Abstract
Xenotransplantation defines the use of living cells, tissues, or organs from a nonhuman animal origin transplanted into a human; or these materials have ex vivo contact with human body fluids, cells, tissues or organs that are subsequently given to a human recipient. Xenotransplantation has been investigated as a promising alternative to material of human origin by recent developments in immunology and in the genetic engineering of organ and tissue rejection. While the serious shortage of human donated organs worldwide, the significant improvements in biotechnology and immunology refuel scientists’ interest to reinvestigate the possibilities of xenotransplantation.
Xenotransplantation is expected not only applying in organ transplantation, but also for the treatment of diabetes, Parkinson's disease, intractable pain, and other diseases involving tissue destruction. The social and ethics concerns of xenotransplantation are critical because xenotransplantation might carry risks, in particular of transmission of known or as yet unrecognized infectious agents from animals to human beings and from recipients of transplants to their contacts and the public at large.
In addition to the above safety issues, the controversial issues about the implications of xenotransplantation for human rights, common goods, community interest and consent, social equity in access to novel biotechnologies, allocation of human allografts, and animal welfare are concerned. Thus, in order to create a better environment for Taiwan to develop xenotransplantation-related regenerative medicine industry, it is important to have throughout research on its ELSI (ethical, legal and social implications) issues.
摘要
異種移植定義上涵蓋將非人類動物的活細胞、組織或器官移植到人類。近年來免疫學 及基因工程之快速發展，異種移植因而被認為具有極大的潛力作為人體器官組織障礙時之 替代修補來源。然而異種器官移植同時也帶來許多風險，特別是在移植過程中已知或還未 被確認的從動物到人類異種移植上的感染物原，並且受移植者潛在可能性地將此種感染原 擴散到其所接觸的社會大眾。除了上述安全性議題，另有許多個人及團體十分關切異種移 植在其他相關議題上所可能引發的衝擊及影響，諸如告知同意、人權、公共資產、社區利 益、使用新興生物科技所產生之社會平等、人類器官移植之公平分配以及動物福利等等議 題。因此，為了建構再生醫學之異種移植於台灣之健全環境，針對異種移植進行全面性倫 理、法律與社會衝擊之探討乃為必要。
1. Introduction
Due to recent, dramatic advances in molecular biology, genomics, immunology, and transplant biology, new medical therapeutics are being developed for providing better treatment options for genetic disease, organ failure and aging. In this complex territory straddling pure biotechnology research, commercial exploitation, therapeutic and health applications interwoven with policies, principles, ethics, and new special perspectives, the traditional regime of legal regulation is facing the challenge of adequately protecting the common good.
Even though some resolutions have emerged at the international level, such as the UNESCO, the OECD and the WTO, that have provided more explicit ethics-related clauses, a lot of controversial problems remain unresolved.
Regenerative medicine is no exception and it represents one of the most disputed issues in this new era.
Regenerative medicine is an emerging field that approaches the repair or replacement of tissues and organs by incorporating the use of cells, genes or other biological building blocks along with bioengineered materials and technologies. The objective of this research is to examine how the current legal system deals with the controversial issues in regenerative medicine, particularly in xenotransplantation. Reviewing applications of xenotransplantation from governmental, industrial and academic perspectives is critical if we are going to make the right decisions. These decisions include how to leverage breakthroughs in scientific research for the benefit of society in an ethical and responsible manner as well as how to promote private, industrial interests. A number of issues have to be identified and an argument has to be put forward for a comprehensive solution to the problems raised herein. The goal of this research project is, therefore, designed to construct a more feasible and suitable system for developing regenerative medicine for physicians, the biotechnology industry, political decision-makers, academic scholars, and the general public in Taiwan to cope with the challenges that the current legal, social, political and moral issues which have been raised in international fora. The long-term objective of this project is to provide explicit recommendations to the government of Taiwan for public policy development.
Scientific advances enable conditions that were previously incurable or irreversible to become possible, particularly since the cloning of Dolly the sheep in 1997. Recently, continued breakthroughs in animal research in relation to animal cloning and stem cell research has greatly enhanced the possibility of bodily regeneration.
In general, regenerative medicine includes the applications of xenotransplantation, stem cells, umbilical cord cells, cartilage and bone repair, neuro-regeneration, immunology, and skin and soft tissue repair.
Xenotransplantation research aims to provide a nearly limitless supply of organs for transplantation, and alleviate human suffering, such as repairing damaged or diseased tissues and organs through the development of tissue and organ therapies. Recent research and government policies in regenerative medicine in many countries, however, have begun to face public challenge.
2. Current Situation for organ transplantation
Recently several significant developments in the use of live animal cells, tissues and organs in the treatment or mitigation of human disease haveraised thepublic’sinterestin xenotransplantation.Thecriticalshortageof
human organs is a world-wide phenomenon. The number of patients in need of organ transplantation, local or foreign, is steadily on the rise; and in spite of the rising number of volunteer organ donors, there is an ever-expanding number of patients needing for an organ transplant. Each day, about 60 people around the world receive an organ transplant, while another 13 patients die during the period of waiting to receive a life-saving transplant to replace a damaged, vital organ. The United Network for Organ Sharing (UNOS) presents comprehensive, up-to-date information that gives the status of people awaiting organ transplants.
There are reportedly over 92,4100 people in the USA waiting for organ transplants, but the number of transplants performed from deceased and living dornors was only 9,379 in 2006.125. The disproportional disparity between the number of donors and receivers has propelled organ shortage as a major obstacle in transplant medicine. It is precisely this shortfall that has compelled us to ponder how best to expand the source of organ donation.
In other words, roughly one-third of the patients queuing for a transplant would receive donated organs, while the other two-thirds would have to wait for another year. In the U.S., a liver transplant recipient would need to queue for an average of one year in order to receive a donated organ, while the queuing time for a kidney or a heart consistently exceeds two years. The same scenario also occurs in Western Europe and Australia. In the U.K., at any given time, there are 6,000 patients queuing for organ transplants, of whom only 3,500 have the chance to receive a donated organ. In Taiwan in 1999, with more than 30,000 patients suffering from organ exhaustion, over 5,000 of them are queuing for an organ transplant. The small number of organ donors has made alternatives to human organ transplantation, particularly xenotransplantation, ever more important.126
3. The importance of xenotransplantation
Organs can be transplanted into humans using human homogeneous organs or non-human animal organs. A major downfall of using homogeneous organs lies in its short supply, which has led to exploring the feasibility of developing animal organ transplantation, i.e. xenotransplantation; however xenotransplantation is still hindered by a host of resistant reactions that need to be overcome. Presently, xenotransplantation studies focus primarily on exploring the fundamental mechanisms and reactive processes of immune resistant reactions, and in devising the treatment method for easing these resisting phenomena.
Xenotransplantation involves the use of living cells, tissues, or organs from a non-human animal origin transplanted into a human; or these materials have ex vivo contact with human body fluids, cells, tissues or organs that are subsequently given to a human recipient127. Xenotransplantation recently has been investigated as a promising alternative to material of human origin by recent developments in immunology and in the genetic engineering of organ and tissue rejection. While there is a serious shortage of human donated organs world-wide,significantimprovementsin biotechnology and immunology haverekindled scientists’interestto reinvestigate the possibilities of xenotransplantation. Xenotransplantation is expected to be applied not only to
125 SeetheUNOS EthicsCommittee’sweb siteathttp://www.unos.org/data/default.asp?displayType=usData.
126 Lee, C.M. 2003. The future and present status of xenotransplantation. Marple News and Comments, No 119. See http://www.mc.ntu.edu.tw/~maple/maple119/mono.html#mono1
127 Florencio, Patrik S. and Ramanathan, Ramanathan, 2004. Legal Enforcement of Xenotransplantation: Public Health Safeguards, Journal of Law, Medicine & Ethics, 32-117.
organ transplantation, but also for the treatment of diabetes, Parkinson's disease, intractable pain, and other diseases involving tissue destruction. The social and ethical concerns of xenotransplantation are critical because xenotransplantation carries risks, in particular, the transmission of known or as yet unrecognized infectious agents from animals to human beings and from recipients of transplants to their contacts and the public at large.
With organ donors that are few and far between and often bound by legal restrictions, xenotransplanation has emerged to be as important as ever. Taking into account post-transplant human immune reaction, the primary source of xenotransplantation would be primates such as baboons or chimpanzees as the optimal choice because the dissected structure, physiological functions and other aspects of the physical conditions of their tissues and organs most closely resemble that of humans. Yet the great apes are protected species as their numbers are dwindling due to reproductive difficulties and extended nurturing time, so it is, in fact, not feasible to count on the great apes as a reliable source of routine xenotransplantation. Other types of primate also share similar difficulties. In addition, primates often pose inherent risks of the infectious diseases, particularly viruses because they share a similar genetic structure and physiology as humans. This can lead to severe and uncontrollable consequences. For instance, primates carry exogenous and endogenous retroviruses such as simian foamy viruses, simian T-cell lymphotropic viruses, etc., which may result in unexpected illnesses once they have been transmitted to humans through transplantation128. Hence xenotransplantation relying on primates as the organ source, is hindered by many constrains which has, in fact, proven it to be infeasible for reasons of global public safety.
Scientific breakthroughs in molecular biology and in the immunology of organ/tissue rejection have renewed scientists' interest in reconsideration of whether xenotransplantation is a potentially promising way to solve the serious shortage of donated organs. Besides, xenotransplantation might also an alternative to treat diseases such as chronic intractable pain syndromes, epilepsy and degenerative neurological diseases such as Parkinson's disease and Huntington's disease.
However, the application of xenotransplantation presents a number of significant challenges. The source of xenotransplantation research came from genetic manipulation which gives rise to serious ethical and public policy concerns.
4. The safety issue of xenotransplantation
Xenotransplantation is not a new treatment. Physicians have attempted cross-species transplantation as early as the 17th century. After the failures of cross-species transplantation for several centuries, pig insulin was first developed to treat diabetics in the 1930s. Pig heart valves have been used for heart patients for several decades;
however, the pig heart valves are chemically treated first to kill any pig cells. The major difficulties of xenotransplantation are the source of the donor organs and the strong immune-response from incompatible organ tissue.
The method of thework isto “mask”theimmune-response producing markers of the animal organ such that
128 Allen, Jonathan S. 1998. The Risk of Using Baboons as Transplant Dornors. Xenotransplantation: Scientific Frontiers and
the immune system of the human recipient fails to recognize the organ as being foreign. With this accomplished, rejection of the organ is no longer a problem. In spite of the potential controversy, a first step has been taken toward this end with the development of a pig that produces human haemoglobin in its blood.129 Due to the serious immunologic barriers that the human host presents to vascularized xenotransplantation products, physicians and researchers prefer to apply avascular cells or tissues rather than solid organs in the majority of clinical xenotransplantation procedures. However, with recent genetic advances, xenotransplantation is being investigated to develop the potential for whole solid organ transplantation. Besides, xenotransplanation is much needed in the development of the use of in vitro production of whole human organs from human cells. Although the latter may reduce the risk for rejection from immunoreactions, the technology is still not very successful and is much more expensive than xenotransplanation. Due to the long-term shortage of donated human organs, xenotransplanation would be a first-rate alternative treatment provided that the ELSI issues have been well dealt with.
In 1997, Robin Weiss discovered that the porcine endogenous retrovirus (PERV) could infect human cells in culture.Weiss’ssignificantdiscovery caused greatconcern and theU.S.FDA halted allclinicaltrialsin porcine xenotransplantation until those conducting the trials provided data to demonstrate their ability to perform appropriate tests and updated their Informed Consent documents to reflect the PERV risks. Weiss said,“In xenotransplantation . . . the pig organs and the pigcellswillbe‘humanized’by theinsertion ofhuman DNA to try and overcome the rejection process. Is that significant, in terms of what viruses could potentially do in that situation?”130 It is known that infectious viruses, including the Epstein-Barr virus and cytomegalovirus can be transmitted during allotransplants -- transplants between different individuals of the same species. Thus, the public are concerned that using animal organs for transplantation into humans may cause viruses to cross the species barrier and be a serious risk to human health.
In comparison, harvesting pig organs as the source for xenotransplanation could avoid the foresaid constraints.
Pigs have emerged as a prime supply due to their availability and the general consensus that pig organs are the mostsuitableforhuman transplantation.Forinstance,thesizeand agility ofapig’sheartclosely resemblesthat ofahuman heart.Thepig’sdissected structureand physiologicalfunctionsofvarioustissuesand organs, among all mammals, are deemed closer to that of humans. In addition, pigs easy to breed and in large quantity, making pig-oriented studies a major mode for research into human diseases, including heart disease, hypertension, arterial sclerosis, coronary myopia, xenotransplantation and so forth. As a result, attempting to genetically transplant pig organs into humans has emerged as a primary solution. Given that pig organs transplanted to humans often encounter extra acute, acute and chronic resistant reactions, selective breeding and screening out probable resistant genes is being conducted to solve a host of resistant phenomena, enabling the production technology in pig genetic transplantation to become a key to solving resistant phenomena.
It is still in doubt whether current developments in bioscience can establish a risk-free environment in xenotransplantation. Therefore, it is necessary for thoughtful screening for the potential risk of transmission of
129 ThomasTraian Moga,1994.“TransgenicAnimalsasIntellectualProperty”JPTOS. 7: 527-545.
130 Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nat Med 1997; 3: 282.
infectiousagentsfrom sourceanimalsto patients,patients’partnersorpatients’futurebabies,and thegeneral public.
5. Informed consent of xenotransplantation
In earlier xenotransplantation studies, there was little control, as human clinical treatments were often sought.
Currently, however, industrialized countries in Europe, Canada, Australia, New Zealand, the U.S.A., and Japan are not only bound by the interests of animal rights and protection groups, but have established relevant xenotransplantation regulations and laws.
What kind of ethical disputes can xenotransplantation trigger? Being that any medical treatment act would need to respectthevoluntary willofthepatientand her/hisfamily,itisimperative to heed to thepatent’s informed consent.Theterm “informed consent”refersto thefactthatapatient’sconsent needs to be one that the patient has fully understood the pros and cons of various medical treatment options. Suppose a medical treatment act is beneficial to the patient, the harm it brings shall not exceed the good it brings. Naturally, when harm becomes unavoidable, a more ethical conduct would be to choose the less harmful option of the two, which is also referred to as the lesser evil principle.
6. Ethical issue of xenotransplantation
Besides the source of human homogeneous organs, xenotransplantation should be regarded as a hope in human medical care; and under the circumstances that the severe organ shortage is unlikely to change, society needs to confront and jointly discuss the technological, legal social, ethical, moral and religious ramifications
The European Convention on Human Rights (ECHR) has a clear statement on human rights: it grants certain rights to people by reason of their being humans, implying that humanity is a sufficient condition for the possession of these rights. However, if some non-human animals possess some features that are part of a human’snatureand areresponsiblefortheirpossessing theserights,then can italso logically beinferred that these partial agents are entitled to rights? Beyleveld and Brownsword presented the Precautionary Principle to prevent the risk of wrongly justifying the status of the creature and subsequently depriving the creature of its rights to the protection of the PGC.131
This argument entails that some non-human animals, especially high-intelligence beings (such as dolphins, whales, gorillas, chimpanzees, and so on) should be accorded rights in the similar way that human beings have
This argument entails that some non-human animals, especially high-intelligence beings (such as dolphins, whales, gorillas, chimpanzees, and so on) should be accorded rights in the similar way that human beings have