Future Systems of Xenotransplantation: Melding Historical and Bioethical Methodology

Abstract

The future of xenotransplantation is promising. However, the scientific process behind xenotransplantation, shown through the methodology of history and bioethics, involves stakeholders beyond the laboratory. We present three short vignettes, the history of a 20th-century pioneer in solid organ transplantation, the xenoheart received by David Bennett, and a global system of illegal organ procurement, to highlight the complexity of biomedical practice. Current solid organ transplantation systems are seemingly unsustainable and ineffective in satisfying a growing global demand for organs. Despite the shortcomings of current systems, we argue that the discourse surrounding xenotransplantation science is insufficient to construct a long-lasting and equitable replacement for solid organ transplantation. Xenotransplantation is more than a surgical technique, an interdisciplinary health concern, or a biomedical technology—it is deeply dependent on a series of cultural, historical, and social factors. Incorporating a greater variety of perspectives and disciplines into ongoing discussions of xenotransplantation science, while potentially frustrating in the short term, will act to maximize its potential as a paradigm-shifting science.

Framing Biomedicine, History, and Bioethics

Biomedical researchers and healthcare professionals being interested in and utilizing information from the past as a vehicle for present-day meaning-making is not a new phenomenon. For instance, the University of Minnesota’s Medical School recently held a series of presentations commemorating the life and career of the late Dr. John Najarian (1927–2020), a famed surgeon and transplant specialist. This event memorialized Dr. Najarian while also taking stock of the transplantation field, if not biomedicine more broadly, with presentations ranging from new developments in helping to prevent allograft rejection to ex vivo lung optimization and repair ¹ . The Najarian Symposium was a convergence of biographical, biomedical, and historical contexts to frame a forward-looking exploration of transplant-related science. From this perspective, Dr. Najarian’s passing acted as the catalyst to review historical developments in transplantation alongside projected and predicted innovations that, as many of the presenters assured the audience, are right around the corner. These include a growing interest in xenotransplantation, or the transplantation of organs and tissue from non-human animals into human subjects (Table 1).

Table 1.

Key Factors Associated With Xenotransplantation. Includes Sources (Both Present & Historical), Perceived Benefits, and Current Biomedical Challenges to Xenotransplantation.

Sources of organs and cells for xenotransplantation • Porcine • Baboon • Chimpanzee • Goat • Sheep • Frog

Benefits of xenotransplantation • Overcome limited supply of human allografts • Address widespread transplant needs • Broden treatment options for dangerous illnesses

Biomedical challenges to xenotransplantation • Hyperacute rejection • Immune accomodation and tolerance • Zoonotic spillover • Ethical treatment of animal sources

The history of medicine becomes a prominent interest to those that practice medicine during times of crisis. Solid organ transplantation, for example, is currently in a rough spot: while the chances for long-term patient survival have steadily increased over the years, organ scarcity, or the disparity in number between those in need of an organ transplant versus available organs, has been a persistent and growing concern ² . In addition to preexisting structural issues within solid organ allocation and transplantation, the ongoing COVID-19 pandemic has stretched the system to critical levels ³ .

For example, transplantation services require enormous resources, including hospital beds, ventilators, blood, personal protective equipment, and a host of healthcare and biomedical personnel—to say nothing of the infrastructure often required to get an organ into its intended recipient. Those resources become even more challenging to manage ⁴ as selecting donors and transplant candidates requires navigating a dangerous, widespread virus. Additionally, consideration for transplant status includes many factors evaluated on both biological and social measures. Transplant programs often rely on judgments about social support for candidacy status ⁵ and prompt critical ethical questions over whether receiving a life-saving organ should depend on relationships one may (or may not) have in postoperative care. Transplant programs also need to consider that brain death in human donors has significant effects on the soon-to-be-transplanted organs. This illustrates that a system experiencing scarcity also requires intense and efficient management to facilitate timely transplantation procedures. Finally, solid organ transplantation is marred, both presently and historically, by the so-called “black market” ⁶ body brokers exploiting organ scarcity around the globe for immense profit.

Thus, the growing interest in xenotransplantation comes as no surprise as biomedical and transplant communities scramble for solutions. Relying solely on human donors to supply human organs creates a system where there are too few organs to meet the demand of a growing population of would-be recipients alongside a host of other transplant-related disparities. According to the data released by the Organ Procurement and Transplant Network (OPTN) and the Scientific Registry of Transplant Recipients (SRTR) ⁷ , despite the increasing number of successful liver transplants from year to year, the need for liver transplants continues to outstrip the organ supply. Using large animals, such as those in the porcine family, as biological incubators for human organs ostensibly offers immediate solutions to many issues with current organ transplantation practices. Indeed, these interspecies chimeras are often touted as a panacea for the ills and inefficiencies in our current system ⁸ .

This brief commentary aims to explore the myriad of factors that have coalesced to bring xenotransplantation to the forefront of medical research. We also aim to apply lessons learned through historical analysis to reveal bioethical concerns that are critically underdiscussed. Organ transplantation appears poised on the precipice of spectacular, paradigmatic change. However, little has been done to show that xenotransplantation will not also fall victim to the issues currently troubling traditional organ transplantation. Without this analysis, researchers, physicians, and patients may adopt ostensible solutions plagued by the same problems they were meant to solve. If the set of reasons concerning why so many would-be transplant recipients suffer and die are connected to a broader network of social and cultural considerations, it would follow that simply replacing human donors with non-human donors would fail to rectify the many problems within today’s transplant practices.

Using the current shortfalls of traditional organ transplantation as a justification for shifting to xenotransplantation leaves us vulnerable to repeating past mistakes, particularly when we discover that the rhetoric around xenotransplantation research today paints an alarmingly optimistic, solution-oriented picture. Moreover, xenotransplantation has not yet engaged with a number of critical ethical issues, such as how human subjects will be used as the proving ground for this therapy. Broad and thorough bioethical outlining can protect against a similar fate befalling xenotransplantation practice in the future. In other words, if we work to synergize historical and bioethical perspectives today, we may generate positive downstream effects on researchers, patients, and non-human animals within a new biomedical system of relationships and practices.

One tool at our disposal for generating these positive effects is bioethics, one of the most important institutions in biomedical research for helping to orchestrate, buffer, and rebuff the complex web of interactions guiding medical research. This system includes a robust legal framework guiding research and protecting patients, a governing and review body present at most research institutions, and an informal network of academics, scientists, lawyers, researchers, theologians, philosophers, and, indeed, the public itself. All individuals and groups involved are tasked with protecting the most vulnerable in society while biomedical research continues to seek new heights in knowledge and understanding.

Nevertheless, bioethics was born in response to history. A global regime of horrific human subject research from the early to mid-20th century prompted a sharp, introspective examination of biomedicine that saw patients, practitioners, and experts in research, law, and what was to be known as the burgeoning field of bioethics focus on explicit and implicit rights within the researcher–subject relationship. In the United States, the 1970s saw a radical change in biomedical practice “from a narrow focus on the physician’s or the researcher’s obligation to disclose information” to a new paradigm of patient–practitioner relationships that emphasized the “quality of a patient’s or subject’s understanding.” Notably, this paradigm included newfound rights to “authorize or refuse a biomedical intervention” ⁹ . In other words, these years saw a “dramatic solidification” of specific research and care-oriented perspectives, including biomedical researchers’ new “moral and legal duty” ⁹ to seek consent from patients. This duty includes a continuous process of providing sufficient information for subjects to establish and maintain informed consent ⁹ .

The purpose of this article is not to provide a comprehensive or even robust history of bioethics. Rather, we refer to this history to highlight the historical purpose of the institution’s function: to protect those most vulnerable to potential abuse by biomedical researchers. When examining bioethics’ interaction with xenotransplantation, we find the ethical discussion of relevant issues, particularly the utilization and treatment of initial transplant recipients, underdeveloped. Ethical issues concerning human and non-human research subjects within the realm of xenotransplantation ought to be openly discussed with a host of different stakeholders, including the public (comprised of would-be transplant recipients), biomedical researchers, and experts in as many fields that still allow for coherent and progressive discourse. We hope that by identifying ethical areas in need of attention, both the animals and research subjects will meet a better fate than their predecessors. Additionally, if it can truly operate as a panacea for so many preexisting issues within solid organ transplantation systems, xenotransplantation’s role in society should be constructed with these sociohistorical consequences in mind.

Xenotransplantation, as a concept, is shaped by more than being a surgical technique, an interdisciplinary healthcare concern, or a biomedical technology. Much like our current organ transplantation system, the discourse surrounding—and eventual success of—xenotransplantation is deeply dependent on a series of cultural, historical, and social factors. In what follows, we have attempted to meld bioethical and historical analysis to briefly show the messy foundations of solid organ transplantation, including many failures that proponents of xenotransplantation promise to replace or address. By examining the story of Alexis Carrel, a prominent figure in early 20th-century transplantation research, the vulnerability of xenotransplant recipients, and contemporary global markets in organ trafficking, we hope to show that issues in solid organ transplantation ought to be discussed without the use of ideological or disciplinary restraints. Instead, by telling a holistic story of the history and ethics of transplant practice, we may improve the chances of xenotransplantation truly being a successful alternative to current practices and systems.

Transplanting Alexis Carrel

Historians have pointed out that the origin of modern organ transplantation, or the act of replacing damaged or diseased body parts inside the body—as opposed to external surgical interventions commonly referred to as plastic surgery—was “the result of a particular human activity at a particular time, dependent upon particular technological, social, and cultural conditions” ¹⁰ . In other words, not only did organ transplantation need to be invented, but the process of invention was also deeply rooted in historically contingent systems. Inventing a new medical technology, practice, or therapy does not necessarily mean it will be an instance of self-evident progression in a given period’s standard of care. Indeed, we must be careful not to assume that any invention is predetermined to be adopted by the medical community or the public it serves. X-ray technology, for example, in its inception, was loud, uncomfortable, and many patients walked away with serious burns. In many aspects, this strange and harmful technology was anathema to medical care during the early 1900s, and a fundamental change in the organization of the hospital and practitioners was necessary before the technology could be readily applied in practice ¹¹ . The majority of the medical community at the turn of the 20th century saw little value in peering into the body when the prestige and expertise accompanying a medical license were strongly associated with the ability to examine a suspected broken leg or arm with one’s hands ¹² .

Additionally, the public feared X-ray technology as an invasion of bodily privacy ¹³ , often along gendered lines: why would respectable practitioners feel the need to leer underneath clothing and skin to diagnose a patient when medicine had been doing fine without such technological interventions for centuries? Nevertheless, changes in imaging technology are often heralded today as one of the most significant transformative factors in practicing (and being practiced on) medicine. Modern readers may find humor in these somewhat antiquated interpretations of critical, life-saving medical technologies, but it is vital to acknowledge that a gulf exists between early reactions and current attitudes—a large, but not insurmountable, gulf that reveals key themes in the history and practice of biomedicine.

In telling the story of the x-ray and biomedicine, storytellers must be wary of mixing present-day values and perspectives with those of an earlier era or risk failing to capture historical actors’ thoughts, feelings, and attitudes. Today, a variety of imaging technologies are tools available in a researcher or practitioner’s arsenal to combat disease and debility, and, perhaps not too contentious of a claim, patients within the United States have become accustomed to the idea of having their insides transformed into black-and-white artifacts of medical investigation. Understanding the history of x-ray technology reveals much about how medical tools are advocated for, objected to, and otherwise interacted with sociohistorical trends. As alluded to previously, the rise and fall of medical technologies, including xenotransplantation and x-rays, depend on human activity in particular temporal, social, and cultural conditions. Investigations into these complicated histories allow us to see how healthcare systems result from social and cultural processes and may provide key insights into ongoing research programs.

Like x-ray technology, detailing a fully fleshed, holistic history of organ transplantation, and xenotransplantation requires nuance and patience. Fleshing out that history helps us to identify those conditions and elements that gave rise to what we now recognize as solid organ transplantation—elements that are doubtlessly important for framing future ventures into xenotransplantation. It is easy, for example, to point to a series of prior contributors, pioneers, and trailblazers in the science of transplantation to tell a compelling story of triumph through adversity. In fact, many accounts do just that. From Mathieu Jaboulay and Alexis Carrel’s efforts to develop organ revascularization using xenografts of non-human animal kidneys in 1906, Serge Voronoff’s treatment to rejuvenate men and women by grafting slices of chimpanzee testicles and ovaries into their bodies in the 1920s, to Keith Reemtsma’s kidney xenotransplantation using immunosuppressant therapies in the 1960s, historical narratives of organ transplantation and xenotransplantation written by transplant specialists are often iterative, progressive, and simplified into neat tables and charts for ease of viewing^14–17. Historian Thomas Schlich ¹⁸ has criticized this “impressive genealogy” that traces the “founding fathers of modern transplantation” as lacking in critical analysis—bordering, in his words, on the “absurd.” Schlich’s accusation of absurdity should not be taken as describing the words of researchers qua historians as anything less than genuine. Rather, attempting to appreciate a complex system like solid organ transplantation or xenotransplantation through the genealogies of researchers fails to capture the rich tapestry of human experience throughout history.

Take the figure of Alexis Carrel. Heralded as an early 20th-century pioneer in the field of transplantation by today’s transplant specialists, Carrel won the Nobel Prize in 1912 for his work in anastomosing blood vessels and was, according to authors writing a century later, “clearly a man of vision” ¹⁹ . For most histories that originate in biomedicine, Carrel’s story ends there, one of many touchpoints within the overall trajectory of organ transplantation. From this approach, even if not explicitly stated by the authors, the historical figure of Carrel exists only as a vehicle to drive present-day conversations forward. Carrel, Reemtsma, Starzl, Najarian, and many others, names intimately familiar to transplantation specialists today, are simply pieces of a larger, looming puzzle of predicting future progress. Such histories are often neat and tidy and relatively uncontroversial.

However, a slower, more critical analysis of Carrel reveals a supremely interesting story: one of magic, miracles, and public imagination. As historian Susan E. Lederer ²⁰ has shown, Carrel actively cultivated his own image as a cross between surgeon and “miracle-worker.” To garner public interest and support for his work in “transporting kidneys” or “grafting the leg of one dog onto the body of another dog,” ²¹ Carrel happily adopted public accounts of his exploits that used biblical allegory to describe the significance of his work. In the international press, Carrel was often portrayed as a magician with a pointed hat and a wand and had “strange animal hybrids,” such as a “lizard with a rooster’s head,” ²⁰ accompanying him. In domestic publications, such as Woman’s Home Companion, Carrel was praised for his “scientific needlework,” ²² highlighting the reach and popular interest of his experiments. Furthermore, while juxtaposing his own work to that of H. G. Wells’ Dr. Moreau, Carrel and his contemporaries received a preponderance of letters from women desperate to have children and willing to take the risk of engaging in a fast-changing medical landscape that saw human bodies as things that “could be disassembled and reassembled with interchangeable parts” ²⁰ . In one sense, Carrel’s work paved the way for future developments in more “effective” organ transplantation with the recognition of immunosuppressive therapies several decades later—a perspective readily adopted by specialists in the field today. In another sense, Carrel’s efforts in his experimental laboratory were as crucial as those outside his laboratory. Namely, Carrel could actively tap into the public imagination of organ transplantation to elevate what was otherwise a series of failed experiments putting parts of one dog into another. Through this direct blending of medical and popular depictions of developing technologies, Carrel was able to make the public care and, specifically, care about his own work. Carrel helped to shape a social and cultural environment in which these new “inventions,” or at least the concept of the inventions, could thrive.

Within this analytical framework, we could then start asking why Carrel’s work found success given the radical characterizations rendered in popular media, how one might measure success during the period, and how Carrel, by most accounts, paved the way for subsequent generations of researchers to invent new methods of successful organ transplantation. According to some transplantation specialists in the 21st century, all “hetero (xenotransplants) from animals into humans” during Carrel’s era were “unsuccessful” ²³ until Keith Reemtsma’s experiments melded transplantation science with immunological theory in the 1960s. Others prefer to quickly gloss over Carrel’s complexity and focus narrowly on his Nobel Prize-winning work on blood vessels, with a brief note that he “developed an interest in cross-species transplantation from an experimental perspective” ¹⁵ . Yet still, some transplant specialists in recent years have pointed to a burgeoning “knowledge and technical skill base” in the early 20th century “upon which experimental visceral organ transplantation, principally kidney, could be performed in animals” ²⁴ as a significant turning point in transplantation history. Carrel, of course, was instrumental in that experimental history. From a biomedical perspective, Carrel’s work highlighted the importance of failing upward—after Carrel successfully performed kidney reimplantation between dogs but failed to achieve recognizable long-term success, the stage had been set for mid-20th century biomedical researchers to invent immunological countermeasures to, again, push the boundaries of organ transplantation.

The quick portraits of Carrel, almost exclusively meant to trace the genealogy of transplantation science, fail to say much about how and why Carrel’s work captured the imagination of scientists and the public alike—a necessary ingredient in bringing any medical invention to the mainstream medical marketplace. Even treatises that engage in a bit more historical nuance, although still written by transplant specialists, fixate on this genealogy: was it Carrel or Mathieu Jaboulay that invented the “full-thickness blood vessel suturing technique” ²⁵ ; or who should we credit with the first successful kidney transplant, Emerich Ullmann in 1902, Ernst Unger in 1906, or Carrel a few years later ²⁵ ? Despite the claims of researchers in the field that “the history of [organ transplantation] has involved a series of breakthroughs in medicine” and that it is “one of [the] most successful advances in modern medicine” ²⁶ , it behooves us, as researchers and eventual patients alike, to critically examine instances of “breakthroughs” and “successes” within the history of science and medicine. Who is doing the breaking, what is being broken, and what purpose does telling these stories serve? Is it serious men battling biomedical complacency to reach new heights in surgical science? Or, perhaps, was Carrel’s public-facing work engaging a broad audience of stakeholders and drumming up public support for the nascent science of solid organ transplantation just as important as grafting one dog’s kidney to another dog’s neck?

As a small slice of the overall history of organ transplantation, Carrel represents two sides of the biomedicine-historical divide. From the biomedical perspective, Carrel was responsible for organ revascularization, and that small, albeit significant, contribution enabled subsequent generations of scientists and experimentalists to keep building and keep progressing toward the system of organ transplantation we have today. However, in stark opposition, the more critical historical perspective places Carrel within a broader sociohistorical context that is messy and difficult to assess.

Carrel did experiment on non-human animals, but those experiments occurred in a social milieu that quickly assimilated the promise of organ transplantation within existing systems. For example, people were happy to accept the idea of human bodies as akin to interchangeable machines, and Carrel’s science fit well within the cultural dogma of the period. Additionally, many surgical specialists of the era actively worked to make the idea of organ transplantation appealing to the general public—a type of labor that is often lost in more traditional stories of biomedical exploits.

The narratives of historians show a critical truth: the work of medical professionals engaged in experimental organ transplantation during the 20th century was a product of, and inextricable from, sociohistorical contexts. To understand where we have come from and where we might proceed regarding xenotransplantation, a careful appreciation of biomedicine immersed in historical context is necessary. The current state of xenotransplantation is entangled in sociohistorical contexts similar to those that shaped X-ray and early organ transplantation systems. Understanding and harnessing the complexity of those processes should not be seen as hampering the development of new technologies. Instead, that complexity should be seen as an inevitability and actively factored into present-day efforts to look for new ways to translate laboratory science into clinical settings—or, as they say, from bench to bedside.

Carrel’s story here shows that the early history of organ transplantation intersected with a variety of themes. As Lederer explains, the human body needed to be “remade” within the public eye and become a “site for rationalization” ²⁰ around the turn of the 20th century in order for organ transplantation to have any staying power. However, this act of remaking was inextricable from the growing “public curiosity” fed by “human-interest” stories in popular publications, many of which focused on displaying the “spectacle” and “freaks” ²⁰ behind the biomedical procedures. Lederer uses the history of organ transplantation to defy ongoing conversations regarding transplantation reluctance, such as bioethicist Leon Kass’ ²⁷ “wisdom of repugnance.” Whereas Kass ²⁷ argues that we are repelled by the science behind cloning—arguably similar in kind to that found in xenotransplantation—because we feel “the violation of things that we rightfully hold dear,” historical evidence shows otherwise. While a sense of fascination might be unavoidable, revulsion or repugnance toward certain biomedical technologies is clearly not an innate feature of the human psyche and is instead rooted in powerful sociohistorical forces. In other words, there was a point when the public readily accepted the promises of organ transplantation, including xenotransplantation. This all took place before immunosuppressants were actively used in post-operative care and before we created global organ procurement and allocation systems. That mess, the sociohistorical context, did not simply vanish—if anything, it became even more complex. Xenotransplantation has and will continue to exist in a similar web of relations, some of which are sketched below. We owe it to future generations of practitioners and patients to engage with that web to help produce effective and long-lasting avenues of care.

Responding to David Bennett

With themes of public reaction and the promise of synergizing historical and bioethical lines of discourse, we now turn to an underdiscussed aspect of current xenotransplantation practice: the vulnerability of xenotransplant recipients. The case of Mr. David Bennett Sr. received worldwide acclaim when a “xenoheart” ²⁸ , or a human heart sourced from a genetically modified pig, was transplanted into a profoundly ill patient. Mr. Bennett experienced “8 weeks of post-operative success” with his new xenoheart that, according to a care provider involved in the case, “continued to function until his death” ²⁸ .

Mr. Bennett’s case is complex, touching on a wide range of potential ethical issues. While Mr. Bennett’s life was extended by 2 months through the use of a xenoheart (also referred to as a “porcine” or “pig” heart in the popular press), several notable characteristics of Bennett as a patient highlight how medically risky it is to replace traditional forms of solid organ transplantation and life-sustaining treatment. For example, during the time that Bennett was kept alive through the use of a xenoheart, he was described as bedridden and on life support. Some of the promotional material coming out of the University of Maryland School of Medicine’s animal-to-human transplant program, where Bennett was receiving care, certainly suggested a less-than-pleasant quality of life ²⁹ . Additionally, Bennett, 57 at the time of the operation and suffering from life-threatening arrhythmia, was categorized as historically “medically noncompliant.” In simpler terms, Bennett was not eligible for placement on the national organ waiting list due to a history of “failing to follow doctors’ orders” ³⁰ . The doctor that performed the transplant described Bennett as “someone with no alternatives” and “who very likely wouldn’t be able to leave the hospital without a transplant”—an ideal candidate to receive a “genetically modified pig heart transplant” ³¹ .

In these initial, groundbreaking cases, recipients of xenohearts, porcine, or other non-human organ transplants are likely to be similarly situated: incredibly vulnerable patients deserving of increased bioethical scrutiny. A host of ethical recommendations and legislative protections prevent or limit experimentation on particular groups, including fetuses, children, incarcerated individuals, or others that, for one reason or another, are limited in their autonomy and agency in biomedical interactions. Bennett and his care team received permission by virtue of a loophole in these ethical guidelines through an emergency use authorization, a federal method of fast-tracking research and treatment that has seen a fair amount of political and scientific scrutiny ³² in recent years.

Some may argue that participating in a xenotransplantation trial is similar in kind to early-phase drug trials, often commenced under compassionate use or right-to-try criteria. However, such arguments fail to protect the autonomy of patients involved in xenotransplant experiments adequately. Drugs considered for compassionate use or right-to-try need to have completed a phase one trial—a phase meant to establish safety protocols and maximum doses of the drug. To be eligible under emergency use authorization, which Bennet applied for and received approval under, the following criteria needed to be met:

• “The patient has a life-threatening or serious disease or condition.”

• “There is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition.”

• “Potential patient benefit justifies the potential risks of the investigational device.” ³³

Clearly, Bennet met the first two conditions. However, the third criterion should give the bioethics community and the general public pause. Bennet and his medical team had to justify that the surgery’s benefit to him would outweigh the potential risk. Based on existing evidence and research ³¹ , the risk to Bennett was death, and his time in the hospital on the heart-lung bypass machine was only delaying the inevitable. Death, however, is a worrisome criterion to base the progress of an entirely new branch of biomedical practice, given that the finality of death can quickly lead to justifying more human suffering than might otherwise have been permitted.

It would be disingenuous to claim that the researchers behind the xenoheart failed to employ any ethical reasoning or consideration, however. For example, a member of the xenotransplantation team outlined the “ethical algorithm” at use during the xenoheart’s development and eventual transplant. The clinician-scientist in question, Martine Rothblatt ²⁸ , reassured readers in a commentary published in Xenotransplantation that a balance was struck between the “public’s concern not to face a new pandemic” with the “patient’s concern not to die from their disease.” The ethical dilemma, as perceived by the xenotransplantation team, was primarily concerned with how to “comply with infection control procedures,” diminish the “possibility of transmissible pathogens,” a “commitment to biosurveillance,” and “humane care practices” ²⁸ for the donor pigs. In other words, an ethical algorithm that intended to balance the desire to break new grounds in xenotransplantation science with the all-too-real fear of zoonotic spillover. It should come as no surprise that many of the ethical considerations at the forefront of the biomedical team are, in a sense, deeply rooted in pragmatic scientific considerations.

The immunological response has been one of the most significant stumbling blocks for replacing solid organ transplantation with xenotransplantation. Current studies often utilize genetically modified porcine donor organs that lack the alpha-1,3-galactosyltransferase gene (“alpha Gal”), which is thought to prevent hyperacute rejection of the transplanted non-human organ as well as acute vascular rejection events ³⁴ . However, it is not just the knockout of alpha-Gal which may need to occur to prevent rejection. Some studies are exploring the combined effect of alpha-Gal knockouts and randomly inserted human alpha 1,2-fucosylosyltransferase (HT) transgene in the hopes that the addition of the human HT gene will produce better results than just the null porcine line ³⁴ . These alterations and research lines refer to the porcine donor’s genetic makeup. This work does not touch on the pharmaceutical course and immunological therapies that need to be developed or altered to prepare human and animal donors for transplantation. Additionally, this does not include the pharmaceutical supports that will need to be developed to prevent the rejection of the organs throughout the recipient’s life. Getting the genetic basis of the porcine donor is just one step of many that will need to be perfected to make xenotransplantation a legitimate real-world solution to the crisis of demand for organ transplants. Notably, the xenotransplantation team at the heart of Mr. Bennett’s story recalled the difficult biomedical journey that resulted in a transplant-ready xenoheart as “based on trial-and-error over a decade” with “many dozens of experiments carried out” ²⁸ .

Surmounting one of the immunological hurdles previously preventing xenotransplantation from becoming a mainstay of biomedical practice is undoubtedly a result to be celebrated. However, it seems likely that the biomedical focus on donor-to-host immunological response has overshadowed other serious bioethical concerns. Bennett’s new xenoheart was not the product of a clinical study. Instead, as stated, it resulted from a unique, singular approval by the United States Food and Drug Administration for an operation on an otherwise poor candidate for traditional transplantation with no alternatives. Other ethical treatments of the Bennett case similarly focus on the welfare of donor animals and the prevalence of zoonosis. In the latter case, the emphasis is still on “xenogeneic diseases” and how to account for informed consent given the “Ulysses contract,” or a contractual agreement that “waives the right to withdraw from the clinical trial” ³⁵ . Discussion of whether Bennett ought to have been the target of this xenotransplantation team, given his markedly vulnerable status, is conspicuously absent.

It is not necessarily the number of studies conducted that will automatically confirm or deny the permissibility of xenotransplantation from a bioethical perspective. Instead, to be seen as a safe and effective solution to the shortage of human organs for organ transplantation, xenotransplantation science needs to grapple with a greater variety of ethical considerations. While the dangers of xenogeneic diseases are real and need to be factored into future biomedical systems, bioethics has been accounting for a host of other considerations in biomedical practice, including patient autonomy and measures of consent, for decades. To fail to include such discourse in the xenotransplant space is concerning. If we take the historical precedent for organ transplantation and xenotransplantation seriously, we see that there is no inherent disgust or revulsion of such practices and instead attitudes that are constructed and deconstructed over time. The actions and considerations of biomedical researchers are an essential factor in the messiness of historically contingent systems. It would likely befit us all to see experts in the field rise above disciplinary blinders and address bioethical issues outside their immediate wheelhouse.

Brokering Bodies and Organs

A final example of the synergy of historical and bioethical discourse that may help stakeholders from a variety of backgrounds assess the future of xenotransplantation is that of the (illegal) systems created in the wake of organ scarcity, namely the global traffic of human bodies and organs. While the problems of organ trafficking, transplant tourism, organ harvesting, or the so-called “body brokers” are difficult to summarize quickly, it is necessary to include them in discussions of organ scarcity and developing xenotransplantation research. Since at least the 1980s, rumors of organ theft on the global stage have steadily increased and, arguably, have become a staple of the public’s imagination of organ transplantation (albeit non-consensual transplants)—for example, the motif of waking from a drug-induced slumber only to find yourself in an ice bath with a kidney missing. Fueled by the aforementioned organ scarcity, a global trade of ill-gotten organs has been the focus of activists, policymakers, and bioethicists for decades.

The bioethical discourse surrounding organ trafficking has been primarily focused on to what degree organ markets ought to be regulated and how compensation should be factored into the system (if at all). Some, for example, argue that a “regulated system of compensation” ³⁶ is necessary to alleviate supply-demand discrepancies in kidney transplantation. In other words, paying kidney donors would increase organ donations, decrease waiting list death, and work to cripple “the core economic support for transplant tourism” ³⁶ , or the activity of crossing international boundaries for an operation wherein the likelihood of receiving a trafficked organ is high. Others ³⁷ have argued that such notions are both morally objectionable and refuted by decades of evidence to the contrary.

Extending the discourse beyond regulation, other authors have argued that focusing on market powers for resolving issues of exploitation in illegal organ trafficking is misguided in and of itself. The “economic reality,” one author writes ³⁸ , is that many within our international and interconnected system of healthcare simply cannot afford to partake in the benefits of solid organ transplantation, regardless of whether their specific context of organ supply and demand would allow for it. Specifically, an abundance of available organs means little when the cost of receiving a transplant is still prohibitive. A “wiser” approach, they continue, would be to invest in “primary health care” rather than “expensive bio-technologies” ³⁸ . In other words, society should work to prevent organ failure “as opposed to instituting transplant programs with limited accessibility” ³⁸ .

An illegal market in trafficked organs is nearly universally identified as a moral wrong arising in response to global organ scarcity. However, it is not yet clear to what degree developments in xenotransplantation would disrupt the current system. If, for example, organ tourism is a concern in the existing network of policies and market powers, does it follow that shifting biomedical interest away from human donors to non-human donors would eliminate that practice? Or would organ tourism be replaced with a type of xenotourism, where wealthy would-be xenotransplant recipients could search the world for biomedical facilities with relatively lax rules and limited ethical oversight? As we recover from the zoonotic SARS-CoV-2 pandemic, other contributors to the bioethical discourse argue that “robust precautions” are necessary to safeguard against the transmission of non-human diseases to “human xenograft recipients” ³⁹ in what many envision as a global market in xenotransplantation. Despite earlier evidence that xenotransplantation teams are acutely aware of the risk of xenogeneic diseases, brief published commentaries and ethical algorithms pale compared to global markets pushing for further exploitation of xenohearts and other organs.

While it remains to be seen how and to what degree xenotransplantation might address the black market of trafficked organs, we can use our current system to speculate on how to implement what is seemingly the inevitable rise of xenotransplantation practices. As researchers around the globe attempt to invent the necessary connections between non-human donors and human recipients, it seems likely that a differential approach to xenotransplantation will arise. Some countries, for example, may eventually have open and unrestricted policies concerning xenotransplantation and human xenograft recipients. Others may be far more restrictive. If our current system of organ transplantation can teach us anything, it is that market powers, sometimes insidious in nature, will take advantage of the difference in xenotransplantation practices and policies around the globe and, unless properly accounted and defended against, will result in continued harm and exploitation.

Preparing for Xenotransplantation

In Martine Rothblatt’s ²⁸ commentary on the achievement of the first lifesaving xenoheart transplant, the author remarked that they “used to bristle at the comment that xeno would always be the future of medicine,” namely because it seemed to “discount” the scientific process. The sentiment is well-taken: a biomedical achievement of this magnitude requires a myriad of collaborators working together for years with no guarantee of success. To discuss the potential of xenotransplantation as an inevitability is apparently as frustrating to biomedical researchers as it is to historians. Moreover, as scholars on the periphery of the subject, historians and philosophers are acutely aware that their influence on the practice or development of biomedicine is limited. It perhaps speaks to some entitlement that humanities-aligned authors can enter a space like this and criticize or otherwise claim what ought to be done in a discipline they do not immediately practice. However, we are members of a global community struggling to adapt decades-old solid organ transplantation practices to ever-changing global systems, and we share an interest in bolstering either current practices or helping to create sustainable and equitable alternatives. After sifting through marketing and promotional material, xenotransplantation remains an exciting new science with promising results. However, because xenotransplantation science affects all of us, it seems reasonable to solicit feedback from as many stakeholder groups as possible.

Rothblatt’s call to appreciate the scientific process is perhaps shrewder than most realize. The “process” at hand, evidenced by the case studies above, is far more complex than biomedical experts performing science in laboratories. Brief investigations into solid organ transplantation history reveal a complicated and messy story at the intersection of public attitudes, emotionality, and wonderment. Alexis Carrel’s science and magic did not exist separately from public excitement over the potential for replacing organs and limbs at will—the two were intimately intertwined. Organ transplantation was “invented” through particular human activity dependent on particular sociohistorical contexts, much like xenotransplantation is currently being “invented.” That history is an underutilized tool in ongoing xenotransplantation science. Additionally, David Bennett successfully received a heart grown in a non-human animal, a statement that reads more like science-fiction than fact. Bennett lived an extra 2 months than he would have otherwise as a xenoheart pumped blood throughout his body. Yet, the process that landed him under the auspices of the xenotransplantation team lacked an engagement with a thorough bioethical analysis. The history of bioethics has shown it exists to improve the practice of biomedicine, and the future of xenotransplantation will only be further secured by good faith collaborations between researchers and ethicists to outline a system of practice that engages issues beyond biosurveillance and infection control procedures. Finally, illegal systems of global organ procurement exemplify the systemic problems with current transplantation practices. Xenotransplantation will likely disrupt those practices, but it remains unclear how and to what degree. Unless xenotransplantation accompanies policies and practices intended to address global inequities in healthcare and organ procurement, it seems unlikely xenotransplantation will be the panacea for existing issues in current transplantation practices (Fig. 1).

Figure 1.

Map of interactions and outcomes under consideration regarding xenotransplantation. Focusing on genealogies of biomedical researchers and narrow bioethical algorithms is not sufficient for a future system of xenotransplantation that is just, equitable, and truly a panacea for existing issues. Notable bioethical and sociohistorical factors include preexisting systemic issues with legal organ procurement, anticipated disruptions to ongoing illegal markets that trade in human organs, continuing robust clinical study programs, protecting vulnerable patients, considering the long and complex history of transplantation, and the importance of engaging the public’s interest and imagination in xenotransplant science.

Conclusion

In conclusion, current and past biomedical researchers are not to blame for a less-than-complete assessment of xenotransplantation. However, space needs to be made for a broader discourse on the future of xenotransplantation in order to secure an equitable and sustainable biomedical future for us all. While the process of interdisciplinarity may be slow and frustrating in the short term, the methodologies of history and bioethics are critical tools for understanding where the biomedical practices in question have come from and, importantly, how they might proceed.