How is a Pig's Heart Made Compatible with Humans?

 by Hamish Orr

Recently, doctors at the University of Maryland Medical Center transplanted a pig heart into a human in the world's first successful xenotransplantation. The genetically modified pig heart, which came from biotech company Revivicor. The pig heart was used as a last resort as the patient was not suitable for a human heart and doctors were running out of options, so got authorisation from the FDA for “compassionate use” as an experimental treatment.

In order to create a pig heart that is suitable for transplant, a number of genes had to be edited to ensure that the heart would survive as long as possible in the recipient, without being rejected. Xenotransplantation carries a high risk of rejection as the pig cells are identified as foreign due to certain sugars on the surface of pig cells. In order to effectively transplant a pig heart, many of the antibody binding sites would need to be removed. In order to remove the sugars, there were three genes coding for enzymes removed. The enzymes removed are those required for synthesising the sugars.

In addition to removing the genes allowing the production of the cell surface sugar, six genetic changes involving the addition of human genes were added. To make the pig heart more human-like, these changes included, two anti-inflammatory genes, two genes involved in normal blood coagulation and to prevent blood vessel damage and two regulatory proteins to reduce the antibody responses.

 In addition to these changes to the heart, the patient will need to take regular very strong experimental immunosuppressants. The experimental immunosuppressant (called KPL-404) is different from standard immunosuppressants in that it binds to a cellular receptor known as CD40. It’s method of action is inhibiting the activity of B-Cells, responsible for the production of antibodies and preventing the cross talk with T cells which coordinate the immune response. Although there are many altered genes, this immunosuppressant, is the game changer that was needed, says researcher Muhammad Mohiuddin. In more detail the immunosuppressant inhibits B cell response by inhibiting the CD40-CD40L co-stimulatory pathway, inhibiting B cell response and proliferation. This is important because the B cells produced would likely be able to attack the heart as if it was a foreign object in the body.

Before transplant the pig's heart, after its harvest, requires perfusion in a circulatining mixture of water, hormones (such as adrenaline and cortisol) and dissolved cocaine, (the exact reason why cocaine is beneficial is unknown).

The use of pig hearts in xenotransplantation could be the much needed solution to the lack of donor human hearts available for the larger number of people in need of a new heart. Although there is still much more research required, the future almost certainly lies with xenotransplantation for not only hearts but other organs in short supply.