Notes on Engineering Health, April 2023: Notes on Xenotransplantation

“Xenotransplantation is the future, and always will be”.

The apocryphal quote by the late Stanford surgeon and heart transplantation pioneer Norman Shumway highlights the hopes and difficulties of this endeavor. Xenotransplantation, or transplanting an organ from one species to another, concentrates many biological challenges and some thorny ethical considerations.

According to the Organ Procurement & Transplantation Network, more than 100,000 people in the United States are currently on the waiting list to receive an organ transplant, and an average of 17 people die every day on the list. Mastering xenotransplantation could end the organ shortage and thus save countless lives.

This idea is not new. Beyond the mythological past, where efforts to merge animal features with human capabilities were not rare (Icarus paid the price of this hubris), people started transfusing blood from animals to humans as early as the 17th century. The results were mixed, however, for reasons that were only revealed some two centuries later. Because all proteins and cells produced by an organism are covered in antigens that are both specific to the species and to the individual, transplanting organs from one individual to another requires either finding the right match or depleting the recipient organs of their antigens. In the absence of a match or a depletion of antigens, the immune system recognizes the transfused blood as foreign and mounts a violent immune response against it. The rejection is all the more acute in the case of cross-species transplantations as the antigens present in the host and the donor evolved separately, sometimes for millions of years. Despite the early challenges, scientists continued to explore this field, with more vigorous efforts dating back to the early 20th century when research on xenotransplantation ran parallel with research on allotransplantation (human-to-human transplants).

In the 1920s, Voronoff transplanted a slice of chimpanzee testis into aged men whose “zest for life” was deteriorating, believing that the hormones produced by the testis would rejuvenate the patients. While there is no record of side effects, they must have been severe with patients likely suffering from necrotic transplants and infections. Some men still reported a significant increase in their energy levels. At the time, the basic principles of immunity had just been established, but specific mechanisms around the recognition of self had yet to be uncovered.

In the 1960s, scientists and researchers again turned to non-human primates (primarily chimpanzees) as potential organ donors as they were the closest species to humans evolutionarily. As human kidneys were in very short supply then, Keith Reemtsma, then at Tulane University, transplanted 13 chimpanzee kidneys into human patients. Most of the transplants failed within four- to eight-weeks, either from rejection or from an infectious complication. Nevertheless, one of Reemtsma's patients lived for 9 months, returned to work, and remained in good enough health until she died suddenly. An autopsy revealed that the chimpanzee kidneys appeared normal and showed no signs of acute or chronic rejection.

The primary challenge in allo- and xeno-transplantations is to avoid the rejection of the organ. A way to tame the immune system is to administer immunosuppressive drugs. Too little of it and the patient risks rejection of the organ, either hyperacute, acute or chronic; too much of it and the patient will eventually die from an infection or cancer. In the 1980s, the development of immunosuppressive drugs such as cyclosporine made transplants between humans much more effective. This led to some renewed optimism that such pharmacological treatments could enable cross-species transplants.

In the 1990s and 2000s, pushed by ethical concerns over animal welfare, supply shortages and progress in genetic engineering, the field moved away from non-human primates and turned its focus to pigs. The size and shape of their organs and the fact they are widely raised to be consumed made them ideal transplant candidates. Since then, pigs have been genetically modified to lack a specific antigen on their cells that triggers an immune response in humans in order to lessen immune rejection. They have also been engineered to improve transplantation by controlling organ size and regulating complement, coagulation and inflammation. These efforts went a long way in erasing the nearly 80 million years of evolution between the two species and making the idea of xenotransplants more than a pipe dream.

A US team was recently able to keep a pig’s heart beating in a monkey for three years. The study, published in Nature Communications, still showed the importance of intense immunosuppression therapy in order to ensure minimal production of anti-pig antibodies that could destroy the transplanted organs. More recently, pig kidneys transplanted into three brain-dead recipients (one in Alabama and two in New York) seemed to remain functional for the duration of the experiment.

Finally, in January 2022, with much fanfare, a 57-year-old man with severe heart disease who was not eligible for an allotransplantation underwent surgery to receive a genetically modified pig heart at the University of Maryland. He died after about two months with what seemed like a functional heart in his chest. While the causes of his death are still unclear, he likely suffered from an infection due to a pig-specific virus. This raised another major challenge in the xenotransplantation field, that is xenozoonosis, or the transfer of known or unknown pathogens from one species to another. On the heels of the COVID-19 pandemic, the threat of a pathogen going from animals to humans echoes as a cautionary tale. These safety considerations will undoubtedly play an essential role as regulators start considering the first xenotransplantation clinical trials.

For some scientists, like Megan Sykes from Columbia University, the last attempt was a positive signal, and the first trials leading to the generalization of xenotransplantation could be less than two years away. For others, there is a belief that the challenges will remain intractable and, between the risks of pathogen transfer and the harm done to animals, humanity should find other solutions to the organ shortage.

Whether humans will eventually live with organs from animals, the efforts to get there have already had beneficial effects. Similar to the way landing on the Moon required the development of a myriad of technologies that later integrated into our daily lives, the xenotransplantation moonshot has shed light on many key aspects of immunology and virology that are benefitting the treatment of numerous health issues.

– Jonathan Friedlander, PhD & Geoffrey W. Smith



First Five
First Five is our curated list of articles, studies, and publications for the month. For our full list of interesting media in health, science, and technology, updated regularly, follow us on Twitter or Instagram.

1/ The self in all its states
A team of researchers created an atlas of all mutations that accrue throughout a person’s lifetime, beginning in utero. They showed with great granularity how these mutations increase as time goes by and how they affect different organs and the health of the whole organism beyond cancer.

2/ The bear necessity for anticoagulation
Acute immobility caused by illness or injury can increase the risk for potentially deadly venous thromboembolism in humans. By contrast, hibernating bears remain immobile for months every year without experiencing any such complications. By comparing blood from humans in chronic immobilization, healthy volunteers on extended bed rest, and free-ranging brown bears during their periods of activity and hibernation, researchers identified specific proteins that protect from thrombosis.

3/ Should we extend our Roman Holiday?
A recent study found that compared to similarly high-income European countries the United States continues to have substantially higher death rates at all but the oldest ages, resulting in more “excess deaths,” and this gap widened during the COVID-19 pandemic.

4/ A real curve ball
A new study looking at baseball games found that more than 500 home runs since 2010 can be attributed to warmer, thinner air caused by global warming. Rising temperatures could account for 10% or more of home runs by 2100 if greenhouse gas emissions continue at the current rate.

5/ Monkey tricks
When not being used as organ donors, monkeys are sometimes shown some magic. An illusion involving a hidden thumb (the video is worth a look) managed to fool monkeys with opposable thumbs (like capuchin and squirrel monkeys) but not ones with five equidistant digits (like marmosets). The research adds to evidence that animals struggle to predict movements outside of their own biomechanical ability.



Digitalis Commons
Public-Interest Technologies for Better Health

Digitalis Commons is a non-profit that partners with groups and individuals striving to address complex health problems by building public-interest technology solutions that are frontier-advancing, open-access, and scalable.

Complex problems require a multitude of solutions. The plastics pollution crisis is one such example where technological advances have to be matched by innovative public actions and scalable solutions. This Nature publication makes a strong case for how more-sophisticated policies, smarter recycling and new materials could stem the tide of waste. This hybrid approach is what Digitalis Commons strives to achieve in health.

‍

‍