A xenograft is the transplant of living cells, tissues, or organs from one species to another. This process, also called xenotransplantation, is explored as a solution to the worldwide shortage of human organs. For many patients with end-stage organ failure, a transplant is the only effective treatment. Xenotransplantation offers a way to increase the supply of organs and save lives for individuals on long waiting lists.
Sources and Types of Xenografts
Pigs are the most common source animal for xenografts intended for human use. Their organs, such as the heart and kidneys, are anatomically and physiologically similar to those of humans in size and function. Pigs also have high breeding rates and large litters, making them a practical source. Compared to non-human primates, pigs pose a lower risk of transmitting diseases to people.
Xenografts come in several forms, depending on the medical need. Cellular grafts involve transplanting specific types of cells, such as pancreatic islet cells to treat diabetes. Tissue grafts include skin grafts and heart valves, while the most complex type is the whole-organ xenograft, which involves transplanting entire organs like hearts or kidneys.
Applications in Research and Medicine
In clinical settings, xenografts have been used for many years. Porcine (pig) heart valves are a well-established medical device used to replace damaged human heart valves. Porcine skin grafts serve as temporary biological dressings for severe burn victims, protecting the wound from infection and fluid loss while the patient’s own skin regenerates or a human graft is available.
A significant application is in cancer research through Patient-Derived Xenograft (PDX) models. In a PDX model, a piece of a patient’s tumor is surgically removed and implanted into an immunodeficient mouse. This allows the human tumor to grow in the mouse, preserving the original tumor’s cellular and genetic characteristics.
These “avatar” mice become stand-ins for the patient, allowing researchers to test the effectiveness of various anti-cancer drugs on the tumor. The response of the PDX model to a therapy often correlates with how the patient’s tumor will respond, making it a powerful tool for personalized medicine. These models are used to study drug resistance and discover new biomarkers.
The Immune System Response to Xenografts
The primary obstacle in xenotransplantation is the recipient’s immune system, which recognizes the animal organ as foreign and mounts a powerful attack. The most immediate form is hyperacute rejection, which can destroy the organ within minutes to hours. This response is mediated by pre-existing antibodies in the human recipient that target antigens on the donor’s cells.
A primary target for these antibodies is a sugar molecule called galactose-alpha-1,3-galactose, or alpha-gal. This molecule is abundant on pig cells but is not found in humans. The human immune system identifies the alpha-gal epitope as a threat, initiating a cascade that leads to blood clotting, inflammation, and rapid failure of the transplanted organ.
If hyperacute rejection is avoided, the transplant still faces acute rejection over days to weeks, which involves T-cells attacking the foreign tissue. Over the long term, chronic rejection can occur, where a slow inflammatory response causes gradual damage to the organ, eventually leading to its failure.
Overcoming Rejection Through Genetic Engineering
To make xenotransplantation a reality, scientists use advanced genetic engineering tools to modify the source animal’s genome. The most prominent tool is CRISPR-Cas9, which acts like “molecular scissors” to precisely edit an organism’s DNA. This technology allows for multiple, efficient genetic modifications in pigs.
A primary step is “knocking out,” or inactivating, the genes responsible for producing molecules that trigger immune rejection. This includes the gene that produces the alpha-gal sugar molecule, thereby eliminating the main target of hyperacute rejection.
In addition to removing problematic pig genes, scientists “knock in” human genes into the pig’s genome. These added genes can produce human proteins that help the organ evade the recipient’s immune system or prevent blood clots. Combining multiple gene knockouts and knock-ins creates pigs with organs that are significantly less likely to be rejected.