Could genetically modified animal organs solve the human transplant crisis?

Emma Nance discusses the pig-culiar story of the man who had a pig’s heart.

While using animals as organ donors for humans may seem like something out of an 80s horror movie, doctors in the USA recently transplanted a pig’s heart into David Bennett, a 57-year-old man with terminal heart disease.

David was in critical condition, bedridden for six weeks prior to the surgery and attached to a heart-lung machine. As David was ineligible for a human heart transplant or a heart pump due to heart failure and an irregular heartbeat, his doctors were granted emergency authorisation to conduct the experimental surgery. “Compassionate use” emergency authorisation is only available when patients like David have “no other options”.

After surviving for almost two months after receiving the pig heart transplant, David Bennett died on the 8th March 2022.

This experimental surgery could offer hope to many people worldwide currently waiting for organ transplants. In the USA, over 106,000 people are on the national transplant waiting list, with 17 people dying each day as a result. In the UK, the NHS Organ Donor Register and the National Transplant Register estimate that 7,000 eligible people are on the waiting list, with 470 people dying in 2020–21.

Organ recipient eligibility has an interesting medical ethical history, currently depending on several criteria including donor age, medical history, and likelihood of success. Additionally, while transplant organ availability is increasing in the UK due to legislative change, some organs may not be suitable due to average donor age, smoking habits, and other lifestyle factors. 

Until recently, transplants between species have seemed possible in science fiction but not in reality. However, cutting-edge advancements in science and medicine, such as genetic modification, have solved many practical barriers, making animal organs viable options for humans.

Though the scientific hurdles of xenotransplantation have been cleared, there are still many upcoming obstacles. Will individual societies and the global community accept the widespread use of animal organs for transplants? What laws should regulate xenotransplantation? Could this lead to an increase in medical tourism, dividing countries which allow xenotransplants from those which don’t? This ground-breaking surgery could mark the first of many lifesaving procedures using animal organs but also poses several questions. 

Pig-ture This: What is xenotransplantation?

Normally, organ transplants are performed between humans, with one person donating an organ to a patient.

For example, in 2017 Selena Gomez received a kidney donation from her best friend to treat lupus, an autoimmune disease that damages organs and tissues. This is an example of allotransplantation, a transplant between individuals from the same species.

In contrast, transplanting organs between species is called xenotransplantation, which comes from the Greek word xenos-, meaning “strange”, “foreign”, or “alien”. While xenotransplants may initially seem strange, these procedures could potentially save many lives. 

Swine Not: What happens when the body rejects transplanted organs?

Apart from seeming strange, there is a fundamental problem in conducting xenotransplants: the body’s readiness to attack foreign tissue.

Because our immune systems are primed to defend our bodies against foreign invaders such as bacteria, our immune systems also identify transplanted organs as foreign, potentially harmful invaders and launch attacks. This attack is called transplant rejection and is common even in human-to-human transplants. To prevent transplant rejection, the recipient usually takes immunosuppressant drugs, which can be dangerous due to infection risks. 

To further reduce transplant rejection risks, doctors attempt to closely match the donor’s organs with the recipient’s. Organ matching is done through tissue typing, where doctors identify proteins covering the surface of the organ, called antigens, and try to closely match the antigens of the donor to the recipient. However, only identical twins have identical tissue antigens; all other organ matching is imperfect.

A Series of Un-Porcine-ate Events: What is the history of human-to-human transplants?

The importance of closely matching antigens in human-to-human surgeries has taken decades to understand.

  • 1902 – Alexis Carrel pioneers blood vessel joining (anastomosis), making organ transplantation feasible for the first time (and earning him a Nobel Prize).
  • 1954 – Dr. Joseph Murray performs the first successful kidney transplant operation between identical twins, a procedure which has since saved ~400,000 lives.
  • 1960’s – A series of successful transplant firsts, including the UK’s first heart transplant and first liver transplant.
  • 1980s – Transplantation expands to include pancreases, lungs, and, corneas
  • 2005 – The world’s first full face transplant in France.
  • 2015 – Wales introduces laws which mandate that adults 18 and older who die automatically consent to organ donation unless they explicitly “opt-out”.
  • 2017 – English and Scottish Governments also switch to “opt-out” organ donation legislation.

Today, while human-to-human organ donations are well-researched and have relatively low risks, there still remains an organ shortage, leading researchers to consider animals.

A Fly in the Oinkment: What is the history of animal-to-human transplants?

Imagine the body’s response to an organ that is not even human but animal. The human body’s immune system would have an even stronger reaction to xenotransplants.

Xenotransplant rejection has been documented several times throughout history. Following Dr. Murray’s successful kidney transplant operation in the 1950s, from 1963–1964, Professor Keith Reemtsma attempted to transplant chimpanzee kidneys into humans on the hypothesis that primate organs were evolutionarily similar to human organs. However, of the 13 chimpanzee-to-human xenotransplants, none of the patients survived beyond nine months.

In 1966, using improved immunosuppressants, Dr. Thomas Starzl also attempted transplants using nonhuman primates on patients as young as seven; however, his patients all died soon after surgery.

In 1984, Dr. Leonard Bailey transplanted a baboon heart into the American infant Baby Fae who had a fatally underdeveloped heart. Though otherwise healthy, Fae was only expected to live for two weeks with the condition; however, she lived for 21 days with the transplant. Baby Fae lived two weeks longer than any previous simian heart transplant recipient but ultimately died, most likely due to an unavoidable blood type mismatch.

Snout Possible: Could xenotransplanted organs cause (another) pandemic?

Xenotransplantation advancements have been sparse due to another daunting barrier: animal-to-human transplants have a high risk of transferring microorganisms, like bacteria and viruses, from animals to humans.

Infectious diseases that jump from animals to humans are called zoonoses, with the Covid-19 pandemic showing how serious this risk can be. Zoonosis risks following xenotransplantation are high and merit extreme caution.

While early xenotransplants were taken from nonhuman primates due to perceived immunological compatibility, researchers have begun using pig organs. There are several reasons why pig organs are potentially preferable to non-human primates: pigs reproduce quickly and numerously; pig organs and adult human organs are similarly sized; and pigs grow rapidly and are cheaper to maintain than primates.

However, pig organs inherently carry a risky retrovirus, a virus that uses RNA to replicate as opposed to DNA, called porcine endogenous retrovirus (PERV), that would inevitably be transferred to human donors without intervention via gene editing. HIV is the best-known example of retroviruses in humans.

Let’s Get Microsco-pig: What is gene editing and how is it relevant to xenotransplants?

Gene editing serves as the final stepping-stone in overcoming the zoonotic barrier.

Gene editing changes an organism’s DNA, allowing scientists to precisely add, remove, or alter specific DNA sequences. One of the most famous gene editing technologies is CRISPR-Cas9, a system which revolutionised the field due to its fast, cheap, accurate, and efficient process. With CRISPR-Cas9, scientists are able to remove or “knock out” the genes which cause PERV as well as remove a sugar in pig cells that would lead to immediate organ transplant rejection in humans.

As a proof-of-concept, in September 2021, surgeons at N.Y.U. Langone Health successfully attached a genetically edited pig’s kidney into a brain-dead patient, with the patient’s family’s consent.

Following this successful pig kidney xenotransplant, a team of doctors led by Dr. Bartley Griffith performed David’s novel pig-heart surgery on 7 January 2022 at the University of Maryland Medical Centre.

The pig heart came from Revivicor, a company founded by PPL Therapeutics, the same UK company which created Dolly the Sheep. Dolly was the first mammal to be cloned from an adult cell at the Roslin Institute at the University of Edinburgh in 1996.

To make the pig heart that David received safe, scientists genetically edited 10 genes, removing three genes to reduce the risk of antigen rejection, adding six human genes to promote acceptance, and knocking out one porcine growth gene to ensure the heart does not grow after the xenotransplant.

In a Pig-le: What are the ethical, legal, and social issues of xenotransplantation?

While the promissory nature of xenotransplantation is exciting, there are several pressing questions. Is it morally acceptable to farm animals for their organs? How certain are scientists that the risks posed by animal organs have been properly reduced and mitigated? And, given finite resources, who “deserves” animal organs most? 

The idea of “deserving” organs has been recently scrutinised as it came to light that David was convicted of stabbing Edward Shumaker in 1988, leaving Edward paralysed. Edward’s family has subsequently questioned whether David deserved to have the “groundbreaking” surgery.

However, the transplant team quickly responded that a person’s criminal past could never prohibit them from receiving treatment, with officials at the University of Maryland Medical Centre writing that it is the “solemn obligation of any hospital or health care organisation” to treat all patients. Officials further stated that “any other standard of care would set a dangerous precedent and would violate the ethical and moral values that underpin the obligation physicians and caregivers have to all patients in their care”.

Perhaps we should consider also animal autonomy. Animal rights activists, such as the PETA and the UK-based animal rights group Animal Aid, protest against the use of animal organs for human transplants. PETA argues that animals should not be treated as “tool-sheds” to be raided but as “complex, intelligent beings”. Animal Aid asserts that animals have the “right to live their lives”.

Questions of medico-ethical permissibility often beget questions of religious permissibility, for example, with Jehovah’s Witnesses explicitly refusing blood transfusions. In the case of animal organs, since some religious laws prohibit the consumption of pork, like in Judaism or Islam, concerns have been raised about religious objections to using pig organs in humans. However, leaders from both religions have so far agreed that the use of animal organs to preserve human lives justifies xenotransplantation procedures. These practical and ethical considerations will continue to evolve, with the future of xenotransplantation uncertain but hopeful. 

Not Taken for Grunted: What is the future of xenotransplantation?

Xenotransplantation could be the silver bullet which solves the human transplant crisis and offers hope to numerous people around the world on transplant waiting lists.

The scientific advancements that have led to the successful transplantation of a pig heart into a human recipient are fascinating and could be applied in different contexts to solve a range of other medical problems.

However, we must be cautious of overpromising and under-delivering. While David’s surgery represents a landmark moment in the field of xenotransplantation, it doesn’t mean that pig organs will immediately become available for every person on organ transplant waiting lists. Before the widespread use of animal organs becomes a reality, we – scientists, healthcare practitioners, bioethicists, policymakers, and the public – must first actively address the multitude of practical and ethical issues surrounding xenotransplantation.

Emma Nance (she/her) is studying a PhD in bioethics and bioscience, focusing on One Health models of disease: science, ethics and society. Her Twitter: @emmaLNance.

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