Only about 50% out of 100,000 Americans waiting for transplants each year will find a human donor. Nearly 37 million American adults suffer from chronic kidney disease, with 786,000 of those diagnosed with end-stage renal disease (ESRD). Those with ESRD and 4.5 million adults in the US diagnosed with liver disease face a ticking clock as they await life-saving transplants.1 In addition to the human and medical need for these patients to receive organ transplants, the financial costs to maintain these patients are staggering. The American Society of Nephrology reports, for example, that Medicare annually spends $35 billion treating kidney failure and $114 billion managing kidney diseases.
Xenotransplantation, or cross-species organ transplantation, is currently being developed as a means to alleviate this tragic medical problem. Xenotransplantation involves the transplantation or infusion into a human recipient of either organs, tissues, or live cells from a non-human animal source such as a pig.
In the last year, there has been a great deal of progress in applying xenotransplantation to humans in need of an organ. The first-ever landmark gene-edited pig heart transplant to a human occurred in January 2022. The patient, David Bennett, was deemed ineligible for human heart transplantation and mechanical circulatory support, based on a history of non-compliance. He received a gene-edited pig heart and survived for 50 days. After his death, the research team learned that the transplanted organ was infected with a pig herpesvirus that had not been detected by pre-transplantation tests.2
A few months after the heart transplant, scientists independently reported3 transplanting the first pig kidneys into three people who had been declared legally dead because they lacked central brain function. These studies showed that the transplanted kidneys in these subjects produced urine and were not rejected by the human immune system, even two to three days after the procedure. In June and July of 2022, surgeons performed two more pig heart transplants on brain-dead people, and we are awaiting the outcomes of these procedures.
While pig-to-human transplants are relatively new, hundreds of pig-to-baboon transplants have been done over the past 50 years. The organs transplanted were mostly hearts, kidneys, and insulin-producing islet cells, and many of these baboons lived for several years.4,5 In the 1990s and earlier, pigs were chosen as potential organ donors for xenotransplantation because they are available in large numbers, are easy to breed, and are more likely to receive public acceptance over non-human primates. Pigs are well-suited candidates as animal organ donors because their organs are similar in size and anatomy to human organs.
Animal organs also have some clinical advantages over human equivalents because there is no need for the patient and a surgical team to be available at a moment’s notice when a genetically compatible human donor dies. In addition, it is much easier to screen animals, such as pigs, to determine their health as organ donors.
One of the significant obstacles in pig-to-human xenotransplantation is the risk of organ rejection by the recipient. However, it was discovered that mutating a pig gene encoding a protein that triggers human rejection (α-Gal) allows organs transplanted from these modified animals to survive much longer in non-human primates. Moreover, new gene-editing technologies such as CRISPR will reduce some of the risks associated with xenotransplantation. The pig whose heart was transplanted into David Bennett was engineered by Revivicor and had 10 genetic changes, including four human genes that suppress the immune response and two genes that prevent blood from coagulating in response to inflammation. Other companies are engineering pigs with altered genes to prevent the development of preformed and human neo-antibodies against non-human leukocyte antigens, the presence of which can lead to organ rejection and decreased long-term graft survival.6
Not all potential animal organs will require extensive genetic engineering. For example, pig pancreata lacking the immunogenic sugar (α-Gal) and containing two extra genes that dampen the human immune response were used in pig-to-baboon transplants. These transplanted pancreatic islets cured diabetes in five baboons, who lived for nearly two years without insulin or even constant immunosuppressive drugs.7
Another health concern about using pigs as organ donors is that pigs contain porcine endogenous retroviruses (PERVs). These viral elements embedded in the pig genome are harmless to pigs but might be harmful when transmitted to people receiving the transplant leading to a disruption of normal gene function or oncogenesis.8 Efforts to eliminate these PERVs have proven successful by using CRISPR gene-editing technologies to scramble all known PERVs in the pig genome.9
The costs of xenotransplantation must also be considered. Genetically engineered pig organs are not inexpensive because these engineered animals must be grown in carefully controlled and quarantined settings. The caretakers for the pigs must wear what are essentially spacesuits to ensure the animals do not get infections, and they must monitor the pigs frequently to ensure they are not carrying diseases.
There are additional monitoring costs in xenotransplantation. The patients will not only be monitored to ensure that their immune system does not reject the animal organ but also to ensure these patients do not contract any sort of post-transplantation infection. In addition, patients will have to be monitored to determine whether they acquire novel zoonotic diseases from the pig that could potentially spread to others, creating a new viral pandemic.
Currently, the cost of a heart transplant in the United States is around $1.66 million, according to the most recent estimates.10 Some scientists claim that the price of a pig heart transplanted into a baboon is only $500,000.10 Unlike pig transplants, transplanting a human organ is more expensive because of the costs associated with keeping a deceased donor’s organs viable during transport and the need to fly out transplant surgeons and other experts at a moment’s notice.
The reduced expense of xenotransplants is also due to the fact that potential recipients no longer have to wait in an intensive care unit for months or be on dialysis for years as they wait for a human organ to come available. Most importantly is that the cost in terms of saving human lives is immeasurable.