How does a pig save humans? Xenotransplantation has moved from the laboratory to the clinic

Recently, the world’s first pig heart transplant to a human was successful, which caused a stir in the medical community.

On January 12, local time, the patient, 57-year-old David Bennett (David Bennett), successfully removed the extracorporeal membrane oxygenation device (ECMO).

He was treated at the University of Maryland Medical Center (UMMC) for end-stage heart failure, and had been on a machine for 45 days.

Historic pig heart recipient was convicted in 1988 stabbing

According to reports, since the completion of the transplant operation on January 7, Bennett has been in stable condition without hyperacute immune rejection, and is now able to breathe on his own and speak in a low voice.

“There is a lot of discussion about this in China, but not many physicians are familiar with xenotransplantation. They think it is exciting and far from clinical.” Chief Expert of the Third Xiangya Hospital of Central South University (hereinafter referred to as the Third Xiangya Hospital), Hunan Provincial Xenotransplantation Project Wang Wei, director of the Technology Research Center, told the “medical community” that the UMMC event represents that the door to xenotransplantation has been further opened, and key technical issues such as xenotransplantation safety, functional consistency and immune rejection have been resolved. All that remains is to examine the medium- and long-term effects.

In the past few decades, the global medical community has been exploring the possibility of xenotransplantation, including the transplantation of organs, tissues, cells, etc. from animals into humans.

Historic pig heart recipient was convicted in 1988 stabbing

Islets are the first successful xenotransplantation. Wang Wei told the “medical community” that, unlike solid organs such as the heart and kidneys, there is no hyperacute rejection after xenotransplantation of pancreatic islets.

For most organs, hyperacute rejection is the species’ natural defense mechanism to maintain germline continuity.

Pig vascular endothelial cells, for example, have a glycoprotein molecule called alpha-gal. In primates, including humans, there is an antibody that attacks the glycoprotein molecule, causing widespread thrombosis and rapid loss of function and death of the transplanted organ.

Studies have shown that hyperacute rejection generally occurs within 48 hours after surgery. In the past, the academic community has studied some drugs, trying to control and deal with this situation, but have not been successful.

In this pig heart transplantation, no hyperacute immune response occurred nearly 1 week after the operation. Wang Wei believes that we may have effectively removed the huge barrier to xenotransplantation.

Pig heart transplant recipient stabbed a man seven times in 1988 leaving  him wheelchair-bound | Daily Mail Online

Mature gene editing technology is the key. “We can knock out specific genes so that the lining of blood vessels in pigs doesn’t make the alpha-gal glycoprotein molecule.”

At the end of the last century, the theory of gene editing took shape. Since then, the scientific community has done a lot of animal experiments, including the National Institutes of Health researchers anastomosing the heart of a genetically modified pig with a branch of the aorta of an experimental baboon. This “partially connected” heart survived for more than 900 days.

In animal experiments of orthotopic heart transplantation, the hearts of transgenic pigs can completely replace the hearts of baboons and survive for nearly one year.

Kidney transplantation in transgenic pigs has also achieved good results. In October 2021, a transgenic pig kidney was transplanted to a brain-dead patient by the Transplant Institute of New York University Langone Medical Center. No hyperacute rejection was observed for 54 hours and normal urinary function was exhibited.

U.S. man recovering after 'breakthrough' pig-heart transplant | The Japan  Times

This pig heart transplant is a step forward on the shoulders of the predecessors: the recipient is a conscious person.

Patients knew that xenotransplantation was their only hope of survival, and the surgery was granted an “emergency authorization” by the U.S. Food and Drug Administration (FDA) under expanded access (compassionate use) provisions.

The results remain inconclusive, Arthur L. Caplan, chair of the bioethics department at New York University Langone Medical Center, said in an interview. “Bennett remains at risk for immune rejection and viral infection in the coming weeks.”

Wang Wei said that judging whether the operation of xenotransplantation to humans is “successful” depends on two major indicators.

First, on the basis of overcoming hyperacute rejection, whether acute rejection (including acute rejection mediated by T cells) and chronic rejection of acquired immunity can be controlled to achieve long-term survival. This can occur in the weeks, months or years following a clinical transplant, or lead to necrosis of the transplanted organ.

Recipient of pig heart continues to recover after world-first transplant

Second, to test whether the pig heart can completely replace the human heart in function and withstand the daily activities of the human body.

Observing whether the human neuro-humoral regulation system can regain control of the transplanted heart is one of the secondary indicators for evaluation. Under the action of the human body’s neuro-humoral regulatory factors, the heart rate increases during exercise and agitation, and decreases during sleep. However, the transplanted heart is autonomously controlled by the myocardium, which will break away from the above-mentioned regulatory system to a certain extent.

According to the International Xenotransplantation Steering Committee, the goal of xenotransplantation clinical trials is to “permanently replace the original organ, and more than 50% of recipients must survive longer than 6 months”.

From this point of view, the heart xenotransplantation technology has achieved a revolutionary breakthrough, but it is still on the road to maturity. Whether it can further benefit all living beings still needs to be observed and studied.