Pontifical academy for life prospects for xenotransplantation scientific aspects and ethical considerations

Pontifical Academy for life prospects for xenotransplantation scientific aspects and ethical considerations

Juan de Dios Vial Correa. President Elio Sgreccia. Vice-President

Introduction cal, anthropological, psychological and ethical considerations, as well as an ex- Transplantation represents a highly amination of legal issues and procedural successful means of treating a variety of matters. human illnesses. However, the number of transplants performed is limited by a First Part: Scientific Aspects shortage of human organs and tissues1. Xenotransplantation, the transplantation Historical background of organs, tissues or cells from one species to another, if applied to man, would offer 1. To date, there is only very limited the possibility of a huge supply of organs, experience in transplanting xenogenic tissues and cells for transplantation organs or tissues to humans. The attempts thereby relieving the «chronic» shortage made in the 1960s and early 1970s used of human donors. immunosuppressive therapies on the However, before xenotransplantation recipient to prolong survival of the organ. becomes a clinical reality, there are The most striking success was the nine- practical challenges that must be month survival of a chimpanzee kidney overcome. One is rejection, the process transplanted into a human by by which the body of the transplant REEMTSMA and colleagues2. In the recipient attempts to rid itself of the 1980s, a baboon heart was transplanted transplant. Another is to ensure the to a baby (Baby Fae) that survived correct functioning, across species briefly3; however, rejection occurred within barriers, of the transplant in its new host. a few weeks. In the 1990s, baboon livers Also, there is the need to minimize the were transplanted in two patients by likelihood of the introduction of new STARZL and colleagues4. Those patients infectious agents into the human population via the transplant. 2 Cf. Reemtsma K., McCracken B.H., Schle- In addition there are concerns about gel J.U., et al. Renal heterotransplantation in man, Ann Surg, 1964, 160: 384. xenotransplantation that require theologi- 3 Cf. Bailey L.L., Nehlsen-Canarella S.L., Concepcion W., et al. Baboon-to-human cardiac xe- notransplantation in a neonate, JAMA, 1985, 254: 1 Cf. Evans R., Orians C., Ascher N., The 3321. potential supply of organ donors; an assessment of 4 Cf. Starzl T.E., Fung J.J., Tzakis A.G., et the efficacy of organ procurement efforts in the al., Baboon-to-human liver transplantation, Lancet, United States. JAMA 1992; 267: 239-46. 1993, 341: 65.

Cuad. Bioét. 2003/2ª, 3ª 303 Documentos survived for 70 days in one case and 26 While non-human primates have been days in the other. preferred in the past as source organs for The first patient was placed on an humans, at present the scientific oral diet on the fifth post-transplant day community and the regulatory agencies and spent most of his time in a regular in those countries which are addressing ward, leaving the hospital briefly on one the issue have ruled out the use of such occasion5. However, in one of the two source animals both because of the cases, a baboon pathogen (cytomegalo- increased risk of transmission of infection virus) was apparently transferred to the and because of a variety of other ethical patient, even though this did not result and practical concerns8. As a consequence in a disease process6. However, in both many researchers have settled on the use patients there was evidence of an ad- of pigs as a potential source animals for equately functioning liver mass, suffi- xenotransplantation9. The use of genetic cient to sustain life. The baboon livers engineering has resulted in significant led to the presence of baboon proteins improvement in survival time for a pig synthesized by the liver; in some cases organ in a non-human primate receiving those proteins assumed the blood levels immunosuppression10. However, the that are characteristic of the baboon and not of the human. Possible molecular 8 Cf. Allan J.F. Xenotransplantation at a incompatibility of those proteins poses crossroad: prevention versus progress. Nature Med. a potential problem of functionality for 1996, 2: 18-21; Hammer C., Linke R., Wagner F., Diefenbeck M., Organs from animals for man, Int. humans. Arch. Allergy Immunol., 1998, 116: 5-21. Transplants have also been attempted 9 Cf. Hammer C., Linke R., Wagner F., Die- using pig hearts (three cases) or livers fenbeck M., Organs from animals for man, Int. Arch. Allergy Immunol., 1998 116: 5-21; Cooper D.K.C., (one case); in no case did the recipient Ye Y., Rolf J.L.L., et al., The Pig as Potential Organ 7 survive more than 24 hours . Donor for Man. In: Cooper D.K.C., Kemp E., Ree- mtsma K., White D.J.G., eds. Xeno-transplantation. 5 Cf. Marino I.R., Doyle H.R., Nour B., Starzl The Transplantation of Organs and Tissues Between T.E. Baboon liver xenotransplantation. In: Cooper Species. 1st ed. Berlin: Springer-Verlag 1991: 481- D.K.C., Kemp E., Platt J.L., White D.J.G., eds. Xeno- 500. transplantation, The Transplantation of Organs and 10 Cf. Loss M., Vangerow B., Schmidtko J., Tissues between Species. 2nd ed. Berlin: Springer- et al., Acute vascular rejection is associated with Verlag 1997: 793-811. systemic complement activation in a pig-to-prima- 6 Cf. Michaels M.G., Jenkins F.J., St George te kidney xenograft model, Xenotransplantation K., Nalesnik M.A., Starzl T.E., Rinaldo C.R. Jr., De- 2000, 7: 186-96; Cozzi E., Bhatti F., Schmoeckel M. tection of infectious baboon cytomegalovirus after et al., Long-term survival of nonhuman primates baboon-to-human liver xenotransplantation. J Vi- receiving life-supporting transgenic porcine kidney rol. 2001; 75: 2825-8. xenografts, Transplantation 2000, 70: 15-21; Vial 7 Cf. Taniguchi S., Cooper D.K.C. Clinical C.M., Ostlie D.J., Bhatti F.N. et al., Life-supporting xenotransplantation - A brief review of the world function for over one month of a trasgenic porcine experience. In: Cooper D.K.C., Kemp E., Platt J.L., heart in a baboon, J. Heart. Lung Transplant 2000, White D.J.G., eds. Xeno-transplantation. The trans- 19: 224-9; Bhatti F.N., Schmoeckel M., Zaidi A., et plantation of Organs and Tissues Between Species. al., Three-month survival of HDAF transgenic pig 2nd ed. Berlin: Springer-Verlag 1997: 776-792. hearts transplanted into primates, Transplant Proc.

304 Cuad. Bioét. 2003/2ª, 3ª Pontifical academy for life prospects for xenotransplantation scientific aspects and ethical considerations survival time of such organs does not yet cells and monocytes. In combination these approach that of human organs stimuli (the anti-graft antibodies and the transplanted to other humans activated host cells) result in activation of (allotransplantation). Therefore, certain the endothelial cells of the source organ. barriers to xenotransplantation remain11. Endothelial cell activation leads to general Further genetic engineering of source inflammation with resultant thrombosis animals and/or use of additional/new (platelet aggregation and activation of the immunosuppressive agents are the two coagulation cascade) resulting in organ approaches that are considered most rejection. Third, the xenograft counterpart likely to prolong the survival of a of classical T cell mediated rejection of xenotransplant12. Clearly more research allografts (transplantation between in xenotransplantation is needed and individuals of the same species) will almost should be done. certainly occur. Finally, xenografts may also be subject to chronic rejection in a manner Current Situation analogous to allografts. Rejection: Immunology of Organ Hyperacute Rejection: Recipient Xenografting xenoreactive natural antibodies and complement are the two major factors that 2. There are four immunological barriers result in hyperacute rejection of an that must be overcome for achieving immediately-vascularized organ. Pre- successful organ xenotransplantation from existing xenoreactive natural antibodies pig to primate (human and non-human). bind with vascular endothelial cells of the First, hyperacute rejection, which is caused pig organ13. These antibodies are directed by xenoreactive natural antibodies and primarily towards a sugar moiety, the Gal- complement of the recipient acting against a (1,3)-Gal-ß (1,4)-GlcNac antigens of the endothelial cells of the source animal organ. pig, also known as «a-gal»14. The bound Second, acute vascular rejection caused by antibodies fix and activate complement, the combined effect of elicited xenoreactive with the combination of antibodies and antibodies and activated host natural killer 13 Cf. Platt J.L., Fischel R.J., Matas A.J., et 1999, 31: 958; Diamond L.E., Quinn C.M., Martin al., Immunopathology of hyperacute xenograft re- M.J., et al., A human CD46 transgenic pig model jection in a swine-to-primate model, Transplanta- system for the study of discordant xenotransplan- tion 1991, 52: 214-220; Dalmasso A.P., Vercellotti tation, Transplantation 2001; 7: 132; Lin S.S., Weid- G.M., Fischel R.J., et al., Mechanisms of comple- ner B.C., Byrne G.W., et al., The role of antibodies ment activation in the hyperacute rejection of por- in acute vascular rejection of pig-to-primate car- cine organs transplanted into primate recipients, diac transplants. J Clin Invest 1998; 101: 1745-1756. Am J Pathol 1992, 140: 1157-66. 11 Cf. Starzl T.E., Rao A.S., Murase N., et al., 14 Cf. Good A.H., Cooper D.K.C., Malcom Will xenotransplantation ever be feasible?, J Am A.J. et al., Identification of carbohydrate structures Coll Surg 1998, 186 (4): 383-7. which bind human antiporcine antibodies: impli- 12 Cf. Auchincloss H. Jr., Sachs D.H., Xeno- cations for discordant xenografting in man, Trans- genic transplantation, Annu.Rev.Immunol. 1998, 16: plant Proc 1992, 24: 559-60; Sandrin M.S., Vaughan 433-70. H.A., Dabkowski P.L., et al., Anti-pig IgM antibo-

Cuad. Bioét. 2003/2ª, 3ª 305 Documentos activated complement leading to on in vitro experiments in which a human endothelial activation which result in protein that inhibits human complement thrombosis, rapid graft ischemia and activation is introduced into the rejection. Elimination of xenoreactive membrane of pig endothelial cells. The natural antibodies provides one method molecule first tested was human Decay to overcome hyperacute rejection15. Accelerating Factor, or hDAF. The Hyperacute rejection has also been presence of hDAF in the pig endothelial overcome by methods that inhibit cells prevented lysis of those cells and complement16. would thus, presumably, prevent the Among the different approaches for activation of the cells17. These findings achieving inhibition of complement, the suggested that the production of one that has proven most effective is based transgenic pigs expressing hDAF might provide an approach for overcoming dies in human serum react predominantly with hyperacute rejection of pig organs Gal(a1-3 Gal epitopes, PNAS 1993, 90: 11391-5. 15 Cf. Leventhal J.R., John R., Fryer J.P., et transplanted into primates. al., Removal of baboon and human antiporcine IgG Certain research groups have and IgM natural antibodies by immunoadsorption: produced such transgenic pigs and have Results of in vitro and in vivo studies, Transplanta- tion 1995, 59: 294-300; Cooper D.K.C., Lexer G., demonstrated that organs from these pigs Rose A.G., et al., Effects of cyclosporine and antibo- usually do not undergo hyperacute dy adsorption on pig cardiac xenograft survival in rejection18. Based on these results with the baboon, J. Heart. Transplant. 1988, 7: 238-46; Latinne D., Soares M., Havaux X., et al., Depletion of IgM xenoreactive natural antibodies by injection 17 Cf. Bach F.H., Turman M.A., Vercellotti of anti-mu monoclonal antibodies, Immunol Rev G.M., et al., Accomodation: a working paradigm 1994, 141: 95-125; Rydberg L., Hallberg E., Bjorck for progressing toward clinical discordant xenograf- S., et al., Studies on the removal of anti-pig xenoan- ting, Transplant Proc. 1991; 23: 205-7; Dalmasso A.P., tibodies in the human by plasmapheresis/immu- Vercellotti G.M., Platt J.L., Bach F.H., Inhibition of noadsorption, Xenotransplantation 1995, 2: 253-63. complement mediated endothelial cell cytotoxicity 16 Cf. Gewurz H., Clark D.S., Finstad J., et by decay accelerating factor. Potential for preven- al., Role of the complement system in graft rejectio- tion of xenograft hyperacute rejection, Transplan- ns in experimental animals and man, Ann. NY Acad. tation 1991; 52: 530-3. Sci., 1966, 129: 673-713; Pruitt S.K., Kirk D.A., Bo- 18 Cf. Diamond L.E., Quinn C.M., Martin llinger R.R., et al., The effect of soluble complement M.J., et al., A human CD46 transgenic pig model receptor type 1 on hyperacute rejection of porcine system for the study of discordant xenotransplan- xenografts, Transplantation 1994, 57: 363-70; Koba- tation, Transplantation 2001; 7: 132; Cozzi E., White yashi T., Neethling F.A., Koren E., et al., In vitro D.J.G., The generation of transgenic pigs as poten- and in vivo investigation of anticomplement agents tial organ donors for humans, Nature Medicine FUT-175 and K76COOH, in the prevention of hy- 1995, 1: 964-6; Fodor W.L., Williams B.L., Matis L.A., peracute rejection following discordant xenotrans- et al., Expression of a functional human comple- plantation in a nonhuman primate model, Trans ment inhibitor in a transgenic pig as a model for Proc 1996, 28: 604; Kroshus T.J., Rollins S.A., Dal- the prevention of xenogenic hyperacute organ re- masso A.P., et al., Complement inhibition with an jection, Proc Natl Acad Sci 1994, 91: 11153-7; McCu- anti-C5 monoclonal antibody prevents acute car- rry K.R., Kooyman D.L., Alvarado C.G., et al., Hu- diac tissue injury in an ex vivo model of pig-to- man complement regulatory proteins protect swine- human xenotransplantation, Transplantation 1995, to-primate cardiac xenografts from tumoral injury, 60: 1194-202. Nature Med 1995, 1: 423-7; Cowan P.J., Aminian A.,

306 Cuad. Bioét. 2003/2ª, 3ª Pontifical academy for life prospects for xenotransplantation scientific aspects and ethical considerations transgenic hDAF-expressing pigs, it rejection now represents the principle appears that hyperacute rejection can be immunological barrier to successful overcome, which is the first major xenotransplantation. Studies of acute triumph of gene therapy in the field of vascular rejection in animals has shown organ transplantation. that the use of immunosuppression leads Another possible solution to to organ survival for a far greater length hyperacute rejection is to eliminate, or of time than is seen in untreated cases22. greatly reduce the expression of «a-gal» An alternative approach for overcoming from pigs by knocking out the 1,3 acute vascular rejection is further genetic galactosyl transferase gene, which is engineering animals/organs23. A number needed for the expression of «a-gal»19. of genes that may suppress the This has not yet been accomplished in inflammatory response that appears to pigs, although present-day cloning cause acute vascular rejection are now technology could make this possible. being studied. Acute Vascular Rejection: Acute T Cell Response: If acute vascular Vascular Rejection is precipitated by rejection can be overcome, it is expected elicited xenoreactive antibodies and by that there will be a xenograft counterpart the possible infiltration of host of the allogeneic T cell rejection response24. inflammatory cells, monocytes and There are disagreements whether the natural killer cells, that invade the xenogenic T cell response will be more xenograft20. Endothelial cells are activated difficult to overcome than the allogeneic resulting in thrombosis, compromised one, which today is easily controlled. In blood flow and rejection21. Acute vascular addition to the use of immunosuppression, there is the possibility that in pig-to- Barlow H. et al., Renal xenografts from triple-trans- genic pigs are not hyperacutely rejected but cause primate transplants we might achieve coagulopathy in non-immunosuppressed baboons, tolerance (non-reactivity of the immune Transplantation 2000, 69: 2504-15; Lavitrano M., system of the recipient to pig antigens Forni M., Varzi V., et al., Sperm-mediated gene trans- fer: production of pigs transgenic for a human regulator of complement activation, Transplant Proc 1997;29: 3508-9. 22 Cf. Cozzi E., Bhatti F., Schmoeckel M. et 19 Cf. Sandrin M.S., Fodor W.L., Mouhtouris al., Long-term survival of nonhuman primates re- E., et al., Enzymatic remodeling of the carbohydra- ceiving life-supporting transgenic porcine kidney te surface of a xenogenic cell substantially reduces xenografts, Transplantation 2000, 70: 15-21; Vial human antibody binding and complement-media- C.M., Ostlie D.J., Bhatti F.N. et al., Life supporting ted cytolysis, Nature Medicine 1995, 1: 1261-7. function for over one month of a transgenic porci- 20 Cf. Soares M.P., Lin Y., Sato K., et al., Pa- ne heart in a baboon, J. Heart. Lung Transplant thogenesis of and potential therapies for delayed 2000, 19: 224-9. xenograft rejection, Opin Organ Transplant 1999 23 Cf. Bach F.H., Xenotransplantation: pro- 4: 80-8. blems and prospects, Annu.Rev.Med.1998, 49: 301- 21 Cf. Hancock W.W., Delayed xenograft re- 10. jection, World J. Surg. 1997, 21: 917-23; Platt J.L., 24 Cf. Yamada A., Auchincloss H. Jr., Cell- Lin S.S. and McGregor C.G.A., Acute vascular re- mediated xenograft rejection, Current Opinion in jection, Xenotransplantation 1998, 5: 169-175. Organ Transplantation 1999, 4: 90-94.

Cuad. Bioét. 2003/2ª, 3ª 307 Documentos without immunosuppression)25. Such gether with recipient complement, lead tolerance is the hope of transplantation in to rejection of the organ27. Transplanta- general and may be aided in the xenogenic tion of mouse or hamster hearts to rats arena by further genetic engineering of is therefore thought to be a good model the source animal. of acute vascular rejection. The prelimi- Chronic Xenograft Rejection: There is nary findings that have emerged from evidence that - as with allotransplants, - small animal transplants are the follow- even when a transplant survives all the ing: administration of immunosuppres- above rejection phases, there is the sion to the rat can lead to long-term sur- possibility that it will be rejected months vival of hamster hearts28. In this sense, or years later26. This is referred to as rejection of a hamster organ transplanted «chronic» rejection. The main pathology to a rat appear to differ from acute vas- of chronic graft failure involves smooth cular rejection of a pig organ in a non- muscle cell proliferation and obliteration human primate in which hyperacute re- of the lumens of blood vessels. jection has been overcome. In the pig- to-nonhuman-primate model, immuno- Experimental Models suppression alone is currently unable to lead to long-term survival. The second 3. Xenotransplantation of organs has been finding in the hamster or mouse heart studied primarily in small animal models transplants to rats has been the achieve- and in pig-to-nonhuman-primate ment of «accommodation»29. Accommo- combinations. dation refers to the survival of an organ Small animal models. The principal in the presence of anti-graft antibodies model used involves transplantation of and complement. Short-term inhibition hamster or mouse hearts to rats. For the of complement coupled with continu- most part, the rejection of a hamster ing inhibition of T cells leads to long- heart by a rat is similar to the rejection term survival in these two situations. of a mouse heart. However, the rat does An interesting finding regarding accom- not have sufficient preformed modation is that the surviving organ xenoreactive natural antibodies to reject a mouse or hamster heart hyperacutely; 27 Cf. Soares M.P., Lin Y., Sato K., et al., Pa- thogenesis of and potential therapies for delayed thus rejection is dependent on the syn- xenograft rejection, Opin Organ Transplant 1999 4: thesis of anti-graft antibodies that, to- 80-8; Hasan R.I.R., van den Bogarde J., Forty J., et al., Prolonged Survival of Hamster to Rat Heart xenografts with Cyclophosphamide Therapy, Trans- 25 Cf. Auchincloss H. Jr., Sachs D.H., Xeno- plant Proceedings 1992, 24: 517-518. geneic transplantation, Annu.Rev.Immunol. 1998, 28 Cf. Hasan R.I.R., van den Bogarde J., For- 16: 433-70. ty J., et al., Prolonged Survival of Hamster to Rat 26 Cf. Bach F.H., Ferran C., Soares M., et al., Heart xenografts with Cyclophosphamide Thera- Modification of vascular responses in xenotrans- py, Transplant Proceedings 1992, 24: 517-518. plantation: inflammation and apoptosis, Nat. Med 29 Cf. Soares M.P., Lin Y., Sato K., et al., Ac- 1997. 3: 944-8. commodation, Immunol Today 1999, 20: 434-7.

308 Cuad. Bioét. 2003/2ª, 3ª Pontifical academy for life prospects for xenotransplantation scientific aspects and ethical considerations expresses genes in its endothelium and rejection is avoided, the hDAF transgenic smooth muscle cells that protect the or- organs are rejected in non-human primates gan from rejection30. To what extent these by a process that mimics acute vascular protective genes can be used therapeu- rejection, although rejection can be very tically to aid pig organ survival in pri- much delayed34. Transgenic pig hearts have mates is not clear. Isolated cases of ac- been shown to survive for up to 99 days commodation have been described in when they are not asked to do life- human allogeneic transplants as well31. supporting work (heterotopic transplant)35. Large animal models. The principal When placed in the position of having to model today remains transgenic pigs support life (orthotopic transplant), the expressing hDAF32 and, in some cases, other longest survival periods have been a month human genes inhibiting complement for a cardiac xenograft36 and 78 days for a cascade, coupled with immunosuppression renal xenograft37; most organs are rejected in order to achieve survival. In most cases, in a shorter period of time. Scientists normal pig organs are rejected hyperacutely propose two different approaches, which by non-human primates, and thus, more can be combined for achieving longer rapidly than transgenic pig organs survival periods of pig organs in primates. expressing hDAF33. Even when hyperacute The first is to try different immuno-

30 Cf. Soares M.P., Lin Y., Sato K., et al., Ac- J.L., White D.J.G., eds. Xeno-transplantation. The commodation, Immunol Today 1999, 20: 434-7; Lin Transplantation of Organs and Tissues Between Spe- Y., Soares M.P., Sato K., et al., Accommodated xe- cies. 2nd ed. Berlin: Springer-Verlag 1997: 665-682. nografts survive in the presence of anti-donor anti- 34 Cf. Cozzi E., Bhatti F., Schmoeckel M. et bodies and complement that precipitate rejection al., Long-term survival of nonhuman primates re- of naive xenografts, J Immunol. 1999 Sep 1; 163(5): ceiving lifesupporting transgenic porcine kidney 2850-7. xenografts, Transplantation 2000, 70: 15-21; Bhatti 31 Cf. Alexandre G.P.J, Latinne D., Gianello F.N., Schmoeckel M., Zaidi A. et al., Three-month P., et al., Preformed cytotoxic antibodies and ABO- survival of HDAF transgenic pig hearts transplan- incompatible grafts, Clin Transpl 1991; 5: 583-587. ted into primates, Transplant Proc. 1999, 31: 958; 32 Cf. Cozzi E., Bhatti F., Schmoeckel M. et McCurry K.R., Kooyman D.L., Alvarado C.G., et al., Long-term survival of nonhuman primates re- al., Human complement regulatory proteins pro- ceiving life-supporting transgenic porcine kidney tect swine-to-primate cardiac xenografts from tu- xenografts, Transplantation 2000, 70: 15-21; Vial moral injury, Nature Med 1995, 1: 423-7. C.M., Ostlie D.J., Bhatti F.N. et al., Life supporting 35 Cf. Bhatti F.N., Schmoeckel M., Zaidi A. et function for over one month of a transgenic porci- al., Three-month survival of HDAF transgenic pig ne heart in a baboon, J. Heart. Lung Transplant hearts transplanted into primates, Transplant Proc. 2000, 19: 224-9. 1999, 31: 958. 33 Cf. McCurry K.R., Kooyman D.L., Alva- 36 Cf. Vial C.M., Ostlie D.J., Bhatti F.N. et al., rado C.G., et al., Human complement regulatory Life supporting function for over one month of a proteins protect swine-to-primate cardiac xenografts transgenic porcine heart in a baboon, J. Heart. Lung from tumoral injury, Nature Med 1995, 1: 423-7; Transplant 2000, 19: 224-9. Cozzi E., Yannoutsos N., Langford G.A. et al., Effect 37 Cf. Cozzi E., Bhatti F., Schmoeckel M. et of transgenic expression of human decay-accelera- al., Long-term survival of nonhuman primates re- ting factor on the inhibition of hyperacute rejection ceiving life-supporting transgenic porcine kidney of pig organs. In: Cooper D.K.C., Kemp E., Platt xenografts, Transplantation 2000, 70: 15-21.

Cuad. Bioét. 2003/2ª, 3ª 309 Documentos suppressive protocols, and the second is to could infect human cells in vitro41. There produce pigs that express additional are no satisfactory animal models to test transgenes that might inhibit rejection the pathogenicity of these agents. The blood factors associated with acute vascular of 160 patients exposed to living pig tissues rejection. was studied for the presence of PERV. In 135 patients exposure was for only one hour Xenozoonoses: the Transmission of Infectious or a little more. In a few of the remaining Agents from one Species to another patients exposure was for longer periods, in one case for 460 days. None of the 4. Over sixty porcine infectious agents patients showed evidence of PERV with a potential to cause disease in humans infection, although pig cells containing have been identified38. Development of retroviral sequences were found even «clean» lines of source animals, with a several years after exposure to the pig certified health status, is under way39. tissue. It is a matter open to conjecture the Control measures include the birth of pigs extent to which one can take comfort from by hysterotomy (caesarean derived), negative results in persons exposed for such carefully controlled environments and short period of time, except for a few cases, routine monitoring of pigs and their and in any event to very few pig cells, as handlers. These steps appear to have compared with the years of exposure that excluded almost all known infectious agents would presumably occur in an organ were of concern. However, it cannot be ruled out it successfully transplanted into a human. that an unknown porcine virus might exist Certainly, the elimination from pigs of all which causes no pathology in pigs but which PERV, which represents a continuing may cause disease in humans. concern and hinders the move to clinical As is true for all other mammalian trials, will remain a challenge for years to species, pigs have sequences in their DNA come. that encode retroviruses (PERV -Porcine Endogenous RetroViruses)40. Weiss and Advances in Biotechnology and Molecular colleagues showed that pig retroviruses Genetics

38 Cf. Onions D., Cooper D.K., Alexander 5. The major advances in biotechno- T.J., et al., An approach to the control of disease transmission in pig-to-human xenotransplantation, logy that might favour further deve- Xenotransplantation 2000; 7: 143-155. 39 Cf. Iverson W.O., Talbot T., Definition of 41 Cf. Patience C., Takeuchi Y., Weiss R.A., a production Specification for xenotransplantation, 1997, Infection of human cells by an endogenous Ann. NY Acad. Sc. 1998, 862: 121-124. retrovirus of pigs. Nature Med 3: 282-286. 40 Cf. Boeke J.D., Stoye J.P., Retrotranspo- 42 Cf. Paradis K., Langford G., Zhifeng L., sons, endogenous retroviruses, and the evolution Heneine, Sandstrom P., Switzer W., Chapman L., of retroelements, Chapter 8 In: Retroviruses. (J.M. Lockey C., Onions D., THE XEN111 Study group, Coffin, S.H. Hughes, and H.E. Varmus eds et al., 1999, Search for cross-species transmission of Cold Spring Harbor Press, Cold Spring Harbor, N.Y. porcine endogenous retrovirus in patients treated 1997; 343-435. with living pig tissue. Science 285: 1236-41.

310 Cuad. Bioét. 2003/2ª, 3ª Pontifical academy for life prospects for xenotransplantation scientific aspects and ethical considerations lopment of xenotransplantation relate to Moving to the Clinical Phase producing transgenic pigs that express human genes which inhibit rejection. Two 6. Because transplanted cells and break-throughs are especially important. tissues are not immediately perfused with First, recent studies have led to the recipient blood after transplantation they cloning of pigs43, allowing for simple are not hyperacutely rejected. Clinical genetic manipulation compared with the trials using such transplants have therefore methods currently available. With this progressed further compared to clinical procedure, at least in principle, new genes trials with solid organ transplants. Porcine can easily be introduced into the DNA of pancreatic islets have been transplanted the pig genome during the cloning into a number of patients with diabetes45 process, and other genes «knocked out» and foetal porcine neural cells have been so that they would no longer be injected into a significant number of functional. For instance, the gene that patients (more than 50) suffering from leads to expression of the «α-gal» antigen Parkinson’s Disease, Huntington’s Disease on porcine endothelial cells could be or strokes46. Only limited clinical benefit knocked out so that at least one of the has been reported to date. A significant causes of rejection would presumably be number of patients with acute liver failure reduced. have taken part in multicentre studies Second, although still at the using pig hepatocytes in artificial devices experimental level, methods to regulate (bioartificial liver) with promising initial the expression of transgenes have been results47. devised44. It may well be that a certain There are considerable differences of transgene would be highly desirable at a opinion as to how long a pig organ given moment after transplantation while should survive in a non-human primate it would be undesirable at a different before one proceeds to clinical trials moment. Therefore, being able to regulate involving the transplantation of pig the expression of a transgene would represent a great advance in the 45 Cf. Groth C.G., Korsgren 0., Tibell, A., et development of xenotransplantation. al., Transplantation of Porcine fetal pancreas to dia- betic patients, Lancet, 1994, 344: 1402-1404. 46 Cf. Brevig T., Holgersson J., Widner H., Xenotransplantation for CNS repair: immunologi- cal barriers and strategies to overcome them, Trends 43 Cf. Polejaeva I.A., Chen S.H., Vaught T.D., Neurosci 2000; 23: 337-44. et al., Cloned pigs produced by nuclear transfer 47 Cf. Mc Laughlin B.E., Tosone C.M., Cus- from adult somatic cells, Nature. 2000, 407: 86-90; ter L.M., Mullon C., Overview of extracorporeal Onishi A., Iwamoto M., Akita T., et al., Pig cloning liver support system and clinical results, Ann. NY by microinjection of fetal fibroblast nuclei, Science. Acad. Sci., 1999, 875: 310-325; Calise F., Mancini A., 2000, 289: 1188-90. Amoroso P. et al., Functional evaluation of the AMC- 44 Cf. Harvey D.M., Caskey C.T., Inducible BAL to be employed in a multicenter clinical trial control of gene expression: prospects for gene the- for acute liver failure, Transpl. Proceed., 2001, 33: rapy, Curr Opin Chem Biol 1998, 2: 512-8. 647-649.

Cuad. Bioét. 2003/2ª, 3ª 311 Documentos organs into humans. Some suggest that Part Two: Anthropological and Ethical clinical trials on humans could begin only Aspects after routine survival periods of ninety days or more have been obtained for pig Besides the scientific and technical organs which are transplanted into aspects of xenotransplantation described nonhuman primates and which must in the first part of this document, perform life-supporting functions48. At anthropological and ethical considerations present, survival periods for this type of are also involved. The purpose of this xenotransplants vary from a few weeks second part is to explore these to about three months, and three-month considerations, albeit by way of a brief survival is certainly not routine49. Clearly, overview. a significant improvement on current figures must be achieved before clinical Preliminary Issues trials using solid organ xenografts are warranted. In addition to the problems raised by However, while survival of pig every transplant, it seems us that there organs in non-human primates at are three issues specifically related to present is not sufficiently long to xenotransplantation: 1) the acceptability consider transplanting such organs into of man’s intervening in the order of the humans as a permanent replacement creation; 2) the ethical feasibility of using organ, the option of using pig organs as animals to improve the chances for «bridge’ transplants may well be survival and well-being of human beings; possible in a shorter time. 3) the possible objective and subjective impact that an organ or tissue of animal origin can have on the identity of the human recipient. 48 Cf. Cooper D.K.C., Keogh A.M., Brink J., et al., Report of the xenotransplantation advisory committee of the international society for heart and Human Intervention in the Created Order lung transplantation. The present status of xeno- transplantation and its potential role in the treat- 7. To begin with, we would like to ment of end-stage cardiac and pulmonary disease. deal briefly with a fundamental question J. Heart Lung Transpl. 2000, 19: 1125-1165. 49 Cf. Cozzi E., Bhatti F., Schmoeckel M. et that, generally, is posed by the different al., Long-term survival of nonhuman primates re- religious traditions, albeit with different ceiving life-supporting transgenic porcine kidney accents: this concerns the possibility itself xenografts, Transplantation 2000, 70: 15-21; Vial C.M., Ostlie D.J., Bhatti F.N. et al., Life supporting that man may licitly intervene in the function for over one month of a transgenic porci- realities that exist in the universe in ne heart in a baboon, J. Heart. Lung Transplant general and, more particularly, in those 2000, 19: 224-9; Bhatti F.N., Schmoeckel M., Zaidi A. et al., Three-month survival of HDAF transge- things that concern animals. nic pig hearts transplanted into primates, Trans- In view of the more specifically plant Proc. 1999, 31: 958. theological nature of such a question, we

312 Cuad. Bioét. 2003/2ª, 3ª Pontifical academy for life prospects for xenotransplantation scientific aspects and ethical considerations deem it useful to offer a short summary partly through the mandate received from of the Catholic position on this question, his Creator to subdue, to dominate, the applying the language and the methods earth. In carrying out this mandate, man, proper to theological anthropology. every human being, reflects the very By what right can humans, whom action of the Creator of the universe»51. God created as female and male, and This, therefore, is the deepest meaning whose full human dignity must be of the action of man in relation to the recognized at every stage of life, intervene created universe: certainly not that of in the created order, perhaps even arbitrarily «lording it over» the other modifying some of its aspects? What creatures, reducing them to humiliating criteria must be adopted and what and destructive slavery in order to satisfy limitations must be introduced? any whim that he may have, but to guide, From imagery of the account of through his responsible work, the life of creation «in six days»50, it is evident that the creation towards the authentic and God established a hierarchy of values integral good of man (the whole man and among the various creatures. Moreover, every man). this hierarchy also emerges from a rational Certain documents of the Second consideration of the transcendent richness Vatican Council had already affirmed this and dignity of the human person. truth. In «Lumen Gentium», for example, Man, created «in the image and we read: «Therefore, by their competence likeness of God», is placed at the centre in secular disciplines and by their activity, and at the summit of the created order, interiorly raised up by grace, they (the not only because everything that exists is laity) must work earnestly in order that intended for him, but also because created goods through human labour, woman and man have the task of co- technical skill and civil culture may serve operating with the Creator in leading the utility of all men according to the creation to its final perfection. «Be fruitful plan of the Creator and the light of his and multiply, and fill the earth and Word. May these goods be more suitably subdue it» (Gen 1: 28): this is the mandate distributed among all men and in their that God gives to human beings, own way may they be conducive to «dominion» over the created order, in his universal progress, in human and name. In this regard, Pope John Paul II Christian liberty»52. Also the decree of the writes in his encyclical «Laborem Second Vatican Council on the apostolate Exercens»: «Man is the image of God of the laity takes up this idea when it asserts that «this natural goodness of 50 The reference is made to the narrative scheme, of a theological-liturgical nature, used in Gn 1: 1-31; for a fuller understanding of the biblical 51 John Paul II, Encyclical Letter Laborem anthropological context, from a protological point Exercens, n. 4. of view, the second account of creation, in Gn 2: 1- 52 Second Vatican Council, Dogmatic Cons- 25, must also be taken into consideration. titution Lumen Gentium, n. 36.

Cuad. Bioét. 2003/2ª, 3ª 313 Documentos theirs (of the realities that make up the It should be noted that this role of temporal order) receives an added «service» rendered to man by other dignity from their relation with the creatures occurs in different ways human person, for whose use they have according to the cultural advances of been created»53. humanity. Limiting ourselves to scientific In summary, therefore, there should and technological progress in the be a reaffirmation of the right and duty biomedical field, the service of animals to of man, according to the mandate from man represents a totally new application his Creator and never against the natural in xenotransplantation, which, therefore, order established by him, to act within in principle is not in conflict with the order the created order and on the created of the creation. On the contrary, order, making use as well, of other xenotransplantation represents for man a creatures, in order to achieve the final further opportunity for creative goal of all creation: the glory of God and responsibility in making reasonable use the full and definitive bringing about of of the power that God has given to him. His Kingdom, through the promotion of Furthermore, even if one limits oneself man. The words of St. Irenaeus of Lyons to a purely rational analysis, without still ring out with all their truth: «Living desiring to make use of theological man is the glory of God and man’s life is reasoning, one can reach the same the vision of God»54. conclusions on a practical level. A simple look at humanity’s long The Use of Animals for the Good of Man presence on the earth is sufficient to show an irrefutable fact clearly: it is man who 8. For a theological reflection that will has always directed the realities of the help to formulate an ethical assessment world, controlling the other living and on the practice of xenotransplantation, non-living beings according to determined we do well to consider what the intention purposes. It is moreover in its relationship of the Creator was in bringing animals with man that the axiological measure into existence. Since they are creatures, (moral value) of every existing reality is animals have their own specific value revealed in a universal harmonic and which man must recognize and respect. orderly design that indicates all the However, God placed them, together fullness of the sense of reality. with the other nonhuman creatures, at In particular, man has always made the service of man, so that man could use of animals for his primary needs achieve his overall development also (food, work, clothing, etc.) in a sort of through them. natural «cooperation» that has constantly marked the different stages of progress 53 Second Vatican Council, Decree Apostoli- cam Actuositatem, n. 7. and the development of civilization. 54 Saint Irenaeus of Lyons, Against Heresies, Such a position of «excellence» is a Book 4, 20, 7. witness to and also demonstrates the

314 Cuad. Bioét. 2003/2ª, 3ª Pontifical academy for life prospects for xenotransplantation scientific aspects and ethical considerations ontological superiority of mankind over arbitrarily without being limited by the other beings of the earth; this ethical considerations. superiority is founded on the very nature 9. From our point of view, supported of the human person, whose rational and by the biblical perspective that asserts, spiritual dimensions place man at the as stated above, that man is created «in centre of the universe, so that he may use the image and likeness of God» (cf. Gen its existing resources (including animals) 1: 26-27), we reaffirm that humans have in a wise and responsible manner, seeking a unique and higher dignity. However, the authentic promotion of every being. humans must also answer to the Creator To analyse more deeply the point for the manner in which they treat under discussion, two issues of an ethical animals. As a consequence, the sacrifice nature must be addressed. First, there is of animals can be justified only if required the question of the use of animals in order to achieve an important benefit for man, to improve man’s chances of survival or as is the case with xenotransplantation to improve his health; the obvious of organs or tissues to man, even when starting point here is the particular way this involves experiments on animals in which one views the relationship and/or genetically modifying them. between man and animals55. Second, there However, even in this case, there is is the question of the acceptability of the ethical requirement that in using breaching the barrier between animal animals, man must observe certain species and the human species. conditions: unnecessary animal suffering With regard to the first issue, must be prevented; criteria of real contemporary thinking includes two necessity and reasonableness must be opposing and extreme viewpoints56. respected; genetic modifications that There are those who believe that animals could significantly alter the biodiversity and man have equal dignity and those and the balance of the species in the who believe that animals are totally at animal world must be avoided57. the mercy of man. In the former case, the The theological and moral point of use of animals is seen as species-ism or view sees no substantial problem in the tyranny of man over animals. Even utilization of different animal species reducing human suffering could not (nonhuman primates or nonprimates), justify the use of animals unless the but leaves open the question of differing contrary possibility was also allowed. In the latter case, man can use animals 56 Cf. Singer P., Animal Liberation, 2nd edit., 1995, Pimlico, London; Regan T., The case for Ani- mal Rights, 1983, London, Routledge & Kegan Paul; 55 Cf. Bondolfi A., I rapporti tra uomo e ani- Christian Medical Fellowship, Animal experimen- male nelle tradizioni giudaico-cristiane e la sfida tation, 1997, (http: //www.cmf.org.uk, 10/7/2001). degli xenotrapianti, in L’arco di Giano, 1999; 21: 49- 57 Reflections on human responsibility for 62; D’Agostino F., I diritti degli animali, in Bioetica animal life may be found in Schockenhoff E., Etica nella prospettiva della filosofia del diritto, 1997, della vita. Un compendio teologico, Brescia: Que- Giappichelli Ed., Torino, pp. 239-265. riniana 1997: 407-451.

Cuad. Bioét. 2003/2ª, 3ª 315 Documentos levels of sensibilities between animals of «introduction of a foreign organ into the different species and that of equilibrium human body modifies a person’s identity among species and within a species. and the rich meaning of the human The point should also be made that body?» And if the answer is affirmative, Catholic theology does not have one must ask up to what point is such preclusions, on a religious or ritual basis, modification acceptable. in using any animal as a source of organs Certainly, the concept of «personal or tissues for transplantation to man58. The identity» is replete with implications and question of the acceptability of an animal subtleties of meaning, given the different organ, - once it has been established that contributions of philosophy and science60. personal identity is not affected by More concisely, in keeping with the scope xenotransplantation, and once all the of this document, we can indicate personal general ethical requirements of identity as the relation of an individual’s transplantation have been met, - becomes unrepeatability and essential core to his one on the cultural and psychological level. being a person (ontological level) and Therefore, it may be possible to overcome feeling that he is a person (psychological initial misgivings by providing the level). These characteristics are expressed necessary support in an effective manner. in the person’s historical dimension and, in particular, in his communicative Xenotransplantation and the Identity of the structure, which is always mediated by Recipient his corporeality. It must be affirmed, then, that 10. In addition to considerations of a personal identity constitutes a good of theological nature, and perhaps even the person, an intrinsic quality of his very before these are made, an ethical being, and thus a moral value upon evaluation of the practice of xenotrans- which to base the right and duty to plantation must be measured against promote and defend the integrity of the current anthropological findings, personal identity of every individual. especially that branch of philosophical We can therefore conclude that, in anthropology that deals with personal general, the implantation of a foreign identity59. Any ethical appraisal of organ into a human body finds an ethical xenotransplantation must ultimately limit in the degree of change that it may address the question of whether the entail in the identity of the person who receives it. 58 The Old Testament precept by which cer- tain animals were held to be impure (cf. Lv 11: 3-8, 11. Such a modification, as already 26-29), is considered abolished by Christ (cf. Mk 7: noted, affects the historical dimension of 14-23; Acts 10: 14-15; Rom 14: 14). 59 It should be noted that «identity indica- 60 Cf. Grinberg L. and R., Identità e cambia- tors» in human beings are many (objective: name, mento, Roma: Armando, 1992; Jervis G., La con- sex, age, etc.; cultural: language, religion, ideology, quista dell’identità: essere se stessi, essere diversi, etc.; group - social - professional). Milan: Feltrinelli, 1997.

316 Cuad. Bioét. 2003/2ª, 3ª Pontifical academy for life prospects for xenotransplantation scientific aspects and ethical considerations the person, and thus the individual’s as being purely functional and those with communicative structure as mediated by greater personalized significance must be his corporeality. assessed, case by case, specifically in In light of a renewed appreciation of relation to the symbolic meaning which the body and of the symbolic they take on for each individual person62. understanding of it that much of 12. The questions and issues connected contemporary anthropology offers, it with the defence of the personal identity should be observed that not all organs of of the recipient patient is a central point the human body are in equal measure an not only for philosophical anthropology expression of the unrepeatable identity of but also for moral theology, as is the person. There are some which demonstrated by certain official exclusively perform their specific function; pronouncements of the Magisterium on others, instead, add to their functionality xenotransplantation, which see this as one a strong and personal symbolic element of the fundamental criteria for the moral which inevitably depends on the legitimacy of xenotransplantation. First subjectivity of the individual; and others Pius XII (Address to the Italian Associa- still, such as the encephalon and the tion of Corneal Donors, Clinical gonads, are indissolubly linked with the Ophthalmologists and Legal Medicine, 14 personal identity of the subject because of May 1956), and more recently John Paul II their specific function, independently of (Address to the Eighteenth International their symbolic implications. Therefore one Congress of the Transplant Society, 29 must conclude that whereas the August 2000, n. 7), have clearly upheld transplantation of these last can never be the moral legitimacy, in principle, of this morally legitimate, because of the therapeutic procedure, on the condition inevitable objective consequences that they that «the transplanted organ does not would produce in the recipient or in his affect the psychological or genetic identity descendants61, those organs which are seen of the person who receives it» and «that there exists the proven biological 61 We do well to specify that, while the en- possibility of carrying out such a cephalon is related to the personal identity of the subject insofar as it is the organ representing the «principal seat of psychological consciousness», and rent, however, is the case of a gonad transplant the «deposit» of existential memory, the gonads are performed exclusively for hormonogenetic purpo- likewise related, insofar as they are organs charged ses (that is, to restore a sufficient hormonal func- with gametogenesis (the production of gametes); tion); once the integrity of the subject’s personal they represent, in a manner of speaking, the «trans- identity has been ensured, and once the disassocia- mitter» - by means of procreation - of the subject’s tion with procreation has been established, there personal identity (genetic patrimony) to offspring. would be no particular moral reservations. In this For this reason, while an hypothetical encephalon regard, see M.P. Faggioni, Il trapianto di gonadi. transplant can in no case be considered morally Storia e attualità, Med. Mor., 1998, 48, 15-46. licit, neither can an eventual gonad transplant - if 62 Cf. Cuer P., Quelques considérations éthi- performed for the purpose of supplying the game- ques, notamment sur l’identité lors de xénotras- togenetic function - be morally acceptable. Diffe- plantations, Path Biol (Paris) 2000, 48: 426-428.

Cuad. Bioét. 2003/2ª, 3ª 317 Documentos transplant with success, without exposing The Health Risk the recipient to excessive risks». We may observe here that together 13. As previously stated, one of the with the defence of personal identity, these fundamental ethical questions that pronouncements of the Magisterium should be examined when judging the indicate a second criterion for the moral legitimacy of xenotransplantation is that legitimacy of xenotransplantation: health of the health risk involved in such risk. We shall discuss this in greater detail procedures. This risk is dependent on shortly. various factors which cannot always be With regard to all other issues, from predicted or assessed. Before going on, the standpoint of moral theology, the therefore, it may be useful to recall some ethical conditions required for every other general aspects of the ethics of risk. kind of transplant apply also for xenotransplantation63. Hanson M.J., The Seductive Sirens of Medical Pro- gress. The case of Xenotransplantation, Hastings Bioethical Issues Center Report 1995, 25: 5-6; Nuffield Council of Bioethics, Animal-to-Human Transplants: the Ethics of Xenotransplantation, London: Nuffield Council Further investigation and clarification of Bioethics, 1996; Mc Carthy Ch.R., A New Look at is needed for a wider bioethical analysis. Animal-to-Human Organ Transplantation, Kenne- The ethical evaluation of the practicability dy Institute of Ethics Journal, 1996, 6: 183-188; U.S. of xenotransplantation, in light of the Institute of Medicine Committee on Xenograft Transplantation, Xenotransplantation: Science, current situation as summarized in the first Ethics, and Public Policy, Washington: National part of this document, requires the Academy Press, 1996; Bach F.H., Fishman J.A., Da- consideration of a whole series of factors, niels N., et al., Uncertainty in Xenotransplantation: Individual Benefit versus Collective Risk, Nature some of which are derived from the general Medicine, 1998, 4: 141-144; Hughes J., Xenograf- moral norms valid for all transplants, and ting: Ethical Issues, Journal of Medical Ethics, 1998, others of which are more specifically related 24: 18-24; Vanderpool H.Y., Critical Ethical Issues 64 in Clinical Trials with Xenotransplants, The Lancet, to xenotransplantation . 1998, 351: 1347-1350; Clark M.A., This Little Piggy Went to Market: The Xenotransplantation and Xe- nozoonose Debate, Journal of Law, Medicine and 63 Cf. also John Paul II, Address to the Parti- Ethics, 1999, 27: 137-152; Comité Consultatif Natio- cipants at a Congress on Organs Transplantation nal d’Éthique pour les Sciences de la vie et de la (20 June 1991) in Insegnamenti di Giovanni Paolo santé (France), Avis sur l’éthique et la xénotrans- II, XIV/1, 1991, p. 1711, 20/6/1991; Catechism of plantation, n. 61, 11 June 1999; Cooper D.K.C., Lan- The Catholic Church (1994) n. 2296; John Paul II, za R.P., Xeno, the Promise of Transplanting Animal Enc. Lett. Evangelium Vitae (1995) n. 86; Pont. Organs into Humans, New York: Oxford Universi- Counc. Past. Assist. Health Care Workers., Charter ty Press 2000; U.S. Dpt. Health & Human Services, for Health Care Workers (1995), nn. 83-91; John Food and Drug Administration, Center for Biolo- Paul II, Address to the Eighteenth International gics Evaluation and Research, Source animal, pro- Congress of the Transplant Society, 29/8/2000. duct, preclinical, and clinical issues concerning the 64 For an overview of the current debate see: use of Xenotransplantation products in humans: Caplan A.L., Is Xenografting Morally Wrong?, guidance for industry (Draft, February 2001), (http: Transplantation Proceedings, 1992, 24: 722-727; //www.fda.gov/ cber/guidelines.htm).

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Risk - understood as an unwanted or Lastly, it is necessary to distinguish damaging future event, the actual acceptability from what we can define as occurrence of which is not certain but the acceptance of the risk, as defined by possible65 - is defined by means of two the reaction of the individual or of the characteristics: the level of probability general public to the existence of the risk. and the extent of damage. The probability This is a response that has a significant of the occurrence of a certain damaging subjective component, one which is not event in particular circumstances can be always completely thought out and expressed as a risk percentage or as a which is influenced by culture, by the statistical frequency. Furthermore, the information available and how it is presence or absence of certain chance understood, by the way in which the factors of risk can sometimes alter the information itself is communicated, and probability that a certain event will take by common sensibilities66. place. The extent of the damage, in In the absence of data that allow a contrast, is measured by the effects that reliable assessment of such a risk, greater the event produces. Naturally, a very caution should be used; this does not probable risk is easily tolerated if the necessarily mean, however, that a total extent of damage associated with it is «block» should be put on all experi- very small; on the contrary, a risk that mentation. Indeed, to move from ignorance causes a high level of damage, however to knowledge, from the unknown to the improbable, gives rise to much greater known requires the exploration of new concern and require greater caution. approaches which in all likelihood, It is important to distinguish between especially during initial experimental a probable event (albeit with varying stages, will not be without risks, at least degrees of probability) and an event that potentially. In this situation, therefore, the is only hypothetical; this latter is an event imperative ethical requirement is to proceed which is not theoretically impossible but by «small steps» in the acquisition of new which is so improbable as to require no knowledge, making use in experiments of change in behaviour or choices. the least possible number of subjects, with Together, these two criteria - careful and constant monitoring and a probability and extent of damage - define readiness at every moment to revise the the acceptability of the risk, as reflected design of the experiment on the basis of by the risk/benefit ratio. Only when a new data emerging. risk can be concretely assessed it is It is important to consider the possible to apply criteria for evaluating distinction between risk assessment and its acceptability. 66 An overview of social reactions to diffe- rent aspects of xenotransplantation: Appel J.Z., 65 Cf. Schöne-Seifert B., Risk, in Reich T.W. Alwayn I.P., Cooper D.K., Xenotransplantation: The (ed.), Encyclopedia of Bioethics, vol. 4, New York: Challenge to Current Psychological Attitudes, Prog MacMillan 1995 (revised edition), 2316-2321. Transplant 2000, 10: 217-225.

Cuad. Bioét. 2003/2ª, 3ª 319 Documentos risk management. To achieve an ethical therapy can only be based on hypothesis. assessment, both elements must be There is, therefore, an ethical requirement carefully examined. to proceed with the greatest caution. 14. This general discussion of the When the moment for clinical ethics of risk must now be applied to the application of xenotransplantation specific case of xenotransplantation. arrives, it will be necessary to select First of all, we note that there are issues patients carefully, based on clear and connected with xenotransplantation, such well-established criteria67, and to monitor as the probability of rejection and the the patient very closely and constantly. increase in the probability of infection One must also contemplate the possibility because of immunosuppressive therapies, of placing the patient in quarantine to about which some degree of knowledge prevent the epidemic spread of an already exists, although further study is infection. Arrangements for some kind necessary. The data which the scientific of monitoring of those having close community already possesses, together contacts with patient should also be with new data being gathered, can help made. to establish the threshold of risk that must Moreover, during the experimental not be crossed if a transplant operation to phase of clinical trials, patients should be considered morally acceptable. agree not to procreate because of the More complex and uncertain is the possible risk of genetic recombination that assessment and evaluation of risks could affect the patient’s germ cells. Sexual connected to one specific aspect of abstinence would also be necessary to xenotransplantation: the possible avoid the venereal transmission of possible transmission to the recipient of infections viruses. arising from the xenotransplant In the clinical application of (zoonoses) by known or unknown xenotransplantation, psychology should pathogenic agents which are not harmful also play an important role. It should to the animal but which are possibly address the probable repercussions that dangerous for man. Such infections could the recipient could undergo in their psyche escape detection, with the consequent (e.g. because of the modification of one’s possibility of the spread of the infection «bodily schema») arising from the to those having close contacts with the acceptance of a foreign organ68, especially patient, leading eventually to its being spread to the entire population. 67 Cf. Beckmann J.P., Xenotransplantation aus ethischer Sicht. Eine Skizze, Zentralbl Chir 1999, Since clinical experience of xenotrans- 124: 636-640; Welin S., Starting Clinical Trials of plantation is quite limited and certainly Xenotransplantation. Reflections on the Ethics of insufficient to provide reliable statistics on the Early Phase, J Med Ethics 2000, 26: 231-236. the real probability of occurrences and 68 In this regard, polls have been taken to ascertain the level of public acceptance of eventual spread of infections, any decision xenotransplantation. See, for example, Mohacsi P.J., concerning clinical development of the new Blumer E.C., Quine S. et al., Aversion to Xenotrans-

320 Cuad. Bioét. 2003/2ª, 3ª Pontifical academy for life prospects for xenotransplantation scientific aspects and ethical considerations when it comes from an animal69. In the man’s responsibility towards the created post-transplant stage, psychology must order and towards the pursuit of also provide clinical support the for the improving health by means of certain patient in the process of integration. types of genetic manipulation, we will now enumerate some fundamental ethical Trangenesis conditions which must be respected: 1. Concern for the well-being of 15. The use of organs from engineered genetically modified animals should be animals for xenotransplantation raises the guaranteed so that the effect of the need for certain reflections on transgene’s expression, possible modi- transgenesis and its ethical implications. fication of the anatomical, physiological The term «transgenic animal» is used and/or behavioural aspects of the animal to indicate an animal whose genetic may be assessed, all the while limiting the make-up has been modified by the levels of stress and pain, suffering and introduction of a new gene (or genes). In anxiety experienced by the animal; contrast, the term «knock out» is used to 2. The effects on the offspring and designate those animals in which a given possible repercussions for the endogenous gene (or genes) is no longer environment should be considered; expressed. In either case, such animals 3. Such animals should be kept under will express particular characteristics tight control and should not be released which will be transmitted to the offspring. into the general environment; As we have already observed, the 4. The number of animals used in possibility of working out such genetic experiments should be kept to a bare modifications, using genes of human minimum; origin as well, is morally acceptable when 5. The removal of organs and/or done in respect for the animal and for tissues must take place during a single biodiversity, and with a view to bringing surgical operation; significant benefits to man himself. 6. Every experimental protocol on Therefore, while recognizing that animals must be evaluated by a transgenesis does not compromise the competent ethics committee. overall genetic identity of the mutated animal or its species, and reaffirming Informed Consent plantation, Nature, 1995, 378: 434; National Kidney 16. In the ethical discussion on Federation, Survey reveals positive feelings on ani- mal-to-human transplants, Dialysis and Transplan- xenotransplantation, the subject of informed tation, 1995, p. 677; Mohacsi P.J. et al., Patients atti- consent also deserves special attention70. tudes to xenotransplantations, Lancet 1997, 349: 1031. 70 Cf. Barker J.H., Polcrack L., Respect for 69 Cf. Crafen J., Rodin G.M., Psychiatric As- persons, informed consent and the assessment of pects of Organ Transplantation, New York: Oxford infectious disease risks in xenotransplantation, Med Medical Publications, 1992. Health Care Philos 2001, 4(1): 53-70.

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Given the animal source of the organs procedures to be used offers a reasonable which will be transplanted, this issues hope of benefit for the patient. concerns only the recipient and, secondly, The patient’s relatives should also be his relatives. At the outset the recipient informed about what the transplant could should be given every information entail regarding their contact with the regarding his pathology and its prognosis, patient and about the possible risks of the xenotransplant operation and contagion should an infection, as subsequent therapy, and the probability mentioned above, set in. In a strict sense, of success and the risks of rejection. Special however, consent cannot be requested attention should be paid to making sure from them, since it is the patient who is that the patient is informed about the real ultimately responsible for the choices and hypothetical risks of zoonoses, in light concerning his own health. of current data, and about the precautions to be adopted in the case of infection (in Allocation of Health Care Resources particular the possible need for quarantine, which involves avoiding physical contact 17. Xenotransplantation certainly with others while the risk of contagion is represents a form of possible treatment present). The patient must also be requiring a great outlay of both health care informed about the need to remain under resources and economic resources71. For this medical supervision for the rest of his life, reason, some people have expressed doubts so that the necessary constant monitoring about its ethical validity; given the large following the transplant may be carried amounts of resources that it would take out. In addition, adequate information on away from the other forms of therapeutic possible alternative therapies to treatment and from other area of research, xenotransplant therapy should not be they consider both the uncertainty about withheld. its success and the risk entailed to be This informed consent on the part of excessive. Faced with these doubts, it is the patient should be understood as important to remember that, even taken personal. For this reason, minors and into due consideration the costs-benefits those unable to give valid consent are to balance, the huge amount of health care be excluded from the experimental phase. resources used in this case is justified by However, if a patient incapable of the urgent need to try to save the lives of giving valid consent should find himself so many patients who would otherwise in a previously unforeseen situation have no chance of survival. where there is danger of imminent death, recourse may be made to a legal 71 Cf. Kress J.M., Xenotransplantation: ethics representative (e.g. in the hypothetical and economics, Food Drug Law Journal 1998, 53 (2): 353-384; Urruela Mora A., Workshop on the case of a life-saving xenotransplant as a ethical, sociologic, economic and legal aspects of temporary solution for a patient in a xenotransplantation, Law Hum Genome Rev 2000 coma), provided that the medical Jan-Jun; (12): 245-6.

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It should also be added that as long as however that the norms drawn up by xenotransplantation on man remains at an the European Community to regulate this experimental stage it should not be subject matter could not, at the time they were to the criteria applied to treatment in strict being drafted, take into account the use sense; rather it should be evaluated of such organs for transplant from animal according to the criteria used for trials. to man, since this therapeutic procedure Therefore, the foreseeable collective had not yet been accomplished in clinical benefits that it may accrue in the future practice. should also be taken into account. We do We therefore stress that, given the well to recognize here that the research extraordinary financial commitment that into xenotransplantation which has taken has been made, now is the time to place so far has also brought about greater reconsider - or rather to be more precise medical knowledge in the area of about - the specific norms that apply. allotransplantation. We are aware of the broad debate underway on the basic question of Patentability and Xenotransplantation whether the possibility itself of patenting living beings (even though genetically 18. Research on xenotransplantation modified) or parts of them, especially has hitherto in large measure been carried when they contain genetic elements out largely by private pharmaceutical derived from humans (as is the case with companies which have committed animal organs genetically engineered for substantial economic resources to this xenotransplantation into man), is endeavour; they have also been providing ethically acceptable. We are also aware financing to public institutions for the that there is a difference between a purpose of obtaining better therapeutic «discovery» (which cannot be patented) results. It is therefore reasonable for them and an «invention» (which can be to expect an economic return on the patented). Although it is our view that investment made; one of the possible the transgenic animal as such - and all ways to do this is by acquiring patents. the more when they are used for From a formal point of view, there is transplantation into man - should be no technical or legal obstacle standing in considered «nonpatentable», we the way of the patenting genetically nonetheless believe that it is not the engineered animal organs intended for purpose of present document to address transplants72. It should be emphasised this complex question directly. Here, we shall limit ourselves to 72 Cf. Trattato di Cooperazione sui Brevetti emphasising that, whatever answer may (Washington, 1970), art.33; Convenzione del Bre- be given to this basic question, it is vetto Europeo (Munich, 1973), 54-57; vedi anche Marchetti P., Ubertazzi L.C., Commentario breve al always necessary - as a bare minimum - diritto della concorrenza, Padova, CEDAM, 1997: to guarantee respect for the fundamental 1343. right of every person to equitable access

Cuad. Bioét. 2003/2ª, 3ª 323 Documentos to the health care they may be needed, When the moment arrives, it will be without discrimination and without ethically correct, respecting the rules of being impeded by excessive costs. This informed consent indicated above, to applies above all else to accessibility to involve initially only a restricted group treatment. This objective - in the of patients, patients who cannot be hypothetical case of patents connected chosen - in the given circumstances - for with xenotransplantation, a procedure allotransplantation (whether because of which should be viewed from a waiting lists or individual counter- therapeutic standpoint - can be reached indications), and for whom no better by making appropriate legal requi- alternative treatment is available. rements apply (for example, the A commensurate moral imperative is introduction of compulsory licences), that of ensuring careful and detailed thus allowing «production» at accessible monitoring of the individuals who prices73 which would hopefully be receive a xenograft, a situation which controlled by a supranational body could foreseeably continue for the rest of specifically set up for this purpose. the patient’s life, watching for any sign of possible infection caused by known Practical Guidelines and unknown pathogenic agents. In addition, every experimental 19. Bearing in mind all that has been clinical trial should be carried out in said above, we can now present a highly specialised centres with proven practical approach which will guide the experience in pre-clinical pig-to-primate path of research and development in the models; these centres should be area of xenotransplantation as applied authorised and supervised by the to man. competent health care authorities. Regarding the xenotransplantation of The results thus obtained, if solid organs, it is of course necessary that unequivocally positive, would constitute pre-clinical experiments (from animal to the basis for extending the practice of animal) should continue for as long as xenotransplantation, making it an scientists should require and until accepted surgical therapy. repeatable positive results are obtained, 20. The questions and issues related to results which are considered sufficient to xenotransplantation have implications of allow trials on man to begin. a very wide social character. There is thus an ethical need to acquire correct 73 Cf. WIPO/OMPI, Introduction to Intellec- information on the topics of greatest public tual Property: Theory and Practice, Kluwer Law interest with regard to the potential International, London 1998: 145-150; Accordo di benefits and risks. This information should Marrakech istitutivo dell’Organizzazione Mondia- le del Commercio, Annesso lC: Accordo sugli as- be communicated to as large a segment of petti della proprietà intellettuale relativi al com- the public as possible. Moreover, by means mercio (Marrakech, 1994), art. 31. of debates and public discussions in small

324 Cuad. Bioét. 2003/2ª, 3ª Pontifical academy for life prospects for xenotransplantation scientific aspects and ethical considerations and large groups, society itself, through this complex sector, offering helpful its representatives, should help to identify operational directives. the conditions under which they would On our part, we do not believe that find it acceptable to invest resources and this document should enter into hope in this new therapeutic approach, in procedural political-legislative matters. We light of the scientific uncertainties which therefore limit ourselves to emphasizing are still present and the urgent need to the importance and desirability that a increase the availability of organs which substantial convergence of international can be transplanted. legislation in this area should be achieved A serious ethical commitment on the as soon as possible, by means of a genuine part of scientists should not neglect to coordination at the different levels. On the explore therapeutic paths which may one hand such legislation must provide represent alternatives to rules for the continuation of scientific xenotransplantation, such as seem to be research, guaranteeing its validity and promised by many recent discoveries in safety; on the other hand it must watch the field of genetics, as in a longer period over the health of the citizens involved the therapeutic use of adult stem cells. and the potential risks (especially 21. With respect to the specific fields infective) connected with xenotrans- of health-related policies and legislation plantation. Furthermore it must offer on matters of xenotransplantation, it is criteria for organizing the necessary our heartfelt hope that the considerations information campaigns aimed at the entire offered in the present document will population. provide a useful point of reference for all We conclude this document with the those who - at an international, national, sincere hope that the effort made on this regional and local level - are responsible study by those who have participated in for leading society. Many countries74 have it - scientists, jurists, theologians and already developed guidelines to regulate bioethicists - will represent a concrete contribution to the development of the 74 To give a few examples of some impor- discussion on the important theme of tant organizations that have drafted guidelines in xenotransplantation. May it also be seen this area, we list the following: the Council of as a further expression of the close Europe, the Health Council of the Netherlands, the Swedish Committee on Xenotransplantation, the attention which the Catholic Church pays Spanish Xenotransplantation Sub-committee, the on problems related to human disease Argentine National Commission on Xenotransplan- and suffering. tation, the U.S. Department of Health and Human Services Committee on Xenotransplantation, the United Kingdom Xenotransplantation Interim Re- Agency for the Security of Health Products and of gulatory Authority, and the Italian Xenotransplan- the Ministry of Health. In Germany, the German tation Commission. In France, the ethical aspects Medical Council has established a committee to are currently being examined by the French Natio- prepare guidelines on xenotransplantation. In Ca- nal Ethics Committee and applications for clinical nada «Health Canada’ has the authority to regulate trials will need the approval of the newly formed xenotransplantation as a new technology.

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* As is the custom, this document of University of Cambridge Addenbrooke’s the Pontifical Academy for Life is Hospital, Hills Road - Cambridge, UK published under the editorship of the President and Vice-President. - Prof. Marialuisa Lavitrano (xenotransplantation, biotechnologies, In drafting its contents, the Academy molecular biology and genetics) received input from an international work Coordinator of «Italy Xenotransplant group with specific expertise in the various Project» Member of Working Group on disciplines connected with Xenotransplantation Council of Europe xenotransplantation; this work group met Department of Experimental Medicine many times in the Vatican earlier this year. and Pathology University «La Sapienza» Rome, ITALY Members of the work group are the following: - Prof. Ignazio Marino (transplantation) Mediterranean -Bishop Elio Sgreccia Institute for Transplants and Highly Vice-President of the Pontifical Specialized Therapies City Hospital Academy for Life Palermo, ITALY Chairman for the scientific section: - Prof. Eraldo Seren -Prof. Fritz H. Bach (xenotransplantation, veterinary expe- (xenotransplantation, immunoge- rimentation) Professor of Veterinary Phy- netics). Harvard Medical School Boston, siology State University - Bologna, ITALY USA - Prof. Angelo Serra, S.J. -Prof. Fulvio Calise (human genetics) Professor Emeritus (xenotransplantation, clinical expe- of Human Genetics Sacred Heart Catholic rimentation). Head of Hepatobiliary University Rome, ITALY Surgery and Liver Transplants. Liver Unit, Cardarelli Hospital Naples, ITALY - Prof. Jonathan P. Stoye (xenotransplantation, virology- - Prof. Felix Cantarovich microbiology) Division of Virology, (transplantation, health care policies) National Institute for Medical Research Coordinator of the National London, UK Commission on Xenotransplantation Buenos Aires, ARGENTINA for the ethical-anthropological section:

- Prof. Emanuele Cozzi - The Rev. Maurizio Calipari (xenotransplantation, preclinical (moral theology, bioethics) Pontifical experimentation) Department of Surgery, Academy for Life VATICAN CITY

326 Cuad. Bioét. 2003/2ª, 3ª Pontifical academy for life prospects for xenotransplantation scientific aspects and ethical considerations

- Msgr. Ignacio Carrasco De Paula - Msgr. Angel Rodriguez Luo (moral theology, bioethics) Professor (moral theology, bioethics) Professor of Bioethics Bioethics Institute, Sacred of Moral Theology Holy Cross Pontifical Heart Catholic University Rome, ITALY University Rome, ITALY

- Prof. Maurizio P. Faggioni, O.F.M. - Prof. Antonio G. Spagnolo (moral theology, bioethics) Visiting (bioethics) Associate of Bioethics Professor of Bioethics Alphonsian Sacred Heart Catholic University Rome, Academy Rome, ITALY ITALY

- Msgr. Nunzio Galantino - Justice C.G. Weeramantry (philosophical anthropology) (international law) Former Vice- Professor of Philosophical Anthropology President, International Court of Justice Southern Italy Faculty of Theology Dharmaraja, Mawatha - SRI LANKA Naples, ITALY Representatives of the Holy See - Prof. Bonifacio Honings, O.C.D. - Msgr. Tullio Poli (moral theology) Professor Emeritus Secretariate of State (Sect. for Relations of Moral Theology with States) VATICAN CITY

- Msgr. Osvaldo Neves de Almeida - Dr. Maria Isabel Telleria Tapia (international law, business law) Secretariate of State (Sect. for Relations Secretariate of State (Sect. for Relations with States) VATICAN CITY with States) VATICAN CITY

- Prof. Renzo Pegoraro (bioethics) General Secretary of Lanza Foundation Padova, ITALY

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