Mathieu Jaboulay's (1860–1913) contribution to xenotransplantation

Abstract Mathieu Jaboulay (1860‐1913) was a professor of clinical surgery in Lyon, France who is best known for his development of vascular anastomosis and for conducting the first reported renal xenotransplantation experiments on humans, using pig and goat kidneys to treat end‐stage renal failure in 1906. His insights and pioneering techniques contributed significantly to allotransplantation and contemporary attempts at xenotransplantation. He is also credited with inventing several surgical instruments and novel surgical techniques that continue to influence vascular, general, and urological surgery to this day. However, this article will focus specifically on his notable contributions to xenotransplantation research and surgery.


INTRODUCTION
The modern and routine practice of solid organ transplantation is undertaken worldwide and is now a safe and effective means of treating acutely and chronically ill patients. In 2020, 129 681 organs were transplanted worldwide, 1  Greek, African, Norse, and Roman mythology and folklore in the form of human-animal hybrids, or humans with animal parts such as the minotaur and gorgon. 3,4,5 Historically, experiments in xenotransplantation have been driven by clinical necessity in terminally ill patients in a final attempt to prolong life. In 1906, the first recorded solid organ xenotransplantation procedure in humans was performed by the French surgeon Mathieu Jaboulay. This pioneering surgery utilized his clinical experience and experimentation with novel techniques of vascular anastomosis, establishing him as a pioneer for modern xenotransplantation research and surgery today.

EARLY LIFE AND MEDICAL EDUCATION
Jaboulay ( Figure 1) was born on July 5th, b 1860, in Saint Genis Laval  Jaboulay was a popular lecturer and surgeon who was revered by his students and internationally among his peers, primarily for his originality and pioneering surgical techniques. 7 Two of his most well-known and influential students were René Leriche (1879-1955) and the Nobel Laureate Alexis Carrel (1873-1944), the latter of whom went on to develop and improve his work on vascular anastomosis. He therefore made significant direct and indirect contributions to vascular surgery through both his own work and that of his students. 9

THE FIRST SOLID ORGAN HUMAN XENOTRANSPLANT
In 1902, Emerich Ullmann (1861-1937) performed the first "successful" kidney transplant, when he removed and autotransplanted a dog's kidney to the vessels of its neck where it produced urine for a short period. 10 Later that year, he also conducted dog-todog allotransplants as well as a dog-to-goat kidney xenotransplant that both produced urine. Ullmann used Payr's method, whereby the blood vessels are connected by tubes of absorbable magnesium metal. In the same year, the Vienna physician Alfred von Decastello On the third day, Jaboulay observed that the kidney was no longer functioning; it was removed on the same day. Following examination, Jaboulay identified the cause of the failure to be vascular thrombosis and erroneously lamented that the cause was his suturing technique. 12 It would be decades before organ rejection would be definitively recognized as an immunological phenomenon, 13,14 which was the most likely cause of the xenograft failure.
The second of Jaboulays' kidney xenotransplants took place nearly 3 months later on the 9th of April 1906. Although Jaboulay gives no definitive reason for changing his animal of choice from a pig to a goat, he does note that the goat kidney was smaller and had better quality vessels. 12 In this case, a 50-year-old woman suffering from renal failure had a left-sided goat kidney grafted to her left elbow fold. f Despite an uneventful operation, the same outcome was observed, and the goat kidney was similarly removed on the third day.
In both cases, the surgical wounds were left to heal by secondary intention. g

DEATH
Jaboulay-like Ullman and Decastello-would later abandon his work on xenotransplantation to continue his work on cancer, which was his primary focus in the latter years of his life. 15 He unfortunately suffered an untimely death at the age of 53 on the 4th of November 1913 following a horrific train crash in Melun, France. The severity of the crash was such that his remains were not discovered until four days later on the 8th of November. 7 In honor of Jaboulay's many accomplishments there is a road in Lyon named after him-Rue Jaboulay.

JABOULAY'S XENOTRANSPLANTATION LEGACY
The kidneys have historically been one of the primary organs of interest for transplantation. Because of their great need-the kidney is consistently the most transplanted organ in many countries. The immediate production of urine may indicate a successful transplant operation. They also have the surgical benefit of being vascularized by a single main vessel, the renal artery. It is perhaps easy and intuitive to deem Jaboulays' two kidney xenotransplants to have been prima facie unsuccessful since neither resulted in long-term function and patient survival. Nevertheless, arguably, they were in some meaningful sense "successful," since in both cases the xenografts were vascularized and produced urine. Some of the human kidney transplants performed over the next few decades never produced any urine. 11 After many failed xenotransplantation experiments using primarily non-human primates as the source of organs. Jaboulay's early use of a pig for xenotransplantation would be re-explored. Non-human primates were a rational choice due to their genetic similarities to humans. However, the heightened risk of zoonotic disease transmission in primates, difficulty of large-scale breeding, and greater hesitancy among the public for the use of primates in experimentation, in part led researchers away from non-human primates. Surely a primary reason why Jaboulay used a pig in his initial experiment was because of its ready availability and few people would object to his killing a pig for this purpose. Nonetheless, his choice of pigs as the source of kidneys for clinical transplantation was taken up by others many years later. 21 Today, the gene edited pig is the primary potential source of organs for clinical xenotransplantation. h One observation made by Jaboulay was a particularly astute one. In his 1906 report, he commented that xenografts ". . . must create favorable conditions for blood clotting that the autograft avoids." This correlates with studies carried out almost a century later in which significant discrepancies between the coagulation systems between pigs and primates were defined. These have only been overcome by the transgenic introduction of human coagulation-regulatory proteins into the pig. 22 Despite the complications and failures that plagued attempts at xenotransplantation for decades, Jaboulay had initiated the exploration of the pig-or goat-as a source of organs for humans. It has required solutions to numerous technological, immunological, and ethical hurdles, which over 100 years later, are now beginning to show the potential that many early proponents foresaw. Jaboulay, like many other pioneers before him, was willing to try something unconventional and risky in the hope of success and the restoration of health.

ORCID
Daniel Rodger https://orcid.org/0000-0002-2121-7167 Daniel J. Hurst https://orcid.org/0000-0003-0592-2592 ENDNOTES a The original term used to describe this was heterotransplantation. b There is some disagreement between the available secondary sources to whether Jaboulay was born on the 3rd or 5th of July, 1860. c Jaboulay clearly recorded that he connected the renal artery to the patient's humeral artery: 'L'artère rénale fut soudée au bout central de l'artère humérale, la veine rénale au bout central de la veine médiane céphalique. . . . However, this does raise some interesting questions, because strictly speaking, the humeral artery does not supply blood to the elbow. d Some secondary sources state that the transplanted kidney did not produce any urine or that there was no visible function. However, Jaboulay in his 1906 article states that-a strong diuresis was the only result of this graft ['Une forte diurèse fut l'unique résultat de cette greffe. . . '] and so it is clear that the first xenograft did produce urine. e Examples of this claim can be found in the following sources. 16,17,18,19 f McCauley 20 states that the goat kidney was grafted to the patient's thigh but Jaboulay describes it being grafted to the left elbow-'Je lui avais greffé au pli du coude gauche un rein gauche de chèvre enlevé. . . ' . g It is not unusual to read that the two female patients died shortly after the surgery, but this is not described in Jaboulay's description of the two cases. He gives no indication that the patients were followed until the wounds healed, which by secondary intention would be around six weeks, though it is unlikely that they lived that long. h For a recent example see Porrett et al. 23