Xenotransplantation 2003: 10: 194–203 Copyright Ó Blackwell Munksgaard 2003 Printed in UK. All rights reserved XENOTRANSPLANTATION ISSN 0908-665X THE ETHICS OF XENOTRANSPLANTATION Position Paper of the Ethics Committee of the International Xenotransplantation Association Sykes M, d’Apice A, Sandrin M. Position Paper of the Ethics Megan Sykes,1 Anthony d'Apice2 Committee of the International Xenotransplantation Association. and Mauro Sandrin3 (IXA Ethics Xenotransplantation 2003; 10: 194–2003. Ó Blackwell Munksgaard, 2003 Committee) 1Transplantation Biology Research Center, Abstract: Xenotransplantation (XTx) provides a potential solution to Massachusetts General Hospital/Harvard Medical the shortage of human organs and tissues, and has several advantages School, Boston, MA, USA, 2Department of Clinical over other possible solutions to this problem. However, a number of Immunology, St Vincent's Hospital, Fitzroy, Victoria, scientific and ethical barriers exist, and need to be addressed in order to Australia, and 3Austin Research Institute, Austin and advance the field of XTx in a manner that optimizes its potential to Repatriation Medical Center, Heidelberg, Victoria, benefit society and minimizes its risk. Some of the most pressing ethical Australia issues are discussed, and the position of the Ethics Committee of the International Xenotransplantation Association is presented. Key words: ethics – guidelines – infectious risk – pig – porcine – religion – retrovirus – XTx Address reprint requests to Megan Sykes, MD, Head, Bone Marrow Transplantation Section, Trans- plantation Biology Research Center, Massachusetts General Hospital/Harvard Medical School, MGH-East, Building 149-5102, 13th Street, Boston, MA 02129, USA (E-mail: megan.sykes@ tbrc.mgh.harvard.edu) Received 13 November 2002; Accepted 4 December 2002 and membership at large, and numerous thought- Introduction ful comments have been received in response. The subject of ethics in relation to xenotransplan- Many of these have been incorporated into the tation (XTx) has been widely explored [1–7]. The final document. While the overwhelming majority purpose of this paper is not to reiterate these of these responses were supportive of the views discussions in detail, but to provide an overview expressed herein, some were not, and we have of the major issues and a brief statement of the attempted to defend our views in these instances. International Xenotransplantation Association Thus, the final document does not represent a (IXA) Ethics Committee’s present position on unanimous viewpoint of the IXA, but represents these issues. The paper is not meant to be the the best consensus from the responses received, ‘‘final word’’ of the IXA on all aspects of ethics in and has been agreed upon by the Ethics Com- XTx, but instead it is intended to present a few mittee and endorsed by the IXA Council. We conclusions and recommendations that are felt by thank all of those who have taken the time to the IXA Ethics Committee to be warranted and comment on the draft, and we hope that the of highest priority at the present time. A draft paper will continue to stimulate thought and document has been circulated to the IXA Council engender further responses from within and out- 194 IXA Ethics Paper side the IXA membership. We encourage written 5. The use of inbred, immunologically standard- responses via letters to this journal, and we look ized source animals would facilitate pre- forward to participating in an ongoing dialogue transplant tolerance induction. Source tissue on the topics discussed herein. could also be modified by genetic engineering The inadequate supply of organs for transplan- to minimize its rejection, optimize its function tation is well established and widespread. The and provide other potential advantages to the number of patients dying while waiting for alloge- recipient. neic organ transplants is unacceptably high, and However, a number of scientific and ethical new solutions to the problem are needed. For barriers to XTx exist, and these will need to be example, approximately 75 000 individuals were properly addressed in order to move the field of on the American UNOS waiting list in March XTx forward in a manner that optimizes its 2001, and less than one-third of those were potential to benefit society and minimizes its risk. transplanted that year. An unacceptable propor- The ethical considerations include some that are tion of patients die while on organ transplant unique to XTx and others that apply to any waiting lists. These figures represent just the tip of experimental therapy. Our considerations will the iceberg, as many more individuals with organ focus mainly on the ethical issues that are unique failure who could benefit from organ or tissue to clinical research in XTx, including the potential transplants, if these were available, are not on risk to society that it imposes, and considerations transplant waiting lists or are withdrawn prior to relating to the use of non-human source animals. their death. While the discussion below focuses mainly on Xenotransplantation provides a potential solu- organ and cell transplants from non-human animal tion to the organ shortage. Other potential solu- sources, similar considerations apply to XTx as tions include the use of artificial organs, as well as defined by the United States Public Health Service, organs and tissues engineered from stem cells. i.e. any procedure that involves the transplanta- While the latter possibilities are attractive and tion, implantation, or infusion into a human promising, many workers believe that the solution recipient of either live cells, tissues or organs closest to clinical application is XTx of organs, derived from a non-human animal source, or of tissues and cells; XTx of tissues and cells and ex human body fluids, cells, tissues or organs that vivo perfusion of natural and bioartificial porcine have had ex vivo contact with live, non-human livers have already entered into clinical trials [8– animal cells, tissues or organs. However, the level 12]. The potential benefits of XTx to mankind are of potential risk to the patient and society must be enormous. In addition to solving the organ short- considered on a case-by-case basis and taken into age problem, XTx offers a number of other account in decision-making regarding each XTx potential benefits [13]: trial. 1. In countries where human organ donation has not been accepted for ethical or cultural Ethical considerations relevant to xenotransplantation reasons, XTx might provide an acceptable alternative. It is widely accepted that certain ethical principles 2. In several respects, xenogeneic organs would must be applied to experimentation conducted in offer advantages similar to those associated humans, and these have been outlined in the with the use of human live donor organs – the Belmont Report [14]. They include respect for transplant procedure can be scheduled; re- persons, beneficence, and justice, which call for cipient pre-treatment is feasible; the quality of certain ethically required actions or applications. the organs will be known in detail; there will Respect for persons requires informed consent. be minimal warm and cold ischemia times; the Beneficence (the duty to benefit others) calls for an influence of the various pathophysiologic assessment of risks and benefits. Justice requires an consequences of brain death on organ quality equitable selection of research subjects. An ethical will be avoided. review is done for the purpose of ensuring that 3. With ready access to organs, recipient selec- studies are conducted according to these principles tion criteria could be broadened. and their applications [15, 16]. 4. Xenogeneic transplants might not be suscept- ible to the human autoimmune diseases or Beneficence and risk/benefit analysis viral infections that caused organ failure in the first place and which often limit the In most types of human research, assessment of survival of allogeneic organ transplants. risks applies mainly to the research subject, 195 Sykes et al. whereas the potential for benefit may be to others that they will survive the procedure for more than a in society, with or without potential benefit to the few days or weeks. A xenotransplant procedure research subject. In the case of XTx, both the risk that provides a short prolongation of survival to and the benefit may be to society as well as to the already moribund patients would be difficult to subject, and the nature of the risk to society raises justify in terms of the risks to society and to public special considerations that are discussed below. perception of XTx. On the other hand, the risks First, risk assessment is based on the principle associated with XTx mandate that the procedures that the possible harm of the research must be be evaluated in patients who lack reasonable outweighed by its probable benefits. In other alternatives. Both of these considerations must be words, research must be justified on the basis of a balanced in order to identify the most suitable favorable risk/benefit assessment [16]. In instances candidates for XTx trials. involving significant risk to the research subject or Secondly, for any ethically conducted trial, risks society, there must be significant potential for to the patient and to society must be minimized. benefit. This is an especially important considera- Major efforts have been carried out by national and tion in the field of XTx, in which there is international bodies to develop guidelines for considered to be a potential risk of introducing minimizing the infectious risks of XTx. It is widely new infections into the human population, and in agreed that animals used for XTx should be bred in which major barriers to success still exist. closed colonies in captivity, to permit the exclusion Thus, clinical trials of XTx must be scientifically from the colony of known potential pathogens to sound and associated with significant expectation humans. However, potential pathogens which have of benefit to the transplant recipient and hence, not been previously identified and which therefore ultimately, to society.