Pig heart successfully implanted in human

Surgeons at the University of Maryland Medical Center in the United States recently revealed that a patient with advanced heart disease received a genetically modified pig heart transplant on January 7, 2022. The patient was in good condition after surgery, with normal heartbeat, pulse and blood pressure detected. And no obvious rejection. This is the first time that a genetically modified pig heart has been successfully transplanted into a living patient, marking the beginning of a new era of xenotransplantation and bringing hope to a large number of heart disease patients who lack human heart donors.

But experts also admitted that it is too early to say that the operation in the United States will be successful, and it is necessary to ensure that the patient is still in good condition in the next few months before the operation is successful. Not only will the technology need to overcome ethical issues, it will also take time to develop. As of January 19, patients undergoing surgery were weaned off ECMO (Extracorporeal Membrane Oxygenation) and were able to get out of bed.

The shortage of organ transplant donors is a global medical problem. According to the official website of US organ donors, about 110,000 Americans are currently waiting for organ transplants, but every year, more than 6,000 patients die because they cannot wait for organs. More than 41,000 Americans will receive organ transplants in 2021, with more than 3,800 receiving hearts from human donors. Organ donors mainly rely on volunteer donations, but the low rate of voluntary organ donation and the difficulty of matching organs have led to a serious shortage of organ donors. Genetically modified pigs are considered to be an important choice to solve the organ shortage.

The biggest challenge in transplanting pig organs into humans is immune rejection, that is, the human immune system will recognize the graft and attack the graft for multiple rounds through an immune response to prevent it from growing indiscriminately in its own body. After more than 20 years of exploration, scientists have found that this kind of immune rejection can be greatly reduced or eliminated through genetic engineering technology.

Genetically modified pigs use genetic engineering technology to destroy the endogenous immune rejection-related genes of pigs, so that they no longer express antigens that cause immune rejection, such as α-1,3-galactose, a unique antigen on the surface of pig cells. At the same time, the genes of some human cell-specific proteins were transferred, and the pig cells were disguised as “human cells”, hoping to deceive the human immune system and finally realize the “peaceful coexistence” of human and pig tissues and organs.

For late-stage heart disease patient David Bennett (right), pig hearts are the only viable option and worth the risk. Pictures of Southern Weekend

Since the mid-1990s, scientists have successively bred various transgenic pigs, gene knockout pigs, and gene-edited pigs that can reduce immune rejection, and have carried out a series of preclinical research studies on xenotransplantation. After the researchers transplanted these genetically modified pig kidneys, livers, hearts and other organs into primates such as chimpanzees, baboons or monkeys, the survival of the grafts was continuously extended. The kidney transplants can survive for up to more than 400 days, and the liver transplants can survive for up to 400 days. The longest survival time of transplantation is more than 200 days, and the transplantation of cornea, neurons and islet cells can survive for more than 1 year.

In April 2016, the National Institutes of Health’s Cardiothoracic Surgery Research Project team published exciting research results in “Nature-Communications”. As early as 3 years ago, the team bred a genetically modified pig carrying the human membrane cofactor gene and the human thrombomodulin gene, while the α-1,3-galactosyltransferase gene was knocked out. The researchers took out the hearts of the genetically engineered pigs and transplanted them into 5 baboons. With the help of some anti-rejection drugs, the pig hearts survived in the 5 baboons for an average of 298 days, and the longest transplant survival time was 945 days, creating the longest transplant. Xenogeneic Organ Survival Records. This preclinical trial also provides a key foundation for clinical trials of porcine cardiac xenotransplantation.

As these preclinical research studies continue to make major breakthroughs, clinical trials of xenotransplantation are also on the agenda. On December 14, 2020, the U.S. FDA officially approved a genetically modified pig without α-1,3-galactose developed by the American company Revivicor, which can be used for potential uses such as the production of food and pharmaceutical products. This is the first approval in the world. The genetically modified pig product is also the first approval for the dual use of genetically modified animals for food and medical use, which is a milestone. Based on this, many hospitals in the United States are using genetically modified pigs produced by Revivicor to accelerate clinical trials of multiple xenotransplantation.

Doctors at the University of Maryland Medical Center show a pig heart that is about to be transplanted. Image | Southern Weekend

From October to December 2021, the research team from the New York University Langone Health Center announced that the α-1,3-galactose-free gene-modified pig kidneys produced by Revivicor were successfully transplanted into two brain-dead and dependent pig kidneys. The ventilator maintains signs in the patient’s body. After 54 hours of observation and testing, the researchers found that the kidneys of the genetically modified pigs not only continued to filter waste and produce urine at a normal rate, but also restored the patient’s abnormal creatinine levels caused by poor kidney function to normal levels, while at the same time during the observation period Serious rejection was also not observed. Although this clinical trial was only carried out on brain-dead patients, the genetically modified pig kidney could function normally in vitro without causing severe rejection, which is a great encouragement for the upcoming clinical trial of xenotransplantation.

David Bennett, a 57-year-old Maryland patient with terminal heart disease, has become the first person to undergo a clinical trial of a pig xenotransplantation. After a thorough evaluation of Bennett’s medical condition and medical records, doctors at the University of Maryland Medical Center in the United States, like several other medical institutions, concluded that he could not receive a traditional heart transplant or artificial heart pump because of the fatal arrhythmia and other reasons. Operation. Pig hearts are “the only viable option at the moment”. Bennett knew transplants were highly experimental, but was willing to take risks. “Die or do this transplant,” he said in a statement released before the operation. “I want to live. I know it’s an attempt in the dark, but it’s my last option.”

Bennett’s special heart transplant, considered the world’s most important animal organ transplant, was performed by Dr. Mohamed Mohyeddin and Bartley Griffith, professors of surgery at the University of Maryland Medical Center in the United States. one of the experts. This time, the heart donor was still provided by Revivicor, but it was derived from an upgraded version of a pig without α-1,3-galactose gene modification. A total of 10 genes were edited in advance in genetically modified pigs that provided heart donors, among which 3 genes related to acute rejection of xenogeneic organs, including the α-1,3-galactosyltransferase gene, were knocked out, and 6 genes were knocked out. The human gene responsible for “camouflaging” pig cells was transferred into the pig genome, and a pig growth hormone gene was knocked out to prevent pig heart tissue from overgrowing in humans.

The U.S. Food and Drug Administration has yet to formally approve pig heart xenotransplants, but the agency granted emergency authorization for the procedure on New Year’s Eve under so-called “compassionate use” provisions. This clause allows experimental treatments to be performed when no other method is available. On the morning of the transplant, a surgical team led by Dr. Griffiths and Dr. Mohiddin removed the pig’s heart and placed it in a perfusion device designed to keep the donor heart alive prior to heart transplant surgery. Inside Bennett. After three days of observation, the University of Maryland Medical Center announced the initial success of the first human-pig heart transplant. Doctors observed that the transplanted pig heart produced normal pulse, heartbeat and blood pressure in the patient, and with the help of anti-rejection drugs, no serious immune rejection was temporarily observed.

As of January 13, detailed experimental data has not been released, and it remains to be seen what risks patients will encounter in the later stage. However, for the field of xenotransplantation that scientists have been exploring for more than 50 years, the launch of this clinical trial marks that xenotransplantation is one step closer to success.

Although there is still a long way to go before clinical application, xenotransplantation, as an emerging medical field, is attracting extensive attention from the public and the media, and even attracts the favor of capital. In January 2020, the journal Science predicted that xenotransplantation clinical trials could make the top 10 science headlines in 2020, just over a year earlier than it actually is. In May 2021, the journal “Science” and Shanghai Jiaotong University will once again publish 125 major scientific issues that are international frontiers, global common needs, and focus on human well-being. Whether xenotransplantation can solve the shortage of donor organs is included again.

Pig hearts are “the only viable option at the moment”. Bennett knew transplants were highly experimental, but was willing to take risks. “Die or do this transplant,” he said in a statement released before the operation. “I want to live. I know it’s an attempt in the dark, but it’s my last option.”

The public is most concerned about the safety and ethical controversy of xenotransplantation. For example, can viruses in pigs, especially endogenous retroviruses, be transmitted to patients? Harvard scientists have disrupted all endogenous retrovirus-related genes through gene editing technology, eliminating their potential risk of infection. To conduct a clinical trial of xenotransplantation, strict ethical review is required in advance.

Capital is extremely sensitive to this emerging field, and many companies engaged in xenotransplantation have received huge venture capital. Revivicor has long been owned by the international biotech giant United Therapeutics. eGenesis, an American xenotransplantation company founded by Professor George Church, an academician of the National Academy of Sciences and Harvard University, has successively received $38 million in Series A investment and $100 million in Series B financing. In June 2021, the US Miromatrix company, which is also committed to the clinical trial and industrialization of xenotransplantation, was listed on Nasdaq with financing of US$43 million. The company plans to launch a clinical trial of xenotransplantation in 2023. There are also many companies in China that carry out research and industrialization of xenotransplantation. Among them, Hangzhou Qihan Bio, a subsidiary of eGenesis in China, has successively obtained more than 100 million US dollars in Series A financing, and Chengdu Zhongke Aoge Biotechnology Co., Ltd. The company received 30 million yuan in venture capital in 2018, and another 45 million yuan in Series A financing in September 2021.

Under the joint promotion of scientists and investors, the clinical trial of genetically modified pig xenotransplantation is bound to be further accelerated, and it is expected to achieve breakthrough progress in the next few years, bringing new hope to more patients who lack human organ donors.