Prospects of xenotransplantation

The complicated story of animal organ transplantation to humans: will it have a happy ending?

Laura Beil, Science News: Will animal-to-human organ transplants overcome their complicated history?

Translated by Maria Tolmacheva, XX2 century

A 57-year-old man from Maryland has been living with a transplanted heart of a genetically modified pig for more than three weeks. His doctor called the operation a "breakthrough surgical intervention" that could help solve the organ shortage crisis. But, from a scientific point of view, it is too early to judge how far this will advance the case.

Using animal organs to treat humans is an idea with a long, dramatic and often frustrating history. According to Joe Leventhal, a surgeon who heads the kidney transplantation program at Northwestern University Feinberg School of Medicine in Chicago, about xenotransplantation, as this promising branch of medicine is called, there is an old saying: "It's literally around the corner. The problem is that it's a very, very, very far corner."

But a series of new experiments, including three experiments with pig kidney transplants to people who are temporarily supported on ventilators, have provided encouraging evidence that it has finally become possible to achieve the goal that has been sought for decades.

The latest operations on humans were carried out after large-scale trials to create genetically modified pig organs that would not be subjected to abrupt rejection, along with further improvement of drugs that suppress the immune system and increase the survival rate of these organs. However, heart surgery in Maryland was a desperate attempt to save lives, and not part of a clinical trial — a carefully designed study that is ultimately necessary in order to show whether pig organs can function in humans, and safely.

One case can provide valuable information about how the body reacts to the organ, says Karen Maschke, bioethicist at the Hastings Center in Harrison, New York, editor of the journal Ethics & Human Research.

"You can find things you didn't expect to find," she says.

But one piece of data does not have the context necessary for conclusions, especially if we are talking about a seriously ill patient and a completely new technology. Without a study comparing several carefully selected patients, it is difficult to know whether one person's experience is typical.

However, the latest wave of pig-to-human organ transplant experiments may help unlock the potential of clinical trials that researchers need. This is the only way to significantly advance science, says cardiac surgeon David Cooper from Massachusetts General Hospital in Boston, who has been studying the idea of xenotransplantation for a long time.

Pork hopes

If clinical trials are ultimately successful, animals can help alleviate the acute shortage of donor organs. In the United States alone, out of 106,000 people waiting for an organ transplant, about 90,000 need a kidney. Many of them will die without waiting for a transplant.

Doctors have already turned to animal organs in bold, attention-grabbing endeavors. The famous Houston heart surgeon Denton Cooley transplanted a sheep's heart in the 1960s in a desperate effort to save a dying man; the man's body quickly rejected the organ.

One of the most high-profile xenotransplantation operations occurred in 1984, when doctors from Loma Linda University Medical Center (Loma Linda University Medical Center in California) in California transplanted a baboon heart to a two-week-old baby born with a fatal heart defect. Baby Fairy, as she was called, lived for 21 days, and her operation caused a lot of controversy. Some medical ethicists have called the operation a "brutal affair" that lacks moral purity. The scientists "hastily retreated back to the laboratory," according to a report published in 1995 in the Journal of the American Medical Association.

During a controversial 1984 heart surgery Stephanie Fairey Beauclerk, known as "baby Fairey", has been replaced by a baboon's heart. The experiment conducted at the Loma Linda University Medical Center in California surprised both the public and doctors. The girl lived for 21 days.

Recently, scientists have focused on pigs, mainly because pig organs are about the same size as those of adults, and these animals are already being grown on an industrial scale. However, the feasibility of this idea was questioned after it was discovered in the 1980s that pig cells were coated with a disaccharide known as alpha-gal (galactose-alpha-1,3-galactose), which causes a strong reaction of the human immune system.

In the 1990s, the development of this field also failed when it turned out that the pig genome contains embedded viruses — fragments of the viral genetic code woven into the genetic instructions of pigs. (This is not just a pig feature; similar viral genes make up about 8 percent of the human genome). These viruses, called endogenous pig retroviruses, do not bother pigs, but can cause problems by suddenly being in the body of another species.

In the early 2000s, researchers reported the creation of genetically modified pigs devoid of alpha-gal, which theoretically made them more compatible with the human immune system than pigs straight from the farm. This message marked the beginning of attempts to breed animals without alpha gala, primarily in the USA, by Revivicor, owned by United Therapeutics, located in Blacksburg, Virginia. Then, in 2020, a giant leap towards the possibility of organ transplantation from pigs to humans was made when the Food and Drug Administration (FDA) The US has approved Revivicor pigs for medical use for the first time.

Xenotransplantation has also received a boost in the form of CRISPR/Cas9 gene editing technology with its remarkable ability to "cut" genes at the discretion of researchers. Using CRISPR, scientists can remove unwanted viral genes from pigs.

In recent experiments, pig kidneys and hearts have been successfully transplanted to baboons. Although baboons died within a few days during the first xenotransplantation attempts, in 2018 researchers reported that transplanted pig hearts continued to beat in the abdominal cavities of two baboons for about six months, which at that time was a record. Other similar experiments have repeated this survival period.

Then, in October 2021, scientists from Langone Health in In New York, they made the transition to humans: during the trials, they transplanted a Revivicor kidney to a person with clinical brain death and observed the organ's work for 54 hours - presumably long enough to detect signs of immediate rejection. Less than two months later, the same team of surgeons repeated the experiment. The third such transplant, conducted by researchers from the University of Alabama (University of Alabama) in Birmingham, this time into the abdominal cavity of a person who, after a motorcycle accident, was temporarily kept alive with a ventilator, was described on January 20 in the American Journal of Transplantation.

None of the kidneys transplanted into people caused immediate immune rejection, and the organs even began to produce urine, doctors said. Given the overwhelming need for kidneys and the trial operations already carried out, most experts predicted that the first modern patient to receive a xenograft would need a kidney.

Then came the unexpected news about David Bennett.

I want to live

Bennett suffered from acute heart failure and was not suitable for a human heart transplant. On New Year's Eve, the FDA gave doctors from the University of Maryland Medical Center permission to transplant a pig heart according to a special protocol, which is sometimes called compassionate use and which allows very sick people to get urgent access to experimental drugs or devices — even when the patient, for example, is not suitable for any drug research, or when a suitable study does not exist. Bennett's new heart was obtained from a genetically modified Revivicor pig.

In a statement released by the hospital, Bennett said he agreed to the experimental surgery because he simply had no options. He was bedridden, and no hospital would offer him a heart transplant, at least in part because he had not followed doctors' recommendations in the past. "Either die or do this transplant,— he said. "I want to live." The eight-hour operation was carried out on January 7.

A little over three weeks later, Bennett continues to recover, says Muhammad Mohiuddin, a surgeon who runs the xenotransplantation heart program at the hospital and was part of the team that performed the operation. Everyday achievements, such as talking to the staff about football, are tiny victories.

David Bennett (pictured with his family in 2019, third from left) has been living with a transplanted heart of a genetically modified pig since January 7, 2022.

"We count all these small victories and hope that this heart will support him further. The heart is so strong that doctors had to reduce its power because it turned out to be too powerful for Bennett's body, weakened by weeks of lying in bed. We put the engine of a brand new Ferrari in a 1960 car," says Mohiuddin.

However, Cooper of Massachusetts General Hospital said he was surprised to learn that the first living patient to receive a pig organ received a heart, not a kidney.

"What will they do if this graft gradually starts to fail? "What is it?" he asks. — I thought there would be a kidney first. Because if it fails — say, rejection occurs that you did not expect, or an infection occurs that you cannot cope with — you can remove the kidney, stop all immunosuppressive therapy and return the patient to dialysis. A heart transplant is not so reversible."

Cooper and surgeon Hidetaka Hara, who worked together in The University of Alabama at Birmingham proposed that the first xenotransplantation be a phased clinical trial with four patients waiting for a kidney. The test should take place as follows: three months after the organ transplant to the first patient, if he has no complications, perform an operation with the second. If these two are doing well, a third pig kidney is transplanted three months later, and a fourth one is transplanted three months after that. The researchers proposed this protocol in September in the journal EBioMedicine.

According to Cooper, it also makes sense to start clinical trials with kidneys because the need for them is much higher. About 83 percent of the transplant waiting list are people who need kidneys; 3 percent need a heart.

That's why eGenesis, based in Cambridge, Massachusetts, has focused its research efforts on kidneys. Mike Curtis, the company's president of research and development, says, "This is the place where need dominates." eGenesis, which breeds pigs with gene modification and immune compatibility, hopes to start clinical trials on six to ten patients with transplanted pig kidneys around 2024.

Mohiuddin says the reason he had heart surgery is simple: he is a heart surgeon and the patient was near death. "My 30-year interest was only in hearts," he says. According to him, his research team has applied to the FDA for permission to conduct clinical trials, but the agency wants to get more complete data on baboons first.

That's not all

If Bennett is discharged from the hospital and goes home, this high-profile event may serve not only to allow him to spend more time with his family: According to Cooper, this could help convince the FDA to give the go-ahead for a larger, scientifically based trial.

If Bennett continues to feel well, then doctors "will be able to conduct a study on several patients [with a heart] over the next few months. And then they'll come back to the FDA and say, "Look, these patients have generally coped. Now we can conduct an appropriate series where we will take patients from our own waiting list and perform a transplant?"

Leventhal has the same hopes for approved clinical trials: "The only way to see if these organs provide meaningful function in the long term in humans in a way that justifies their use is to transplant them to people and observe them for a long time."

However, it is not yet clear whether this will happen within the framework of compassionate use, as was done with Bennett, or within the framework of official research. The FDA's expanded Access provision was designed to help people obtain medications and procedures that they would not be able to obtain under normal conditions.

"Whether it [extended access] should have been used in the case of the organ is an interesting ethical, regulatory and political question," says Maschke, a bioethicist.

"One of the problems associated with the fact that they have gone down this path is that there are probably hundreds of heart disease patients in the country who are not on the waiting list because they are too sick. Some of them may say, "I will never agree to an animal organ." But some may say, "Yes, I would take a pig's heart. I want to do it too. Can you provide me with access?"" — adds Mashke.

But the discovery of these opportunities may complicate the search for volunteers for clinical trials. And in some cases, this can lead to the opposite result. This is exactly what happened in the 1990s, when doctors began offering women with advanced breast cancer huge doses of chemotherapy followed by bone marrow transplantation to restore the destroyed immune system. Thousands of women received experimental treatment as part of expanded access — so many that it was difficult for scientists to find participants for research. And when the scientific tests were finally carried out, the treatment did not show any effectiveness.

That is why there is often a fear that it is not necessary to move too fast, "because we do not want to derail science, science is developing gradually," says Mashke.

At the moment, pig-to-human transplantation has logistical problems that will limit its use. Firstly, such pigs are difficult to get. In addition to a rare genetic pedigree, they must be grown in sterile conditions so that they do not become infected with microbes that can be transmitted to humans. Another possible obstacle: animal rights groups have condemned the idea of using pigs as spare parts for humans as "cruel and dangerous," and society will have to somehow reconcile this position with the urgent medical need.

But first, doctors need to find out if xenotransplantation is possible at all, or everything will fail again.

"We don't know," says Leventhal, "how long and how well these organs will work in patients. The only way to appreciate it is to transplant them."

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