American David Bennett now lives with a pig’s heart. Surgeons accomplished the feat of transplanting a heart organ from a genetically modified pig on Friday, January 7, in Baltimore (United States). This world premiere, unveiled Monday by the University of Maryland School of Medicine (article in English), attests to the immense progress made in the field of xenografts, these transplants of animal organs in humans. The 57-year-old patient’s days were numbered, and he was declared ineligible for a human transplant. “It’s pretty hit and miss, but it was my last option”, he summed up on the eve of his operation, after remaining connected to a machine for several months, as a reprieve.
This medical feat has not yet given rise to a scientific publication. But on the university’s website, researcher Muhammad M. Mohiuddin, co-director of the program, celebrated “the culmination of years of very complicated research to perfect this technique in animals, with survival times that exceeded nine months “. In the past, this world specialist in xenografts had also succeeded in obtaining three years of survival for a porcine heart by transplanting it into the abdomen of a primate, for experimental purposes and in addition to the functional heart.
The history of xenografts begins in the 1980s. In 1984, in California, the infant “Baby Fae” had received a primate heart transplant, before dying the following month. Over time, research has focused on pig organs, for ethical reasons and to limit the risks of viral transmission. In 2016, a South Korean team transplanted a pig’s heart to a monkey, which had survived about 50 days. Two years later, a baboon’s survival time had reached six months after a similar procedure, according to work published in Nature (article in English).
“Transfer to humans was a long overdue hope, but there were still many problems due to the mismatch of species.”, notes Gilles Blancho, director of the Institute of urology-nephrology transplantation (ITUN) at the Nantes University Hospital and president of the French-speaking society of transplantation. Until there, “there was not enough prolonged survival of porcine organs in a primate situation to take the risk of going to humans”.
This great first, above all, is a feat of immunology. Certainly, pigs are ideal organ donors due to their size, rapid growth and litters, which have lots of young. But in order to avoid rejections, the risk of which is increased between two different species, it was necessary to make numerous genetic modifications by combining two approaches. The first is to “make disappear [chez le porc] the genes which encode “ molecules and which induce an immune response in the recipient, explains Gilles Blancho. The second aims to endow the porcine organ with a capacity to block the human immune response.
This work was carried out by the American company Revivicor, which had also supplied a pig kidney that surgeons had successfully connected to the blood vessels of a brain-dead patient in New York, in October. “Three genes, responsible for the rapid rejection of pig organs by human antibodies, have been deactivated in the donor pig”, specifies the University of Maryland. Furthermore, “six human genes responsible for immune acceptance of the pig heart have been inserted into the genome”.
But there was still one detail to be settled. Indeed, in order for the size of the heart to correspond to the human thorax, it is generally necessary to remove the organ from “a teenage pig, probably still able to grow”, explains Gilles Blancho. But the heart is then likely to continue to grow, with the risk “to find yourself cramped and no longer be able to function normally”. Thanks to their “genetic scissors” (technique known as “Crispr”), the researchers therefore eliminated a gene to prevent “excessive growth of pig heart tissue”. That is to say ten modifications in total. “It’s a significant number, comments Gilles Blancho. They are very sophisticated new generation animals. “
The transplanted porcine heart had been stored in a machine before the operation, and the team used an investigational new drug from Kiniksa Pharmaceuticals, in addition to the usual anti-rejection drugs, to suppress the immune system and prevent the human body rejects the organ. “The heart could have been rejected immediately and never function “, underlines Patrick Nataf, chef of the cardiac surgery department at Bichat hospital, in Paris. “The good hope is that this team managed to avoid hyperacute rejection [pendant les premiers instants]. It’s already an immunological feat. “ From now on, the teams of Maryland will have to watch night and day at the bedside of David Bennett.
Cardiologists, first of all, will check that the organ is functioning properly, monitoring the usual parameters of heart function. “We must also ensure that the patient does not reject this organ, continues Gilles Blancho, however the human immune system is very strongly armed to reject all that is animal. “ It is therefore up to immunologists to find a sufficiently balanced treatment. They will have to block this immune response without setting the patient’s defenses to zero, “so that he can defend himself against viruses and prevent him from developing cancer”.
“A survival of several months, in this patient, will be considered as a positive element. In this pioneering research, you never achieve success straight away.”
Gilles Blancho, director of the Institute of urology-nephrology transplantation (ITUN) at the Nantes University Hospitalto franceinfo
Finally, the teams will have to ensure that no pathogens of porcine origin have been transmitted to David Bennett. Because it is also one of the major challenges of these xenotransplantations. “Research should not be focused only on genetics and immunology, but also on infectious problems, emphasizes Patrick Nataf. Using animal organs could lead to infections transmitted from animals to humans, zoonoses. “ But the surgeon also insists on the ethical and societal dimension of this type of intervention.
“We are happy with these innovations and these medical prowess, but you have to be very suspicious of all aspects of these xenotransplants.”
Patrick Nataf, head of the cardiac surgery department at Bichat hospital (Paris)to franceinfo
This global event comes as Patrick Nataf has been working for several weeks on a project for a university hospital institute (IHU) specializing in organ transplants. This project, currently under discussion between the North Campus of Paris, Inserm and the AP-HP, should also make it possible to launch work related to these interventions of a new kind. “The problems linked to xenotransplantation must be brought together by teams of multidisciplinary researchers, explains the surgeon, including with a contribution from the human sciences. The societal aspect is part of the scientific aspect. “
This scientific event, described as “major” by the professor, however, opens up immense perspectives. Organ shortages, in fact, are a global problem today. In France, where 400 heart transplants are performed each year, one in two applicants is left out due to a lack of available grafts. Pig hearts, however, are not yet a short-term solution. David Bennett’s case was hopeless (and still is, despite the transplant) and this type of intervention “will first be addressed to a few dozen people“, estimates Gilles Blancho. “It will take prolonged survival, of several years, to consider this a success.”
This intervention, however, represents years of work. “We’ve been talking about it for twenty-five years, and here we are.” Well almost, because France seems relegated to the role of spectator. “In Nantes, ne were one of the first centers to transplant transgenic animals in the world, in 1995, with kidney transplants from transgenic pigs in experimental primate models. But European funding has stopped. ” Apart from a center based in Munich, the heart of research now beats in the United States, Asia and Australia.