The Promise and Perils of Modern Xenotransplantation

A sense of both hope and trepidation hung over the surgical theatre. 

 

On the operating table lies 57-year-old David Bennett; his body is connected to an intricate labyrinth of tubes. For years, he had been battling a failing heart. After an especially life-threatening arrhythmia, he was admitted to the University of Maryland Medical Center where he, under the care of Dr Bartley Griffith and his team, agreed to a heart transplant surgery. 

 

The room fell into hushed silence as the surgeons began their elaborate dance. Steady hands holding razor-sharp blades skillfully navigated the complex network of veins and arteries, delicately disconnecting and removing the weakened heart. The new heart was then gently nestled in the empty chest cavity. Pairs of hands began meticulously suturing and connecting it back to the intricate web of vessels. 

 

Afterwards, the surgeons slowly restored the nourishing flow of oxygenated blood into the foreign heart. In a breathtaking spectacle of medical triumph, the heart began to beat. The room echoed with the steady, rhythmic pulse of heart monitors. 

 

Truthfully, this sounds just like an ordinary heart transplant procedure, which is performed more than 5,000 times every year worldwide [1]. Except David was actually deemed ineligible for a conventional heart transplant. Nobody donated their heart to David — that is, no human. The heart pumping in David’s chest came from a genetically-edited pig.

 

Previous attempts at transplantations involving non-human organs often failed because the human immune system naturally attacks these transplanted animal organs, leading to acute rejection and further complications. This landmark case of xenotransplantation carried out in January 2022, however, was unique in that the pig’s DNA was edited using CRISPR-Cas9. Specifically, to make a pig heart more compatible for transplant, scientists knocked out three genes that code for porcine antigens. Six genes of human origin were then inserted into the pig’s genome to make the organ more biocompatible. Finally, the gene for growth hormone receptors was snipped away to prevent the heart from proliferating so it remained the same size [2]. At first, these edited organs were transplanted into baboons in 2018 [3]. After the primates survived more than 2 years, the conversation started to shift towards actually helping human patients with animal organs, eventually leading to David’s transplant surgery. 

 

Xenotransplantation offers many benefits. Most notably, it has the potential to greatly mitigate the current global organ shortage. 50,000 patients die yearly worldwide because healthcare centres cannot find a suitable organ to transplant [4]. In Hong Kong, where the organ donation rate is 5.6 deceased donors per million people in 2020, nearly 3,000 people are currently in need and waiting for an available organ [5].

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Figure 1: Number of patients waiting for transplantation of various organ in HK [6]

 

Furthermore, pigs are great candidates as organ donors due to their anatomical similarities with humans, relative ease of care, and fast maturation rate. Pig heart valves, for instance, have been a staple in heart valve replacement surgery over the past three decades [7]. Therefore, xenotransplantation of major organs could serve as an incredibly helpful approach to reducing the burden of organ shortage. 

 

Additionally, as demonstrated in David Bennett’s case, the risk of rejection is no longer a severe concern thanks to CRISPR editing. Though David passed away two months after the surgery, the University of Maryland claimed it was not due to rejection issues, as the heart “displayed none of the typical signs of rejection by the patient's body, even when it was carefully examined during an autopsy”  [8]. In fact, just last month in August, surgeons at New York University Langone Health announced that a kidney from the same line of genetically modified pigs has been functioning well after its 32nd day of transplant into a brain-dead patient – the longest period for such an experiment [9]. Editing the organ to make it more ‘human-like’ also reduces the need for constant immunosuppression; transplant patients often required lifelong anticoagulant therapy, which can be an inconvenience for them whilst posing potential adverse side effects. 

 

Despite the strong potential of xenotransplantation, however, significant ethical concerns remain. Animal rights activists, for example, opine that as xenotransplantation will give rise to a market for medical-grade organs, animals will be confined to a sterile environment and an unnatural lifestyle. Revivicor, the company that edited and raised the pig used in David’s surgery, have several procedures to create a sterile pig, including performing a C-section of the pregnant sow, not allowing the piglets to suckle their mother, and keeping the piglets in a hermetically sealed “pig-in-the-bubble” environment [10]. Coupled with altering their genetic code and undergoing invasive, and eventually fatal, procedures, it is apparent that the well-being of these donor animals will be violated from multiple fronts. Consequently, new guidelines will need to be established for the care of transgenic animals, which is another complex process in and of itself. Ultimately, a key question we have to ask is: Do we have the right to use other species for our own medical purposes? 

 

 

 

 

 

 

 

 

 

 

 

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Figure 2: A conceptual illustration of a pig farm for raising transgenic pigs at Revivicor [11]

 

While some may argue this doesn’t differ from killing other species for consumption, which has been practised for millennia, one could contend that the xenotransplant recipient has an animal organ permanently and biologically integrated into him, whereas consuming another species is more transient. So what if, hypothetically, a person eventually gets transplanted a pig’s heart, kidneys, and pancreas? Just as the ancient ship of Theseus gradually had all its timber replaced over time, we would need to ask ourselves just how much of that individual is still a human anymore. If portions of our biological systems are derived from non-human sources, where do we draw the line when it comes to defining and measuring humanness? These concerns are challenging to address because we must explore the complexities of identity and reconsider what truly makes us human. 

 

The results from a more detailed discussion about these questions could have far-reaching implications in social, cultural, and legal spheres. For instance, we would also need to consider from the perspective of the pig donor too: In the future, if more human genes are genetically inserted into a pig’s genome to make it more biocompatible, how ‘human’ is that pig? Is it entitled to rights normal pigs don’t have because of its part-human genetic makeup? Perhaps this debate about humanness puts us on the edge of a slippery slope – a perpetual one too, prompting concerns as to whether we can really ever achieve a definitive answer. 

 

Aside from these philosophical quandaries, we must grapple with practical issues like the complications of cross-mixing species DNA. Pigs, like all animals, carry specific remnants of ancient encounters with contagious retroviruses and cytomegalovirus in their DNA. While pig endogenous retroviruses and cytomegalovirus (PERVs and PCMVs) do not harm the pig itself, there is an unpredictable concern that if a pig organ is transplanted into a human body, the viral genes could recombine and get altered, bringing the virus back from latency to cause zoonotic infections. In May 2022, David’s transplant surgeon Bartley Griffith revealed that the pig’s heart was infected with PCMV, which may have contributed to David’s death [12]. Scientists have been exploring ways to use CRISPR to knock out the PERV genes for the past decade [13], but this apprehension is well-founded, especially in a world still emerging from the shadow of the COVID pandemic.

 

In fact, this risk of epidemic-causing viral infection entails several ethical compromises for the xenotransplant recipient. During the process of informed consent, the xenotransplant recipient must be given a comprehensive explanation of the risks and novelty of the surgery. This not only includes restrictions on movement and travel, mandatory long-term monitoring for xenogenic diseases, but also unavoidable invasions of privacy such as sexual contact reporting. Our previous lessons with zoonoses like HIV taught us that these classes of pathogens have latency periods of extended periods of time, so this level of intense monitoring is necessary, albeit undesirable for patient autonomy and freedom of choice [14].

 

Another logistical difficulty of xenotransplantation concerns whether we can determine a fair allocation process for animal organs. Just like human organs, animal organs used for transplants cannot be treated as ordinary economic goods because hospitals and healthcare services need to reckon with the needs of each patient. Aside from balancing the struggle of who needs the organ most versus who can recover or live a higher quality life with the organ, health institutions must also weigh the explicit and implicit costs of xenotransplantation with the efficacy of alternative treatments. Zhang et al. found that in Sweden, while the cost of maintaining a patient with end-stage renal failure on dialysis is less than the cost of a transplant in the first year, the latter becomes evidently cost-effective after three years [15]. This links to one more concern: if we now have a reliable supply of organs available for transplantation, will xenotransplants still be under the public sector, or can they become a privatised service? The question comes with its own host of ends to untangle, as it could upturn the current organ allocation system globally. If it goes private, how regressive will this be for less affluent patients desperately needing an organ? What kind of vested interests will companies like Revivicor and other for-profit enterprises have? Just because a medical market for animal organs becomes available does not mean the resources will be allocated justly.

 

Clearly, David Bennett’s surgery, made possible through gene editing, is a testament to a medical procedure with an immense potential to alleviate the global organ shortage. However, further explorations are needed to navigate the complex landscape of ethics and socio-economical implications to mitigate the risks involved in xenotransplantation. Ultimately, whatever our final decision is, the discussion revolving around xenotransplantation demands a delicate balance between saving lives and the ethical deliberation surrounding animal welfare, resource allocation, and human dignity.

 

References:

1. UpToDate [Internet]. Uptodate.com. 2019. Available from: https://www.uptodate.com/contents/heart-transplantation-beyond-the-basics

2. Park A. Revivicor’s genetically modified pig heart is first successfully transplanted in human patient [Internet]. Fierce Biotech. 2022. Available from: https://www.fiercebiotech.com/medtech/revivicor-s-genetically-modified-pig-heart-first-successfully-transplanted-human-patient

3. Researchers keep pig hearts alive in baboons for more than 2 years [Internet]. www.science.org. Available from: https://www.science.org/content/article/researchers-keep-pig-hearts-alive-baboons-more-2-years

4. The Global Organ Shortage: Doctor Explains How World Organ Donation Day Can Make A Difference? TheHealthSite [Internet]. 2023 Aug 13 [cited 2023 Aug 19]; Available from: https://www.thehealthsite.com/diseases-conditions/the-global-organ-shortage-doctor-explains-how-world-organ-donation-day-can-make-a-difference-1000369/

5. Organ Donation Knowledge – HKOTF [Internet]. [cited 2023 Sep 11]. Available from: https://hkotf.org/en/odknowledge/#:~:text=However%2C%20the%20organ%20donation%20rate

6. Organ Donation Knowledge – HKOTF [Internet]. Available from: https://hkotf.org/en/odknowledge/#:~:text=However%2C%20the%20organ%20donation%20rate

7. Pick A. Pig Valve Replacements: 10 Important Facts [Internet]. Adam’s Heart Valve Surgery Blog | Just another WordPress site. 2020. Available from: https://www.heart-valve-surgery.com/learning/pig-valve-replacement/#:~:text=For%20over%2030%20years%2C%20pig

8. 2023 News - Lessons Learned from World’s First Successful Transplant of Genetically-Modified Pig Heart into Human Patient | University of Maryland School of Medicine [Internet]. www.medschool.umaryland.edu. Available from: https://www.medschool.umaryland.edu/news/2023/Lessons-Learned-from-Worlds-First-Successful-Transplant-of-Genetically-Modified-Pig-Heart-into-Human-Patient-.html

9. Pig Kidneys Performing Effectively in Two Brain-Dead Patients. 2023 Aug 16; Available from: https://www.nytimes.com/2023/08/16/health/pig-kidney-organ-transplants.html

10. Bajaj S. Inside the Pig Heart Transplant and Ethical Dilemma That Followed [Internet]. Sentient Media. Available from: https://sentientmedia.org/inside-the-pig-heart-transplant-and-ethical-dilemma-that-followed/

11. Ethical & Regulatory Considerations in Xenotransplantation Clinical Trials: Patient Selection & More [Internet]. www.youtube.com. [cited 2023 Sep 11]. Available from: https://youtu.be/L-gUfCKqpOE

12. Yang M. Man who received landmark pig heart transplant died of pig virus, surgeon says [Internet]. the Guardian. 2022. Available from: https://www.theguardian.com/us-news/2022/may/06/man-landmark-pig-heart-transplant-death-pig-virus

13. Brouillette M. Four Breakthroughs That Led to the Pig Heart Transplant [Internet]. Proto Magazine. 2022 [cited 2023 Sep 11]. Available from: https://protomag.com/transplants/four-breakthroughs-that-led-to-the-pig-heart-transplant/#:~:text=In%20the%20pig%2Dto%2Dhuman

14. Wadiwala IJ, Garg P, Yazji JH, Alamouti-fard E, Alomari M, Hussain MWA, et al. Evolution of Xenotransplantation as an Alternative to Shortage of Donors in Heart Transplantation. Cureus [Internet]. 2022 Jun 24;14(6). Available from: https://www.cureus.com/articles/102367-evolution-of-xenotransplantation-as-an-alternative-to-shortage-of-donors-in-heart-transplantation

15. Zhang Y, Gerdtham UG, Rydell H, Lundgren T, Jarl J, et al. Healthcare costs after kidney transplantation compared to dialysis based on propensity score methods and real world longitudinal register data from Sweden. Sci Rep. 2023 Jul 3;13(1). Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10318027/