David Talbot
The use of xenotransplantation goes back a long way. Blood transfusions from animals were tried in the 1600’s, which was probably better than the alternatives (beer, milk etc.) and survival probably depended on whether or not the transfusion was a small amount or not! John and William Hunter were brothers and anatomists and worked in London and Glasgow. John was interested amongst other things in teeth transplants as the wealthy wanted to replace their teeth that were lost. These teeth usually came from cash-strapped individuals whose teeth were removed with no anaesthetic. The teeth will have acted as a crown and were presumably avascular. An idea was evolved that the tooth would be improved by keeping it “alive” in something before being implanted. John Hunter then did a series of experiments where human teeth and teeth from other species were implanted into the comb of a cockerel. Which, according to Hunter, worked but infrequently. This was probably less to do with the fact that it was a xenotransplant but that it wasn’t a vascularised graft. The blood vessels that were seen in the tooth sometime later could have been cockerel, but they would have just been growing into a “space”.
Skin and cornea were grafted from different animals onto humans but these probably acted more as a dressing than a graft. Serge Voronoff a Russian doctor working in Paris in the 1920’s became obsessed with declining male libido with age, so started transplanting slices of either monkey or ram testicles into human male testicles. This practice spread and probably upwards of 500 men had such transplants and many reported a distinct improvement! Some of this was probably a placebo affect, however the testicle is a “special” immunological site which means that the body has a tolerance of non-self genetic tissue so it’s not completely impossible that this worked, probably by the production of presumably monkey/sheep testosterone.
Vascularised grafts have been tried intermittently since then and have universally failed. The most impressive series was by Thomas Starzl who was working in Denver in the 1960’s who transplanted a series of 6 baboon kidneys into humans, all of which failed. Starzl was always moving forwards but must have felt guilty about this series to the extent that he “rectified” it by going to the local prison and asking for volunteers to donate their kidneys for the hope of a commuted sentence!
Starzl received many accolades for his pioneering development of human liver transplants. It may be because of this that he had a desire to come up with something original at the award ceremonies such that in 1992 when he received a life time achievement award which included the reading of a letter from Nancy Reagan which finished with “God bless Tom Starzl’s hands”! At this meeting he announced that he had revisited the baboon/human xenotransplant. In this case it was the liver, the recipient being someone with hepatitis, HIV and cirrhosis who, not surprisingly, had been turned down for liver transplant by several other centres.
Liver xenotransplants had been attempted from other animals before with limited success. George Abouna was an interesting character who originally trained in Newcastle and became interested in cross-circulation where the patient’s blood is passed through the liver from 2 another species and then back to the host. The idea for this being to detoxify the blood of the patient with liver failure.
Ironically the liver was the one organ that seemed to be successful for xenotransplantation because the primary reason for graft failure in the xenotransplant is complement activation. This occurs via the classical pathway where first there is antibody binding to the target and then the proximity of the Fc portion of the antibody binds and activates complement. In addition the alternative and lectin pathways exist which are the more primitive mechanisms that don’t require antibodies and the complement is activated by bacterial proteins/sugars if there is an absence of host complement control mechanisms. The complement punctures a hole in the cell membrane thereby killing the cell, in addition platelets clump and intravascular coagulation occurs shutting off the blood supply to the organ. In patients with liver failure there is a reduction of serum protein which includes the host’s complement proteins and therefore the normal hyperacute rejection, which includes intravascular thrombosis and infarction of the organ within minutes of connecting the blood supply to a blood supply of a xenotransplant, does not occur.
As a consequence, the recipient of the baboon liver survived for a while (baboon having been chosen because it is a phylogenetical species which is closer to human). The patient ran into problems with their bile duct a few weeks after the transplant and an ERCP was planned which first involved correcting his clotting factors which included being given fresh frozen plasma which presumably was a new source of human complement and the patient died shortly after this. I was at the meeting when this case was presented and overheard a surgeon discussing the case over coffee after commenting that these patients (HIV and hepatitis) were great because they would consent to anything as they were so desperate!
The Cambridge group (White/Wallwork) before this had been working on inserting human complement control proteins (decay-accelerating factor and membrane cofactor protein) onto the cell surface of pig ova and then breed them in such a way that they obtained homozygous pigs and then used a surrogate baboon recipient instead of man and transplanted the heart of the pig into the abdomen of the baboon. The heart then continued to work although the animal wasn’t dependent on its function for up to 60 days. The failure of the heart was thought to be due to insufficient immunosuppression, although they did get through the hyperacute rejection problem. When the experiment was switched to orthotopic placement of the heart (native heart removed) and the immunosuppression beefed up the animals didn’t survive as long as the original 60 days.
This approach was copied by the Roslin Institute (Edinburgh) which repeated the human MCP and DAF proteins into the pig cell walls but combined it with elimination of alfa-gal which is one of the main glycoprotein identifiers of porcine cells. The results weren’t reported, so most would conclude that this was still unsuccessful.
Shortly after this there was an embargo on further experimentation on xenotransplantation because of the concern of zoonoses. Claus Hammer (Grosshardern) trained as a veterinary surgeon and became a general surgeon with the express purpose of developing xenotransplantation. He spent many years pursuing this and in a concluding lecture stated to 3 make xenotransplant possible “we needed to outwit 180 million years of evolution” (the separation of the pig and primate lines).
This point has been re-affirmed by a publication by the Hastings group in response to the recent use of a pig heart transplant into man. It does seem to be extraordinary that xenotransplantation research was stopped because of concern about zoonoses and now we are hopefully just at the end of a worldwide pandemic which was thought to have arisen because of a virus from a bat contracted because of the close proximity of bat and human in a market in China.
To have allowed this transplant to go ahead seems highly unethical. This is particularly so when you think of the motives that drove Starzl. In this recent case the patient was judged not to be suitable for a mechanical device because of “abnormal electrical activity” within the heart. In addition he was judged not to be suitable for a human heart transplant because he was “too sick”. In addition there was a history of poor compliance to medication and he had spent 10 years in prison for stabbing and paralysing a man who later died. There are echoes to me of a man desperate for a transplant who has been turned down for a human heart and then accepting this xenotransplant because there wasn’t an alternative. The pig had been genetically manipulated so it’s likely to at least have had human complement control proteins inserted with possible deletion of other porcine glycoproteins. In view of the 180 million year difference the genetically modified animal would be unlikely to have more than a few differences corrected. So my prediction would be that the recipient will be re-transplanted with a human heart or a mechanical assist device will be inserted or he will die. Sadly I think it also demonstrates what a rotten bunch some surgeons are!
DT 2/2/2022