Dr. Alexis Carrel. Photo originally published by Bain News Service, June 1922. From Flickr Commons project and The Evening World via the Library of Congress George Grantham Bain Collection. Via Wikimedia. No known restrictions on publication.

In the early 1990s a distinguished scientist predicted that within twenty years thousands of lives would be saved by xenotransplantation. His optimism was unfortunately premature and in America today more than 100,000 people are waiting to receive human hearts, livers, or kidneys. Yet despite false starts and disappointments, the dream of using animal organs in medicine remains alive.

Already in the nineteenth century surgeons tried to perform skin grafts using material taken from various animals such as frogs. Corneal xenografts were first attempted in 1838. In 1878 the distinguished neurologist Charles Brown-Sequard claimed he was rejuvenated by injecting himself with extracts of dog and guinea pig testes.¹ The Russian-born surgeon Sergei Morozoff, who became known as the “monkey gland man”, made a fortune in the 1920s by claiming he could retard aging and restore vigor and potency by implanting slices of animal testicles into the scrotum, a procedure eventually carried out in Europe and America on thousands of men.¹ In 1994 Growth and his colleagues transplanted fetal porcine pancreatic islets into patients with diabetes but with no clinical benefit.

To remain viable, transplanted organs clearly need to receive an adequate blood supply, and to achieve this Julius Droller in Germany (1895) and Mathieu Laboulaye in France (1896) worked on developing techniques to suture blood vessels to one another. This approach was further perfected by Alexis Carrel, a pupil of Laboulaye’s, who received the Nobel prize and in the process stimulated several other surgeons to try their hand at performing organ transplants.²

In 1902 Emerich Ullmann successfully transplanted kidneys from one animal species to another, such as between dogs and goats. Four years later Jaboulay grafted a pig kidney into one human and a goat kidney into another, and in 1909 Ernst Unger followed up with two transplants of monkey kidneys in humans. None of these kidneys functioned for more than a few days and all were promptly rejected.² Successful transplantation had to await the development of immunosuppressive drugs in the late 1950s, while porcine heart valves and orthopedic devices could be used only after the antigenic pig cells were first removed from the material.

In 1963 Keith Reemtsma at Charity Hospital in New Orleans transplanted thirteen patients with monkey kidneys, one of which functioned for one year. In 1966 Thomas Starzl carried out chimpanzee-to-human liver transplants, and later, in 1992, one of his patients survived for seventy days after receiving a liver from a baboon.^2,3 Equally unsuccessful was the use of chimpanzee, sheep, or baboon hearts, attempted by James Harvey in 1964 and subsequently by several others, notably in 1983 by Leonard Bailey’s grafting a baboon heart into Baby Faye, an infant girl with life-threatening congenital heart disease. The surgical procedure was technically successful, but the graft underwent acute rejection and the girl died twenty days later.^3-5 In 1997 in India a 32-year-old man with ventricular septal defect received a heart from a monkey but died from infection seven days later. The surgeon was severely criticized for operating without official approval.⁶

It has long been understood that a whole host of mechanisms, cellular and humoral, act to oppose the successful transplantation of animal organs into humans. Natural antibodies, complement, killer cells, MHC antigens, and failures in immune regulation may all play a role in causing rejection.⁴ But in recent years advances in molecular science such as deleting genes from organ donors by a new technology called Crisp have begun to offer a glimmer of hope. In late 2021 Drs. Robert Montgomery in New York and Jayme Locke in Birmingham, Alabama, connected genetically modified pigs to the blood vessels of recently dead persons maintained on respirators, and found that at least for a few days there was no acute rejection. More dramatically, in January 2022, surgeons at the University of Maryland replaced the failing heart of a fifty-two-year-old patient with a porcine heart. There was no immediate rejection and the patient lived on for two months.

Although studies with antigenically modified pigs are continuing, many problems remain unsolved, and optimism and enthusiasm need to be tempered by the possibility that dangerous viruses could be transmitted to man. The procedure has also unleashed a whole flood of reservations from ethicists concerned about the use of organs taken from animals. On the whole, one is left with the sobering conclusion that the future of xenotransplantation still remains quite uncertain.

 

Further reading: 

1. Franklin JL. Rejuvenation: “The Adventure of the Creeping Man” from The Case-Book of Sherlock Holmes. Hektoen International. Fall 2021.
2. Clyde F. Barker CF and Markmann JF. Historical Overview of Transplantation. Cold Spring Harb Perspect Med 2013; 3(4): a014977.
3. Lanza RP, Cooper DKC, and Chick WL. Xenotransplantation. Scientific American 1997;277:54.
4. Ogata K, Platt Cardiac xenotransplantation. Future limitations. Cardiology 2004;101:144. 
5. Cooper DHC, Ekser B, and Tector AJ. A brief history of clinical xenotransplantation. Int J Surg 2015;23:205.
6. Mudur G. Indian surgeon challenges ban on xenotransplantation. Int J Surg 2015;23:205 and BMJ 1999;318:79.

 

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GEORGE DUNEA, MD, Editor-in-Chief

 

Winter 2022 | Sections | Science