**2. History**

Xenotransplantation experiments were described as early as the seventeenthcentury [2], with sporadic attempts made to transplant a variety of animal tissues and organs into patients throughout the nineteenth and early twentieth centuries [3–7]. After World War II, organ transplantation from living humans was considered too high risk, and cadaveric organs were insufficient in both quality and number to meet clinical needs. Development of immunosuppressive drugs suggested the possibility that organs from more closely-related mammals could potentially be used in humans. As a consequence, xenotransplantation efforts shifted to the use of organs from primates in human patients. In the 1960s, experiments by Reemstma et al. [8, 9], Hardy et al. [10], and Starzl et al. [11, 12] showed that while it was technically possible to transplant animal organs into humans, there were still too many clinical challenges at that time for the approach to be viable. More research was required to understand and overcome the barriers to the practical application of xenotransplantation in humans.

One of the major advances in xenotransplantation research in the past few decades has been the focus on the use of pigs as donors [13]. This was based, in part, on purely practical considerations. Unlike primates, pigs are an agricultural species for which large scale breeding is well-established. In addition, the evolutionary distance between humans and pigs reduces the risk of transmission of zoonoses from pig organs to patients compared with primate organs. Most importantly, the use of porcine organs does not present the same ethical barriers as the use of non-human primate organs [14].

Although the anatomy and physiology of pig organs is closely analogous to that of humans, the advantages of porcine organ production and availability do not address the critical issue of incompatibilities of non-human tissues and organs with the human immune system [15]. Significant advancements have been made in recent years in understanding the molecular mechanisms of xenorejection responses, and a variety of genetic modifications have been made to overcome these mechanisms. Experiments transplanting pig organs into non-human primates have demonstrated a progressive improvement in organ survival and function as new genetics and drug regimens have been implemented [16]. The FDA is currently developing guidelines for clinical xenotransplantation [17], and efforts to initiate clinical trials in the near term have been announced [18].
