Doctors at the University of Maryland Medical Center demonstrate a porcine heart to be transplanted. (University of Maryland Medical Center/Photo)
Surgeons at the University of Maryland Medical Center recently revealed that a patient with advanced heart disease who underwent a genetically modified pig heart transplant on January 7, 2022, is in good postoperative condition, detecting normal heartbeat, pulse and blood pressure, and no obvious rejection. This is also the first time that humans have successfully transplanted a genetically modified pig heart 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.
The biggest challenge
The shortage of organ transplant donors is a global medical challenge. According to the official website of the American organ donor, about 110,000 Americans are currently waiting for organ transplants, but more than 6,000 patients die each year because they cannot wait for organs. In 2021, more than 41,000 Americans received organ transplants, more than 3,800 of them received hearts from human donors. Organ donors mainly rely on volunteer donations, but the low rate of voluntary organ donation, difficulty in organ matching and other problems have led to a serious shortage of organ donors, and genetically modified pigs are considered to be an important choice to solve the shortage of organs.
The biggest challenge facing pig organ transplantation into the human body is the immune rejection reaction, that is, the human immune system will recognize the graft and attack the graft through multiple rounds of immune response to prevent it from growing freely in its own body. After more than two decades of exploration, scientists have found that genetic engineering techniques can significantly reduce or eliminate this immune rejection.
Genetically modified pigs use genetic engineering technology to destroy the endogenous immune rejection-related genes of pigs, so that they no longer express the antigens that trigger the immune rejection reaction, such as the antigen unique to the surface of pig cells - α1, 3 galactose, and at the same time transfer some genes of proteins unique to human cells, camouflage pig cells as "human cells", hoping to deceive the human immune system and ultimately achieve "peaceful coexistence" of human and pig tissues and organs.
Since the mid-1990s, scientists have bred a variety of transgenic pigs, knockout pigs and gene-edited pigs that can reduce immune rejection, and carried out a series of preclinical trial studies of xenotransplantation. After the researchers transplanted the kidneys, livers, hearts and other organs of these genetically modified pigs into primates such as chimpanzees, baboons or monkeys, the survival time of the grafts was continuously extended, of which kidney transplantation can survive up to 400 days, liver transplantation can survive up to 200 days, and cornea, neurons and islet cells can survive for more than 1 year.
In April 2016, the National Institutes of Health Cardiothoracic Surgery Research Project team published exciting results in Nature Communications. The team has bred a genetically modified pig carrying the human membrane coenporotein gene and the human thrombomodulatory protein gene as early as 3 years ago, while α-1,3-galactosidine transferase gene knockout. The researchers took the hearts of the above-mentioned genetically engineered pigs and transplanted them into five baboons, and with the help of some anti-rejection drugs, the pigs' hearts survived an average of 298 days in the five baboons, and the longest transplant survival time reached 945 days, creating the longest record for heterogeneous organ survival. This preclinical trial also lays a key foundation for clinical trials of swine heart xenotransplantation.
As these preclinical trial studies continue to make major breakthroughs, clinical trials of xenotransplantation have also been put on the agenda. On December 14, 2020, the US FDA officially approved a genetically modified pig without α1,3-galactose developed by Revivicor in the United States, which can be used for potential uses such as food and pharmaceutical products, which is the world's first approved genetically modified pig product and the first approval of the edible and medical dual use of genetically modified animals, which is of landmark significance. Based on this, several hospitals in the United States are using genetically modified pigs produced by Revivicor to accelerate clinical trials of multiple xenotransplantations.
For David Bennett (right), a patient with advanced heart disease, a pig heart is the only viable option at the moment and worth the risk. (University of Maryland Medica lCenter/Photo)
Risk surgery
From October to December 2021, a research team from NYU Langone Health at New York University announced that the alpha-free, 3-galactose-modified pig kidney produced by Revivcor had been successfully transplanted into two patients who had died and relied on ventilators to maintain signs. After 54 hours of observation and testing, the researchers found that the kidneys of the genetically modified pigs not only continued to filter waste products and produce urine at normal rates, but also returned the patients' abnormal creatinine levels caused by poor kidney function to normal levels, while no serious rejection was observed during the observation period. Although this clinical trial was only conducted in brain-dead patients, the genetically modified pig kidneys can function normally in vitro and did not trigger a serious rejection reaction, which is a great encouragement for the upcoming clinical trial of xenotransplantation.
David Bennett, a 57-year-old patient with advanced heart disease in Maryland, became the first person to receive a clinical trial of a swine xenotransplantation. After a thorough review of Bennett's physical condition and medical records, doctors at the University of Maryland Medical Center and several other medical institutions believed that he could not receive a traditional heart transplant or artificial heart pump surgery for reasons such as fatal arrhythmias. The heart of the pig is "the only viable option at the moment". Bennett knew transplants were highly experimental, but was willing to take risks. "Either die or do this transplant." A statement he posted before the surgery said, "I want to live." I knew it was an attempt in the dark, but it was my last resort. ”
Dr. Muhammad M. Mohiuddin, a professor of surgery at the University of Maryland Medical Center, and Dr. Bartley P. Griffith, performed this special heart transplant for Bennett, who is considered one of the world's foremost animal organ transplant specialists. This time the heart donor is still provided by Revivicor, but is derived from an upgraded version of the alpha-1,3-galactose gene-modified pig. A total of ten genes were edited in advance in the gene-modified pigs that provided the heart donor, including the alpha1,3-galactosetransferase gene, including three genes associated with acute rejection of heterogeneous organs, six human genes responsible for "camouflaging" pig cells were transferred to the pig genome, and one pig growth hormone gene was knocked out to prevent pig heart tissue from overgrowing in the human body.
The U.S. Food and Drug Administration has yet to formally approve a swine heart xenotransplantation, but the agency granted emergency authorization for surgery on New Year's Eve under a so-called "compassionate use" clause. The provision allows experimental treatments to be carried out in the absence of other methods available.
On the morning of the transplant, a surgical team led by Dr. Griffith and Dr. Mohidin took the pig's heart out and placed it in a perfusion device dedicated to keeping the heart donor active before performing the heart transplant, which was then transplanted into Bennett's body. After three days of observation, the University of Maryland Medical Center in the United States announced the initial success of the first human-pig heart transplant. Doctors observed that transplanted pig hearts produced normal pulses, heartbeats, and blood pressure in the patient's body, and with the help of anti-rejection drugs, no severe immune rejection was observed for the time being.
At present, the detailed experimental data has not yet been released, and it remains to be seen what risks patients will encounter in the later stages. However, for the field of xenotransplantation that scientists have been exploring for more than 50 years, the launch of this clinical trial marks a step closer to the success of xenotransplantation.
Safety and ethics
Although there is still a long way to go from clinical application, xenotransplantation, as an emerging medical field, is attracting widespread attention from the public and the media, and even attracting the favor of capital. In January 2020, Science predicted that xenotransplantation clinical trials could make top ten scientific headlines in 2020, just over a year ahead of what actually happened. In May 2021, Science magazine and Shanghai Jiao Tong University once again released 125 major scientific issues at the international frontier, global demand, and focus on human welfare, and whether xenotransplantation can solve the shortage of donor organs was once again included.
The public is most concerned about the safety and ethical controversy of xenotransplantation. For example, will viruses in pigs, especially endogenous retroviruses, be transmitted to patients? Harvard scientists have destroyed all endogenous retrovirus-related genes through gene editing techniques, eliminating their potential risk of infection. Conducting clinical trials of xenotransplantation requires rigorous ethical review in advance.
Capital is extremely sensitive to this emerging field, and several companies engaged in xenotransplantation have received huge venture capital. Revivicor has long been under the umbrella of international biotech giant United Therapeutics. eGenesis, an American xenotransplantation company founded by Professor George Church of the American Academy of Sciences and Harvard University, has received $38 million in Series A investment and $100 million in Series B financing, and again received $125 million in Series C financing in 2021. In June 2021, Miromatrix, also dedicated to clinical trials and industrialization of xenotransplantation, went public on the NASDAQ with $43 million in financing, and the company plans to conduct xenotransplantation clinical trials in 2023. There are also a number of companies in China that carry out heterogeneous organ transplant research and industrialization, among which eGenesis's subsidiary in China, Hangzhou Qihan Biologics, has also received more than 100 million US dollars in Series A financing, while Chengdu Zhongke Aug Biotechnology Co., Ltd. received a venture capital of 30 million yuan 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 make breakthroughs in the next few years, bringing new hope to more patients who lack human organ donors.
Southern Weekend Contributing Writer Tombo