By La Rissa Vasquez, Neurobiology, Physiology, and Behavior ‘23 and Shaina Eagle, Global Disease Biology ‘24

In 1818, Mary Shelly published what is now regarded as the pioneer of the science fiction genre, the story of Frankenstein. In this novel, an ambitious scientist named Dr. Victor Frankenstein challenges the laws of nature by bringing the dead back to life. Sewn from animal and human remains, the “Creature” was sentient and desired love and acceptance like all humans but would later be known only as the infamous monster of Frankenstein. But these are no longer just stories. In recent decades, scientists have made huge strides in transplantation technology, even experimenting with the transplantation of non-human organs, redefining the laws of nature.

On January 7, 2022, David Bennett became the first person to successfully undergo the transplant of a non-human organ, or xenotransplantation. Bennett was suffering from end-stage heart disease and was ineligible for a human heart transplant, but the U.S. Food and Drug Administration granted a compassionate use for the experimental transplant of a genetically modified porcine heart [1]. The surgery was performed by Bartley Griffith, M.D. at the University of Maryland Medical Center in Baltimore [1]. 

The shortage of organs available for transplantation is an ongoing problem, especially for patients like Bennett in end-stage organ failure, for which transplantation is often the only option. For decades, medical geneticists and surgeons have worked to make xenotransplantation a reality. The Transplant Wait List has over 100,000 people on it in the United States alone [2]. As surgical technology and the understanding of genetics have advanced, so too has the number of patients in need of organ transplants. 

‘Porkensteen:’ Bennett’s New Heart

David Bennett’s porcine heart came from Revivicor, a United Therapeutics Corporation. On their website, the organ is advertised as “UHeart ™.” Also in the United Therapeutics pipeline are xenokidneys and xenolung lobes, which are both designed to target end-stage organ failure, and are in the same pre-clinical stage as the porcine heart used in the Maryland surgery.

The heart transplanted into Bennett is not the exact heart removed straight from a pig. Revivicor altered ten genes, knocking out a few pig genes and incorporating human genes to prevent rejection by the patient’s immune system and to prevent the heart tissue from growing excessively large inside Bennet’s chest. In a collaboration between the University of Maryland School of Medicine’s cardiac xenotransplantation program and Kiniksa Pharmaceuticals, Bennet was also given KPL-404, an experimental immunosuppressant used to prevent immune-rejection of the organ by suppressing T-cell-dependent Antibody Response [3]. 

Genetic modifications and immunosuppressive therapies are integral to the success and scaling of xenotransplantation. After decades of experimentation with non-human primates, the domestic pig was identified as the ideal donor, due in part to the similarity in size and physiology between pig and human organs, as well as the reduced risk of zoonotic disease transmission [4]. However, genetic differences between pigs and humans serve as a complication due to an increase in the likelihood of rejection by the human immune system. Bennett’s medical team was initially able to avoid concerns such as hyperacute rejection and coagulation system dysregulation, in which the recipient’s own antibodies attack the foreign organ. 

Unfortunately, on March 8, 2022, it was announced that Bennett had died [5]. The University of Maryland Medical Center has not yet announced an official cause of death but plans to publish a full clinical study in the future. Despite the outcome, Bennett lived with the transplanted organ for more than three months post-procedure. His surgery is another step in a long line of recent breakthroughs in xenotransplantation [6] and will guide researchers in their quest for sustainable and effective porcine organ transplantation in the future.

Reanimating the past 

The first known xenotransplantation was the blood of a lamb into a 15-year-old French boy in 1667. Nearly two hundred years later, French physician Paul Bert warned against cross-species transplantation in “On Animal Transplantation” [7]. Cases of xenotransplantation picked up speed in the early 1900s, using organs from various species, but all ended in the death of the recipient. The first pig organ transplant on record was in Lyon, France in 1905 by surgeon Mathieu Jaboulay, using a porcine kidney; the patient only survived for three days [7]. A surgeon attempted the transplantation of a porcine heart for the first time in 1968 in London; this time, the patient only survived post-procedure for four minutes [7]. 

A number of attempts at xenotransplantation have been made throughout the decades, varying in levels of success, and reflecting the improvements in allotransplantation (transplantation between the same species) as well as immunosuppressive and gene-editing technology. Gene modification technology such as clustered regularly interspaced short palindromic repeat (CRISPR-Cas9) allows scientists to genetically modify genes so that transplanted organs are less likely to be immunologically rejected [4, 7]. One setback came with the discovery of porcine endogenous retroviruses (PERVs) in 1994, but in 1998, the FDA allowed porcine transplants to resume under strict guidelines after it was shown that PERV infections could be detected in recipients. In 1999, they banned the use of primate organs in xenotransplantation because the risk of infectious disease was too high [8]. The beginning of the twenty-first century saw a number of trials of pig to non-human primate transplantations, and just four months before Bennett’s surgery, surgeons in New York City transmitted genetically modified porcine kidneys to brain-dead recipients [6]. Although the recipients were being sustained on ventilators, the fact that the organs were not rejected was a milestone.

When Pigs Fly: The Future of Xenotransplantation 

Ancient Greek mythology tells the story of Daedalus attaching the wings of a bird onto his son Icarus’ back, in an attempt to escape the island of Crete. Icarus falls to his death after boldly flying too close to the sun and melting his wings off: his fatal flaw was unfettered pride and ambition. 

Will our pension for progress and self-congratulation in the wake of our discoveries be our downfall? An often overlooked part of the story of Icarus are the instructions that Daedelus gave to his son before their flight: “fly too low and the sea will dampen and clog the wings.” Ambition can surely lead to disappointment but so can complacency. If medical and scientific technology were not allowed to advance then we would drown in a sea of ignorance. To keep from drowning, we use our current understanding to build a raft and we preserve ethical quandaries instead of boundaries to survive the turbulent seas and ride the tides of progress. 

When we think about the future of xenotransplantation, we should be excited about the possibilities of this new application. CRISPR-Cas9 allows scientists to precisely modify genes— resolving many immunological concerns while producing viable animal subjects within short periods of time; this is promising for the scaling of xenotransplantations. These engineered pigs carry fewer xenoantigens (an antigen that is found in more than one species) reducing the risk of organ rejection or the development of fatal xenozoonosis (an infectious disease that is transferred from animal to human via the transplanted organ). Reducing the risk of organ rejection caused by zoonotic diseases is paramount to the success of xenotransplantation in all human organ systems. 

Xenografted porcine fetal neurons are a promising treatment for Parkinson’s disease and Huntington’s disease, in addition to biologically engineered organs grown in vitro and 3D printed organs [13]. These medical applications could shorten transplant waitlists and help those who are ineligible to receive an organ due to other illnesses [9]. Patients who are older and in a late stage of disease, like David Bennett, are also less likely to be given priority on a waitlist [10]. Xenotransplantation allows scientists to create and edit the tissue of a working animal model and tailor it to a patient’s distinct genetic disposition in abundance. 

Too Close to the Sun: Ethical Concerns

“Fly too high and the sun will melt your wings:” xenotransplantation is an ambitious operation but it is not unfettered. The existence of ethics in science is not a dilemma but a framework for us to navigate the horizon of change for animal rights, the welfare of patients, and religious exemptions. The genetic engineering and subsequent raising of pigs within sterile lab conditions to prevent disease for the sole purpose of organ harvesting comes at a great cost to the animals’ welfare [11]. There are also religious considerations that could further stigmatize the practice of xenotransplantation because of the premise of mixing the human with the non-human which is often seen as a taboo [12]. 

The heart as an organ has philosophical and physiological definitions, but the heart as a cultural and societal symbol has carried inexplicable and global significance since ancient times. So what does it truly mean to be human? Even after being composed of dead human and animal flesh, Frankenstein’s creature still had a heart. He felt love and sorrow like any human. He was an abandoned creation who became a monster because those around him lacked the ability to show him compassion. What makes us human is our ability to adapt, advance, and most importantly, our ability to show empathy. The topic of xenotransplantation requires just as much an open mind as it does an open heart to help make the treatment more accessible to others. 

Stories and fables are woven into our morality. They can help explain why we fear change at the risk of uncertainty and chase after discovery at the prospect of reward. In both tales, Dr. Frankenstein and Icarus are warned not to take pride in their intelligence because knowledge is a power equivalent to the gods. But within the realm of science and society, knowledge is not a deity or a harbinger but a vital part of our survival. As a species, we are obligated to share knowledge when it can save lives. And as humans, survival is ingrained in our biology and consciousness. It is etched in our history, pursued in our present, and foreseen in our futures. Xenotransplantation as a medical practice to save a person’s life is not inhuman nor is it hubris, but to deny ourselves a known resource in the ongoing odyssey of survival would be monstrously heartless. 

References:

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