Transplantation of foreign or allogeneic tissues has captivated human imagination since antiquity, and what began as the medicine of mythology now spans a timeline of three millennia. Indeed, Greek mythology and religious texts are rich with examples of xeno- and allotransplantation. Icarus and his father, Daedalus, for example, attempted to fly across the sea from Crete to Greece with the help of bird wings attached to their arms—one of the earliest writings illustrating xenotransplantation [1]. Ancient folklore in many cultures describes the amalgamation of physical attributes from multiple species into one, such as the Chimera in Homer’s The Odyssey, which is the fusion of a goat, lion, and a dragon, or the deity Zu in Babylonian myth, which is a lion-headed eagle with human arms. Perhaps the most famous of these chimeric heroes or gods is Ganesha, a Kumar child whom the Hindu god Shiva xenografted the head of an elephant, transforming him into the god of intellect and wisdom, the patron of art and science, and the remover of obstacles [2].

Interestingly, the concept of transplantation transcended temporospatial boundaries and has been reported in Egyptian, Chinese, Indian, and early Christian mythology as early as 2000 BC [3]. In ancient Chinese texts, the physician Pien Ch’iao exchanged the hearts of two warriors to cure the unbalanced equilibrium between the two men’s energies [4]. In the Old Testament, the prophet Ezekiel also refers to cardiac transplantation, stating “a new heart also I will give you… I will take away the stony heart out of your flesh, and I will give you a heart of flesh,” perhaps the earliest reference of a cardiac allograft. However, the most famous legend highlighting transplantation in antiquity is the “miracle of the black leg” in the third century AD by Saint Cosmas, a physician, and Saint Damian, a surgeon [5]. These twin brothers removed the malignant and gangrenous leg of an aged Roman deacon of the church, and successfully transplanted the leg of a recently deceased Ethiopian Moor to the patient while he slept. Upon waking, the Roman discovered he had a new, healthy leg, albeit a black one. Although it is unlikely that any of these legends are derived from historical fact, it underscores human fascination with the practice of transplantation. In particular, the legend of Cosmas and Damian describes for the first time a new concept: cadaveric transplantation—where the body of the dead can help the living.

Experimentation with various types of transplants continued in the following centuries. Although the earliest recorded human surgery only dates back to the Bronze Age, archaeological evidence suggests that Proto-Neolithic [6] and Neolithic [7] civilizations performed trephination, the removal of a circular disc of calvarium to relieve intracranial pressure, and this practice continued well into recorded history . Yet, the first reference to organ transplantation does not occur until AD 200, when the Chinese physician Hua Tuo is said to have replaced diseased organs with healthy ones [8]. Unfortunately, all of Tuo’s medical texts were destroyed and he was executed, causing his surgical practices and expertise to fall into disuse.

Although it seems unlikely that proper surgical techniques were available to facilitate successful performance of solid organ transplantation (SOT) at that time, the procedure of skin grafting had already been performed for many centuries. In the second century BC, the Indian surgeon Sushruta pioneered skin grafting and rotational pedicle flaps for nasal reconstruction and described over a dozen ways to reconstruct ears and lips. His forward-thinking concepts were compiled in the Sushruta Samhita, which served as the primary treatise on plastic and reconstructive surgery for centuries [9]. The prognoses for skin grafts improved considerably through the fifteenth century AD as these surgical techniques continued to be optimized.

In the sixteenth century, Gaspare Tagliacozzi emerged as a popular figure in transplantation, and he, like Sushruta, was a specialist in rhinoplasty. Tagliacozzi successfully performed nasal reconstruction on a patient who had lost his nose using a flap from the patient’s upper arm—one of the earliest records of a human autograft . Although the practice of donor consent did not exist, tissue transfer from slave to master had become common during this time, and as the Italian Poet Calenzio wrote, slaves would often “donate” their noses to their masters [10]. Possibly due to sectarian and secular objections, nasal reconstruction via allografting became the subject of satire, and was criticized by writers such as Voltaire. Similarly, in Samuel Butler’s play, Hudibras [11], he highlights the injustice of such practices in a scene that ends with, “When the date of Nock was out, off dropt the sympathetic Snout.” Although allografts were commonly attempted during this era, they did not enjoy the same success as autografts, and invariably failed. Tagliacozzi and other surgeon-scientists of the era became acutely aware that the limitations and failure of allografting were likely due to “the force and power of individuality” [12]. This was one of the earliest recorded indications that individual differences precluded tissue transfer between genetically disparate individuals; however, very little was known about genetics at this time, and the pioneering work of Mendel would not be conducted for another 250 years .

Reports of successful allografts began to circulate around the turn of the nineteenth century, when the Scottish surgeon, John Hunter, successfully transplanted the testes of a chicken into a hen “without altering the disposition of the hen” [13]. These experiments led Hunter to conclude that “transplantation is founded on a disposition in all living substances to unite when brought into contact with each other;” one of the earliest revelations regarding chimerism and allograft acceptance, which seems compatible with current philosophy on the matter. In 1804, the Milanese surgeon Baronia claimed to perform successful autogenous and xenogeneic skin transplants as well as free tendon allografts in sheep [.14]. However, Baronia’s results were unable to be duplicated, and were subsequently disputed by Paul Bert in his 1863 thesis, De la Greffe Animale [15]. In his manuscript, Bert describes his own animal experiments with many kinds of allogeneic and xenogeneic skin transplants and notes that the results of Baronia seemed unlikely. Nevertheless, experimental transplants continued and by the end of the century, stable corneal transplants were performed in animals and humans, and skin, tendon, nerve, tooth, and cartilage-free grafts had all been reported.

The 1800s were truly a Renaissance for transplantation after the darkness of the Middle Ages. Indeed, the concept of cadaveric transplantation reemerged in popular culture during this time, which is highlighted by Mary Shelley’s popular novel Frankenstein [16]. The novel describes a physically and morally superior creature constructed with organs and parts taken from a graveyard. Unfortunately, the creature turns to violence after his creator rejects him, thereby providing one of the earliest positive and negative depictions of transplantation in literature .

At this point, organ transplantation was still not technically feasible due to limitations in suturing techniques for vascular anastomosis . This obstacle was overcome in 1902 when Alexis Carrel introduced his vascular anastomosis technique [17], which unlocked a continuum of research in experimental organ transplantation, including an orthotopic canine head transplant. Within the same year, Austrian surgeon Emmerich Ullmann performed the first experimental kidney transplantation in animals in Vienna [18], which was followed a few years later by reports of unsuccessful attempts in humans by Mathieu Jaboulay [19]. In 1905, Carrel and Charles Guthrie performed the first cardiac transplant in animals [20]; however, the graft was rejected early, which was hypothesized to be due to malnutrition of the grafting tissue by Paul Ehrlich in the following year [21]. Renal transplantation reemerged as the most promising model of clinical transplantation, and allogeneic canine transplants, xenogeneic transplants into humans, and cadaveric human kidney transplants (performed in 1933 by Ukrainian surgeon Voronoy) were attempted—all of which were invariably unsuccessful [22].

The mechanisms of rejection were nebulous at this time and presented a major hurdle to successful organ transplantation. In the early 1900s, major advances were made in the understanding of humoral immunity; however, very little was known about lymphocyte function and cell-mediated immunity. The discovery of ABO blood groups in 1901 by Austrian biologist and physician Karl Landsteiner was a major advance for transplantation and led to the introduction of clinical blood transfusion [23]. In 1912, Murphy and Rous described the predominance of lymphocytes in a tumor rejection model, but several decades would pass before the activation of T cells was understood to be the molecular basis for acute allograft rejection.

Unfortunately, the 1930s marked a period of decline for transplant immunology research, due to limited success in skin and organ transplants secondary to rejection . Then came World War II and the bombings of cities led to a significant increase in burn victims in need of skin allografts . At this time, long-term outcomes for skin allografts were still plagued by a high failure rate due to the rejection response. This led to the pioneering work of Sir Peter Medawar, who transplanted skin onto badly burned soldiers in London, although the procedure was only successful when performed between identical twins [21]. Medawar concluded that the rejection of human skin allografts is a result of actively acquired immune reactions—work that was later summarized by Billingham, Brent, and Medawar in their manuscript “Actively Acquired Tolerance,” which became the preeminent treatise on engineering the immune system [24]. In this manuscript, they implicitly discuss the importance of chimerism for tolerance induction , noting the development of donor-specific tolerance by injection of donor cells into neonatal animals. Soon thereafter, this concept was explicitly demonstrated by Main et al., when it was shown that an immature or immunologically weakened (irradiated) organism was prone to tolerance through chimerism induction [25]. This knowledge of immunology facilitated one of the most remarkable advances in medicine in the twentieth century: the advent of successful SOT .

Prior to the 1950s, early outcomes after organ transplantation were poor; however, the incorporation of the aforementioned findings led Dr. Joseph Murray to perform the first successful living-related kidney transplantation between identical twins in 1954 [26]. Shortly thereafter, a rapid development and utilization of chemical immunosuppressive drugs took place. The use of agents such as azathioprine, 6-mercaptopurine, and steroids in the 1960s allowed for the success of cadaveric renal transplants in 1962, and ushered in a new era in SOT [27

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