Xenotransplantation, trust, and trustworthiness: Ethical issues for African Americans

Ethics, Medicine and Public Health (2018) 7, 59—67

Available online at

ScienceDirect www.sciencedirect.com

THOUGHTS

Xenotransplantation, trust, and trustworthiness: Ethical issues for African Americans Xénotransplantation, confiance et fiabilité : problèmes éthiques pour les Afro-Américains D.A. Hodge Sr. (Associate Director of Education & Associate Pofessor of Bioethics) National Center for Bioethics in Research and Health Care, Tuskegee University, Kenney Hall, Suite 44-107, 1200 W. Montgomery Road, 36088 Tuskegee, AL, USA Received 25 July 2018; accepted 29 September 2018 Available online 16 November 2018

KEYWORDS Animal rights; Chauvinism; Clinical trials; Speciesism; Syphilis study; Trust; Trustworthiness; Xenotransplantation; African Americans

Summary Xenotransplantation, i.e., the transplanting of organs, cells or tissue from one species to another, is a constantly expanding quest to provide treatment for those with endstage organ failure. The limited availability of donor organs is decreasing in comparison to the amount of people placed on the donor registry annually. Genetically modified donor pigs, working in concert with recipient treatment, can be in greater abundance since they are bred for this purpose. These genetically engineered pigs are bred to lack specific proteins that are antagonistic to the host/recipient. There are at least two basic ethical problems with xenotransplantation: animal rights ethics and trust ethics. Animal rights ethics asserts the equality of animals with humans, thus there is never a good reason for disregarding the interests or suffering of an animal since there can be no absolute argument prioritizing one species’ pain over another’s. Nonetheless, if one can overcome the animal rights objection—–i.e., speciesism is inherently unethical—–objections derived from a historical and epidemiological tendency toward racism would have to be resolved. Recent clinical trials data show that African Americans have a (justifiable) distrust of medical research, clinical trials, and certain healthcare providers. Unless the governance of these systems can show themselves trustworthy, African Americans would have no good faith basis to trust them. Thus, African American mortality and morbidity rates would increase as the potential genius of xenotransplantation would fail to thrive in their communities. ‘‘We must study, we must investigate, we must attempt to solve; and the utmost

E-mail address: [email protected] https://doi.org/10.1016/j.jemep.2018.10.003 2352-5525/© 2018 Elsevier Masson SAS. All rights reserved.

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D.A. Hodge Sr. that the world can demand is, not lack of human interest and moral conviction, but rather the heart-quality of fairness, and an earnest desire for the truth even despite its possible unpleasantness.’’—–W.E.B. Dubois, The Philadelphia Negro. © 2018 Elsevier Masson SAS. All rights reserved.

MOTS CLÉS Droits des animaux ; Chauvinisme ; Essais cliniques ; Spécisme ; Étude de la syphilis ; Confiance ; Fiabilité ; Xénotransplantation

Résumé La xénotransplantation, c’est-à-dire la transplantation d’organes, de cellules ou de tissus d’une espèce à une autre, est une quête en croissance pour fournir un traitement aux personnes en défaillance terminale d’organe. La disponibilité, déjà limitée, d’organes est en baisse par rapport au nombre de personnes inscrites chaque année sur le registre des donneurs. Les cochons donneurs génétiquement modifiés, travaillant de concert avec le traitement pour le receveur, peuvent être plus abondants puisqu’ils sont élevés à cette fin. Ces cochons génétiquement modifiés sont élevés en l’absence de protéines spécifiques qui sont antagonistes envers l’hôte/le receveur. La xénotransplantation pose au moins deux problèmes éthiques fondamentaux : l’éthique des droits des animaux et l’éthique de la confiance. L’éthique des droits des animaux affirme l’égalité entre animaux et hommes, donc il n’y a pas de bonne raison pour ne pas tenir compte des intérêts ou de la souffrance d’un animal, puisqu’il n’y a pas d’argument absolu priorisant la souffrance d’une espèce par rapport à une autre. Néanmoins, si l’on peut surmonter l’objection relative aux droits des animaux —– c’est-à-dire que le spécisme est intrinsèquement immoral —– les objections dérivées de la tendance historique et épidémiologique au racisme devraient être résolues. Les données récentes des essais cliniques montrent que les Afro-Américains ont une méfiance (justifiable) envers la recherche médicale, les essais cliniques et certains fournisseurs de soins de santé. À moins que la direction de ces systèmes puisse se révéler digne de confiance, les Afro-Américains n’auraient aucune raison pour leur faire confiance. Ainsi, les taux de mortalité et de morbidité chez les Afro-Américains augmenteraient car le génie potentiel de la xénotransplantation ne pourrait pas prospérer dans leurs communautés. « Nous devons étudier, nous devons examiner, nous devons essayer de résoudre ; et ce que le monde peut demander, ce n’est pas le manque d’intérêt humain et de conviction morale, mais plutôt la qualité de l’équité et un désir sincère pour la vérité même en dépit de son éventuel désagrément. » —– W.E.B. Dubois, The Philadelphia Negro. eserv´ es. © 2018 Elsevier Masson SAS. Tous droits r´

Introduction Thomas E. Starzl, often referred to as ‘‘the father of transplantation’’ after he successfully performed the first ever human liver transplant in 1963 [1], made the following claim in 1982, ‘‘History tells us that procedures that were inconceivable yesterday, and are barely achievable today, often become routine tomorrow’’ [2]. Strazl died in 2017. He didn’t live to see the next phase in the journey he helped to create (i.e., successful xenotransplantation), but he certainly never left his zenith. His ‘‘retirement’’ from active research neither curtailed his work as professor of surgery at the University of Pittsburgh School of Medicine, nor diminished his profile as being among the most prolific writers and the most cited scientists in his field of expertise [3]. The University of Alabama at Birmingham (UAB)1 seeks to begin clinical trials by 2020, adding to its 12,000 trans-

plantations over the last 5 decades [5]. Although it ‘‘seems likely that clinical trials of pig organ or cell transplantation will be initiated within the next couple of years’’ [2, p. 13], what seems unlikely is that two major ethical issues will be resolved in that timeframe: the use of animal donors and the absence of African Americans in clinical trials. D.K.C. Cooper et al. carefully itemized a priority list for clinical trials: • organ transplant candidates who are allosensitized; • older patients; • infants; • patients dying of fulminant hepatic failure, for whom no alternative therapy is available; • brittle diabetics with hypoglycemic unawareness; and • diabetic patients with previous kidney allotransplant [2, p. 12]. Conspicuous by absence is the population most needing this procedure yet most underserved: African Americans.

1

With ongoing grants from the National Institutes of Health—–UAB received $238 million from the NIH in 2016, where it ranks among the highest recipients in the nation [4]—–and United Therapeutics

Corporation(UTC) from whom UAB received a $19.6 million grant in 2016 [5].

Xenotransplantation, trust, and trustworthiness One may choose to argue that African Americans are not a separate category because they are implicit in the other six, but this would be a disingenuous and false narrative since UAB and any other scientific researchers should know that African Americans lead in being absent from clinical trials. The primary reason for their absence (their lack of trust in the trustworthiness of researchers and clinicians), incidentally, is also conspicuously absent from UAB’s own observations of necessary factors for considerations: • whether the current experimental trials of conventional immunosuppressive therapy in NHPs [Non-Human Primates] with genetically engineered pig grafts successfully prevent a T cell-mediated elicited antibody response; • whether the transplantation of organs from pigs in which the key antigens have been deleted in fully successful in experimental NHP models, or whether the expression of human complement and/or coagulation-regulatory proteins is also required; • what requirements relating to porcine endogenous retroviruses will the regulatory agencies, e.g. the FDA in the USA, place on those initiating the trial [2, p. 12—3]. The science is clearly making headway, and certainly, thousands of human lives hang in the balance (not to mention billions of dollars in healthcare taxpayers would be saved annually), but the ethics—–research ethics, public health ethics and bioethics—–have not kept pace with the scientific advancements. What I take to be missing ‘‘factors,’’ needing inclusion, ought to have been: • what resolutions or consideration have been given to arguments in defense of animal equality with humans? Or how do we resolve the prioritization of human animals over nonhuman animals; • since it is a well-known fact that African Americans have a historical and justifiable distrust of medical research, and at once lead in most statistical categories for excess deaths, shouldn’t African Americans noteworthy exclusion be studied and resolved? Trustworthiness should be built into the overall xenotransplantation budget. Arguably, there is no biomedical research offering as much fodder for an intractable ethical debate as that of xenotransplantation. Given the scarcity of organ and tissue donations from deceased human donors and the worldwide increase of end-stage organ failure, the microeconomic law of supply and demand weighs more heavily on the demand side. With only 20% of end-stage allograft being completed annually, and if an abundance of xenografts can be made available, the number of human lives saved from pain, suffering, and death would be immeasurable. Nonhuman domesticated animals (both as pets and food source), have been of instrumental value to humans for several millennia. From an evolution standpoint, Jessica Lear, reporting on Alan K. Outram, head of archaeology at the University of Exeter, argues that ‘‘The first animals to be domesticated for food use are thought to be sheep, between 11,000 and 9,000 B.C. in Southwest Asia. Goats followed later around 8,000 BC. Both animals were used for their meat, milk, and coats, and became an integral part of nomadic communities’’ [6, p. 2]. Biblically, from as far back as God’s first command to humankind there has been a tacit instruction for humans to govern the animals: ‘‘Then God said, ‘Let us make man in our image, according

61 to our likeness; let them have dominions over the fish of the sea, over the birds of the air, over the cattle, over all the earth and over every creeping thing that creeps on the earth’’’ (Gen.1:26, NKJV, emphasis added). This theological (and spiritual) way of thinking reigned for several millennia until it became residue to the Enlightenment preoccupation with reason and the Romantic preference to sentimentalism. Both of these played a part in the birth of Charles Darwin’s (and others) evolutionary program. And this, in turn, created and maintained a growing shift in favor of biology and agnosticism rather than theology and theism. But what survived, even with the rejection of the theological and the spiritual, is a human (and masculinist) chauvinism with respect to the prioritization of human life over non-human life. In 1907 Alexis Carrel, when he coined the term ‘‘heterotransplantation’’ (the precursor to our modern xenotransplantation), could not have known that the 21st century would begin with the death of roughly 33% of those awaiting organ transplants for chronic diseases such as diabetes, organ failure (liver, kidney, heart, etc.), and other debilitating and life-threatening terminal illnesses like cancer and Parkinson’s. Most illnesses and deaths from diseases tend to influence a host of other physiological, emotional, and sociological issues, including the mental trauma that the patient and his/her family undergo, the financial burden imposed on most families, and perhaps even a re-assignment of values as patient and family journey through the conundrum of what should be more or less important as they approach end of life realities. Consequently, it’s not surprising that several major religions are far more accepting of xenotransplantation than they are to other types of transplants, including allotransplantation, especially embryonic stem cells and (for groups like the Jehovah’s Witnesses) blood transfusion. The value is real, i.e., life is sacred, says most people, religious and irreligious alike, and we should follow our genius in doing whatever is necessary to sustain human life and human happiness as long as possible. The buoyancy of this point can be seen in the extremes of how prolife activists put their own lives on the line to defend the unborn or to the extent anti-capital punishment activists rally in support of a convicted murderer. The (potential) life of an unborn human and the life of a person who took another’s life have value. It is also clear the need is real, given the thousands of humans who die annually from diseases that could be treated if the xenotransplantation science thrives—–as I’ve already intimated. To be sure, given the extraordinarily high odds against the success of xenotransplantation - rejection of the xenograft, the potential transmission of unknown diseases from a family of porcine endogenous retroviruses, the life expectancy of a pig being about 15 years verses the life expectancy of a human - the science has had several positive gains worldwide. In 2004 Jay A. Fishman and Clive Patience published an article entitled, ‘‘Xenotransplantation: Infectious Risk Revisited,’’ in which they demonstrated the progress made up to that point, but they also gave a clear review of the limitations as well: • the xenograft serves as a permissive reservoir in which donor organisms bypass host defenses without a need for a ‘vector’ to achieve disease transmission;

62 • lack of knowledge about the behavior of organisms from the donor species in immunosuppressed humans; • inability to recognize novel clinical syndromes resulting from infection with such pathogens; • lack of clinical laboratory assays for organisms from nonhuman species; • donor-driven organisms may not cause disease in the native host species but may cause disease in a new host (‘xenotropic organisms’), or may acquire new characteristics (genetic recombination or mutation); • and donor-recipient incompatibility of major histocompatibility (MHC) antigens may reduce the efficacy of the host’s immune response to infection within the xenograft [7, p. 1384].

Certainly, these are all extremely complex and intractable concerns for scientists, nevertheless, in 2012 the heart of a genetically modified pig was transplanted into a monkey. Although some xenotransplantation was accomplished as far back as 1994, and with the 2009 successful genetically reconstructed piglet that more closely shared the genetic makeup of humans, it is becoming clearer that the puzzle is fitting together in such a way that we may see successful transplantations of animal to human major organs very soon. In 2010, Australian scientist used human blood to keep a pig’s heart alive and functioning [8]. The science is clear, at this point, but the ethics are not. There is more than one ethical issue at work with xenotransplantation, and more than one sphere of ethics seek to unpack the ‘brave new world’ science is creating. There are at least three spheres of ethics chiming in on this debate: public health ethics, research ethics and biomedical ethics. Public health ethics is obviously concerned with the issues identified by Fishman and Patience as stated above, for we can certainly envision an almost science-fiction like crisis where a pathogen is passed from person to person due to a virus mutation from the disharmony of pig-to-human transplantation. If this occurs, we may most likely not have an immediate cure for a disease of this kind, making the consequence(s) quite dire. Research ethics may have as a primary concern the trustworthiness of the scientists. Their initial cost/benefit analysis must be of such integrity that the overall good of the work is not undermined. This accountability process to ensure the integrity and ethical standards of the research is the primary role of the Institutional Review Board. Historical infractions, including the process to determine who is included and excluded as research subjects, were of such reprehensible behavior that the IRB was formed and remains integral. Bioethics should be most concerned about ensuring systems are in place to avoid the violation of human agency and improve the safeguards that would be necessary during the clinical trial period, like informed consent, respect for autonomy, confidentiality, social justice, non-maleficence, benevolence, and beneficence. But these are just three ethical frameworks and, of course, there are overlaps both in the undergirding theories and the categories. For example, informed consent is generalizable to each of the three, and so is respect for autonomy and social justice. A disregard for any of these spheres of ethics could result in ethical issues.

D.A. Hodge Sr. There are two ethical issues that are extremely potent, and both are grounded upon chauvinistic principles, namely, a group holds a blind superiority toward their own kind and embraces a prejudicial and inferior view of others. The first ethical issue, animal rights, is not the focus of my present consideration, but as an ethical issue in xenotransplantation, some of the same chauvinistic and discriminatory policies are at work, thus giving it relevance. Therefore, I will frame the structure of the animal rights/animal welfare debate, after which I will be most concerned about correlating the second ethical issue, namely, xenotransplantation with African Americans and the trust and trustworthiness problematic that comes forth. If it can be shown that there are at least justifiable reasons in defense of xenotransplantation, then I think the overall project should proceed to clinical trials when appropriate. But let me state anticlimactically that overcoming the first hurdle, i.e., prioritizing human life over animal life, does not fix the second hurdle—– establishing a culture of trust and trustworthiness in clinical trials by actively seeking out and including African Americans. I will give now give a clearer articulation of the two ethical issues mentioned above.

1st Ethical issue: animal rights Xenotransplantation by its very definition requires two significant ethical considerations: the donor (nonhuman animal) and the recipient (rational human animal). The donor has the most to lose; the recipient has the most to gain. The former will eventually lose its life (i.e., as it is sacrificed for another) and the latter’s life will be saved (at the expense of the sacrificed). Hanging in the balance of this death/life dichotomy is an unflinching collision between what makes for intrinsic value, namely, something has value independent of any external factor, and what makes for instrumental value, namely, something’s value is based upon its utility—– its usefulness. A compromise of that intrinsic value/worth is an unethical rights violation. For example, several ancient thinkers were proponents of animism. This is the belief, quite roughly, that animals have souls not unlike humans. Pythagoras (c. 580—c. 500 BCE), the philosopher and mathematician, was a primary defender of animism, arguing that at death the animal’s soul would experience a transmigration (a reincarnation) to a human body and vice versa. This argument was sufficient to foster a respect for animals, animal welfare (and their equality with humans) and, by definition, a precursor to animal rights. A contradicting thesis was defended by Aristotle who believed that animals lacked rationality and intrinsic value; they only have instrumental value. Aristotle clearly states this anthropocentric view in his Politics where he argues ‘‘that plants were created for the sake of animals, and animals for the sake of men; the tame for our use and provision; the wild, at least the greater part, for our provision also, or for some other advantageous purpose, as furnishing us with clothes and the like. Now if nature makes nothing incomplete, and nothing in vain, the inference must be that she has made all animals for the sake of man’’ [9, p. 21]. The Aristotelian view (coupled with Christian views of using and not abusing animals) has persevered as a reasoned based argument that is later defended by Immanuel Kant. Clearly,

Xenotransplantation, trust, and trustworthiness if animals are valuable instruments for ‘‘food. . .clothes, and the like,’’ why shouldn’t their parts be instrumentally valuable as xenografts for humans? Thus, xenotransplantation would be unethical if animals have intrinsic value and ethical if they have instrumental value [10]. There has been a long-standing debate about animal rights and animal welfare along the theoretical matrices outlined above. Christian ethics (or theological ethics) conjoins Kantian ethics at certain points put forth an argument in support of xenotransplantation. At the same time, Peter Singer, the modern philosopher who has done the most in articulating philosophical presuppositions that would aid in animal rights advocacy, has highlighted the incongruity between Christian ethics and utilitarian ethics’ questions regarding the meaning of life, thus arguing against xenotransplantation, porcine or otherwise. First, locked in the historical and homo sapiens memory is many human being’s theistic belief that we were ‘‘created in the image of God,’’ and we were given ‘‘dominion over all things,’’ and as such, our species has precedence in any deliberation concerning human animals and non-human animals. And because ‘‘the prophecy came not in old time by the will of man: but holy men of God spoke as they were moved by the Holy Ghost’’ (2 Peter 1:21), how can animals ever win a battle? Most religious traditions don’t support the mistreatment of animals, and most philosophical traditions are likewise, but many support hierarchy where human animals are ranked over nonhuman animals. In other words, human interests always trump animal interests because of human supremacy and animal inequality [11, p. 55—61]. Immanuel Kant is consistent with this way of thinking. He believed that nonhuman animal’s lack of rational capacity and moral worth meant that rational human animals can use them for their purposes, just as long as the latter weren’t cruel to the former: [W]e have duties only to human beings—–ourselves and others. Properly speaking, there can be no duties whatever to nonhuman living things, or to the natural, or to God (or other nonhuman spirits). Strictly speaking, all beings for Kant falls either into the category of persons (rational beings) or things (non-rational beings). Persons are ends in themselves, while things have value only as means. But Kant realizes that we do seem to have duties to animals. He thinks we ought not to treat them as mere tools to be disposed of for our convenience, and does not intend his theory to slight those duties or release us from them. Kant’s solution is to claim that although there appear to be duties to nonhuman beings, all duties in regard to nonhuman or superhuman beings are really duty to oneself [12, p. 244]. Even Kant’s penchant for cruel-avoidance with respect to nonhuman animals was not predicated upon an in-principle kindness for (and to) nonhuman animals, neither was he affording them rights, like the right to be left unharmed; rather, Kant’s justification for cruel-avoidance is human based—–our duties to any nonhuman being is a duty to ourselves. In other words, if one practiced harming animals they may develop the attitude to harm, and this attitude may carry over to harming other humans—–and this is wholly unacceptable and antagonistic to Kant’s sacrosanct

63 categorical imperatives. Trivializing or harming an animal in some way was unacceptable. Utilizing nonhuman animals, i.e., nonhuman, non-rational beings, to a positive human end is permissible. Kant had a fundamental disregard of the utilitarian doctrine of, ‘‘the ends justifying the means.’’ The consequences were—–yes—–inconsequential, so long as the needs of the rational human animal were prioritized. This is the rational human duty. Kant demonstrates this fundamental point in his imperative’s second formulation, ‘‘Act in such a way that you treat humanity, whether in your own person or in the person of any other, never merely as a means to an end, but always at the same time as an end’’ [13, p. 46]. Humans ought never to be used as a means to an end, but animals are not so propitious in Kant’s way of thinking. So, whether by theological ethics or (Kantian) deontological ethics, non-rational, nonhuman animals deserve less consideration than, and can be used by, humans. Animals exist and serve at the pleasure of humans—–they are property of humans, and their organs are property as well. Thus, xenotransplantation is not unethical according to Kantian (deontological) ethics. It is never trivial, all parts being equal (i.e., we are not referring to saving the life of a murderer or any such thing), to save a life if that is the rational conclusion of a calm (nonemotional) person of average intelligence. This is quite clear for Kantians. Since animals are non-rational they have no rights that humans are duty bound to acknowledge, neither do they have any interest that should be prioritized over the humans. The existing shortage of human donor organs, especially kidneys, must be the priority: Prospects for [end-stage renal disease] patients seeking transplantation remain bleak, and continue to worsen. In the USA alone, in 2016, 98,000 patients started the year on the waiting list, with 19,800 (20%) transplanted after a median waiting time essentially too long to calculate. Since 2005, over 9000 wait-listed patients died or became too sick to transplant. Thus, the current system supporting the recovery of human kidneys for transplantation must be viewed as woefully inadequate. It is against this backdrop that recent efforts utilizing genetically modified pig kidneys (and other organs) are moving towards clinical trials [2, p. 125]. It seems obvious that the austerity of the current system is adequate justification, given donor limits and recipient needs, for xenotransplantation. From a Kantian perspective, there is no ethical violation of animals. Such that nonhuman animals aren’t being mistreated or harmed, they are providing a basic service for human survival that is not dissimilar to how humans use animals for sustenance. The only major difference is that the pig is not being ingested as a meal, its parts are being genetically modified to work as natural human organs, thereby preserving human life. Secondly, also flowing from the Christian community is the belief that ‘‘all life is sacred.’’ This utterance may be good syntax, but the semantical integrity is questionable. All life is sacred genuinely means all human life (as I will show later, white human life) with little regard to animal life. A prolife activist carrying a sign that says, ‘‘All life is sacred’’ while eating a hamburger can be called into question about how he defines ‘‘life.’’ Either he can admit to

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hypocrisy or redefine life in terms of a generalized human life. Speaking to this point, Singer says in his Practical Ethics (1993), ‘‘People often say that life is sacred. They do not mean, as their words seem to imply, that life is sacred. If they did, killing a pig or pulling up a cabbage would be as abhorrent to them as the murder of a human being. When people say that life is sacred, it is human life they have in mind’’ [14, p. 83]. Singer, a utilitarian, is an excellent contrast to religious thinkers and Kantians whose animal ethics is chauvinistic, to say the least. The typical arguments against animal rights aren’t promising. On the biblical account, there are many good reasons to resist a wholesale purchase of human rights over animal rights, but for the sake of space we must ask an end-stage question: biblical theology has an extremely robust eschatological agenda. Much hangs on the resurrection, being present with the Lord, and the eschaton. Christians are not ‘‘citizens of this world,’’ they say. They are simply ‘‘pilgrims passing through this barren land.’’ As a matter of fact, one of the grandest articulations of St. Paul is ‘‘to be absent from the body, and to be present with the Lord’’ (2 Corinthians 5:8). Why, then, should death be something to fear, as opposed to envisioning death as an expectant hope with heavenly rewards? With respect to the rational arguments, that humankind are creatures of reason, wouldn’t the slippery slope of this argument, i.e., the quantification of reason, lead to a justification of prioritizing a more rational trained pig over a non-rational infant? Or, should we consider harvesting the organs of low-rational, mentally challenged humans to sustain the life of healthy rational humans suffering with end stage organ failure? Clearly, any rational person of average intelligence would dismiss these options as morbid, hideous, and unethical. So why isn’t the same consideration that is given to infants, severely mentally challenged individuals and persons with dementia given to low-rational, nonhuman animals? Peter Singer calls this chauvinistic mentality ‘‘speciesism,’’ which is the animal discriminatory equivalent of racism—–and for my present purposes, anti-black racism [15, p. 94]. For Singer: The idea of using animals as a source for organ donation is an example of speciesism, premised as it is on the idea that animals are things for us to use as best suits our own interests, without much concern for the interests of the animals themselves. Perhaps the easiest way to see this is to ask yourself the following question; why should we be prepared to accept the use of organs from animals, but not be prepared to take them from human infants who are, and always will be, less intellectually developed than the nonhuman animals? [11, p. 415] Singer finds much purchase in his utilitarian predecessor Jeremy Bentham’s primary assertion, ‘‘Nature has placed mankind under the governance of two sovereign masters, pain and pleasure. It is for them alone to point out what we ought to do, as well as to determine what we shall do’’ [16, p. 1, emphasis added]. In the primary difference between Singer and Bentham seems to be the term ‘‘mankind,’’ which seems to imply that pain and pleasure is particular to humankind, but this is not the case. Elsewhere in Bentham’s magnum opus entitled Introduction to the Principles of Morals and Legislation, he poignantly avers, ‘‘The question

is not, Can they reason? nor Can they talk? but, Can they suffer? [16, chap. 18, sec. 1, n.]. From the point of view of the nonhuman animal (and this is not an easy challenge ala Linda Alcoff’s ‘‘The Problem of Speaking for Others’’ [17]), they have as much right not to suffer, or to have their interests preserved, rather than exploited, as any other sentient being. Disrespect of their autonomy, simply because they are a different species, is in principle no different from white disrespect and exploitation of black Africans, simply because they are of a different race. For Singer, speciesism is wrong and racism is equally wrong for similar reasons. This leads to a second ethical issue: the historical exploitation and vilification of blacks. African Americans tend to be visible when their presence is in some way aiding a white supremacist agenda and invisible otherwise.

2nd ethical issue: trust and trustworthiness All humans trust as a natural matter of course. Trust is so germane to our existence that it’s hardly possible to be definitive about trust without an immediate and strict bifurcation: trust as non-cognitive human emotion and trust as cognitive human reasoning. Non-cognitive trust is instinctively easy to comprehend and is of little philosophical interest for this essay. It is more of a natural (or neurological) process as, say, a baby in her mother’s womb may ‘‘trust’’ her mother for protection, comfort and nutrition as a natural course of action (or behavior) and express some level of stress or discomfort otherwise. As fully developed humans, living and thriving outside the womb, we tend to trust our environment until it has violated our non-cognitive sense of trust and is no longer trustworthy. When and if this violation takes place, such that we no longer find our environment trustworthy, we very quickly (and justifiably so) shift into cognitive mode. For example, trusting our breathable air or drinkable water is a non-cognitive function—–it’s a very innocent act—–until we discover pollutants in either one, fully justifying our utter disdain in a cognitive way. Our non-cognitive (and innocent) trust shifts quickly to cognitive distrust. The polluted air and water no longer merit our innocent trust; they are more prone to our fully cognitive mistrust, distrust and (perhaps) disgust. And at the same time trust is violated, the object of trust is no longer trustworthy (perhaps trustworthiness may not be totally obliterated on a non-cognitive trust violation, but given our propensity for adaptation, I doubt it). Cognitive distrust is an intrinsic preservation tool in all thinking creatures. Sometimes this distrust is the result of an irrational fear of the unknown. Other times this distrust is due to what’s known. African Americans fit squarely in the second category. Past and present trust violations have been so plentiful that they continue to foster distrust. The politics of (dis) trust for African Americans began with the capture of Africans, their incarceration on the shores of West Africa, their dehumanization through rape and other kinds of insidious indignities, the trivialization of their lives and the prevalence of death throughout the Middle Passage, the enslavement of blacks in the Caribbean and the Americas, the lynching and murder of freed blacks [18],

Xenotransplantation, trust, and trustworthiness the re-enslavement of freed blacks [19], and continues to mass incarceration [20,21] and the repeated acquittal of law enforcement personnel for the killing of unarmed blacks, even with video recordings. These unyielding violations to black bodies are pervasive and visible. As such, they continue to maintain black Americans’ visceral distrust of white institutions, white systems, and indeed, white people. Trust is never singular; it’s reciprocal. It has a direction of fit. Trust only works if its object is trustworthy. In her examination of black trust, Shayla C. Nunnally, defines the terms in this way, As an evaluation of one person about another person, entity, or context, trust involves the trustor (the person making the evaluation) making normative judgments about how the behavior of others (the trustees) should be conducted in social, political, or economic contexts. The evaluation also involves the trustor considering what should be the effect of the behavior on him or her personally. The general expectation is that people trust when they feel as if the trustee will not cause a negative outcome, especially one that will harm the trustor [22]. If the trustee is in anyway not trustworthy, the trustor is under no obligation to trust. In the case of xenotransplantation and its preceding clinical trials, African Americans must perform a risk/benefit assessment to determine if the positive gains are enough to overrule their justification for recusing themselves from clinical trials and xenotransplantation. There can be no gainsaying that the African American health situation is in crisis mode. As a matter of fact: In 1985, the United States Department of Health and Human Services released the Report of the Secretary’s Task Force on Black & Minority Health also known as the Heckler Report. This pivotal report was the first time in United States history the federal government acknowledged that morbidity and mortality could be reported by race and ethnicity. Over thirty years later, African Americans still suffer from similar health gaps and disease prevalence as presented within the report. The US Department of Health and Human Services’ Office of Minority Health was established as an outcome of the 1985 finding [23, p. 9]. That the United States government had to establish an office in the Centers of Disease Control and Prevention speaks to how significant the disparity is and the needs are with respect to African American health concerns. Indeed, ‘‘as of 2012, African Americans have the highest mortality rates for all cancers combined and the highest rates for most major cancers of any racial and ethnic group (United States Department of Health and Human Services, Office of Minority Health [DHHS-OMH], 2016a)’’ [23, p. 9]. As I’ve already stated, the issue is real. Because African Americans lead in excess deaths in most statistical categories (diabetes, kidney and heart disease, etc.), they remain excellent candidates to benefit from the significant positive gains in health and healthcare that xenotransplantation research can offer [24, p. 14S—15S].

65 Traditionally, blacks have been pursued and used in studies, but they were not equally pursued and luxuriated with the positive genius that came as a result of these studies. This maintains a distrust they didn’t initiate and leads to a suspicion of systems, even if the systems are noble. Philosopher Mark Owen Webb in his essay, ‘‘The Epistemology of Trust and the Politics of Suspicion’’, extends this distrust to moral epistemology. In other words, (in accordance with Webb) African Americans are justified in being suspicious of medical projects (e.g., Henrietta Lacks; J. Marion Sims) [25]. African Americans are also justified in being suspicious and distrusting of researchers’ motives (recall U.S, Public Health Service Syphilis Study at Tuskegee). These are just some of the suspicions, but there are other concerns needing attention. For example, the risk/benefits calculations and how statistical numbers are represented and demystified, the canvasing of the community to ensure an equitable distribution of the moral education on this very controversial medical area. How are terms in the informed consent material like ‘‘sterile’’ to be understood and trusted? How is the social stigma to be addressed? Is there a chance that an unknown disease can be contracted, then passed on during intimate contact? And to what extent are recipients obligated to inform their partners that they have non-human animal parts in their person? Is there a chance for an unknown contagion to be passed in utero? If the life expectancy of the pig is 15 human years, are we to believe that a transplanted organ can sustain life for humans who have a life expectancy of about seventy-five years? If a donor human organ becomes available post-xenotransplantation, would the recipient be able to change the non-human animal organ for a human one? Who will decide when events like these present themselves? And how are African Americans to trust this process? These are no doubt salient questions from a scientific and biomedical perspective, but the next practical step for African American’s is clinical trials. But given the African American historical and ‘‘institutional memory,’’ [23, p. 12] this is not a step easily taken. ‘‘According to Institute of Medicine (IOM) (2010), researchers failed to recruit an adequate number of subjects for clinical research 27% of the time, and 90% of clinical trials worldwide failed to enroll subjects within the allotted time. Overall, the rate of participation in clinical trials is poor among certain groups and declining; however, it is poorest among African Americans.’’ [23, p. 10—11] In general, most groups don’t participate in clinical trials en masse, but African Americans, based upon the disparities, apparently need the results the most but participate the least. The Clinical Trials investigators’ results were as most assumed: African Americans don’t trust the biomedical community. The study further showed that they may not have been versed on the specifics of the historical ethical violations, but there was enough in the myth they believed to justify their distrust of white led institutions and health systems. One interviewee said, ‘‘When you look at the younger generation, they may not have the historical perspective of the mistreatment and the ethical conduct from years past of African Americans in experiments, but their mistrust would come more from the whole system of government, many of the things we’re experiencing now with our young people’’ [23, p. 12]. The historical memory plays out in different ways for the older generation, the

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millennials and generation X, but the number of participants in the clinical trials have not changed much.

Historical justifications for distrust The history of African Americans in the western hemisphere has been tenuous at best. Whether or not African Americans should participate in clinical trials is almost a no-brainer. As mentioned before, African Americans lead in excess deaths in most of the measurable statistical categories. Nevertheless, they have not been participatory in the same clinical trials that may eliminate their diseases, reduce their malignancy, or offer them hope for a longer life expectancy with a more abundant quality of life. The basic reason for distrust is well documented, but the entire ethical issue is far more sophisticated. LaVera M. Crawley cites another complication: While these beliefs and concerns my indeed exist among some members of the African-American community, such analyses may promote an unfair portrayal of African Americans as inherently mistrustful. Such stereotypes contribute to negative provider beliefs about the willingness of minority patients to participate in research. This may subsequently influence their decisions to exclude clinically eligible patients from protocols [24]. This is a salient point. There is no a priori distrust in black consciousness. All distrust is experience based—– historical and sociological—–but Crawley’s overarching point is not without merit. If institutions or systems appreciation of any notion that suggests a kind of a priori distrust, further increasing black skepticism of clinical trials, thus promoting another unhealthy distrust, the issue would worsen. It is already a problem, as one study suggests, that ‘‘white doctors might not have the knowledge and understanding of the problems faced by black people from a biological perspective’’ [24, p. 15], further increasing the distance, but there is the problem of communication and cultural sensitivity. Crawley further states: the role of communication in developing and maintaining trust is vital to all three categories, but is particularly salient in influencing the perception of researcher trustworthiness. For example, focus group participants in one study described the health care workers that they encountered as rude and impatient—–behaviors that did not engender trust. For the virtues of trustworthiness to be conveyed, providers must communicate verbally and non-verbally in a manner that is both respectful and culturally appropriate. Fostering trustworthiness also requires that researchers and institutions be able to use language that is accessible and meaningful to the patient—–particularly in obtaining informed consent [24, p. 15S]. A cultural disrespect, for example, as the seemingly innocent or friendly first name congeniality, may be quite acceptable in white America and fundamentally disrespectful in black America. Martin Luther King, Jr.’s 1963 words are no less potent or meaningful today:

‘‘Daddy, why do white people treat colored people so mean?’. . .when your first name becomes ‘nigger’ and your middle name becomes ‘boy’ (however old you are) and your last name becomes ‘John,’ and when your wife and mother are never given the respected title ‘Mrs.’; when you are harried by day and haunted by night by the fact that you’re a Negro, living constantly in tiptoe stance never quite knowing what to expect next, and plagued with inner fears and outer resentments; when you are forever fighting a degenerating sense of ‘nobodiness’. . .’’ [26, p. 293]. If researchers are not informed or sensitive to the cultural nuances of what it means to be an African American, or what it means to be black in general, they may unwittingly foster a greater divide.

Conclusion In conclusion, with a grant from Eli Lilly and Company (ELC), the National Center for Bioethics in Research and Health Care at Tuskegee University (NBC) did an investigation into the causes for this defiance. Under the leadership of Rueben Warren, the director of the National Bioethics Center, the investigators were charged ‘‘to discern the ethical problems related to historic and current challenges borne out of the lived experiences of African Americans related to human subject research and health care delivery’’ [23, p. 6]. For many years, clinical trials have been conducted without African American participation, but why is this the case? To answer this question, the NBC and ELC commenced using the following questions to guide their investigation: • why don’t African Americans trust research conducted by the scientific community? • what is needed to eliminate the barriers to participation in research and to enhance the trustworthiness among the scientific community? • what recourse would be available when bioethics and public health ethics violations occur? Traditionally, many have anecdotally assumed that the reason for the African American non-participation in clinical trials was due to unethical biomedical infractions on blacks by white, the most major being the notorious United States Public Health Service Syphilis Study at Tuskegee, but the issue is far more complex than this. Those who seek to gain the trust of African Americans can no longer choose a non-empathic, non-altruistic, or non-compassionate method [24,p. 16S]. Resources and practice need to be given toward, first, building a network of trustworthiness. African Americans have made themselves vulnerable, which is a basic tenet of trust, to the point of being perceived as gullible. But with the educational and technological advances of the late 20th century and the 21st century, African Americans, like most other ethnic groups, are demanding visibility. Trust can no longer be so blind, innocent and weak until it is vulgarized. Trust should be the result of a proven caring relationship. As Crawley nicely articulates, ‘‘Research should be conducted in a manner that conveys humanistic concerns, including compassion, empathy and honesty. Communication skills, particularly those that foster cultural

Xenotransplantation, trust, and trustworthiness competence and sensitivity, can serve to encourage provides and institutional trustworthiness’’ [24, p. 16S]. If UAB and other research institutions considering xenotransplantation would invest in building a trustworthy space, they may be able to shift the present clinical trials exclusivity to something more positive. At present they have at least two major ethical hurdles: the ethics of animal rights and welfare and the ethics of trust and trustworthiness with African Americans. I am unaware of no good argument to overcome the former, but I am certain that we can overcome the latter with empathy, care and hard work.

Disclosure of interest The author declares that he has no competing interest.

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