The first pig heart transplant patient died | The pig heart beat for two months, what did he go through?

On January 7 this year, 57-year-old David Bennett, a patient with advanced heart disease, made his last attempt in life - he received a pig heart transplant. He was also the first patient in history to receive a pig heart transplant.

Two months later, on the afternoon of March 8, Bennett died at the University of Maryland Medical Center (UMMC).

On March 9, local time, the University of Maryland Medical Center published an obituary on its official website. Doctors have not yet given the exact cause of Bennett's death, but the details mentioned are: his condition began to deteriorate a few days ago. After learning that he could not recover, he received palliative care. In the last few hours of his life, he was able to communicate with his family.

Image source: Twitter @UMMC

When a terminal heart patient was faced with the choice of death or a pig heart transplant, he inserted the key of his life into the hole of the xenotransplant. Whether the original key can be matched with the "high-imitation lock" will be the focus of the medical community and even the whole society in the next period of time. Why the pig heart is used and how much risk the patient actually bears are also curious questions.

01

"This case is enough to change the new pattern in this field."

The pig heart has been gene-knocked out for hyperacute rejection and viruses lurking in the pig genome, and some human genes have been introduced. However, the gene targets that cause acute immune rejection and chronic rejection have not been processed. Therefore, organ rejection is theoretically inevitable, and it is only a matter of time.

The result was indeed not as good as expected, but when we look back at history, it is not difficult to find that this gene-edited pig heart transplant surgery was a huge step forward.

It is reported that the pigs used in the heart transplant surgery performed in January were genetically modified to "knock out" genes that cause human rejection reactions, as well as a specific gene to prevent excessive growth of pig heart tissue implanted in the human body.

This undated photo shows heart patient David Bennett (right) with doctors before receiving a pig heart transplant. Xinhua News Agency/Reuters

The University of Maryland Medical Center said that Bennett first came to the center for treatment in October last year. At that time, he was bedridden and relied on an extracorporeal life support system, extracorporeal membrane oxygenation (ECMO), to maintain his life. His condition was not suitable for conventional heart transplant surgery. Before receiving the pig heart transplant, Bennett was fully informed of the risks of the transplant surgery. This operation was experimental and had unknown risks and benefits.

The center said Bennett's transplanted heart was functioning well in the weeks after the surgery, with no signs of rejection, and he lived with his family and received physical therapy to help him regain his strength until a few days ago when his condition began to deteriorate.

Although he did not return home during the extra two months of life, Mr. Bennett had time to communicate with his family, walk, eat with his family, and happily watch the Super Bowl live.

For him, this inevitable choice may reduce the regrets in life.

Bennett's surgeon, Bartley Griffiths, said Bennett had been fighting the disease until the end. The operation provided researchers with valuable information that will hopefully help doctors better perform transplants and help save future patients undergoing surgery.

Mohammad Mohieldin, professor of surgery at the University of Maryland School of Medicine and director of the cardiac xenotransplantation program, said researchers gained valuable information through Bennett's surgery and plan to continue related clinical trials in the future.

The New York Times reported that xenotransplantation has provided new hope for thousands of patients with kidney, heart and other organ diseases, as the number of donated human organs cannot meet the demand of these patients waiting for organ transplants.

It is reported that Bennett said the day before the operation: "Either die or have a transplant. This is my last choice." Although Bennett's life only lasted for two more months, his family also said: "I hope this is a beginning, not an end."

02

Pig heart transplantation is the result of human efforts

At present, organ transplantation has been widely accepted by society. It is a very effective means to solve many problems of end-stage organ failure, saving thousands of critically ill patients from the shadow of death and prolonging their lives.

"With the promotion and use of effective and safe immunosuppressants in clinical practice, organ transplantation has become more and more popular, especially the number of heart, liver and kidney transplants has increased year by year," said Xiu Dianrong, chief physician of general surgery at Peking University Third Hospital.

But unfortunately, there is a huge gap in organ transplantation both at home and abroad.

Taking the United States as an example, more than 120,000 people wait for organ transplants every year, but only 30,000 people can get organ transplants, and 21 people die every day due to lack of organs available for transplantation.

The relevant data in our country is even more serious. Every year, more than 300,000 people in our country suffer from organ failure and need transplant surgery, but only about 10,000 people can receive transplant surgery each year.

Lei Ruipeng, executive director of the Center for Bioethics Research at Huazhong University of Science and Technology, and Qiu Renzong, a researcher at the Institute of Philosophy of the Chinese Academy of Social Sciences, wrote in China Science Daily that in the 1920s, 1930s, 1960s and 1970s, most xenotransplants in Europe and the United States used gorillas or baboons as animal sources for organ transplants, but all ended in failure with extremely poor survival results. Moreover, using primates as a source of transplanted organs is very expensive and difficult to promote.

Therefore, scientists thought of using pig organs as a source of xenotransplantation. Chen Zhonghua said that because the size of pig organs, such as the heart, kidneys, and liver, are similar to those of humans, they may play a similar role in replacing functions. Moreover, pigs are economical and can be mass-produced, so they are considered an ideal source of organ donors.

Gene editing is the basis for the successful transplantation of xenogeneic organs such as pig hearts.

Through gene editing, the pig heart can be made closer to the human heart in order to avoid as many rejection reactions as possible and survive for a long time.

The first step is to knock out the hyperacute rejection target.

Following up on some of the information currently disclosed, this gene-edited pig heart should have at least knocked out the α-gal (α-galactosidase) gene, which is an important target for causing hyperacute rejection reactions.

Other genes that may be knocked out include the CMAH gene, β4GalNT2 gene, ASGR1 gene, etc. The proteins they express may be quickly recognized and attacked by the recipient's immune cells, causing reactions that endanger the recipient's life.

The second step is to knock out latent virus-related genes.

For example, porcine endogenous retrovirus (PERV) is similar to HIV. It converts its genetic information into DNA and integrates it into the gene of the receptor, achieving permanent latency. Once conditions permit, this gene will begin to be transcribed and translated, and finally packaged into a finished virus, infecting the receptor and making it sick. Like HIV infection, it cannot be completely cured.

Thanks to the work of Dr. Luhan Yang, since 2015, CRISPR-Cas 9 technology has become increasingly mature and can completely cut out proviruses in pig genes through the use of "gene scissors".

The third step is to introduce some human genes.

Some human genes can also be introduced into the genome of gene-edited animals, such as human CD55 and human CD59, both of which are important human complement inhibitory factors. This factor can be understood as a natural inhibitory immunomodulator that can reduce the occurrence of hyperacute rejection and inflammatory reactions and protect xenotransplanted tissues and organs.

The above are the technological advances that have been mature and disclosed for xenotransplantation.

However, in addition to hyperacute rejection reactions, there are also acute and chronic ones. The acute one is mainly mediated by ABO blood type and HLA complex related to human allogeneic organ transplant rejection. To solve these, more gene loci are involved, and there is also uncertainty.

Whether other gene editing technologies were used in this pig heart transplant remains to be announced later.

It is undeniable that this attempt has taken a big step towards the goal of practical gene-edited animal organ transplantation in humans. It is very likely that our generation will witness the practical application of this technology.

However, we still need to be cautious about this progress and wait for the release of many technical details, such as the most important points:

What was the direct cause of death? Infection? Rejection? Drug-induced organ failure?

What are the edited genes? What functions are they responsible for?

How severe is the patient's body's immune attack on xenogeneic organs?

The solution to these puzzles will hopefully be reported in serious academic journals in a few months. There may be autopsies, heart tissue biopsies, immunological tests, and detailed medical history information. Only by clarifying them can we know how far this step has come.

03

How to deal with rejection

Allogeneic organ transplantation already has rejection reactions, and the rejection reactions caused by xenotransplantation are only more worrying.

The first 48 hours after transplantation is called the hyperacute rejection period, during which the transplanted organ may suffer from ischemia or necrosis. Fortunately, the patient who received the transplant safely passed the "life-threatening" 48 hours. Although he still used ECMO equipment to maintain his cardiopulmonary function, the transplanted pig heart has begun to beat normally, and the medical team will help the patient gradually get rid of the auxiliary machine.

Organ transplantation between humans carries the risk of disease transmission. After a pig heart enters the human body, it may also transmit pathogens carried by the pig to humans, making them sick. In a study of pig heart transplantation for baboons, some baboons died after the operation due to infection with porcine cytomegalovirus.

Most pig viruses, bacteria and fungi can be eliminated through detection and selection, controlled breeding conditions, early weaning and embryo transfer, etc. However, porcine endogenous retroviruses can be integrated into the pig genome, making inactivation more difficult.

Patients who successfully survive the hyperacute rejection period will also face more complex and severe cellular transplant rejection reactions that may occur within days to weeks after transplantation. The entire immune system will attack the "foreign uninvited guest". However, with the development of genetic engineering, scientists are gradually overcoming the problem of immune rejection in xenotransplantation.

Compared with the heart and kidney, pig liver transplantation is more difficult to perform because the molecular mechanisms involved in xenogeneic rejection are more complex, and thrombotic microangiopathy and coagulopathy appear to be more serious. Currently, the survival time of pig liver transplants in baboons is about one month. Pig lungs are the organs most severely damaged by coagulation disorders. Recently, the survival time of primates that received gene-edited pig lung transplants was about half a month. In addition, research on transplantation to treat diseases such as diabetes and Parkinson's disease is also underway.

Therefore, the heart and kidney may be the first two solid organs used for clinical xenotransplantation , and transplantation of other organs may require further genetic engineering and immunosuppressive therapy adjustments before being applied to humans.

04

Tribute to Explorers

It is worth noting that one of the biggest constraints of organ transplantation, which saves countless lives, is the extreme shortage of donor organs. This has also led scientists to try xenotransplantation for a long time. As for xenotransplantation of hearts, as early as 1964, Dr. James Hardy of the University of Mississippi Hospital in the United States transplanted a chimpanzee heart into a human for the first time.

Wu Jun, assistant professor at the University of Texas Southwestern Medical Center, once said that human organ transplantation is a very important development in modern medicine. By removing diseased and necrotic organs and replacing them with healthy and vibrant organs, life-threatening patients can be given life again.

"In the current social context, the most important constraint on organ transplantation is not technology, but the source of organs." He explained that organs need to be transplanted into a new body within a certain period of time after leaving the mother's body in order to survive. In most accidental deaths, a donation agreement must be signed before the individual is alive, and the individual must not have any major illness. These harsh conditions make it difficult for us to obtain a source of replaceable organs.

One of their ideals is to use stem cell technology to obtain functional, independent human organs, thereby providing a legal and effective source of organs for patients in need of organ transplants. "Of course, this is only the ultimate goal, and this road seems to be a long way to go."

The team that performed the surgery. The surgery was performed on January 7 at the University of Maryland School of Medicine. | ​​University of Maryland School of Medicine

In 2020, Huang Jiefu, chairman of the China Organ Transplant Development Foundation, publicly stated that there are about 300,000 patients waiting for organ transplants due to end-stage organ failure every year, while the number of organ transplants each year is only about 20,000, and there is a huge gap in transplants.

"Organ transplantation is currently an important medical method to save patients with end-stage organ failure, but without donation there would be no transplantation."

The shortage of organ transplant donors is a very serious problem worldwide, and developing alternative technologies for the same organ transplant can be said to be a helpless measure in a desperate situation.

Yet we are the descendants of a people who, when faced with desperate odds, chose to risk everything and challenge fate rather than go gently into that good night like lambs to the slaughter. This indomitable courage and the wisdom to transform the world run deep in our genes.

As Kennedy, the founder of the Apollo moon landing program, once said:

We choose to go to the moon in this decade and do the other things, not because they are easy, but because they are hard.

"We hope that this story can be the beginning of hope, not the end."

Salute to all explorers!

References:

[1] https://www.theguardian.com/us-news/2022/jan/10/maryland-pig-heart-transplant-human-medical-first

[2] https://www.umms.org/ummc/news/2022/first-successful-transplant-of-porcine-heart-into-adult-human-heart.

[3] https://apnews.com/article/pig-heart-transplant-6651614cb9d73bada8eea2ecb6449aef

[4]https://edition.cnn.com/2022/01/10/health/genetically-modified-pig-heart-transplant/index.html

[5] Lu T, Yang B, Wang R, Qin C. Xenotransplantation: Current Status in Preclinical Research. Front Immunol. 2020;10:3060.

[6] Platt JL, Piedrahita JA, Cascalho M. Clinical xenotransplantation of the heart: At the watershed. J Heart Lung Transplant. 2020;39(8):758-760.

[7] Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: The final step toward clinical xenotransplantation? J Heart Lung Transplant. 2020;39(8):751-757.

[8] Cooper DKC, Gaston R, Eckhoff D, Ladowski J, Yamamoto T, Wang L, Iwase H, Hara H, Tector M, Tector AJ. Xenotransplantation-the current status and prospects. Br Med Bull. 2018;125(1):5-14.

[9] https://www.bbc.com/news/health-58993696

[10] https://www.usatoday.com/story/news/health/2022/03/09/human-pig-heart-transplant-patient-dies/9437650002/

[11] https://www.medschool.umaryland.edu/news/2022/IN-MEMORIAM-David-Bennett-Sr.html

Comprehensive sources: Xinhua News Agency, China Youth Daily, China Science Daily, The Paper, etc.