Registered Members    Remember credentials Bibliography Background information In general terms, xenotransplantation is defined as transplantation from one species to another; for example, from a pig to a human. The term covers transplantation of solid organs (such as kidney or heart), tissues (such as skin) or clusters of specialised cells (such as brain cells or the pancreatic cells that produce insulin). Xenotransplantation can also involve the infusion or transplantation of body fluids, tissues or cells that have been in contact with the tissues or cells of another species outside the recipient's body. For example, a person might be treated for liver failure by having their blood passed through an artificial device containing pig liver cells. Some nonliving animal devices, such as pig heart valves, have been used in humans for many years. Xenotransplants differ from these devices in that they are alive and can perform the same functions as the organ, tissue or cells that they replace. According to the Recommendation Rec. (2003)10 of the Committee of Ministers to Member States of the Council of Europe, xenotransplantation is defined as “any procedure that involves the transplantation or infusion into a human recipient of: A) live animal cells, tissues or organs, or B) human body fluids, cells, tissues or organs that have had ex vivo contact with live animal cells, tissues or organs”. Therefore, by its very nature, research on xenotransplantation does not allow complete nor incomplete replacement of the use of animals. Indeed, animals necessarily constitute the source of solid organs, tissues, or cells intrinsic to the xenotransplantation approach explored as a potential strategy for solving the lack of human organs (xenotransplantation type A. The reasoning behind the question concerning why xenotransplantation is being considered includes the possibility of providing a potential solution to the organ shortage. Transplantation between members of the same species is known as allotransplantation, and in humans this is a very successful way to treat a variety of illnesses. However, very few human tissues and organs are available for transplantation, so that many patients who could benefit from a transplant wait in vain for a suitable donor. In this sense, xenotransplantation could be used to “buy time” while potential transplant patients wait for a suitable donor. There have been promising results from overseas trials in which isolated pig liver cells contained in a bioreactor were used to treat acute liver failure. Transplant specialists are therefore considering animals as a possible source of organs and tissues for human transplantation. The greatest benefit of xenotransplantation would be a potentially unlimited supply of cells, tissues and organs for use in humans. Recent advances in technology have increased the possibility of successful xenotransplantation and stimulated research in this area. For example, genetic engineering has allowed human genes to be inserted into pigs so that their cells, tissues and organs are less likely to be rejected when transplanted into humans. In summary, these are some of the reasons which explain why xenotransplantation should be considered: The shortage of human organ donors has prompted research into the benefits of xenotransplantation and the development of guidelines as a regulatory framework for research; The demand for donor organs has resulted in patients waiting in vain for suitable donor organs to become available. The greatest benefit of xenotransplantation would be a potentially unlimited supply of cells, tissues and organs for use in humans; The potential benefits of xenotransplantation in treating a wide range of life-threatening and debilitating conditions and providing therapy for a variety of illness has further prompted the development of guidelines for research. Recent advances in genetic technology and the mechanisms of transplant rejection have made xenotransplantation more feasible. A major cause of concern on current research involves the genetic modification of donor pigs with some key human genes to reduce the powerful immune response that occurs when pig tissues are transplanted into human recipients. Researchers predict that Animal Cell Therapies (ACT) (such as brain and pancreatic islet cells) or external cell therapies (such as devices using animal liver cells or skin grafts) are more likely to be successful in the short-to-medium term. In comparison, because of the rejection of animal organ transplants, they will be harder to perfect. In relation to what sort of disease or health problems can xenotransplantation help to cure or alleviate, we observe that xenotransplantation has the potential to treat a wide range of life-threatening or debilitating conditions. For example, it is possible that isolated cells could be transplanted to treat diseases such as diabetes, Parkinson's disease, Huntingdon's disease or strokes. In order for xenotransplantation to become an option for human therapy, research is needed that includes: animal-to-animal studies (preclinical studies) -in which proposed xenotransplantation procedures are tested on animals (eg pig-to-baboon kidney transplant); animal-to-human trials (clinical trials) - in which animal products are used for xenotransplantation procedures on human beings (eg pig-to-human pancreatic islet cell transplantation to treat Type I diabetes). Animal-to-animal studies are covered by existing regulations for research involving animals. Concerning the use of pigs, we obverse that these animals are considered the most suitable species as a source of material for xenotransplantation for several reasons: - they reproduce quickly and have large litters; - their organs are similar in size to those of humans; - they are easy to rear in conditions free of particular pathogens (disease-causing organisms); - the risk that they will carry pathogens that can infect humans is smaller than with nonhuman primates (apes and monkeys); - they can be genetically manipulated to reduce the risk of rejection. Nevertheless, in considering pigs as potential xenograft source animals, particular concern has been focused on the potential for endogenous retroviruses, which are vertically transmitted and cannot readily be excluded by breeding procedures in a closed colony. The demonstrated potential of porcine endogenous retroviruses (PERV) to infect human cells in vitro has increased the concern that these could infect xenotransplant recipients, who are likely to be susceptible because of immunosuppressive therapies they are given and because the xenogeneic tissue as introduced directly into the body. Therefore, the main risk to the recipient of a transplant is rejection due to the patient's immune response. In human-to-human transplantation (allotransplantation), rejection has been largely overcome by tissue matching of donors and recipients, and by giving the recipient drugs that suppress their immune response. Nonhuman primates (apes and monkeys) are not being considered as the source for animal-to-human transplants because their close relationship to humans increases the risk of a virus being transmitted across species. The virus that is of most concern in xenotransplantation using pigs as the donor species is, as has been said above, the porcine endogenous retrovirus (PERV). PERV is present in almost all strains of pigs and cannot be removed by raising pigs in sterile conditions. Although PERV is inactive, and therefore harmless, in pigs, there are concerns that transplantation into humans may activate the virus, creating a new human disease that could spread to those close to the transplant recipient and eventually to the wider community. PERV can infect human cells in the laboratory, suggesting that it could infect humans through xenotransplantation. However, studies of around 150 people worldwide who have been transplanted with pig tissue or had their blood pass through pig cells have shown no evidence of infection with a virus or any other infectious agent originating from pigs. Approval of an animal-to-human trial would depend on there being an appropriate policy for testing the xenotransplant recipient and their close contacts for PERV and any other organisms that may emerge as a result of the transplant. The risk of rejection in xenotransplantation is more severe because the differences between the donor and the recipient are much greater. The most promising approach at this stage is to genetically modify the source animals so that they do not cause such a strong immune response. Scientists have already produced several genetically modified strains of pig that show promising results. On the other hand, xenotransplantation carries some risks for the wider community. The major concern for public health is that xenotransplantation might transmit an infectious agent (such as a virus) from animals to humans. Retroviruses are the chief concern, because there are many examples of such viruses moving from one species to become infectious in another. However, retroviruses do not always cause obvious signs of disease initially. If a retrovirus present in a xenotransplant were to infect the recipient of the transplant, it may spread to close contacts, carers and even the general population before it became obvious that an infection had occurred. What steps would be taken to minimise the risks from xenotransplantation? Although most pigs carry PERV, the pig endogenous retrovirus that is of concern as a possible infectious agent in humans, at least one strain of 'minipigs' does not. Researchers are therefore investigating the use of this strain (or breeding others) for xenotransplantation in order to reduce the risk of infection in the recipient. Most importantly, animal-to-human trials will not be approved unless there is an appropriate infection control policy in the hospital where the transplant is taking place, to prevent transmission of infections from the xenotransplant recipient to hospital contacts. In addition, because the long-term consequences of xenotransplantation will not be fully understood for some years, anyone transplanted with cells, tissues or organs from another species will need to be carefully monitored. Therefore, anyone receiving a transplant would be informed about the potential infectious disease risks to themselves and their close contacts and asked to support such long-term monitoring. Xenotransplantation raises a great variety of legal and ethical issues, not all of which have attracted adequate attention. Associated with all of these groups is the problem of increasing methods of communication and consultation on this important topic and the problem of devising adequate overseeing mechanisms which would be operative nationally and internationally. For more information on the issues about animal to human transplantation see our overview of xenotransplantation in this XENOME web site. In this section related to ethical and legal issues, the reader can find bibliographic references to explore the ethical and legal aspects of xenotransplantation. The bibliography has been arranged according to the following main topics: ethical aspects; social debate; benefits and risks; and legal aspects. Each topic includes a short introduction to allow interested people or scholars to make sense of what has been published in different periods of time. By contrast, the legal framework has been arranged in the following order: International, Council of Europe, European Union and national legislation. The laws mentioned in each section are in chronological order. There is also a section related to Reports and other documents where the reader can find a logical framework consistent with the purpose of the project. In the section dealing with Links the reader can find links in a systematic order according to the topic, e.g., non-profit organizations, national centers, local organizations, private companies, etc.