In a first-of-its-kind surgery by the University of Maryland Medicine a 57-year-old patient with terminal heart disease has received a successful transplant of a genetically-modified pig heart.
Prof Chris Denning, Professor of Stem Cell Biology at the University of Nottingham, said:
What are the risks? Why is a pig heart harder to transplant to a human than a human heart?
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. Within minutes, the human body attacks the foreign organ to reduce it to a messy pulp.
Even if this gene is deleted, there are still a series of other molecules that need to be eliminated or modified to make the pig organ compatible with human – e.g. major and minor histocompatibility complexes this is more similar to the matching that is done in human to human, but naturally is more complex between species.
The human genome contains ancient relics of viruses that embedded themselves in our DNA over thousands of years. These are called “human endogenous retroviruses”. In the same way, pigs have “porcine endogenous retroviruses”. There is a potential risk, albeit small, that porcine endogenous retroviruses could cause human infection or could recombine or ‘merge’ with human endogenous retroviruses to create new viruses.
Worth noting is that live organ transfer is very different to use of e.g. heart valves from pigs used in humans. This is because the pig heart values used are not living and so do not pose these risks.
Why was a pig heart chosen? Why/how was it genetically modified?
Pigs are considered for several reasons. The size and anatomy of the pig heart is roughly the same as human, though there are considerable differences (see below). 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 non-human primates), and some people are uncomfortable with the practice. Finally, keeping pigs in sterile conditions is relatively easy, despite common public perception.
I do not know exactly what modifications were made. However, it is likely that the α(1,3)galactosyl transferase was deleted. There was likely modification or elimination of molecules such as major and minor histocompatibility complexes. The number of porcine endogenous retroviruses will have likely been reduced by selective interbreeding and/or genetic modification.
Do you expect this to be a success? What does it promise for the future?
The concept of ‘xenotransplantation’ from pigs to humans is not new and has been considered for many decades. 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.
Will it be successful? The fact that the human patience 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. Also bear in mind that humans are upright whereas pigs are 4 legged. This means the human heart has to pump hard to push blood vertically, whereas the pig heart has an easier time pumping horizontally. Whether the pig heart can generate (or withstand) the pressures needed in humans is unknown. Also bear in mind that there are differences in anatomy between the heart of pigs and humans, so some additional ‘re-plumbing’ will have likely been needed.
The future… well, first there will be a lot of questions on how well the heart lasts, whether it experiences ‘chronic rejection’, how much immune-suppression is needed for the human patient and if he can tolerate those levels, whether the heart can produce the pumping pressures needed, whether there is real risk of new viruses. And then perhaps the biggest hurdle of all – what does the public think? Is it ethically acceptable to harvest organs from animals? One thing that is for sure, is the outcomes of this trial will be watched closely by many.
Mr Francis Wells, Consultant Cardiac Surgeon, Papworth Hospital, said:
“The ambition of utilising the immunologically modified Pig heart for transplantation is not new.
“More than 25 years ago, pigs were bred in Cambridge to express human antigen on the cell surface to modulate rejection aggressiveness. This was achieved with work led by Professor David White. Hearts that were transplanted into monkeys worked successfully in the short term, but there was great concern regarding the release of prion-related diseases from the pig cells as a result of immunosuppression so the programme was halted.
“We wait to see how this has been modulated in the current programme. In addition, although the early function of the heart is vital, it is the mid- and long-term that matters the most. As yet there is no data on this and we wait with interest to learn how this courageous patient progresses. Perhaps it is far too early to make such an announcement to the world.”
A spokesperson for NHS Blood and Transplant said:
“We are always interested in new research that may allow more patients to benefit from transplant in the future. While transplant operations carried out today are very successful, there are still not enough donor organs to help all those in need.
“We have been watching this particular field of research for many years – the possibility of transplant between animals and humans. However there is still some way to go before transplants of this kind become an everyday reality.
“While researchers and clinicians continue to do our best to improve the chances for transplant patients, we still need everyone to make their organ donation decision and let their family know what they want to happen if organ donation becomes a possibility.”
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