▎ WuXi AppTec content team editor
"Are you sure I can't wait for a human heart?" On the way to the operating room, David Bennett asked his doctor. The doctor took his words as a joke to ease the atmosphere, because David knew he would soon be receiving a heart transplant. What was about to be put into his chest was a heart from a pig.
A pig heart is about to be transplanted into David's body (Credit: Authorized by the University of Maryland; University of Maryland School of Medicine)
In a few weeks, David will be the first person to receive a pig heart transplant and appear on the front page of major media outlets around the world. Two months later, the news of David's death will once again lead to discussions about science, technology, and even ethics. Today, renowned science journalist Antonio Regalado published a lengthy article in the MIT Technology Review that added more details to David's death: Some organ transplant experts said the tragedy may have stemmed from an overlooked factor — a virus lurking in David's pig heart.
The first human to receive a pig heart transplant
When David was taken to the hospital last year, his physical condition was already very unsatisfactory. Severe heart failure left him on the brink of death, and a heart transplant was his only chance. But hearts are scarce in the United States, and every patient who needs a transplant needs to go through a series of rigorous reviews to ensure that every transplanted heart brings maximum well-being. David, who originally had a medical record of not following the doctor's advice, was excluded from the list of heart transplants.
Desperate, his attending physician, Bartley Griffith, proposed to David to participate in a study he led: transplanting a pig's heart into his chest. Pig hearts are about the same size as hearts and have long been seen as a potential source of human transplant organs. Of course, the use of pig hearts for human transplantation also requires solving many technical and ethical problems, which is exactly what Bartley's research wants to solve.
David agreed with Bartley's suggestion. After submitting the application to the US FDA, on Chinese New Year's Eve Night in 2021, the FDA sent an email back to Bartley and approved the request for transplantation of pig hearts. In the FDA's view, patients are experiencing irreversible heart failure. As long as the patient and the ethics committee agree, a transplant can be prepared. This belongs to the FDA's "compassionate use" authorization, which is the last straw for patients who are not available for drugs, which is a bit of a dead horse as a live horse doctor.
David Bennett (right) and Dr. Bartley Griffiths (left), who was in charge of the transplant (Credit: Authorized by the University of Maryland; University of Maryland School of Medicine)
But this time, the gambling surgery was a success. The pig heart pumped blood vigorously through David's body, sending oxygen throughout his body. Within days of the operation, David was able to sit up on the bed. Bartley said the pig's heart beat like a rock star, which was incredible. "The person you're chatting with has a pig heart. It's literally a pig's heart. Bartley said. In his opinion, this operation was a complete miracle.
However, about 40 days after the operation, David's condition suddenly deteriorated. Two months after the operation, David eventually passed away. In an official press release in March, the spokesman said no clear cause of the death had been found. But now, scientists have found a potential answer — the porcine cytomegalovirus.
Genetically modified with porcine viruses
The findings were made public at a web conference of the American Transplant Society in April, by Dr. Bartley himself. From past experience, pig viruses are not the biggest challenge of xenotransplantation - to transplant animal organs into the human body, the first problem to overcome is the human immune response. In David's transplant, the heart of the pig came from a genetically modified pig. The scientists removed some of the pig's genes and added other ingredients to make it look as human organs as possible so that they wouldn't be attacked by the immune system.
In subsequent studies, scientists transplanted organs from genetically modified pigs into baboons to understand their transplant potential in primates. Subsequently, three transplant teams from the United States conducted human studies in 2021. Doctors at New York University and the University of Alabama first transplanted pig kidneys into brain-dead patients, showing no short-term immune rejection. Subsequently, scientists at the University of Maryland went one step further and completed the transplantation of pig hearts in January this year, which is exactly what Bartley did.
▲ Pig hearts that are about to be removed from the pig's body (Image source: Authorized use by the University of Maryland; UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE)
As mentioned above, David's recovery was good after the pig heart transplant, and the doctors constantly checked his physical condition to make sure everything was foolproof. The tests included an advanced sequencing technique that could trace the pig's genes in David's blood. If the fragments of the pig gene in the blood rise sharply, it indicates the failure of the experiment, because it means that the cells of the pig heart are constantly dying.
The test also includes another technique that looks for traces of pathogens such as bacteria and viruses in the bloodstream. This is because patients who receive transplants need to take medication to suppress immunity in order to prevent their own immune system from attacking the pig heart. Once immunity is suppressed, other pathogens may take advantage of the void and cause infection.
It was in the second test that doctors found traces of porcine CMV. At first, the detected level of the virus was very low, which also made the doctors think that it was a misunderstanding? After all, in theory, this pig heart obtained from a biotechnology company should not have any pathogens.
However, 6 weeks after the operation, David's body suddenly developed abnormalities. When he got up that day, he started to have a fever and had trouble breathing. Bartley recalled afterwards that it looked like he had been infected. This made it difficult for the doctors who treated him, the sudden situation made it difficult to judge the severity of David's infection, and people did not know how to treat the patient who transplanted the pig's heart.
▲This transplant is the first attempt to transplant a pig heart to a human (Image source: Authorized by the University of Maryland; University of Maryland School of Medicine)
In the end, the doctors decided to give David a drug called cidofovir, which was originally intended to treat CMV infections in AIDS patients. Considering that his immune system was very weak, the doctors gave him human immunoglobulins to enhance his resistance.
David's condition was briefly brought under control. However, just as the doctors breathed a sigh of relief, David's body deteriorated again a week later, and the transplanted pig heart began to fail. In March, doctors failed to perform miracles again. As the first person to receive a pig heart transplant, David died two months after surgery.
Look for the cause of death
Understanding the reasons for David's eventual death is extremely revealing for future xenotransplantations. Previously, if scientists had any concerns about swine heart transplantation, those concerns were more from immune rejection. Today, the biopsy of David's transplanted pig heart does not show signs of immune rejection, indicating that the original genetic modification has indeed achieved its goal. The unexpected appearance of the pig virus has become a new possibility of failure.
Image credit: 123RF
Of course, it's too early to say that the porcine virus was David's cause of death, but it was one of many failure factors. Jay Fishman, a transplant infection specialist at Massachusetts General Hospital, after hearing about David's case, thought the symptoms might be caused by a viral infection. Attempts in baboons also show that cmCMV in pigs is not a good thing for transplants — if the heart of a pig carries the virus, the transplanted baboons will only live for a few weeks. And if the pig heart is not infected, these baboons can live for at least half a year.
In the autopsy of the baboons, the researchers also found that the levels of the porcine virus were surprisingly high. These viruses lurk in the heart of the pig, on the one hand, they are no longer suppressed by the pig's immune system, on the other hand, the baboon's immune system can not work normally, so they multiply rapidly. In the human body, the same situation may occur.
Bartley mentioned at an online conference in April that the damage to David's pig hearts was very similar to the damage to the pig hearts in these baboons. He also described the lethal principle of the swine virus: the accidental discovery of the swine virus in the test quickly triggered a larger infection. The immune cascade caused by these infections is like setting off a cytokine storm in the body, causing huge damage to the organs.
"I personally suspect that he (David) had a leaky capillary after an outbreak of inflammation. This causes the heart to become puffy, which in turn becomes fibrous tissue, eventually causing severe and irreversible diastolic heart failure. Bartley said.
But the potential for a porcine virus to be deadly has put researchers at ease. Because this means that there is no problem with the idea of genetically engineering pigs, the problem is simply that there is no more careful examination of pig organs, and all this can be avoided by conventional means. If these viruses had been removed, the pig's heart might have been beating longer.
Future implications
The role of porcine cytomegalovirus in David's death has given researchers a better understanding of the risks to be aware of in pig organ transplantation. According to the MIT Technology Review article, more biotech companies will open clinical trials of pig organ transplants in the next one to two years.
At the same time, doctors are also reflecting on whether there is room for further improvement in their own treatment methods. For example, to combat the infection in David's body, doctors injected him with human antibodies twice. But after the analysis, they realized that these blood products from healthy people may carry some antibodies against pigs, and these antibodies may also damage David's pig heart.
We hope that these insights will ultimately better advance the path to xenotransplantation. If this path is finally cleared, it will undoubtedly bring good news to the large number of patients who need organ transplants around the world.
In 1967, the first human heart transplant patient survived 18 days after surgery. Two years later, another, less successful heart transplant lasted only an additional 27 hours of the patient's life. This year's xenograft has allowed David to live for two more months. It is believed that after the pain is determined, the field of xenotransplantation will be worthy of more expectations in the future.
The images in this article about transplant surgery have been used by the WuXi AppTec content team authorized by the University of Maryland.
Resources:
[1] The gene-edited pig heart given to a dying patient was infected with a pig virus, Retrieved May 5, 2022, from https://www.technologyreview.com/2022/05/04/1051725/xenotransplant-patient-died-received-heart-infected-with-pig-virus/
[2] Report: Porcine Virus May Have Killed Heart Transplant Patient, Retrieved May 5, 2022, from https://www.biospace.com/article/report-porcine-virus-may-have-killed-heart-transplant-patient/
[3] A virus may have driven the death of the first patient to receive a genetically modified pig heart, Retrieved May 5, 2022, from https://endpts.com/a-virus-may-have-driven-the-death-of-the-first-patient-to-receive-a-genetically-modified-pig-heart/
[4] Signs of an Animal Virus Discovered in Man Who Received a Pig’s Heart, Retrieved May 5, 2022, from https://www.nytimes.com/2022/05/05/health/pig-heart-transplant-virus.html
[5] Doctors transplant a genetically modified pig heart into a human for the 1st time, Retrieved May 5, 2022, from https://www.npr.org/2022/01/10/1071906223/doctors-transplant-genetically-modified-pig-heart
[6] Patient in Groundbreaking Heart Transplant Dies, Retrieved May 5, 2022, from https://www.nytimes.com/2022/03/09/health/heart-transplant-pig-bennett.html
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