Xenotransplantation and the future of medicine
Amid surging Covid-19 infections driven primarily by the Omicron variant comes news of the remarkable achievement by United States (US) surgeons who implanted a heart from a genetically modified pig into a 57-year-old recipient, David Bennett, who suffered from ventricular fibrillation (a kind of heart abnormality) and had advanced heart failure. The historic procedure performed on January 7 at the University of Maryland School of Medicine (UMSOM) is a major milestone in the field of xenotransplantation — the exchange of organs among species, chiefly from pigs to humans.
According to Muhammad Mohiuddin, chief of the cardiac transplantation programme at UMSOM, Bennett urgently needed a transplant and was declared ineligible for a human organ; therefore, a decision was taken to try a xenograft from a pig. The transplant team obtained compassionate use authorisation from the US Food and Drug Administration, and the organ was made available by Revivicor, a US-based biotech company. The team already had years of experience with xenografting pig hearts into baboons with a fair degree of success and were well suited to try out the exercise in humans. In 2016, they had reported that a pig heart was kept functioning in a baboon for three years.
Xenotransplantation uses animals as a source of organs for replacement therapy in humans whose own natural organs have reached the end-stage of function. Since there is always a big gap between those needing a functioning organ (chiefly heart, kidney, liver, lungs and pancreas) and the availability of the same from humans, alternative sources of donor organs have long been an unmet need.
The most significant issue with using animals as a source of transplanted organs for humans is the spontaneous immunological rejection due to the occurrence of specific antibodies produced by the human host against certain sugars present on the surface of pig cells. These get recognised as foreign, leading to “hyperacute rejection” in which the recipient begins to reject the organ as soon as it is implanted.
In terms of evolution, pigs and humans are quite divergent, and the major challenges are both immunological and pathophysiological. The fundamental difference is while the human system expresses the well-known ABH blood group antigens, the pig’s vascular endothelium expresses a unique protein called Galactose oligosaccharide or Gala1 or simply Gal. Humans are a natural knockout for this protein that quickly triggers anti-Gal antibodies against the transplanted organ.
In recent years, significant progress has been made to genetically modify the developing piglets, rendering their tissues and organs resistant to human immune response. The creation of “Dolly” the sheep as the first cloned animal in 1996 provided the much-needed stimulus to do so. In their effort to create a clinical-grade facility for raising engineered pigs, Revivicor scientists produced genetic changes in a total of 10 genes: Three in the pig and seven in humans. They successfully knocked out three genes from pigs that enable the enzymes to synthesise Gal sugars, and thus minimise the formation of anti-Gal antibodies.
Simultaneously, they engineered six genes in the human host with the aim of decreasing inflammation (two genes) and blood coagulation, thereby preventing blood vessel damage (two genes) and also silenced another two regulatory proteins that promote antibody response. The final step was something that they had learnt during baboon experimentation and this included knocking out the gene for a growth hormone that ensured that the pig organ remained matched in size with the patient’s chest and did not outgrow upon grafting.
Two weeks have passed and the pig heart is still functioning in Bennett, making the surgical feat a remarkable achievement. However, the question of whether we have reached the stage for regular use of pig organs for transplantation in humans is still open. More science is needed to determine which modifications are critical and perhaps inescapable. It is also not clear whether different modifications may be required for different organs. For example, could there be differences for kidney versus heart and likewise for other organs? Another major barrier with xenotransplantation is the possibility of endogenous retroviruses carried by pigs and these could create safety concerns.
The other question relates to the type and extent of immunosuppression needed for the recipient because of the possibility of excessive anti-organ-specific antibodies generated in the host. While the standard immunosuppressive regimens may or may not be effective, it would be necessary to investigate immunological tools to suppress the activity of antibody-forming B-cells and inhibit their cross-talk with helper T-cells that effectively coordinate the host immune response.
While there are several issues associated with xenotransplantation, both for the recipient and society at large, the first really successful pig-to-human heart transplant achieved through the meticulous use of the tools of genetic engineering represents a significant step forward in solving the problem of organ shortage, bringing hope to those in desperate need of a transplant.