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Future issues in transplantation ethics: ethical and legal controversies in xenotransplantation, stem cell, and cloning research
Available online at www.sciencedirect.com
Transplantation Reviews 22 (2008) 210 – 214
www.elsevier.com/locate/trre
Section 5: Future Issues in Transplant Ethics
Future issues in transplantation ethics: ethical and legal controversies in xenotransplantation, stem cell, and cloning research☆ Robyn S. Shapiro Center for the Study of Bioethics, Department of Population Health, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Abstract With little prospect of developing a sufficient supply of human transplantable organs to meet the large and growing demand, attention has turned to xenotransplantation, as well as stem cell and cloning research, as possible approaches for alleviating this allograft shortage. This article explores ethical and legal issues that surround developments in these fields. © 2008 Elsevier Inc. All rights reserved.
The demand for organs to transplant into humans continues greatly to outpace supply. Currently, it is estimated that in the United States, there are more than 97000 patients waiting for a lifesaving organ [1]. And in each year from 2001 to 2005, more than 7000 patients on the waiting list died [2]. With little prospect of developing a sufficient supply of human transplantable organs to meet the large and growing demand, attention has turned to xenotransplantation, as well as stem cell and cloning research, as possible approaches for alleviating this allograft shortage. This article explores ethical and legal issues that surround developments in these fields. 1. Xenotransplantation Several factors are responsible for recently increased interest in xenotransplantation—the transplantation, implantation, or infusion into a human of live cells, organs, or tissues from a nonhuman animal source [3]—as an approach for alleviating the allograft shortage. Improved understanding of human and animal immune systems, insights into histocompatibility, the development of new agents to control graft-vs-host disease, and animal breeding programs for the ☆
The data and analyses reported in the 2006 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients have been supplied by UNOS and Arbor Research under contract with HHS. The author alone is responsible for reporting and interpreting these data; the views expressed herein are those of the author and not necessarily those of the U.S. Government. E-mail address: [email protected]. 0955-470X/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.trre.2008.04.004
production of transgenic animals have improved the chances of successful patient outcomes with xenotransplantation. Despite this scientific promise, however, controversial ethical and legal issues surround xenotransplantation and deserve careful exploration. 1.1. Ethical issues For some, one ethical concern surrounding xenotransplantation is that transferring organs or tissue from animals to humans is wrongful interference with what is “natural” [4]. The validity of this concern, however, is questionable because of the difficulty of defining what is “natural” and what is “unnatural.” It could be said that everything that humans do is, by definition, unnatural in that all human actions interfere with the nonhuman natural order. Under this reasoning, because we cannot avoid interfering with nature, the argument that all unnatural actions (including, eg, xenotransplantation) are unethical is not persuasive. Under another view, nothing that humans do is unnatural because humans are themselves a part of nature. If nothing that we do is unnatural, then nothing we do can be wrong simply because it is unnatural. It is difficult to draw a line between natural and unnatural for differentiating ethical from unethical conduct. Moreover, even if what is natural could be clearly distinguished from what is not, it is unclear why the former is ethically superior. After all, it is only by interfering with nature that human lives are protected from destructive effects of natural phenomena such as droughts, hurricanes, and infectious agents [4].
R.S. Shapiro / Transplantation Reviews 22 (2008) 210–214
A second ethical issue surrounding xenotransplantation relates to the morality of killing animals to benefit human recipients. There are several responses to this concern. First, the traditional Judeo-Christian views of the relationship of humans to animals in creation rest on the belief that although animals manifest God's creative power, only humans are made in God's image. Humans occupy a higher niche in creation and have a transcendent moral relationship to God, which surpasses the relationship of other animals to their creator [5]. A second response to ethical concerns about killing animals for human recipients is that humans enjoy relative moral superiority over nonhuman animals because of superior human capabilities. Humans have capabilities, for example, for conceptualization, compassion, creativity, freedom of choice, moral decision making, appreciation of beauty, learning from the past, planning for the future, and altruism. Although some of these traits are possessed in limited ways by animals, the level and complexity of these traits as they exist in humans, it is argued, establish humankind as morally superior to nonhuman animals [5]. Third, throughout history, major elements of human civilization, including the understanding and preservation of the environment, nutrition, clothing, tools, and preservation and promotion of health—for animals and humans—have been dependent on human use of animals. To argue, then, that the use of animals for human ends is immoral is to state that humans cannot and never have been able to live morally upright lives [5]. 1.2. Legal issues 1.2.1. Informed consent The most significant legal issues surrounding xenotransplantation relate to informed consent. There is ample evidence of the transmission of infectious agents from animals to humans. Zoonoses, or diseases transmitted between animals and humans under natural conditions, are exemplified by the human immunodeficiency virus, which is thought to have crossed into the human population by mutation of a related simian immunodeficiency virus acquired from wild primates in Africa and by the leap of the hemorrhagic Ebola virus from primate to man [6]. With specific respect to xenotransplantation, the most likely candidate species for xenotransplantation is the pig, and the potential risk of cross-species infection associated with the use of porcine tissues in humans has drawn considerable attention because of the discovery that porcine endogenous retroviruses can infect human cells in vitro [7]. Moreover, transmitted organisms that are benign in one species can be fatal when introduced into other species. Because xenotransplants involve the direct insertion of animal cells, tissues, or organs into humans, there is reason to believe that the potential for transmission of infectious agents (some of which may not now be recognized) from animals to human transplant recipients is real. Moreover, once an
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infection is established in a recipient, the potential for transmission to the recipient's caregivers, family, and even the population at large is a real threat. All of this has implications for informed consent. First, there are serious questions as to whether the informed consent process in xenotransplantation research can be adequate. The overall purpose of informed consent in human subject research is to give potential subjects information that will enable them to make voluntary and knowledgeable decisions about whether they wish to participate in the research. Federal regulations require that the consent form used in research contain a description of the nature and purpose of the research and its risks, benefits, and alternatives (among other requirements) [8]. Currently, xenotransplant research carries potentially high, yet extremely uncertain, risks in a setting of possibly desperate patient need—a situation that poses serious questions about whether the overall purpose of informed consent is attainable. In addition, there are questions about obligations of the xenotransplant research investigators to provide information to, or seek some form of consent from, not only the prospective research subject but also the prospective subject's family members and/or intimate contacts, involved health care workers, and even the public at large. These groups may bear a risk, however difficult to quantify, of unwitting exposure to emerging pathogens. Currently, there is no legal requirement for investigators to secure informed consent from third parties who are in contact with the prospective research subject, and third party risks are not normally evaluated in the course of the institutional review board approval process. Moreover, there would be a number of significant practical obstacles to obtaining consent from third parties. For example, the prospective research subject's intimate contacts may change over time such that, at some time after the xenotransplantation procedure, the recipient no longer has a close relationship with some individuals but has developed close relationships with persons who were not intimate contacts when the procedure was performed. Tracking these changes over time could prove to be difficult, if not impossible. In addition, obtaining “consent” from intimate contacts of a xenotransplantation recipient would involve disclosure of confidential health care information about the recipient, which could occur only with the recipient's permission. With respect to the notion of “community consent” for xenotransplantation research, which has been the subject of considerable national and international controversy, the practical challenges are even more difficult. How should the “community” be defined in a highly mobile, closely interconnected world, where infectious agents can and do spread rapidly across continents? How could the “community” provide consent? In light of the absence of a legal requirement for investigators to secure informed consent of third parties, and the practical difficulties just discussed, Public Health Services guidelines on xenotransplantation address the issue as follows. First, the guidelines state that the prospective
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recipient should be informed that there is a potential for infection from zoonotic agents (including infections yet to be identified); that there is uncertainty as to the risks (including the likelihood of any latency) with any infectious agents; and that resulting clinical diseases may be unknown. This discussion should also address behaviors known to transmit infectious agents and methods to minimize risks of transmission. In addition, the informed consent process for xenotransplantation research should include a component that informs the recipient of his or her responsibility to educate current and future intimate contacts about the possibility of xenogeneic infections and about the importance of reporting significant unexplained illness to the institution where the xenotransplantation procedure was performed, to their primary care provider, or to a local public health department. Similarly, the guidelines state that the informed consent process should include a component that advises recipients of their responsibility to inform their current and any future health care providers about their receipt of a xenotransplantation product [3]. Regarding “community consent,” the Department of Health and Human Services Secretary's Advisory Committee on Xenotransplantation suggested that an appropriately constituted advisory committee should serve as the mechanism for ensuring ongoing education and discourse in the lay community about public health concerns, as well as other social, medical, and ethical issues raised by xenotransplantation clinical research [9]. Additional approaches for dealing with the potential infectious risks to society have been suggested by the International Xenotransplantation Association. Principles published by this association state that in light of the added risk xenotransplantation presents to society, clinical trials should occur only when there are preclinical data indicating a high probability of benefit to the recipients [10] and that clinical xenotransplantation should occur in the context of a well-developed system of oversight by national health authorities [11]. 1.2.2. Public safety measures Because xenotransplantation research presents the unquantified risk of spreading new infectious diseases, both conventional and innovative public safety monitoring measures may be necessary. For example, if the recipient of a xenotransplantation product has an infectious disease that poses a serious and imminent health threat to others, and the recipient fails to voluntarily comply with public health protection measures, conventional public health laws are available to apply varying degrees of restraint on personal behavior, including detention and quarantine. The US Supreme Court has clearly endorsed the authority of states to enact and enforce quarantine and other public health laws [12-14]. However, it is less clear that current public health laws effectively address situations in which a xenotransplantation recipient who manifests no symptoms of disease fails to comply with surveillance instructions. Under current public health laws, it would probably not be possible to conduct
mandatory periodic monitoring of such individuals and their intimate contacts before the time that the presence of a communicable disease becomes evident. Moreover, mandatory periodic monitoring of such participants would run afoul of current federal regulations that protect research participants' rights to withdraw their consent to participation in the research at any time [15]. 2. Stem cell and cloning research In response to the critical organ shortage, stem cell– derived organ and tissue regeneration is another promising approach for restoring organ function or replacing damaged organs. Because embryonic stem cells are capable of selfrenewal and can differentiate into a wide variety of cell types, potential applications of embryonic stem cell research are far-reaching. For example, for those having type I diabetes, current islet transplantation efforts are limited by the small numbers of available donated pancreases and the toxicity of immunosuppressive drug treatments required to prevent graft rejection. Use of embryonic stem cells that are instructed to differentiate into pancreatic islet cells has the potential to overcome the shortage of effective material to transplant, and use of stem cells from a cloned embryo could provide immunologically compatible tissue and eliminate the need for immunosuppressive drugs. Like xenotransplantation, however, stem cell and cloning research has generated ethical debate and prompted legal questions that merit careful consideration. 2.1. Ethical issues To date, much of the heated ethical debate surrounding embryonic stem cell research has centered on the research involving the destruction of very early human embryos. Embryonic stem cells are derived from the inner cell mass of a 100-cell blastocyst—a very early embryo, usually only 3 to 4 days old—long before the cells have started to specialize to create a nervous system. Typically, these cells are derived from embryos originally created for infertility treatment purposes through in vitro fertilization but that are no longer desired or needed by the infertile couple for treatment. At the present time, the extraction of the stem cells from the blastocyst requires the destruction of the blastocyst. Although researchers at Advanced Cell Technology recently found that at a very early stage of embryonic development, a single cell could be extracted from an 8-cell embryo and used to derive mouse embryonic stem cells, this technique has not been reduced to practice with human material. Moreover, even if this derivation technique were perfected, it likely would not eliminate the ethical debate relating to the moral status of the early embryo because some believe that because 8-cell embryos can naturally divide to produce twins, even at this early stage, removing a single cell might be creating 2 embryos, one of which would be destroyed.
R.S. Shapiro / Transplantation Reviews 22 (2008) 210–214
Some who condemn embryonic stem cell research believe that the embryo is a full person or human subject, with full rights and interests from the moment of conception. Others take a developmental view of personhood, believing that the embryo only gradually becomes a full human being and that the very early embryo is not entitled to the same moral protections to which it would be entitled at a later developmental stage. Still others hold that while the embryo represents human life, such life is not a “person” at any time before birth. The role of science in deciding the difficult ethical question of the moral status of the very early embryo is unresolved. Key issues in deciding this question include the following: • How significant is it that at less than 14 days a blastocyst has no neural tissue? Some contend that this fact makes derivation of stem cells from a blastocyst before this developmental stage no different than allowing organ donation at the point of brain death. • Is it ethically significant that until formation of the primitive streak at 14 days, a blastocyst can undergo complete fission to form an identical twin? Some commentators contend that because individuality is a sine qua non for personhood, it seems appropriate to consider 14 days of normal embryonic development to be the minimum requirement for a human being to emerge. • Is the argument for the protection of the “potential” for human life affected by scientific assertions that an embryo does not have such potential unless it is implanted in a uterus? Ethical debate surrounding cloning focuses on use of cloning for reproductive purposes. Those who seek to prohibit cloning highlight ethical objections to engineering human life in a way that does not involve fertilization and the combination of DNA from 2 donor gametes [16]. Another anticloning argument focuses on concerns about the physical well-being of the cloned individual, in light of the facts that most attempts to clone mammals have not resulted in live births, and in those that have, resulting animals have had significant genetic disorders [17]. Additional ethical concerns are that clones would lack individuality and might have psychological harm by viewing their lives as being preordained by their donors [17]. The concerns discussed previously are inapplicable to the use of somatic cell nuclear technology for nonreproductive purpose that is, when the embryo is not implanted in the woman's uterus, but rather develops for only a few days, at which time stem cells are extracted. Some contend, under a “slippery slope” argument, that therapeutic cloning should, nonetheless, be banned because it would inevitably lead to reproductive cloning. However, in this context, the slippery slope is unlikely to materialize. Implantation of an embryo cloned for therapeutic purposes is unlikely to result
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in a live birth because the nucleus of the somatic cell used to create the cloned embryo would have to be reprogrammed in a way that returns it to its embryonic state before it can develop into a fetus, which is beyond scientists' current capabilities [18]. 2.2. Legal issues Federal and state legislatures have begun to grapple with the ethical questions involved in stem cell research and cloning, but to date, there is no comprehensive or consistent regulation of stem cell research or therapeutic cloning in the United States. Since 1996, riders to federal appropriations language (known as the Dickey Amendment) have prohibited use of federal funds for “the creation of human embryo or embryos for research purposes,” as well as “research in which a human embryo or embryos are destroyed, disabled, or knowingly subjected to a risk of injury or death greater than allowed for research on fetuses in utero… [19]” In January 1999, the General Counsel of the Department of Health and Human Services, Washington, DC, determined that federal law does not prohibit public funding of embryonic stem cell research as long as the research to be funded does not include derivation of the stem cells from the embryo (and, therefore, destruction of the embryo). Cells could be derived from embryos destroyed in private laboratories with private money and then shipped to federally funded scientists for study. On August 9, 2001, however, President Bush announced that federal funding for embryonic stem cell research would be available only under the following conditions: • the stem cells are derived from stem cell lines existing as of August 9, 2001, • the lines were derived with proper informed consent of the embryo donors, • the embryos used were originally created through in vitro fertilization for infertility treatment purposes, and • there were no financial inducements made to the embryo donors. President Bush reiterated his position in 2007 by vetoing a bill that would have permitted federal funding for research on surplus embryos from fertility clinics and by issuing Executive Order 13435 on “Expanding approved stem cell lines in ethically responsible ways.” This Executive Order— pursuant to which the Department of Health and Human Services and National Institutes of Health, Bethesda, Maryland, have issued an implementation plan—promotes “research on the isolation, derivation, production, and testing of stem cells that are capable of producing all or almost all of the cell types of the developing body and may result in improved understanding of or treatments for disease and other adverse health conditions but are derived without creating a human embryo for research purposes or destroying, discarding, or subjecting to harm a human embryo or fetus” [20].
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In addition to these federal funding restrictions, embryonic stem cell research is also subject to some restrictive state laws. Although California is providing government funding for stem cell research through the California Institute for Regenerative Medicine, San Francisco, California, and New Jersey, Connecticut, and Illinois have announced plans to support local stem cell research, other states—including Iowa, Louisiana, Michigan, Arkansas, Nebraska, North Dakota, South Dakota, and Virginia—have laws that limit embryonic stem cell research. With respect to cloning research, bills to prohibit human cloning were introduced in the US House of Representatives and the Senate immediately after the birth of Dolly the sheep, the first mammal created through the use of somatic cell nuclear transfer [21,22]. Also, President Clinton issued a Presidential directive prohibiting the use of federal funds for the cloning of humans [23]. Today, there remains significant support in congress for imposing a regulatory prohibition on cloning for any purpose. The House of Representatives has twice passed the Cloning Prohibition Act, which would outlaw the production of cloned embryos, regardless of their intended use, and subject violators to a criminal penalty of up to 10 years imprisonment. In addition, a number of states have enacted comprehensive cloning bans that do not differentiate among purposes for creating a cloned embryo [24-29]. Federal law that would ban all forms of cloning, and thereby foreclose all potential avenues of scientific and medical advancement offered by therapeutic cloning, may be subject to challenge as a threat to the freedom of scientific inquiry. To date, the US Supreme Court has not had occasion to rule on the degree to which the constitution protects freedom of scientific inquiry because, whereas generalized scientific research regulations have been promulgated, prohibition of specific research endeavors has been extremely rare. However, the court has indicated in dicta that the First Amendment Free Speech Clause and the Fourteenth Amendment Due Process Clause may safeguard scientific inquiry. This case law has suggested that the First Amendment's protection of the marketplace of ideas must also protect the generation of information through scientific research [30] and that the Fourteenth Amendment encompasses not only freedom from bodily restraint but also the freedom to acquire useful knowledge [31]. 3. Conclusion Clinical transplantation is the only effective therapy for many with end-stage organ failure, and the severe shortage of human organ donors leaves many patients in desperate need. Xenotransplantation, stem cell, and cloning research may offer opportunities to address this problem; but ultimately, the success of these approaches will depend not only on scientific development but also careful consideration of the attendant ethical and legal issues.
The author reports no biomedical, financial, or other conflicts of interest. References [1] United Network for Organ Sharing. Web site, http://www.unos.org. Accessed October 23, 2007. [2] US Department of Health and Human Services. 2006 Annual report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 19962005. Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation. Web site. http://www. optn.org/AR2006/106_dh.htm. Accessed October 23, 2007. [3] US Public Health Service. PHS guideline on infectious disease issues in xenotransplantation. http://www.fda.gov/cber/gdlns/xenophs0101. pdf. Published January 19, 2001 at 15. Accessed October 23, 2007. [4] Hughes J. Xenografting: ethical issues. J Med Ethics 1998;24:18. [5] McCarthy CR. Ethical aspects of animal-to-human xenografts. Inst Lab Anim Resources 1995;37:3. [6] Karesh WB, Cook RA. The human-animal link. Foreign Affairs 2005; 84:38. [7] Nicholas JM, Fishman JA. Infectious risk in xenotransplantation. Curr Opin Organ Transplant 2006;11:180. [8] 45 CFR 46.116(a); 21 CFR 50.25(a). [9] US Department of Health and Human Services. Informed consent in clinical research involving xenotransplantation (draft), Secretary's Advisory Committee on Xenotransplantation. Web site, http://www4. od.nih.gov/oba/SACX/reports/IC_draft_030905.pdf. Published June 2004. Accessed October 23, 2007. [10] Sykes M, d'Apice A, Sandrin M. Position paper of ethics committee of the International Xenotransplantation Association. Xenotransplantation 2003;20:194. [11] Sykes M. Commentary: World Health Assembly resolution 57.18 on Xenotransplantation. Transplantation 2005;79:636. [12] Jacobson v Mass, 197 U.S. 11 (1905). [13] Compagnie Francaise De Navigation a Vapeur v State Bd of Health, La. 186 U.S. 380 (1902). [14] Gibbons v Ogden, 22 U.S. 1 (1824). [15] 45 CFR 46.116(a)(8). [16] Charo RA. Ethics and public policy. Hofstra L Rev 1999;27:503. [17] President's Council on Bioethics. Human cloning and human dignity: an ethical inquiry, 80; 2002. [18] Jaenisch R. Human cloning—the science and ethics of nuclear transplantation. New Eng J Med 2004;351:2787. [19] Consolidated Appropriations Act of 2005, Pub. L. No. 108-447, § 509, 118 Stat. 2809, 3163-64 (2004). [20] Exec. Order No. 13,435, 72 Fed. Reg. 34,589 (June 22, 2007). [21] S.368, 105th Cong § 1 (1997) (introduced on Feb. 27, 1997 by Senator Bond). [22] Human Cloning Prohibition Act, H.R. 923, 105th Cong § 1 (1997) (introduced on March 5, 1997 by Representative Ehlers). [23] Memorandum on the prohibition on federal funding for cloning of human beings. 1 Pub Papers 233, 281 (March 4, 1997). This directive was integrated into the 2000 Research Guidelines for Research on Pluripotent Stem Cells, 65 Fed. Reg. 51, 976 (August 25, 2000). [24] Ark. Code Ann § 20-16-1002 (West 2005). [25] Ind. Code §§ 16-18-2-56.5, 16-21-3-4, 25-22.5-8-5, 35-46-5-2, 35-465-3 (2005). [26] Iowa Code Ann. §§ 707B. 2, 707B.4 (West 2005). [27] Mich. Comp. Laws Ann. §§ 333. 16274, 333.16275 (West 2005). [28] N.D. Cent. Code § 12.1-39-02 (2005). [29] S.D. Codified Laws §§ 34-14-26 to 34-14-28 (2005). [30] Coleman J. Consent, playing God or playing scientist: a constitutional analysis of laws banning embryological procedures. Pacific LJ 1996; 27:1386. [31] Meyer v State of Nebraska, 262 U.S. 390 (1923).
Transplantation Reviews 22 (2008) 210 – 214
www.elsevier.com/locate/trre
Section 5: Future Issues in Transplant Ethics
Future issues in transplantation ethics: ethical and legal controversies in xenotransplantation, stem cell, and cloning research☆ Robyn S. Shapiro Center for the Study of Bioethics, Department of Population Health, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Abstract With little prospect of developing a sufficient supply of human transplantable organs to meet the large and growing demand, attention has turned to xenotransplantation, as well as stem cell and cloning research, as possible approaches for alleviating this allograft shortage. This article explores ethical and legal issues that surround developments in these fields. © 2008 Elsevier Inc. All rights reserved.
The demand for organs to transplant into humans continues greatly to outpace supply. Currently, it is estimated that in the United States, there are more than 97000 patients waiting for a lifesaving organ [1]. And in each year from 2001 to 2005, more than 7000 patients on the waiting list died [2]. With little prospect of developing a sufficient supply of human transplantable organs to meet the large and growing demand, attention has turned to xenotransplantation, as well as stem cell and cloning research, as possible approaches for alleviating this allograft shortage. This article explores ethical and legal issues that surround developments in these fields. 1. Xenotransplantation Several factors are responsible for recently increased interest in xenotransplantation—the transplantation, implantation, or infusion into a human of live cells, organs, or tissues from a nonhuman animal source [3]—as an approach for alleviating the allograft shortage. Improved understanding of human and animal immune systems, insights into histocompatibility, the development of new agents to control graft-vs-host disease, and animal breeding programs for the ☆
The data and analyses reported in the 2006 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients have been supplied by UNOS and Arbor Research under contract with HHS. The author alone is responsible for reporting and interpreting these data; the views expressed herein are those of the author and not necessarily those of the U.S. Government. E-mail address: [email protected]. 0955-470X/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.trre.2008.04.004
production of transgenic animals have improved the chances of successful patient outcomes with xenotransplantation. Despite this scientific promise, however, controversial ethical and legal issues surround xenotransplantation and deserve careful exploration. 1.1. Ethical issues For some, one ethical concern surrounding xenotransplantation is that transferring organs or tissue from animals to humans is wrongful interference with what is “natural” [4]. The validity of this concern, however, is questionable because of the difficulty of defining what is “natural” and what is “unnatural.” It could be said that everything that humans do is, by definition, unnatural in that all human actions interfere with the nonhuman natural order. Under this reasoning, because we cannot avoid interfering with nature, the argument that all unnatural actions (including, eg, xenotransplantation) are unethical is not persuasive. Under another view, nothing that humans do is unnatural because humans are themselves a part of nature. If nothing that we do is unnatural, then nothing we do can be wrong simply because it is unnatural. It is difficult to draw a line between natural and unnatural for differentiating ethical from unethical conduct. Moreover, even if what is natural could be clearly distinguished from what is not, it is unclear why the former is ethically superior. After all, it is only by interfering with nature that human lives are protected from destructive effects of natural phenomena such as droughts, hurricanes, and infectious agents [4].
R.S. Shapiro / Transplantation Reviews 22 (2008) 210–214
A second ethical issue surrounding xenotransplantation relates to the morality of killing animals to benefit human recipients. There are several responses to this concern. First, the traditional Judeo-Christian views of the relationship of humans to animals in creation rest on the belief that although animals manifest God's creative power, only humans are made in God's image. Humans occupy a higher niche in creation and have a transcendent moral relationship to God, which surpasses the relationship of other animals to their creator [5]. A second response to ethical concerns about killing animals for human recipients is that humans enjoy relative moral superiority over nonhuman animals because of superior human capabilities. Humans have capabilities, for example, for conceptualization, compassion, creativity, freedom of choice, moral decision making, appreciation of beauty, learning from the past, planning for the future, and altruism. Although some of these traits are possessed in limited ways by animals, the level and complexity of these traits as they exist in humans, it is argued, establish humankind as morally superior to nonhuman animals [5]. Third, throughout history, major elements of human civilization, including the understanding and preservation of the environment, nutrition, clothing, tools, and preservation and promotion of health—for animals and humans—have been dependent on human use of animals. To argue, then, that the use of animals for human ends is immoral is to state that humans cannot and never have been able to live morally upright lives [5]. 1.2. Legal issues 1.2.1. Informed consent The most significant legal issues surrounding xenotransplantation relate to informed consent. There is ample evidence of the transmission of infectious agents from animals to humans. Zoonoses, or diseases transmitted between animals and humans under natural conditions, are exemplified by the human immunodeficiency virus, which is thought to have crossed into the human population by mutation of a related simian immunodeficiency virus acquired from wild primates in Africa and by the leap of the hemorrhagic Ebola virus from primate to man [6]. With specific respect to xenotransplantation, the most likely candidate species for xenotransplantation is the pig, and the potential risk of cross-species infection associated with the use of porcine tissues in humans has drawn considerable attention because of the discovery that porcine endogenous retroviruses can infect human cells in vitro [7]. Moreover, transmitted organisms that are benign in one species can be fatal when introduced into other species. Because xenotransplants involve the direct insertion of animal cells, tissues, or organs into humans, there is reason to believe that the potential for transmission of infectious agents (some of which may not now be recognized) from animals to human transplant recipients is real. Moreover, once an
211
infection is established in a recipient, the potential for transmission to the recipient's caregivers, family, and even the population at large is a real threat. All of this has implications for informed consent. First, there are serious questions as to whether the informed consent process in xenotransplantation research can be adequate. The overall purpose of informed consent in human subject research is to give potential subjects information that will enable them to make voluntary and knowledgeable decisions about whether they wish to participate in the research. Federal regulations require that the consent form used in research contain a description of the nature and purpose of the research and its risks, benefits, and alternatives (among other requirements) [8]. Currently, xenotransplant research carries potentially high, yet extremely uncertain, risks in a setting of possibly desperate patient need—a situation that poses serious questions about whether the overall purpose of informed consent is attainable. In addition, there are questions about obligations of the xenotransplant research investigators to provide information to, or seek some form of consent from, not only the prospective research subject but also the prospective subject's family members and/or intimate contacts, involved health care workers, and even the public at large. These groups may bear a risk, however difficult to quantify, of unwitting exposure to emerging pathogens. Currently, there is no legal requirement for investigators to secure informed consent from third parties who are in contact with the prospective research subject, and third party risks are not normally evaluated in the course of the institutional review board approval process. Moreover, there would be a number of significant practical obstacles to obtaining consent from third parties. For example, the prospective research subject's intimate contacts may change over time such that, at some time after the xenotransplantation procedure, the recipient no longer has a close relationship with some individuals but has developed close relationships with persons who were not intimate contacts when the procedure was performed. Tracking these changes over time could prove to be difficult, if not impossible. In addition, obtaining “consent” from intimate contacts of a xenotransplantation recipient would involve disclosure of confidential health care information about the recipient, which could occur only with the recipient's permission. With respect to the notion of “community consent” for xenotransplantation research, which has been the subject of considerable national and international controversy, the practical challenges are even more difficult. How should the “community” be defined in a highly mobile, closely interconnected world, where infectious agents can and do spread rapidly across continents? How could the “community” provide consent? In light of the absence of a legal requirement for investigators to secure informed consent of third parties, and the practical difficulties just discussed, Public Health Services guidelines on xenotransplantation address the issue as follows. First, the guidelines state that the prospective
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recipient should be informed that there is a potential for infection from zoonotic agents (including infections yet to be identified); that there is uncertainty as to the risks (including the likelihood of any latency) with any infectious agents; and that resulting clinical diseases may be unknown. This discussion should also address behaviors known to transmit infectious agents and methods to minimize risks of transmission. In addition, the informed consent process for xenotransplantation research should include a component that informs the recipient of his or her responsibility to educate current and future intimate contacts about the possibility of xenogeneic infections and about the importance of reporting significant unexplained illness to the institution where the xenotransplantation procedure was performed, to their primary care provider, or to a local public health department. Similarly, the guidelines state that the informed consent process should include a component that advises recipients of their responsibility to inform their current and any future health care providers about their receipt of a xenotransplantation product [3]. Regarding “community consent,” the Department of Health and Human Services Secretary's Advisory Committee on Xenotransplantation suggested that an appropriately constituted advisory committee should serve as the mechanism for ensuring ongoing education and discourse in the lay community about public health concerns, as well as other social, medical, and ethical issues raised by xenotransplantation clinical research [9]. Additional approaches for dealing with the potential infectious risks to society have been suggested by the International Xenotransplantation Association. Principles published by this association state that in light of the added risk xenotransplantation presents to society, clinical trials should occur only when there are preclinical data indicating a high probability of benefit to the recipients [10] and that clinical xenotransplantation should occur in the context of a well-developed system of oversight by national health authorities [11]. 1.2.2. Public safety measures Because xenotransplantation research presents the unquantified risk of spreading new infectious diseases, both conventional and innovative public safety monitoring measures may be necessary. For example, if the recipient of a xenotransplantation product has an infectious disease that poses a serious and imminent health threat to others, and the recipient fails to voluntarily comply with public health protection measures, conventional public health laws are available to apply varying degrees of restraint on personal behavior, including detention and quarantine. The US Supreme Court has clearly endorsed the authority of states to enact and enforce quarantine and other public health laws [12-14]. However, it is less clear that current public health laws effectively address situations in which a xenotransplantation recipient who manifests no symptoms of disease fails to comply with surveillance instructions. Under current public health laws, it would probably not be possible to conduct
mandatory periodic monitoring of such individuals and their intimate contacts before the time that the presence of a communicable disease becomes evident. Moreover, mandatory periodic monitoring of such participants would run afoul of current federal regulations that protect research participants' rights to withdraw their consent to participation in the research at any time [15]. 2. Stem cell and cloning research In response to the critical organ shortage, stem cell– derived organ and tissue regeneration is another promising approach for restoring organ function or replacing damaged organs. Because embryonic stem cells are capable of selfrenewal and can differentiate into a wide variety of cell types, potential applications of embryonic stem cell research are far-reaching. For example, for those having type I diabetes, current islet transplantation efforts are limited by the small numbers of available donated pancreases and the toxicity of immunosuppressive drug treatments required to prevent graft rejection. Use of embryonic stem cells that are instructed to differentiate into pancreatic islet cells has the potential to overcome the shortage of effective material to transplant, and use of stem cells from a cloned embryo could provide immunologically compatible tissue and eliminate the need for immunosuppressive drugs. Like xenotransplantation, however, stem cell and cloning research has generated ethical debate and prompted legal questions that merit careful consideration. 2.1. Ethical issues To date, much of the heated ethical debate surrounding embryonic stem cell research has centered on the research involving the destruction of very early human embryos. Embryonic stem cells are derived from the inner cell mass of a 100-cell blastocyst—a very early embryo, usually only 3 to 4 days old—long before the cells have started to specialize to create a nervous system. Typically, these cells are derived from embryos originally created for infertility treatment purposes through in vitro fertilization but that are no longer desired or needed by the infertile couple for treatment. At the present time, the extraction of the stem cells from the blastocyst requires the destruction of the blastocyst. Although researchers at Advanced Cell Technology recently found that at a very early stage of embryonic development, a single cell could be extracted from an 8-cell embryo and used to derive mouse embryonic stem cells, this technique has not been reduced to practice with human material. Moreover, even if this derivation technique were perfected, it likely would not eliminate the ethical debate relating to the moral status of the early embryo because some believe that because 8-cell embryos can naturally divide to produce twins, even at this early stage, removing a single cell might be creating 2 embryos, one of which would be destroyed.
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Some who condemn embryonic stem cell research believe that the embryo is a full person or human subject, with full rights and interests from the moment of conception. Others take a developmental view of personhood, believing that the embryo only gradually becomes a full human being and that the very early embryo is not entitled to the same moral protections to which it would be entitled at a later developmental stage. Still others hold that while the embryo represents human life, such life is not a “person” at any time before birth. The role of science in deciding the difficult ethical question of the moral status of the very early embryo is unresolved. Key issues in deciding this question include the following: • How significant is it that at less than 14 days a blastocyst has no neural tissue? Some contend that this fact makes derivation of stem cells from a blastocyst before this developmental stage no different than allowing organ donation at the point of brain death. • Is it ethically significant that until formation of the primitive streak at 14 days, a blastocyst can undergo complete fission to form an identical twin? Some commentators contend that because individuality is a sine qua non for personhood, it seems appropriate to consider 14 days of normal embryonic development to be the minimum requirement for a human being to emerge. • Is the argument for the protection of the “potential” for human life affected by scientific assertions that an embryo does not have such potential unless it is implanted in a uterus? Ethical debate surrounding cloning focuses on use of cloning for reproductive purposes. Those who seek to prohibit cloning highlight ethical objections to engineering human life in a way that does not involve fertilization and the combination of DNA from 2 donor gametes [16]. Another anticloning argument focuses on concerns about the physical well-being of the cloned individual, in light of the facts that most attempts to clone mammals have not resulted in live births, and in those that have, resulting animals have had significant genetic disorders [17]. Additional ethical concerns are that clones would lack individuality and might have psychological harm by viewing their lives as being preordained by their donors [17]. The concerns discussed previously are inapplicable to the use of somatic cell nuclear technology for nonreproductive purpose that is, when the embryo is not implanted in the woman's uterus, but rather develops for only a few days, at which time stem cells are extracted. Some contend, under a “slippery slope” argument, that therapeutic cloning should, nonetheless, be banned because it would inevitably lead to reproductive cloning. However, in this context, the slippery slope is unlikely to materialize. Implantation of an embryo cloned for therapeutic purposes is unlikely to result
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in a live birth because the nucleus of the somatic cell used to create the cloned embryo would have to be reprogrammed in a way that returns it to its embryonic state before it can develop into a fetus, which is beyond scientists' current capabilities [18]. 2.2. Legal issues Federal and state legislatures have begun to grapple with the ethical questions involved in stem cell research and cloning, but to date, there is no comprehensive or consistent regulation of stem cell research or therapeutic cloning in the United States. Since 1996, riders to federal appropriations language (known as the Dickey Amendment) have prohibited use of federal funds for “the creation of human embryo or embryos for research purposes,” as well as “research in which a human embryo or embryos are destroyed, disabled, or knowingly subjected to a risk of injury or death greater than allowed for research on fetuses in utero… [19]” In January 1999, the General Counsel of the Department of Health and Human Services, Washington, DC, determined that federal law does not prohibit public funding of embryonic stem cell research as long as the research to be funded does not include derivation of the stem cells from the embryo (and, therefore, destruction of the embryo). Cells could be derived from embryos destroyed in private laboratories with private money and then shipped to federally funded scientists for study. On August 9, 2001, however, President Bush announced that federal funding for embryonic stem cell research would be available only under the following conditions: • the stem cells are derived from stem cell lines existing as of August 9, 2001, • the lines were derived with proper informed consent of the embryo donors, • the embryos used were originally created through in vitro fertilization for infertility treatment purposes, and • there were no financial inducements made to the embryo donors. President Bush reiterated his position in 2007 by vetoing a bill that would have permitted federal funding for research on surplus embryos from fertility clinics and by issuing Executive Order 13435 on “Expanding approved stem cell lines in ethically responsible ways.” This Executive Order— pursuant to which the Department of Health and Human Services and National Institutes of Health, Bethesda, Maryland, have issued an implementation plan—promotes “research on the isolation, derivation, production, and testing of stem cells that are capable of producing all or almost all of the cell types of the developing body and may result in improved understanding of or treatments for disease and other adverse health conditions but are derived without creating a human embryo for research purposes or destroying, discarding, or subjecting to harm a human embryo or fetus” [20].
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In addition to these federal funding restrictions, embryonic stem cell research is also subject to some restrictive state laws. Although California is providing government funding for stem cell research through the California Institute for Regenerative Medicine, San Francisco, California, and New Jersey, Connecticut, and Illinois have announced plans to support local stem cell research, other states—including Iowa, Louisiana, Michigan, Arkansas, Nebraska, North Dakota, South Dakota, and Virginia—have laws that limit embryonic stem cell research. With respect to cloning research, bills to prohibit human cloning were introduced in the US House of Representatives and the Senate immediately after the birth of Dolly the sheep, the first mammal created through the use of somatic cell nuclear transfer [21,22]. Also, President Clinton issued a Presidential directive prohibiting the use of federal funds for the cloning of humans [23]. Today, there remains significant support in congress for imposing a regulatory prohibition on cloning for any purpose. The House of Representatives has twice passed the Cloning Prohibition Act, which would outlaw the production of cloned embryos, regardless of their intended use, and subject violators to a criminal penalty of up to 10 years imprisonment. In addition, a number of states have enacted comprehensive cloning bans that do not differentiate among purposes for creating a cloned embryo [24-29]. Federal law that would ban all forms of cloning, and thereby foreclose all potential avenues of scientific and medical advancement offered by therapeutic cloning, may be subject to challenge as a threat to the freedom of scientific inquiry. To date, the US Supreme Court has not had occasion to rule on the degree to which the constitution protects freedom of scientific inquiry because, whereas generalized scientific research regulations have been promulgated, prohibition of specific research endeavors has been extremely rare. However, the court has indicated in dicta that the First Amendment Free Speech Clause and the Fourteenth Amendment Due Process Clause may safeguard scientific inquiry. This case law has suggested that the First Amendment's protection of the marketplace of ideas must also protect the generation of information through scientific research [30] and that the Fourteenth Amendment encompasses not only freedom from bodily restraint but also the freedom to acquire useful knowledge [31]. 3. Conclusion Clinical transplantation is the only effective therapy for many with end-stage organ failure, and the severe shortage of human organ donors leaves many patients in desperate need. Xenotransplantation, stem cell, and cloning research may offer opportunities to address this problem; but ultimately, the success of these approaches will depend not only on scientific development but also careful consideration of the attendant ethical and legal issues.
The author reports no biomedical, financial, or other conflicts of interest. References [1] United Network for Organ Sharing. Web site, http://www.unos.org. Accessed October 23, 2007. [2] US Department of Health and Human Services. 2006 Annual report of the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients: Transplant Data 19962005. Health Resources and Services Administration, Healthcare Systems Bureau, Division of Transplantation. Web site. http://www. optn.org/AR2006/106_dh.htm. Accessed October 23, 2007. [3] US Public Health Service. PHS guideline on infectious disease issues in xenotransplantation. http://www.fda.gov/cber/gdlns/xenophs0101. pdf. Published January 19, 2001 at 15. Accessed October 23, 2007. [4] Hughes J. Xenografting: ethical issues. J Med Ethics 1998;24:18. [5] McCarthy CR. Ethical aspects of animal-to-human xenografts. Inst Lab Anim Resources 1995;37:3. [6] Karesh WB, Cook RA. The human-animal link. Foreign Affairs 2005; 84:38. [7] Nicholas JM, Fishman JA. Infectious risk in xenotransplantation. Curr Opin Organ Transplant 2006;11:180. [8] 45 CFR 46.116(a); 21 CFR 50.25(a). [9] US Department of Health and Human Services. Informed consent in clinical research involving xenotransplantation (draft), Secretary's Advisory Committee on Xenotransplantation. Web site, http://www4. od.nih.gov/oba/SACX/reports/IC_draft_030905.pdf. Published June 2004. Accessed October 23, 2007. [10] Sykes M, d'Apice A, Sandrin M. Position paper of ethics committee of the International Xenotransplantation Association. Xenotransplantation 2003;20:194. [11] Sykes M. Commentary: World Health Assembly resolution 57.18 on Xenotransplantation. Transplantation 2005;79:636. [12] Jacobson v Mass, 197 U.S. 11 (1905). [13] Compagnie Francaise De Navigation a Vapeur v State Bd of Health, La. 186 U.S. 380 (1902). [14] Gibbons v Ogden, 22 U.S. 1 (1824). [15] 45 CFR 46.116(a)(8). [16] Charo RA. Ethics and public policy. Hofstra L Rev 1999;27:503. [17] President's Council on Bioethics. Human cloning and human dignity: an ethical inquiry, 80; 2002. [18] Jaenisch R. Human cloning—the science and ethics of nuclear transplantation. New Eng J Med 2004;351:2787. [19] Consolidated Appropriations Act of 2005, Pub. L. No. 108-447, § 509, 118 Stat. 2809, 3163-64 (2004). [20] Exec. Order No. 13,435, 72 Fed. Reg. 34,589 (June 22, 2007). [21] S.368, 105th Cong § 1 (1997) (introduced on Feb. 27, 1997 by Senator Bond). [22] Human Cloning Prohibition Act, H.R. 923, 105th Cong § 1 (1997) (introduced on March 5, 1997 by Representative Ehlers). [23] Memorandum on the prohibition on federal funding for cloning of human beings. 1 Pub Papers 233, 281 (March 4, 1997). This directive was integrated into the 2000 Research Guidelines for Research on Pluripotent Stem Cells, 65 Fed. Reg. 51, 976 (August 25, 2000). [24] Ark. Code Ann § 20-16-1002 (West 2005). [25] Ind. Code §§ 16-18-2-56.5, 16-21-3-4, 25-22.5-8-5, 35-46-5-2, 35-465-3 (2005). [26] Iowa Code Ann. §§ 707B. 2, 707B.4 (West 2005). [27] Mich. Comp. Laws Ann. §§ 333. 16274, 333.16275 (West 2005). [28] N.D. Cent. Code § 12.1-39-02 (2005). [29] S.D. Codified Laws §§ 34-14-26 to 34-14-28 (2005). [30] Coleman J. Consent, playing God or playing scientist: a constitutional analysis of laws banning embryological procedures. Pacific LJ 1996; 27:1386. [31] Meyer v State of Nebraska, 262 U.S. 390 (1923).