic human and porcine biology and immune systems. Not least the fact that the pressures on our hearts may be very different due to the upright nature of our posture compared with that of a pig. (20)

The GA animals (mainly genetically altered mice) we normally discuss at FRAME are usually bred for use in basic or exploratory research into different diseases and used in research to increase knowledge of a particular gene or response. Although Mr Bennett only survived with his xenotransplant pig heart for two months, there is an argument that this has contributed to knowledge which may be used in the future to perfect the technique. So, despite the death of Mr Bennett, scientists on the front line of xenotransplant research are still reporting the potential of the procedure to save human lives in the future. Although it must be noted that a significant weight behind this view depends on the cause of failure in this first xenotransplant operation, and therefore how successful the procedure may be viewed moving forward. (21) The pursuit of animal research that is providing little benefit or value must be challenged.

At FRAME we disagree with the pursuit of xenotransplant research as a solution to human organ shortages predominantly for scientific reasons. However, alongside this there are some interesting ethical questions that can be asked to help us weigh up the value of potential outcomes of animal research, in this case xenotransplant research, against the cost in terms of harm caused to the animals. Today, where some animal research and tests still have no viable, robust replacement, this is an essential tool to prevent unnecessary animal use in research and testing.

Let us consider these questions in light of the experimental xenotransplant operation earlier this year:

• Are there alternatives? Evidently there was not a donor human heart available, and we know there are not enough in general. It would also seem a mechanical heart was not an option. Whilst tissue culture methods have advanced, we are still a long way from creating functioning organs in a lab.
• Does the procedure provide direct benefit? Mr Bennett lived for an extra two months. If the heart was not ‘rejected’ but his death proven to be due to other causes, it may be viewed a success and open the door for approval for future experimental xenotransplants on patients. If successful more patients could have their life extended, or potentially saved, including the hundreds waiting on transplant lists for a new heart or dying due to a lack of donor organs.
• How many animals were needed? (Not just for this procedure, but also all the animals that may have been produced as biproducts in attempts to achieve the required animal, and the many animals that were used in any historical ‘failures’ that led to this first success. One pig was needed in this procedure, but we don’t know how many pigs were needed to create this strain of GA pig or successfully breed this pig. This pig had the required 10 mutations. (16) If more are bred potentially not all of them will inherit the 10 mutations correctly. What percentage inherit the gene correctly and what happens to those animals that don’t? We don’t know and it would be a struggle to find these numbers easily.
• How much pain or suffering do the animals experience? (Not just this individual animal, but also collective suffering of all the other animals used in breeding and historical research to get to this point). We know the pig used in Mr Bennett’s case died after having his/her heart harvested. Did the pig suffer from any of the other procedures experienced during its life, such as blood tests or tissue samples being taken? In the UK the government publicly share some information about what research has been granted licenses and the predicted severity of suffering of the animals involved. We can also analyse published research for information. However, it would be difficult to judge the total suffering of all animals required to create this one pig, particularly when you consider research builds on previous studies from across the globe. We also know that in some scenarios induced genetic alterations can cause pain and suffering as a result, and on top of this off-target genetic effects can cause unplanned suffering. (22) Is that the case here – does this strain of pig suffer any unnatural discomfort because of the 10 mutations? Are there any off-target effects which occur when breeding these pigs?
• Are the animals distressed during their lives? By this I am talking about the conditions they experience. We know pigs are intelligent animals that like to be outside foraging. How are these animals kept prior to being used in surgery? If it is in a controlled, bio-sealed environment to maintain sterile conditions, surely this raises red flags for meeting welfare needs, including the ability to express natural behaviours. (18, 22) Can they mix with other pigs, what are they fed, and how much space do they have? If their welfare is compromised, we can assume this impacts their stress levels and quality of life.
• What species are the animals? Leading on from the previous question, the capacity of the individual species to suffer must be considered. This could consider, for example sentience, intelligence, need for social relationships, diet, natural behaviours and the ease with which their needs can be met in a particular environment. This is particularly important with primates as it is impossible to meet their welfare needs in a laboratory setting but is also arguable for other species that show complex cognition and emotion, such as pigs. (23)

In conclusion, when taking these questions and all the available information into account, it is difficult to make an ethical judgement about continuing to pursue xenotransplantation. We don’t have all the information on the numbers of animals needed and the amount of suffering undergone to reach this point. We do know that GA animal creation and use has the potential to use many, animals and cause unplanned suffering. Do the scientific advances to-date, and potential future advances and lives saved outweigh the animal cost of xenotransplantation?

If we are unsure, ethically we must err on the side of caution. In which case no, we should not be pursuing xenotransplants as a solution.

But if you or a member of your family were running out of time waiting for an organ donation would that change your view?

Dolly the sheep was the first animal clone. She was famously the first lamb born alive after 277 attempts. Let’s not go into the ethics of those numbers, or the ethics of cloning animals – not today anyway.

But we know today cloning is much easier and does not require so many animals. What if GA pigs could be produced with fewer animals and less suffering – does that change things?

What if we could find a way to obtain hearts from pigs that were also used for food consumption – as is the current practice for obtaining heart valves? Interestingly the strain of GA pig used for this heart transplant has also been approved for food use to help with certain meat allergies. Would that make this a more ethical process?

Whether xenotransplants could become a viable solution or not, it simply makes better scientific sense to channel more money and time into human-relevant methods and technologies that may one day allow us to grow hearts using human tissue in a lab. Taking into consideration the welfare of the many animals required, the biological differences between species that must be overcome, the precious time and funding being channelled into trying to improve xenotransplant techniques, and the cost in animal and human lives during this time, surely the case for funding and developing alternative approaches that support or replace failing organs is indisputable. Not only has this got potential to provide more effective solutions where one day organs and tissue may be grown on demand and matched to the needs and biology of a patient; but also end the suffering and waste of animal lives which results from trying to fit a square peg in a round hole, or a pig heart in a person.

Ethically and scientifically, this makes much more sense.

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References:
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4684730/
2. XENOTRANSPLANTATION – THE FUTURE OF CORNEAL TRANSPLANTATION? (nih.gov)
3. Joseph E Murray – The Lancet
4. Xenotransplantation: A Historical Perspective | ILAR Journal | Oxford Academic (oup.com)
5. History of Heart Transplantation: a Hard and Glorious Journey (nih.gov)
6. 40 years of heart transplant – timeline | BHF
7. Pig Valve Replacements: 10 Important Facts (heart-valve-surgery.com)
8. Hearts harvested from pigs may soon help solve chronic shortages of these donor organs — ScienceDaily
9. FDA Approves First-of-its-Kind Intentional Genomic Alteration in Line of Domestic Pigs for Both Human Food, Potential Therapeutic Uses | FDA
10. Progress Toward Cardiac Xenotransplantation | Circulation (ahajournals.org)
11. Organ donation achieved three quarters of its normal activity last year despite global pandemic – NHS Organ Donation
12. Statistics about organ donation – NHS Organ Donation
13. Valentine’s Day 2022 – NHS Organ Donation
14. Organ Donation Statistics | organdonor.gov
15. https://www.humanimaltrust.org.uk/one-medicine
16. https://www.newscientist.com/article/2304167-how-a-pig-heart-was-transplanted-into-a-human-for-the-first-time/#ixzz7LALlZGKz
17. First Heart Transplant From Genetically Altered Pig: PETA Statement | PETA
18. Three ethical issues around pig heart transplants – BBC News
19. First heart transplant into a human from a genetically modified pig is not only ethically wrong – it is already obsolete – Animal Free Research UK
20. expert reactihttps://www.bbc.co.uk/news/health-60708120on to pig heart transplant | Science Media Centre
21. https://www.bbc.co.uk/news/health-60708120 b
22. Use of gene altering technology | FRAME
23. https://escholarship.org/uc/item/8sx4s79c#page-1

Further reading & listening: https://www.animalfreeresearchuk.org/the-death-of-the-first-person-to-receive-a-pig-heart-transplant-is-not-in-vain/
The Naked Scientist podcast: Xenotransplantation | Podcasts | Naked Scientists (thenakedscientists.com):XENOTRANSPLANTATION: PAST, PRESENT, AND FUTURE