How much benefit can Second Brother bring to mankind by transplanting a pig's heart into a living human body?

Key Points

★ Every year, less than 10% of those in need of organ transplants worldwide are able to receive organs from human donors.

★ The world's first gene-edited pig heart transplant surgery has achieved initial success, but the long-term effects remain to be seen.

At the beginning of 2022, the medical community broke the news: the University of Maryland Medical Center successfully transplanted a gene-edited pig heart into a 57-year-old male heart patient. This is the world's first human transplant of a genetically modified pig heart. Xenotransplantation has never been successful before. It is reported that the patient is in good condition 5 days after the operation.

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

Why was "Second Brother" chosen?

According to common sense, primates such as orangutans and baboons, which are very similar to humans in species, physiology and anatomy, should be the first choice for allogeneic transplantation. But why did the medical center choose even-toed ungulate pigs for research this time? Scientists have three answers to this question:

First, primates such as gorillas and baboons, which are " distant relatives " of humans, carry some viruses that are more easily transmitted to humans . Moreover, when primate organs are transplanted into humans, there is a high probability that the effect of 1+1>2 will be produced, and the viruses will be "upgraded" in the human body to become more lethal viruses.

The closer the relationship, the higher the risk of disease transmission between species. Pictured is a baboon. | Tuchong Creative

Secondly, pigs are closer to humans in terms of diet, metabolic level, body temperature and heart rate. At the same time, the pig heart is similar to the human heart in size, duct distribution and power output. Moreover, pigs have been selected for xenotransplantation for a long time. Currently, pig heart valves and pig pancreatic cells have successfully entered the human body. Pig skin has also been used as a temporary transplant for burn patients.

Finally, it takes too long for primates like gorillas and baboons to raise a generation, an average of 10 years, and usually one litter per baby, which has high feeding and survival costs. Pigs are different, as they only have one litter per birth and can mature in one year, making them more suitable for targeted breeding and large-scale reproduction.

02

Why choose xenotransplantation?

The organ transplants we are familiar with are usually allogeneic transplants , which means transplanting organs from human donors to people in need. However, according to data from the World Health Organization (WHO), this method can only meet less than 10% of the global organ transplant needs each year .

Take China and the United States as an example. There are about 300,000 people in China who are registered for organ transplants, but only about 16,000 organs can be successfully transplanted each year. In the United States, the organ transplant rate is about 20:1, and an average of 10 people die every day because they cannot wait for a suitable transplant organ. Therefore, the shortage of transplant organs has given scientists the bold idea of ​​xenotransplantation.

From a literal understanding, xenotransplantation is the transplantation or infusion of living cells, tissues or organs of non-human animals into the human body. However, this cross-species technology has huge obstacles: the human immune system may produce a complete rejection reaction to foreign tissues or organs , and even bring fatal consequences.

Doctors prepare to transplant a pig heart. This is the first time such an operation has been performed in the world. It is a huge challenge. | University of Maryland School of Medicine

03

How to deal with rejection

There is already a rejection reaction in allogeneic organ transplantation, and the rejection reaction caused by xenotransplantation is only more worrying.

So in this operation, in order to suppress the rejection reaction and prevent the patient's immune system from attacking the pig's heart, scientists genetically modified the pigs:

They knocked out four genes in pigs, three of which had expression products that would trigger immune rejection. After knocking out these genes, the rejection reaction might be weakened. Another knocked-out gene was responsible for controlling the growth of pigs and their internal organs, preventing the heart from growing too large. While "removing the dross," scientists also inserted six genes from humans into the pigs to prevent the pig heart from clotting in the human body and reduce the risk of rejection.

Gene-edited piglets for transplantation. | statnews

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.

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.

04

Why choose such a high-risk operation?

The patient who received the pig heart transplant had an original heart that could no longer pump enough blood for the whole body before the operation, and relied on an ECMO device to maintain cardiopulmonary function. **Severe heart failure and arrhythmia made the patient ineligible for human organ transplantation. **For him, the only option to survive was to accept the experimental treatment of pig heart transplantation with unpredictable results.

However, xenotransplantation technology has not yet been approved for use, but the "compassionate use" clause of the U.S. Food and Drug Administration (FDA) gives patients a chance to try. When patients face serious or life-threatening medical conditions and only have experimental therapy as an option, they can apply to implement this clause and conduct experimental therapy. This patient obtained a special license from the FDA on December 31, 2021 and seized the opportunity of xenotransplantation.

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

At present, more than a week has passed since the heart transplant operation. Due to the good effect of the new heart, the patient can breathe independently and even speak softly on the fifth day. This makes the attending doctor very satisfied.

However, it will take time to answer whether the subsequent patients will have rejection reactions and whether the transplanted heart can function normally for a long time. **This technology still has a long way to go before it can be promoted clinically. **But at the beginning of 2022, such a groundbreaking operation still brings hope to those patients who are waiting for organ transplants in agony.

Author | Zhu Yehua

Reviewer | Lu Xiuyuan [Japan] Researcher at the Institute of Immunology, Osaka University

Editor | Gao Peiwen

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.

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