**1. Introduction**

Over the course of the past 100 years, the rapid progress in drug development and surgical techniques has created a paradox for the area of transplantation medicine. Surgical protocols have become more successful and medicines have overcome many mechanisms of chronic rejection and allowed increased survival of transplant patients. However, the number of organs available for transplant has remained essentially constant. In addition, not all organs available through donation are viable for transplant. Organs such as lung, which are more prone to damage due to trauma, disease or deterioration, are available in drastically reduced numbers compared with heart or kidneys. Therefore, while there is an increasing number of patients who would survive and thrive long-term after organ transplantation, the limited number of organs available means a smaller percentage of eligible patients can actually undergo transplant surgery.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

A hard truth about human organ donation is that even with exponential increases in donor numbers, it is unlikely that the organ shortage would be relieved. The diversity of the human species, paired with the efficiency of the immune system, significantly reduces the chances that a given organ will be compatible with the patients in greatest need. Although immunosuppressive drugs can enhance length of survival, chronic rejection remains a risk the greater the mismatch between organ and patient. Furthermore, the donor geographic proximity, organ size and timing of availability of a compatible organ with a matching patient may be limiting. Thus, even as human organ donation continues to be optimized, there remains an immense need for additional organs above and beyond the availability of human donors.

During and after WWII, pharmaceutical companies created a series of increasingly effective immunosuppressive drugs which could inhibit some rejection responses, renewing interest

Xenotransplantation

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During 1963–1964, Reemstma carried out a series of transplants into 13 human patients using chimpanzee kidneys, with one patient surviving 9 months after transplant surgery [9]. The need for these experiments was driven in part by the desperate human organ shortage and lack of alternatives. Cadaveric organs often proved insufficient in quality, and volunteer human kidney donation, high risk at the time, was untenable for ethical and legal reasons. Although chronic dialysis had been demonstrated by the early 1960s, it was not widely available for patient treatment [10]. Therefore, despite the risks, xenotransplantation was consid-

Reemstma was not alone in exploring xenotransplantation as a means to overcome critical organ shortages. Hume attempted transplanting a chimpanzee kidney into a human, but the organ failed to show renal function [11]. Hardy and team focused on heart, observing survival for only 2 hours after transplanting a chimpanzee heart into a human patient [12]. Starzl carried out a series of transplants in human patients with baboon kidney [13] and livers, with variable results [14]. These seminal attempts at xenotransplantation showed that although surgical techniques and immunosuppressive drug treatments had greatly improved, they were insufficient to address the multitude of challenges in overcoming the xenorejection response. Indeed, it was nearly a generation later before Bailey used a baboon heart for transplantation

Although the close evolutionary relationship between non-human primates and humans would suggest an advantage in using chimpanzee or baboon organs for xenotransplantation, clinical, practical and ethical considerations prevent them from being a viable option. Non-human primate organs do indeed function almost identically to human organs, but are subject to a variety of diseases which are readily transmissible to humans [16]. Given the relatively fragile state of patients receiving multiple immunosuppressive drugs, the risk of primate zoonoses is too great. In addition, chimpanzees, baboons and many other non-human primates are impractical for large scale breeding. The low numbers of progeny of non-human primates limits the production of large numbers of animals by natural breeding or *in vitro* fertilization compared with agricultural species. Finally, use of non-human primates as organ donors faces insurmountable ethical barriers. A much more viable approach is the use of pig organs for xenotransplantation. Porcine organs are structurally and physiologically close to humans, and therefore can functionally substitute for analogous human organ functions. Unlike non-human primates, pigs are more evolutionarily distant from humans and thus have a greatly reduced risk of transmission of diseases to human patients, which can be essentially eliminated through genetic manipulation [17].

into an infant, who survived several weeks after receiving the organ [15].

**3. First attempts at human xenotransplantation with primate organs**

in xenotransplantation.

ered a potentially viable solution.

**4. A shift in species**

In order to address the above concerns and provide sufficient numbers of compatible organs, a number of approaches, both biological and mechanical, are being actively explored. Use of animal organs provides solutions to the challenges of availability and function. Multiple mammalian species possess organs which may substitute effectively for their human analogs and, in the case of agricultural species, can be rapidly bred in sufficient numbers to overcome organ shortages. Through use of controlled facilities, production of animals can be regulated and disease exposure eliminated. Additionally, careful breeding schedules can provide organs of appropriate size for any given patient on a predictable schedule for optimal timing of surgery. Finally, recent advancements in DNA sequencing and assembly and genome engineering technologies, paired with the advanced understanding of the cellular and molecular immunology responses in transplant rejection, allow the creation of animals which could provide an unlimited supply of rejection-free organs.
