Xenotransplantation Bridges Past and Present, Revolutionizes Field of Transplantation

The prospect of clinical xenotransplantation recently has been invigorated by two pioneering cardiac xenotransplant cases performed at the University of Maryland in 2022 and 2023.

However, there are several renowned surgeons who embarked upon early attempts at cardiac xenotransplantation, including James D. Hardy, MD (1964), Donald Ross, MD, FACS (1967), Denton A. Cooley, MD, FACS (1968), and Leonard Lee Bailey, MD (1984), who performed the first infant heart transplant on “Baby Fae” at Loma Linda University Medical Center in California—a case that captured news headlines around the world.

This historical retrospective traces the history of cardiac xenotransplantation and the controversies associated with previous attempts at human trials, while providing insight into new opportunities for this revolutionary and potentially lifesaving therapy.

From Ancient Greece to the 20th Century

Xenotransplantation, from the Greek “xénos” (foreign, guest, strange), refers to the transplantation of tissues across species barriers. The first successful clinical xenotransplant in ancient legend was performed by Daedalus, who grafted bird feathers onto his arms to escape by flight from Crete to Athens. The first xenograft failure was noted in Daedalus’s son Icarus, who developed hyperacute graft rejection due to a thermolabile reaction.¹

Later attempts at clinical xenotransplantation began in the early 20th century, when advances in the understanding of physiology led to new interest in renal xenografts. In 1906, Mathieu Jaboulay, a professor of clinical surgery in Lyon, France, attempted two heterotopic renal xenografts from a sheep and goat; both grafts failed due to hyperacute rejection with vascular thrombosis.

In 1910, Ernst Unger, a German physician and surgeon, performed a renal xenotransplant from a nonhuman primate to human, which similarly failed after 32 hours due to vascular thrombosis.¹ In 1923, Harold Neuhof, a pioneer of thoracic surgery, performed a renal sheep-to-human xenotransplant at Mt. Sinai Hospital in New York City. This xenograft survived for 9 days and represented a leap forward in xenograft survival.

Dr. Neuhof later wrote: “[This case] proves, however, that a heterografted kidney in a human being does not necessarily become gangrenous and the procedure is, therefore, not necessarily a dangerous one, as had been supposed. It also demonstrates that thrombosis or hemorrhage at the anastomosis is not inevitable. I believe that this case report should turn attention anew.”² Dr. Neuhof was a founding member of the American Board of Surgery in 1937.

The next attempts at renal xenotransplantation followed the development of renal replacement therapy by hemodialysis in the 1940s and 50s. While hemodialysis treatment showed exciting promise at sustaining life, the relative shortage of dialysis machines led to new innovations in renal replacement. In 1964, Keith Reemtsma, MD, a surgeon at Tulane University in New Orleans, Louisiana, published reports of 13 chimpanzee-to-human xenotransplants. While most grafts survived 4-to-6 weeks, one of these xenografts survived for more than 9 months and allowed its recipient to return to activities of daily life, including work as a schoolteacher.³

Also in 1964, Thomas E. Starzl, MD, PhD, FACS, published a report of six baboon-to-human renal xenotransplants with varying success, as well as heterotopic auxiliary liver xenografts.^4,5 Dr. Starzl would pioneer human liver transplantation in 1967, and later the use of cyclosporine and tacrolimus.

From First to Fae (1964–1984)

“We should solve the problem [of organ transplantation] by using heterografts [xenografts] one day if we try hard enough, and maybe in less than 15 years.”
—Sir Peter Medawar, Nobel Prize-winning immunologist, 1969¹

The first human heart transplant was a xenotransplant using a chimpanzee heart performed on 68-year-old Boyd Rush on January 23, 1964, by Dr. Hardy at the University of Mississippi in Jackson. After completing his medical education at the University of Pennsylvania in 1942, Dr. Hardy was later recruited to become the inaugural chair of surgery at the University of Mississippi in 1955. There, he focused the department’s efforts on organ transplantation. This was a reasonably attainable goal, as this area was still an emerging field and the new department could readily compete with more established surgical departments. He also was able to use expertise from Dr. Reemtsma’s transplant laboratory in nearby New Orleans. 

Just a few days before the xenotransplant, Rush experienced a presumed myocardial infarction and was transferred to the University of Mississippi. Over the subsequent days, Rush developed progressive cardiac failure.

At the time, Dr. Hardy was considering performing a human-to-human heart transplant, using the heart of a neurologically devastated trauma patient who was in Mississippi’s intensive care unit, but the potential donor’s heart was still beating (in an era before clinical brain death).

Rush developed fulminant cardiac failure on the night of January 23 and was taken emergently to the OR for cardiopulmonary bypass as salvage therapy. Rush’s sister signed an informed consent form that stated “any heart transplant would represent the initial transplant in man,” though it did not state the heart to be used was from a nonhuman primate. The orthotopic chimpanzee heart functioned for 60-90 minutes following transplant, but Rush was unable to be weaned from bypass and died.

The University of Mississippi’s director of public information released a guarded statement on the priority of this first human heart transplant that included the vague phrase "the dimensions of the only available donor heart" and did not disclose that the donor heart came from a chimpanzee. The Associated Press widely distributed a story that began with, "Surgeons took the heart from a dead man, revived it, and transplanted it into the chest of a man dying of heart failure today," failing to recognize the use of a nonhuman primate as the donor. Dr. Hardy would publish this case report in The Journal of the American Medical Association (JAMA) later that same year.⁶

Dr. Hardy’s career as a pioneering cardiothoracic transplant surgeon is remarkable, as he also performed the first human lung transplant in 1963, using a human donor. Dr. Hardy served as the President of the ACS from 1980 to 1981.

In 1968, Dr. Ross performed a heterotopic pig-to-human cardiac xenotransplant at the National Heart Hospital in London. This xenograft survived less than 5 minutes due to hyperacute rejection. Dr. Ross is best known for developing the pulmonary valve autograft to replace a failing aortic valve in 1967, now known as the eponymous Ross procedure, as well as performing the UK’s first human cardiac allotransplant in 1968.

Also in 1968, Dr. Cooley performed an orthotopic sheep-to-human cardiac xenotransplant at the Texas Heart Institute in Houston.⁷ This xenograft also survived only a few minutes due to hyperacute rejection.

Dr. Cooley is perhaps the most famous American cardiac surgeon to date, with a long list of accolades and “firsts” in cardiac surgery. As a resident, he assisted Alfred Blalock, MD, FACS, in his first subclavian-pulmonary arterial shunt in 1944 (now the eponymous Blalock-Thomas-Taussig shunt). He founded the Texas Heart Institute in 1962 and was the first to implant a total artificial heart in 1969.

In 1977, Christiaan Barnard, a surgeon in South Africa, performed two clinical xenotransplant procedures using hearts from nonhuman primates at the University of Cape Town.⁸ These procedures were unique, as they were heterotopic xenotransplants that were used as a ventricular-support bridge to supplement circulation in two patients who were unable to be weaned from cardiopulmonary bypass. The two xenografts were taken from a chimpanzee and baboon, which functioned for 5 hours and 4 days, respectively. Dr. Barnard is best known for performing the first successful human cardiac allotransplant in 1967.

The next attempt at cardiac xenotransplantation would not come for several years. In 1984, Dr. Bailey performed a baboon-to-human orthotopic heart transplant into an infant at Loma Linda Medical Center. The patient, Stephanie Fae Beauclair, was born prematurely with hypoplastic left heart syndrome.

At the time, there had never been an attempt at heart transplantation of any kind in an infant. Intended as a bridge to allotransplant, “Baby Fae” underwent this procedure on October 26, 1984, at 12 days old due to progressive instability and fulminant cardiac failure with her native heart.

The xenotransplant was performed using cyclosporine immunosuppression across an ABO-incompatible immune barrier using an AB-type baboon donor into the O-type recipient (as the O blood type is nonexistent in baboons).

This procedure and its potential for success captivated the nation, even making the cover of Time magazine in an article “Baby Fae Stuns the World.”⁹ Baby Fae lived for 20 days post-transplant before dying from complications of acute graft rejection.

The Time article revealed some of the sharp divisions regarding xenotransplantation within the surgical community. In the article, John Najarian, MD—chair of surgery at the University of Minnesota and pioneer in the use of antithymocyte globulin for use in transplantation—remarked: “There has never been a successful cross-species transplantation. To try it now is merely to prolong the dying process. I think Baby Fae is going to reject her heart.”⁹

John J. Collins Jr., MD, chief of the Division of Cardiac Surgery from 1970 to 1987 at Brigham and Women’s Hospital in Boston, Massachusetts, said: “It’s easy to sit back and be negative when a new treatment is announced. If we all were afraid to attempt the untried, we would have no new treatments.”⁹ The transplant also sparked new questions regarding the ethics of laboratory animals used for medical research.

Thirteen months after the transplant, JAMA published three articles on the Baby Fae xenotransplant. The first was a detailed scientific paper authored by Dr. Bailey “describing the first case of cardiac xenotransplantation in a neonate.”¹⁰ The second, “Informed Consent and Baby Fae” noted “there has been great public concern about the ethical problems involved in the highly experimental surgery” and ethics of parents deciding experimental cures for their children. The third was an editorial and medical review, which concluded that the transplantation was doomed to fail and that hopes for a successful transplant by Dr. Bailey were “wishful thinking.”

Despite the controversies surrounding Baby Fae’s transplant, Dr. Bailey persisted and would perform the first human cardiac allotransplant in an infant the following year.

Modern Cardiac Xenotransplant and the “Holy Grail”

Xenotransplantation “is just around the corner, but it may be a very long corner.” 
—Sir Roy Calne, organ transplantation pioneer, 1995

Following the Baby Fae xenograft, it would be nearly 40 years before the next attempt at clinical xenotransplantation. On January 7, 2022, Bartley P. Griffith, MD, FACS, and colleagues at the University of Maryland (UM) in Baltimore, performed a life-sustaining orthotopic pig-to-human cardiac xenotransplant into a 57-year-old man using a genetically modified pig donor and novel immunosuppression medications.^11-13 This graft sustained function for 60 days before failing due to diffuse endothelial injury and immune activation.¹⁴ Dr. Griffith and his team then performed a second orthotopic cardiac xenotransplant into a 58-year-old man on September 20, 2023, using a similar protocol. The second transplant functioned for 40 days until it failed due to xenograft rejection.¹⁵ Both xenotransplant recipients were unable to receive clinically available advanced heart failure therapies due to other comorbidities.

Several preclinical breakthroughs have paved the way for the use of xenografts in clinical application. Novel immunosuppressive medications developed to target the costimulation pathway CD40-CD40L have been established in preclinical studies to be superior to clinically available immunosuppression agents like tacrolimus.

Advances in genetic engineering have allowed modification of the porcine donor using transcription activator—like effector nucleases and somatic cell transfer using CRISPR/Cas9 to prevent xenograft rejection. This genetically modified pig included deletion of porcine-specific cell-surface carbohydrates (alpha-1,3-Gal, Beta-4-Gal, and Neu5Gc), deletion of intrinsic growth factor (GHR) and the addition of several human genes that modulate complement regulation (CD46, CD55), anticoagulation (EPCR, thrombomodulin), and innate anti-inflammatory (CD47, HO-1) signaling.¹² Along with improvements in cardiac intensive care and extracorporeal circulatory support to mitigate perioperative early heart dysfunction, these new innovations have re-invigorated the interest in cardiac xenotransplantation.

Cardiac Xenotransplant: Ready for Primetime?

“Xenotransplantation is the future of transplantation, and always will be.”
—Norman E. Shumway, MD, PhD, a cardiac surgeon who performed first heart transplant in US¹

Several barriers still exist before xenotransplantation can be considered a clinically available therapy for patients with end-stage heart failure. Overcoming the remaining immunologic, physiologic, infectious, social, ethical, and regulatory hurdles to xenotransplantation while ensuring foremost patient safety and patient outcomes remains paramount.⁷

Lingering questions include the optimal organ for xenotransplantation trials, recipient functional status, xeno donor, and immunosuppressive regimen to best support the patient post-transplantation. Looking further into the future, advances in tissue engineering and biomechanical engineering may allow for a more tolerogenic or even autologous synthetic organ.

The history of cardiac xenotransplantation is rich with immunologic and technical innovations, as well as courageous patients and compassionate surgeons. Many of the preeminent cardiac surgeons, including Drs. Hardy, Ross, Barnard, Bailey, and Griffith, have built upon years of knowledge and study to pioneer this revolutionary therapy to improve patient care.

Dr. Brendan Lovasik is a clinical fellow in transplant surgery at Washington University in St. Louis, Missouri.

References

1. Cooper DKC, Ekser B, Tector AJ. A brief history of clinical xenotransplantation. Int J Surg. 2015;23(Pt B):205-210.
2. Neuhof H. The Transplantation of Tissues. Appleton and Company; 1923:297.
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4. Starzl TE, Marchioro TL, Faris TD, McCardle RJ, et al Avenues of future research in homotransplantation of the liver with particular reference to hepatic supportive procedures, antilymphocyte serum, and tissue typing. Am J Surg. Sep 1966;112(3):391-400.

5. Starzl TE, Marchioro TL, Peters GN, et al. Renal heterotransplantation from baboon to man: Experience with 6 cases. Transplantation. 1964;2:752-776.

6. Hardy JD, Kurrus FD, Chavez CM, et al. Heart transplantation in man. Developmental studies and report of a case. JAMA. 1964;188(13):1132-1140.

7. Boulet J, Cunningham JW, Mehra MR. Cardiac xenotransplantation: Challenges, evolution, and advances. JACC Basic Transl Sci. 2022;7(7):716-729.
8. Barnard CN, Wolpowitz A, Losman JG. Heterotopic cardiac transplantation with a xenograft for assistance of the left heart in cardiogenic shock after cardiopulmonary bypass. S Afr Med J. 1977;52(26):1035-1038.

9. Wallis C, Holmes S. Baby Fae stuns the world. Time. Nov 12, 1984;124(20):70-72.

10. Bailey LL, Nehlsen-Cannarella SL, Concepcion W, Jolley WB. Baboon-to-human cardiac xenotransplantation in a neonate. JAMA. 1985;254(23):3321-3329.

11. American College of Surgeons. ACS Fellow performs first successful pig-to-human heart transplant. Bull Am Coll Surg. February 4, 2022. Available at: https://bulletin.facs.org/2022/02/acs-fellow-performs-first-successful-pig-to-human-heart-transplant/. Accessed January 4, 2024.
12. Griffith BP, Goerlich CE, Singh AK, et al. Genetically modified porcine-to-human cardiac xenotransplantation. N Engl J Med. 2022;387(1):35-44.
13. Peregrin T. Dr. Bartley P. Griffith discusses landmark pig heart transplant. American College of Surgeons. Bull Am Coll Surg. June 2022. Available at: https://www.facs.org/for-medical-professionals/news-publications/news-and-articles/bulletin/june-2022-volume-107-number-6/dr-bartley-p-griffith-discusses-landmark-pig-heart-transplant/. Accessed January 4, 2024.

14. Mohiuddin MM, Singh AK, Scobie L, et al. Graft dysfunction in compassionate use of genetically engineered pig-to-human cardiac xenotransplantation: a case report. Lancet. 2023;402(10399):397-410.

15. Rabin RC. Second Maryland man to receive altered pig’s heart dies. New York Times. October 31, 2023. Available at: https://www.nytimes.com/2023/10/31/health/pig-heart-transplant-faucette.html. Accessed January 4, 2024.