What the World’s First Pig to Human Heart Transplant Could Mean for the Future of Transplants
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On January 7, a 57-year-old male patient received a genetically-modified pig heart transplant at the University of Maryland Medical Center (UMMC). The surgery was a “world-first” and deemed the patient’s only chance for survival after he was declared unsuitable for a human donor transplant or an artificial heart pump. On January 10, the University of Maryland School of Medicine (UMSOM) published a news release stating that the patient was “doing well”, and “is being carefully monitored over the next days and weeks to determine whether the transplant provides lifesaving benefits”.
Dr. Bartley P. Griffith – the surgeon responsible for transplanting the porcine heart into the patient – and a professor in transplant surgery at UMSOM said, “We are proceeding cautiously, but we are also optimistic that this first-in-the-world surgery will provide an important new option for patients in the future.” Dr. Griffith leads the Cardiac Xenotransplantation Program at UMSOM alongside Dr. Muhammad M. Mohiuddin, professor of surgery at UMSOM.
Xenotransplantation: A brief history
What is xenotransplantation?
The operation at the UMMC is an example of xenotransplantation. Xenotransplantation refers to any procedure involving the transplantation, infusion or implantation of cells, tissue or organs from a nonhuman, animal source into a human.
While the surgery was the first-of-its-kind, the concept of xenotransplantation is not novel. Chris Denning, professor of stem cell biology at the University of Nottingham told the UK Science Media Centre, “Only in the late 1990s did the technologies become available and have steadily been improved ever since. Various academic and industrial teams have worked in this area for over 20 years, so it is not surprising that this has now been tested.”
In the 20th century, non-human primates (NHP) were explored as potentially suitable donors for xenotransplantation due to the genetic similarities between primates and humans. However, concerns such as ethical issues, transmission of infection across species and breeding difficulties halted this research. Consequently, pigs are now considered to be the most appropriate candidate species for xenotransplantation.
"Pigs are considered for several reasons,” Denning said. “The size and anatomy of the pig heart is roughly the same as a human’s, though there are considerable differences:
- Pigs can be bred intensively, with large litters, meaning the number of available organs could be increased rapidly
- The use of pigs is considered by some people as acceptable because of their production for food – this is all relative (e.g., to using NHPs), and some people are uncomfortable with the practice.”
He added that, despite public perception, it is also relatively easy to keep pigs in a sterile condition.
Why porcine hearts are at an increased risk of rejection
Despite these advantages, transplanting a porcine heart into a human is considerably more challenging than transplanting a human heart. There are genetic differences between pigs and humans, which can lead to immunological rejection of the organ. “Pigs have a gene that produces a molecule called α(1,3)galactosyl transferase, which humans do not. This triggers an immediate and aggressive immune response, called hyperacute rejection,” said Denning, ultimately causing the body to reject the organ.
The xenotransplantation conducted at UMMC involved a pig that had reportedly received 10 genetic modifications in total. It’s unclear at this stage exactly what genes were modified, however the news release from UMSOM states “three genes – responsible for rapid antibody-mediated rejection of pig organs by humans” were “knocked out” in the pig, and six human genes responsible for immune acceptance were inserted. An additional gene was also knocked out to stop excessive growth of the heart tissue.
What is meant by "knockout"?
“Knockout” means that an organism has been genetically altered such that it lacks either a single base, a whole gene or several genes. Often, genetic knockouts are utilized in laboratory research to understand how certain genes function, by monitoring changes in the organism when the gene is not expressed.
The culmination of years of work
The porcine heart was provided by Revivicor, a subsidiary of United Therapeutics. You might recall Revivicor as the spin-out company of PPL Therapeutics, the UK-based biotech firm behind the first cloned mammal, Dolly the sheep. In December 2021, Revivicor also supplied New York University Langone Health with a kidney from a genetically-modified pig for an investigational procedure in a deceased human donor. The donor remained on ventilator support, and was closely monitored throughout the procedure and a subsequent observation period, during which the researchers said there were no signs of rejection.
According to the UMSOM news release, it received a $15.7 million research grant to evaluate Revivicor genetically-modified pig UHearts™ in baboon studies. Mohiuddin and colleagues reportedly applied for permission to conduct human clinical trials of the porcine heart from the US Food and Drug Administration (FDA), but were rejected. Under normal circumstances, IMPs must be evaluated in animal studies prior to human clinical trials – this is standard protocol.
However, in the instance of the 57-year-old patient, an exception was made. The FDA granted emergency authorization for the procedure under its expanded access provision. This allows for an individual to access an investigational medicinal product (IMP) outside of clinical trials when there is no alternative therapy option available.
“This is the culmination of years of highly complicated research to hone this technique in animals with survival times that have reached beyond nine months. The FDA used our data and data on the experimental pig to authorize the transplant in an end-stage heart disease patient who had no other treatment options,” said Dr. Mohiuddin.
Challenges in the road ahead for animal–human organ transplants
“Will it be successful?” asked Denning. “The fact that the human patient is alive after a few days indicates that immediate hyperacute rejection has been avoided, which is the first hurdle. Only time will tell whether there are issues with chronic rejection, caused by e.g., incompatibility of major and minor histocompatibility complexes. Continuous monitoring will be needed to monitor transmission of potential pathogens, such as porcine endogenous retroviruses or hybrid porcine/human endogenous retroviruses.”
Should the patient survive and the xenotransplant prove successful, it will likely raise a lot of questions as to how regulatory bodies move forward. Individual emergency authorization procedures do not generate sufficient data for the widespread implementation of xenotransplantation – clinical trials are crucial for demonstrating efficacy.
However, there are logistical hurdles associated with even trialing the procedure. Seventeen people die every day waiting for an organ transplant, according to the Health Resources & Services Administration. There is a severe shortage of organs, and a steep decline in donation has been observed during the COVID-19 global pandemic. While a proposed advantage of xenotransplants is that they could provide “on-demand” organs, the procedure and its unknowns make it a very high-risk surgery. How does a clinician, or regulatory body, decide that a patient has waited “long enough” for a human organ that they qualify for inclusion in a trial?
Furthermore, if xenotransplant clinical trials support widespread adoption of xenotransplant procedures, how do we regulate a system whereby organs are widely available? Policies on patient selection and organ allocation currently exist in healthcare systems across the world. Navigating changes to these policies will require global conversations across different regulatory bodies.
Finally, a hurdle that Denning said could be the biggest of them all is: What do the general public think? Is it acceptable to harvest organs from animals? “One thing that is for sure, is the outcomes of this [patient] will be watched closely by many,” Denning concluded.