Cardiac xenotransplantation – a new frontier or a double edge sword?

Limitations of cardiac xenotransplantation and potential alternatives to address these drawbacks

Writer: Rachel Nguyen
Editor: Madeleine Throssell
Artist: Zach Ng

In January 2022, a team of surgeons from the University of Maryland shook the world of medicine by announcing their successful attempt in transplanting a porcine heart into 57-years old David Benett who had been suffering from terminal heart failure. Although this was not the first-ever attempt at xenotransplantation as far as the history of the subject goes, it was certainly a first-of-its-kind project, combining the finest, state-of-the art knowledge from immunology, transplant surgery, and genetic editing technology.

Unlike other types of organ transplant, cardiac transplant is a tough case to crack for two reasons: Firstly,  heart cells, unlike liver cells, are unable to regenerate inside a living organism; moreover, unlike kidney transplants, living donor heart transplants are impossible. Second – a person is only eligible to donate their heart when he or she is declared brain dead, and the donor cannot have died from cardiovascular diseases. This has created a crisis of heart scarcity, with over 100,000 patients with advanced cardiac failure being on the transplant list each year and many of whom die before they could receive a heart.

Immunological challenges

There are two types of immune responses associated with xenotransplants: hyperacute rejection (which happens over hours to days post-surgery) or delayed xenograft rejection (which happens over weeks to months post-surgery).  Both of these responses are due to the presence of non-self entities (called antigens) on the outer-covering layer of porcine’s tissue, which are detected and destroyed by the patient’s immune system. To address this problem, scientists have attempted to genetically knock out these antigens. However, the high incidence of delayed xenograft rejection suggest that more research needs to be carried out to investigate other novel immune factors that confer this challenge

Infectious challenges 

One of the other major concerns with using pig organs is the risk of zoonotic infection, which, by definition, is “an infectious disease that has jumped from a non-human animal to humans”. Pigs are known to be animal reservoirs for a number of infectious agents; considering the fact that transplanted patients are most likely to undergo immunosuppressive therapies post-op, transpecies infection will therefore put them at a high risk of fatality. 

Pigs are not the only species targeted for cardiac xenotransplantation. Researchers have attempted to utilize organs from primates including chimpanzees, orangutans, and baboons. These species have the advantage of being concordant to humans, meaning that they share a common phylogenetic branch with us. Nevertheless, this concordance means that there is an extremely high chance of porcine virus “jumping” onto human, resulting in a new viral strain that could potentially be lethal to humans – or worse, set off a pandemic. 

A particular ethical challenge with cardiac xenotransplantation is religious condemnation. For example, Islamic cultures forbid medical procedures that utilize porcine organs, including organs that are devoid of living cells like heart valves (although this is subjected to mitigation under extenuating circumstances). On the other hand, Jewish and Judaism xenotransplantation is justified on the ground that the outcomes of such procedures outweigh religious constraints. Lastly, Catholics particularly prohibit the use of embryonic stem cells for any forms of medical purposes – this poses a huge challenge for both xenotransplantation and its potential alternatives (explained further in section 4.1).  

Xenotransplantation is not the only competitor in the race for addressing the question of heart donor shortage. For decades, scientists have been trying to “grow” human organs inside animals – a technique known as blastocyst complementation using embryonic or induced pluripotent stem cells (iPSCs) 

Although this technique triumphs over xenotransplantation by the fact that the resulting organ is technically derived from the patient’s own body cells, thereby, eliminating the risk of organ rejection, there are numerous challenges. Firstly, successful blastocyst complementation has only been done for pancreas and kidney models for animals, which means that no successful cases of human iPSCs heart transplant has been recorded. Secondly, a number of problems have been recorded, including: induced cell death of the transplant organs as they are considered “unfit” by the recipient’s body, 2) insufficient molecular pathways that are essential for the survival of the organ, and 3) failure for the organ to “adhere”, leading to it “being extruded from the embryo due to their inability to form adequate cell-cell junctions with host cells” (Zheng et al, 2021). Lastly, as mentioned in the ethical challenges section, the use of embryonic stem cells is largely condemned by certain religions, making this technique unavailable to a number of populations. 

Another competitor in the race for addressing the shortage of heart organ donors is tissue printing. Depending on the protocol, this technique typically involves 3D printing a bioink (i.e alginate) or onto an extracellular matrix-based gel, using an MRI scan of a heart as the “frame”. After a period of culture, iPSCs are casted onto the newly-printed structure and differentiated into different structures within the heart. Recently, researchers from Harvard’s Wyss Institute for Biologically Inspired Engineering and John A. Paulson School of Engineering and Applied Sciences (SEAS) have further reported successful attempts in printing sophisticated vessel systems necessary to support the printed organ with sufficient oxygen and nutrients. 

Sounds promising, right? Well, the science is not that simple. 

Quoting Professor James Yoo from Wake Forest School of Medicine, it is unclear whether “a printed heart of this sort could withstand the flow of blood under high pressure or that the printed structures would remain stable after implantation in the body”. Another conundrum is the generation of a readily perfusable circulatory network, owing to the delay between implantation of the 3D-printed heart and vascular connection (medically known as anastomosis) with host vasculature. Without this vessel system, cardiac tissues are at risk of lacking nutrients and oxygen, and therefore being unviable to support the recipient.

So….What does that leave us with? 

Scientists are still searching for a suitable animal model as a heart donor. Indeed, each candidate might have its own drawback, however, the development of CRISPR/Cas9 technology means that we can simultaneously knock out a multiplicity of genes that might contribute to adverse immune responses and pathogenic transmission. Moreover, the survival period for patients receiving xenogenic organs, especially xenogenic hearts, is progressively prolonged. Along with the development of blastocyst complementation and tissue printing, it might not be that far into the future until researchers could land the first-of-its-kind cardiac xenotransplant using 3D-printed hearts clinical trial.

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