Xenotransplantation: Are pigs the future of organ transplants?

The frontiers of organ transplantation have been pushed further than ever before. The first organs removed from genetically engineered pigs were transplanted into humans, and the recipient of the first pig heart survived two months.

So how close are we to using pigs for an unlimited supply of organs to solve global shortages?

Silence falls over the operating room and the tension builds until it’s almost a physical presence in the room.

Surgeons just connected a pig kidney to a human body. The clamps have been released and human blood is now flowing into the pig organ.

“You could have heard a pin drop,” says transplant surgeon Dr. Jayme Locke.

Success or failure is decided in moments and there is only one question on everyone’s mind: “Pink or black?”

When the body unleashes a horrific attack on the foreign organ, holes are ripped through every cell of the pig’s tissue and the organ clumps together from the inside out. It becomes blotchy, then blue, and then completely black within minutes.

If “hyperacute rejection” is avoided, the organ will turn pink from the flow of blood and oxygen.

“It turned out beautiful and pink… the sense of relief, the sense of joy and hope just filled the room. We might have given a high-five too,” said Dr. Locke from the University of Alabama at Birmingham in the USA.

This operation was just one of several medical breakthroughs that have sparked renewed interest in the field of xenotransplantation.

The use of animal organs in the human body is an ancient idea, ranging from “lust for life” testicular implants for chimpanzees to replacement kidneys and hearts taken from our primate relatives. The latter often ended soon thereafter in death. The problem is that our immune system treats the transplanted organ like an infection and attacks it.

Today the focus is on pigs because their organs are about the right size and we have centuries of experience keeping them.

But the challenge of hyperacute rejection — keeping organs pink, not black — is the same. You can’t just go to the farm, choose a pig and transplant its organs. It took major advances in genetic engineering to modify pigs’ DNA to make their organs more compatible with our immune system.

In recent kidney and heart transplants, organs have been harvested from the specially designed ’10 gene pig’.

It has a genetic modification to prevent donated organs from reacting to human growth hormone and going out of control.

Another major change removes a sugary molecule called alpha-gal that sticks to the surface of pig cells and acts like a gigantic blinking neon sign, marking the tissue as absolutely foreign.

One wing of our immune system, called the complement system, is constantly patrolling the body looking for alpha-gal. Therefore, organs can be rejected and killed immediately after transplantation.

Two more “neon signs” have been genetically removed and six human ones added, which act like a camouflage net over the pig cells to hide them from the immune system.

The resulting 10-gene pigs are then raised under sterile conditions to be suitable for transplantation.

The pair of pig kidneys were transplanted into Jim Parsons’ brain-dead body in September 2021.

He wanted to be an organ donor when he died and when his kidneys were donated, pig kidneys were transplanted with his family’s permission.

dr Locke describes the moment one of the kidneys started producing urine as “remarkable” and believes that xenotransplantation “can really change people’s lives and, to be honest, save their lives.” She expects to start clinical trials later this year.

This surgery was a three-day experiment, but in the meantime, the University of Maryland Medical Center surgeons wanted to take it a step further.

Her patient, David Bennett, 57, had severe heart failure. He was deemed unsuitable for a human heart transplant and was kept alive by an Ecmo machine that supported his heart and lungs.

Mr Bennett described having a pig’s heart as a “shot in the dark”.

A 10-gene pig was rushed to the hospital and on January 7th its heart was placed in David Bennett’s chest. The operation was tricky because Mr. Bennett’s ailing heart was swollen, so connecting the blood vessels to the smaller pig’s heart was a challenge.

Again there was the jittery moment to see if the heart would eject quickly, but it beat and stayed pink. dr Muhammad Mohiuddin, the hospital’s head of cardiac xenotransplantation, said he did not expect to see it “in my lifetime”.

When I spoke to him on the month-long anniversary of the operation, he said there was no sign of the organ being rejected, but Mr Bennett was still frail.

“We installed a new Ferrari engine in a car from the 1960s. The engine works great but the rest of the body needs some adjustments,” he said.

But Mr. Bennett died two months after the transplant. The cause and thus the effects on xenotransplantation are still uncertain.

Mr. Bennett was very frail before the operation and it is possible that even the new heart was not enough.

No signs of organ rejection have been reported, but if detailed analysis of the heart shows signs that the immune system is attacking it, the 10-gene pig may need further modifications to make its organs suitable for the human body.

Alternatively, it could boil down to anatomy, and pig hearts may not be up to the task in a human body. Our hearts have to fight gravity much harder than a pig’s because we walk on two legs instead of four.

Chris Denning, a professor of stem cell biology at the University of Nottingham, said overcoming hyperacute rejection meant the heart transplant would be considered a “success”. He said that when it comes to frailty, xenotransplantation “may be successful in the future,” but when it comes to anatomy, it “can potentially be a showstopper.”

The hospital plans to continue conducting clinical trials.

According to Prof. John Wallwork, one of the UK’s foremost transplant surgeons, pig hearts don’t have to be as good as a human heart to still save countless lives. Many people die waiting for a transplant.

Prof Wallwork, who performed the world’s first heart-lung-liver transplant and was an early pioneer of xenotransplantation, says it’s better to give 1,000 people with a pig heart a 70% chance of survival than 100 people an 85% chance chance with a human heart .

“So if it’s not quite as good as a human transplant, then we’ve still done more good than not treating the 1,000 patients,” he said.

Xenotransplantation has always felt like the next big thing in transplant medicine. There’s no doubt that a number of landmark surgeries have been undertaken, but only more research will tell us if the field — and its big dreams — will ever come of age.

dr Locke added, “Our goal would be for a pig edited with 10 genes to be able to save a patient with kidney failure, a patient with liver failure, a patient with heart failure and a patient with end-stage lung disease.

“That would be a remarkable achievement and I truly believe that we will be there in my lifetime.”

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