Seventeen people in the United States die every day waiting for an organ transplant. The demand for human organs to help patients of organ failure far exceeds the supply that hospitals receive from donors. As a result, researchers have turned to an alternate solution: xenotransplantation. Xenotransplantation is defined by the Food and Drug Administration (FDA) as being any procedure in which non-human cells, tissues, or organs are used to treat human patients. Xenotransplantation has become more of a focus for researchers due to the ever-growing waiting list for transplants and the extreme shortage of donors. Xenotransplantation also provides a second hope for patients who might never qualify to be on the transplant waitlist, as some medical conditions (such as cancer diagnosis) may cause a patient to be unable to have surgery or take long-term medication, both requirements for transplant patients.
A recent focus has been using organs from pigs. Pig organs are the candidate of choice for xenotransplants as they are similar to human organs in size, anatomy, and physiology, allowing them to work well within the human body. Pigs are also inexpensive to breed and can be raised in relatively large herds in sanitary conditions, which makes immediate transplant surgeries possible for patients with urgent need. Additionally, pigs are different enough from humans that they won’t pass extremely dangerous diseases, such as rabies and West Nile Virus, onto the recipient.
The most common form of xenotransplantation is the replacement of heart valves with ones from pigs, a procedure that has been taking place since the 1960s. However, xenotransplants of complete organs, a much more radical procedure, are growing in number. This is due to recent advances in stem cell and CRISPR technology. (For more information on CRISPR, check out my STEM Feature of the Month from June 2023.) In particular, several types of genetic modifications have been made to improve the utility of pig organs in xenotransplantation.
One of the major issues in organ transplant is the rejection of organs by the patient’s immune system. Transplant rejection occurs when a transplant recipient’s immune system attacks the transplanted organ or tissue as a result of antigens (molecules that signal the presence of a foreign object) present on the transplanted tissue. The host immune system creates antibodies to fight off this target, causing the transplant to fail. To rectify this issue, doctors utilize immunosuppressants, medications that suppress the immune system, to keep the host’s body from attacking the new organ.
Unfortunately, this increases the risk of transplant recipients developing severe infections and diseases. In the case of xenotransplantation, genetic modifications are made in the pig genome to add certain human genes or remove certain pig genes (gene alpha-gal, for instance) to improve compatibility between the organ and the recipient and reduce the chance of patients’ immune systems rejecting the transplanted pig organ.
Another type of genetic modification is the inactivation of viruses present in the pig’s genome, thus lowering the risk of infection in the human recipient upon xenotransplantation. These viruses, called porcine endogenous retroviruses, are present in all pigs and can cause infection in a human recipient.
In the past couple of years, four patients have received organs from genetically modified pigs, including two heart transplants and two kidney transplants. These four patients were all unsuitable for a typical organ transplant, and thus decided to take part in an experiment, hoping that it would lead to the development of treatments which could help many other people. Although all four patients unfortunately died within three months of receiving their organs, they have offered hope for the field of xenotransplantation. For instance, scientists discovered the presence of latent viruses in the grafts of two of these transplants, indicating another factor to be taken into account when modifying the pig genome for transplants. With this strong foundation in xenotransplantation, researchers are planning for complete transplant clinical trials to happen soon. Phase one trials are expected to begin in 2025, offering hope that xenotransplantation may become a standard medical procedure in the future.
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