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References
Goerlich CE et al. (2021). The growth of xenotransplanted hearts can be reduced with growth hormone receptor knockout pig donors. J Thorac Cardiovasc Surg.
Kilic A et al. (2014). Donor selection in heart transplantation. J Thorac Dis 6, 1097–1104.
Längin M et al. (2018) Consistent success in life-supporting porcine cardiac xenotransplantation. Nature, 564, 430-433.
Reardon S (2022). First pig-to-human heart transplant: what can scientists learn? Nature 601, 305-306.
Could Genetically-Modified Pigs Be the Future of Xenotransplantation?
A groundbreaking experimental procedure, where a man received a donor heart from a genetically-modified pig made headlines around the world. David Bennett, who had end stage heart failure, and ventricular fibrillation survived for two months after the procedure. The team of researchers and surgeons behind the transplant are optimistic that his operation will pave the way for more research in xenotransplantation and ultimately help lead to clinical trials. This blog looks at some of the scientific context behind this headline.
More than Just a Tissue Match
Organs suitable for transplants are in short supply because as well as needing donors who are the same blood type and good tissue matches for each person needing an organ, the donor organ needs to be in suitable condition to be used for a transplant. Organ size and transportation time need to also be considered to determine its suitability. For example, hearts need to go to recipients with similar height/weight to the donor and are ideally within a relatively short distance, to prevent organ damage when kept outside the body.
Transplant lists are long and there are stringent criteria prioritizing recipients so that those who are most likely to benefit get an organ soonest. Unfortunately, this means many patients waiting for a transplant will die before a suitable match is found. To try and combat the increase in demand for donor hearts, versus a relatively steady organ supply, the ideal donor's maximum age has gradually increased from 35 to under 55 years (Kilic et al. 2014). However, there is still greater demand than available donor hearts and xenotransplantation may pave the way to save the lives of more people with heart disease.
An Ethical Dilemma
While the concept of xenotransplantation is an interesting possibility, there are a whole host of ethical issues to consider which complicates research attempts. Regulatory bodies, like the US Food and Drug Administration (FDA), need to weigh up the urgency of receiving a donor organ versus the risks of an experimental procedure.
In the case of David Bennett, it was determined that the benefits outweighed the risks of the procedure, However, for any future xenotransplantation procedures consent would need to be gained for each potential patient based on their own individual circumstances. David, who had been in a coma for two months, was not eligible to receive a mechanical heart pump, due to an irregular heartbeat and a history of noncompliance with doctors’ advice. He was therefore ineligible for a donor heart (Reardon 2022). Without a transplant, his condition would have been terminal, and it was this urgency that enabled his medical team to seek a “compassionate use” approval from the FDA to use a heart from a genetically-modified pig, created by a biotech company instead of one from a human donor.
A Highly Skilled Team Pioneering the New Technology
Muhammad Mohiuddin, a cardiac transplant surgeon, led the team at the University of Maryland School of Medicine that performed the transplant. This team has been researching xenotransplantation and working with hearts from the biotech company’s genetically-modified pigs for a number of years. They had previously successfully transplanted genetically modified pig hearts into baboons’ chests with the baboons surviving for nine months after surgery (Längin et al. 2018).
Reportedly, the heart used had ten alterations to help reduce the chance of rejection and limit organ growth. While the exact modifications are proprietary information and not in the public domain, six human genes have apparently been inserted into the pig’s genome and four pig genes inactivated using gene editing technology. According to Science, the insertions included two anti-inflammatory genes, two genes that promote normal blood coagulation and prevent blood vessel damage, and two other regulatory proteins that help dampen the host antibody response. A growth hormone receptor was also knocked out to reduce the likelihood that the heart would outgrow the size of its host, the research team had demonstrated success with this technique in baboons (Goerlich et al. 2021).
Additionally, an experimental drug developed by the surgical team, KPL-404, was administered to David, to reduce the likelihood of his new heart being rejected. This drug works by binding CD40 and suppressing the production of antibodies by the recipient’s immune system that could lead to organ rejection.
David survived for two months after receiving the heart, dying on March 8, 2022. While the procedure was a landmark operation in medical history, for xenotransplantation to become the norm the ethics would need to be well defined, as well as the criteria for what is counted as success. It is unknown how a human body will respond to a pig heart long term and what the risks are from porcine endogenous retroviruses or other complications that could arise. While the research team are optimistic that they will be able to carry out a clinical trial of the procedure in the near future, it will be some time before xenotransplantation becomes routine, if at all.
Study the Porcine Immune System with Bio-Rad Antibodies
The Bio-Rad porcine research antibody range provides monoclonal antibodies to CD markers, cytokines and immunoglobulins, and recombinant porcine cytokine proteins, to study immune responses in pigs.
References
Goerlich CE et al. (2021). The growth of xenotransplanted hearts can be reduced with growth hormone receptor knockout pig donors. J Thorac Cardiovasc Surg.
Kilic A et al. (2014). Donor selection in heart transplantation. J Thorac Dis 6, 1097–1104.
Längin M et al. (2018) Consistent success in life-supporting porcine cardiac xenotransplantation. Nature, 564, 430-433.
Reardon S (2022). First pig-to-human heart transplant: what can scientists learn? Nature 601, 305-306.