Allotransplantations are the first‐‐choice treatment of diseases characterised by terminal organ failure, but the limited supply of organs unfortunately means that only a few potential transplantation candidates can actually be treated in this way.
The hope of being able to replace a diseased organ with a healthy animal organ goes back to Hippocrates, but it was not until the beginning of the twentieth century that the first attempts were made possible by the delopment of vascular anastomic techniques. However, these failed and it was only in the second half of the century that the efficient use of immonosuppressive drugs allowed chimpanzee kdneys to be transplanted into 13 patients in the USA, one of whom survived for months. Initial attempts to transplant chimpanzee ((James Hardy, 1964)) or baboon hearts ((Christian Barnard, 1977)) proved to be unsuccessful because of hemodynamic complications or rejection problems and, although various attempts to transplant baboon livers made in Pittsburgh between 1992 and 1995, a patient who survived for more more than two months died of sepsis due to the degree of immunosuppression necessary to inhibit rejection.
These clinical experiments gave rise to problems and debates of various kinds, but mainly indicated that non‐‐human primates ((chimpanzees and baboons)) were not ideal donors of organs to be transplanted into Man. There are many reasons for this: they are genetically correlated with mankind and therefore present a greater risk for the xenotransplant itself but could also modify the susceptibility of the body to “non‐‐human” infections.
It has recently been shown that some endogenous porcine retroviruses are capable of infecting human cells in vitro and, although in vitro infection is not necessarily predictive of the in vitro development of disease, this finding does demonstrate the possibility of a recombination of animal and human genetic material, and the consequent risk of the silent spread of new pathogens in the population. This risk is not only generated by the transplantation of xenogenic ((non‐‐human)) organs and tissues, but also by the use of in vitro expanded or manipulated animal cells exposed to contact with human blood.
However, despite these considerations, the drive towards the clinical application of recent biotechnological acquisitions in the field of xenotransplantation is very strong, which is why we hope that the competent authorities will soon issue a series of suggestions aimed at identifying and defining:
safety and efficacy criteria for the clinical application of xenotransplantation;
appropriate quality controls for clinical trials;
accreditation criteria for the Centres involved in clinical xenotransplantation research;
criteria for monitoring the qualifications and health of the personnel involved and exposed to the risks associated with xenotransplantations.
We also feel that a number of indispensable preclinical requirements must be met before experimenting xenotransplantations in man. In particular, it must be demonstrated that the animals receiving a xenotransplant survive longer than their controls, and that the duration of this survival is sufficient to guarantee the efficacious clinical application of the technique. Furthermore, the transmission of infective agents from the donor to the transmission of infections; their availability is limited and very expensive; and they take a relatively long time to reach adulthood and are not very fertile. Last but not least, their evolutionary closeness to the human species has ethical implications that are difficult to resolve and make their sacrifice less acceptable.
The advances made in immunogenetics at the end of the twentieth century have allowed us to understand the molecular basis of rejection, and the availability of new immunosuppressant drugs has renewed interest in the possibility of transplanting “non‐‐primate” animal organs in man. In this new perspective of using genetically more discordant species, pigs have taken on a pre‐‐eminent role insofar as they can be bred in large numbers and rapidly reach a size that is suitable for human transplantation, their physiology is similar to that of humans, and they probably present fewer risks in terms of transmittable diseases. Furthermore, as far as ethical considerations are concerned, it seems to be logical to assume that there is no substantial difference between sacrificing them for purposes of food and sacrificing them for life‐‐saving therapeutic purposes. It can therefore be hypothesised that only the minority of the population opposed to the killing of animals for any reason ((even as a source of food)) will not agree with their use as organ donors.
Nevertheless, although these technical and ethical possibilities give rise to great hopes, it needs to be recognised that xenotransplantations between different species creates equally great fears concerning the risks for humankind as a whole that may be engendered by a violation of the between‐‐species biological barriers that have been built up over thousands of years. The infective agents of other species ((viruses, retroviruses, priones, etc.)) could adapt themselves to humans under facilitating conditions such as those induced by immunosuppression, which induces recipient tolerance to the recipient and the personnel involved in the preclinical studies must be carefully monitored.
The production process and final product quality controls of in vitro manipulated cells and tissues must guarantee the safety and efficacy of the products authorised for clinical use, while simultaneously ensuring that further developments and technological innovations are not hampered by unnecessary or excessively complex regulations. “Reasonable” control levels inevitably depend on the different risks involved in the use of different cells//tissues, but what is important is that they must be carried out by competent bodies that are extraneous to the manufacturers, and that the latter must be obliged to respect them.
Finally, any trials involving humans must satisfy the efficacy, safety, quality control and good clinical practice guidelines that apply to all clinical trials of new drugs, as well as accreditation criteria of the trial site.
However, it is also worth remembering that xenotransplantation is only one means of compensating for the lack of transplantable human organs. The advances being made in the fields of basic science, biotechnology and bioengineering make it possible to imagine the use of in vitro tissue reconstruction in the near future, and possibly the use of stem cells to create healthy organs capable of replacing their diseased counterparts.
In conclusion, our own feeling is that, even if it is capable of significantly contributing towards solving the problem, any therapeutic alternative to traditional transplantation should only be considered in the case of emergencies involving patients whose general conditions make them optimal transplant candidates.