English
中文Introduction
The development of the technique of organ transplantation was one of the major medical advances of the twentieth century. Allotransplantation is now a highly successfully way of treating patients for a wide variety of life-threatening medical conditions, but crucially is dependent on an adequate supply of cadaveric human organs. Because of the enormous success of organ transplantation, the ever-increasing demand for human organs means that there are simply not enough to go around. This means that there are currently long waiting lists for urgent medical procedures.
One solution to the problem of organ shortages is xenotransplantation. Xenotransplantation can be defined as the transplantation of animal cells, tissues or organs into human recipients for therapeutic purposes (Melo et al., 2001). The purpose of this essay is to thoroughly evaluate this technique. I will begin by describing how xenotransplantation can be carried out, and discuss the evidence to suggest that such a procedure might be technically feasible in the near future. I will then consider the various advantages and disadvantages of the technique, before concluding the review with my personal opinions on the merits of xenotransplantation.
How is Xenotransplantation Achieved?
The principles behind xenotransplantation are simple. First, the organ is harvested from the animal of choice. The patient then undergoes an operation to remove the damaged organ and to replace it with the animal organ. If the animal organ is sufficiently similar to its human counterpart then it should function in the human body, thus hopefully restoring the recipient to health.
Pigs are the animals of choice as organ donors, due to their comparable anatomy and physiology with humans. Although primates are more closely related to us, pigs have a number of advantages: they can be bred more easily, there is less risk of cross-species infection and their organs are of a comparable size to that of humans (Yuan and Sykes, 2007). The pigs will therefore need to be bred in a suitably controlled way, such that the donated organs are of reliable quality and free from infectious disease. Skilled surgeons are then required to harvest the organ from the animal, remove the dysfunctional organ from the patient and replace it with the donated organ. Finally, the patient will then require careful monitoring to ensure that (1) the new organ is functioning as anticipated, (2) that the immune system is not attacking the foreign cells and (3) that they are not suffering from any zoonotic disease. Indeed it is likely that the first recipients will require detailed long-term monitoring following the procedure, given the initial uncertainty that there will be surrounding the durability of the transplant.
Is Xenotransplantation Scientifically Plausible?
In my view, the best way to assess whether the procedure is scientifically feasible is to examine the success of pig to primate xenograft experiments. Given that primates are our closest relatives, if it can be demonstrated that porcine organs can function in primates then it is highly likely that xenotransplantation will also work in humans.
A number of different groups are currently exploring the possibility of clinical xenotransplantation by carrying out experiments in primates. Some promising initial results have been recently presented; transplanted hearts (McGregor et al., 2005) and kidneys (Baldan et al., 2004) from pigs have been shown to sustain the life of primates for several months. Although preliminary, these reports indicate that that there are no physiological barriers to xenotransplantation. Although a range of technical problems remain to be overcome, in principle the concept appears to be valid (Cozzi et al., 2007).
Currently, most research effort in this field is devoted to developing ways to prevent the immune rejection of the animal organ. Two processes can lead to immediate antibody-mediated attack on the new organ: hyperacute rejection (HAR) and acute humoral xenograft rejection (AHXR) (Yang and Sykes, 2007). Obviously, methods to circumvent these processes will be required before xenotransplantation is possible. In this regard, a major recent breakthrough was the realisation that HAR is mediated by antibodies that recognise the carbohydrate epitope a1,3-Gal present on the vascular endothelium (Yang and Sykes, 2007). By using organs from pigs in which the a1,3-galactosytransferase gene is deleted, researchers were able to prevent the immediate HAR-mediated rejection of organs transplanted into primates (Yamada et al., 2005). In my view, this study illustrates how improved understanding will allow new methods to be developed to overcome the many technical barriers to xenotransplantation.
Finally, it should also be noted that xenotransplantation procedures have already been carried out in some individuals. Some type I diabetics have undergone treatment in which porcine islet tissue are transplanted into the pancreas to restore insulin secretion (the Edmonton protocol). This technique has been able to effectively restore glucose homeostasis in some patients, while most show improved glycaemic control but still require additional insulin injections (Shapiro et al., 2006). This work further illustrates the potential for xenotransplantation to produce major clinical benefits for patients. With further optimisation, porcine islet transplantation could in the future become a routine treatment for type I diabetes.
In summary, I believe the available evidence strongly supports the idea that xenotransplantation is technically feasible. Together, the studies described above demonstrate that, at least in principle, xenotransplantation could potentially be as effective as allotransplantation. Although many technical hurdles still need to be addressed, it is hoped that continued research will be able to overcome the remaining barriers.
Advantages of Xenotransplantation
There is essentially just one advantage to the use of animal organs – their unlimited supply. Clearly the use of human organs for transplantation is preferable since animal organs are not identical to human organs. However, the reality is that there are simply not enough cadaveric human organs to meet the increasing demand. In most Western countries there is currently a major shortage of organs, with many patients on waiting lists dying before a suitable donor can be found (Melo et al., 2001). For example there are approximately 11,500 people currently waiting for kidney transplants in Europe, with an average time of 3.2 years spent on the waiting list (Sprangers et al., 2008).
Although there are measures that can be taken to increase the supply of donated organs, it is unlikely that their supply will ever match demand. In particular, in some countries consent to be an organ donor is presumed, and those who do not wish to participate must actively opt out of the scheme (Melo et al., 2001). This is not the case in the UK, where legal consent must be given before death in order to become a donor. However, even if the laws were changed on this issue, it remains doubtful whether the increase in available organs would be substantial (Daar, 1997). Therefore it is essential that other options are considered, and, at present, xenotransplantation is perhaps the most promising alternative.
Disadvantages of Xenotransplantation
Although xenotransplantation is a promising approach to overcoming the shortage of transplantable organs, there are a number of problems associated with the technique. These are not just scientific; there are also ethical, regulatory, legal and religious issues associated with the technique that need to be considered. Some of these are described in more detail below.
Immune rejection. The transplanted animal organs will be recognised as foreign by the human immune system, and will therefore be subject to an immune response. This is the same for human organs, however, and is prevented with the use of immunosuppressant drugs. Although not an ideal situation, these drugs do prevent the immune system from destroying the new organ. It is also possible that this problem may be overcome by further technical advances. By genetically-modifying the donor animal, it may be possible to create organs which (immunologically) are sufficiently similar to the patient’s own cells to avoid immune rejection (Cooper, 2003). Indeed, as described above, there have already been some promising developments in this area (Yamada et al., 2005)
Zoonotic disease. There is a risk that an animal disease could be transmitted to humans via the donated organ. Although the chances of this occurring are difficult to quantify, this is perhaps the major technical concern with the procedure. It is thought that some of the most serious infectious diseases that affect human populations today originated in animal populations (Weiss, 2003), and so there is obviously the concern that xenotransplantation could facilitate the spread of zoonotic disease into human populations (George, 2006). With effective screening procedures in place it is likely that this risk would be negligible, but it is not possible to screen for unknown pathogens. Moreover, the failure of such a safety procedure can have devastating effects, as was the case when a human organ donor who was falsely classified as being hepatitis C negative infected eight organ recipients in 2000 (Xenotransplantation News, 2003).
regulatory/Legal issues. Given the uncertain nature of the risks involved, regulating the use of xenotransplantation is likely to be problematic (Tallacchini, 2008). Xenotransplantation is radically different from most medical treatments and so a suitable framework for rigorous clinical trials will have to be designed. Furthermore, the cost of implementing the technique in the early stages will be expensive. This inevitably means that biotechnology companies, interested primarily in profit, will play a large role; effective regulation will be required to balance these commercial interests against patient safety (Daar, 1997).
Animal welfare. The welfare of animals is another ethical issue that should be considered when assessing the merits of xenotransplantation (Anderson, 2006). Animals are already used extensively in scientific research at present, and I would consider the use of animal organs merely an extension of this. However, it is probable that a minority of individuals will not believe the use of animal organs to be justified on these grounds. Religious objections. Some people will undoubtedly object to xenotransplantation for religious reasons. However, a detailed study of this issue has concluded that the technique could be justified on religious grounds, on the basis of the theological argument that necessity can allow anything that is forbidden (Daar, 1994). However, as pigs are considered unclean in both Judaism and Islam, it is unlikely that followers of either faith would accept porcine xenografts (Daar, 1997).
Religious objections. Some people will undoubtedly object to xenotransplantation for religious reasons. However, a detailed study of this issue has concluded that the technique could be justified on religious grounds, on the basis of the theological argument that necessity can allow anything that is forbidden (Daar, 1994). However, as pigs are considered unclean in both Judaism and Islam, it is unlikely that followers of either faith would accept porcine xenografts (Daar, 1997).
Altogether, there are a significant number of problems to be overcome before xenotransplantation can be considered to be a realistic option for treating human patients. Importantly, these are not purely technical concerns; even if the science behind the procedure can be improved, the ethical concerns will still remain. In my opinion, this is the major disadvantage with the technique.
Conclusions
My personal views on xenotransplantation are mixed. Scientifically, I think that the procedure represents a highly promising approach to solving the problems or organ shortages. I think it is highly doubtful that the numbers of cadaveric organs available will ever match the necessary demand, and so in my view it is essential that other options are considered. At present, I believe xenotransplantation represents the most promising alternative approach. That said, xenotransplantation is still associated with scientific hurdles that will need to be overcome, in particular the problem of rejection. In the future, further scientific developments may mean that animal organs are no longer the best source of replacement organs. For example it is hoped that further advances in stem cell technology may mean that whole organs can be grown from single cells in the laboratory. In particular, the exciting recent discovery of induced pluripotent stem (iPS) cells (Takahashi and Yamanaka, 2006) could provide a method by which patient-specific embryonic stem cells could be produced. If methods can be developed to enable these iPS cells to be grown into whole organs, there is potential that ‘ready-made’ organs could be produced for individual patients (Yamanaka, 2008). Whilst I believe this is likely to be possible in the long-term, xenotransplantation potentially offers a more immediate solution to the shortage of donated organs.
Although I believe xenotransplantation is feasible on scientific grounds, I have serious doubts about the potential for the technique to be successful given the numerous ethical issues that are associated with it. Unless the procedure is extremely successful in the clinic, I doubt whether the idea of living with an animal organ will ever be socially acceptable. For others the procedure will be unacceptable on religious grounds, while others will not tolerate the breeding of animals purely for their organs. I suspect the reaction of the media to the technique may be critical in determining how successful it could be. The recent debacle over the introduction of genetically-modified foods in the UK is one example of a promising scientific development hijacked by sceptical media coverage misinforming the general public; despite positive public opinion at present (Rios et al., 2004), a similar media reaction to the first trials of xenotransplantation would again be disastrous.
Overall, I would strongly encourage further research into the possibility of xenotransplantation with the hope of initiating clinical trials in the coming years. Although the technique does hold considerable promise to overcome the shortage of cadaveric organs, I am doubtful that xenotransplantation will ever be able to realise its medical potential due to the many ethical issues raised by its implementation.
