This article is written by Zhuang Shilihe
After receiving a heart transplant for 2 months, Mr. David Bennett left this world. He developed a deterioration of his condition a few days ago, and after making it clear that he could not recover, he gave up active rescue and chose to spend the last few hours of his life in the company of his family.
He is also the first patient in the world to undergo a swine heart transplant.
Image source: University of Maryland Medical Center Twitter
At present, a spokesperson for the University of Maryland Medical Center in the United States said that the cause of death of this patient has not yet been clarified, and the medical staff of the hospital will publish the relevant results in medical journals.
Most of the time, the heart stops beating, meaning a person's life may come to an end.
But for researchers and patients who are waiting for a heart, this seemingly short 2 months is the beginning of hope for a historic moment of transplantation.
Heart transplantation, where is the difficulty?
The legend of organ transplantation has existed since ancient times, and in the stories of ancient China and Egypt, there is no shortage of transplantation of various bones, teeth, limbs and even tissues or organs such as hearts.
But the real modern organ transplant began in 1954. Thomas Murray, a surgeon in Boston at the time, spent five and a half hours completing the first living kidney transplant between identical twins in human history, and the patient's kidneys worked normally after the transplant and survived for 8 years. Thomas Murray was also awarded the 1990 Nobel Prize in Physiology or Medicine.
Thomas Murray wins the 1990 Nobel Prize in Physiology or Medicine (Source: Nobel Prize website)
The first successful heart transplant began in 1967, when South African heart surgeon Christiaan Barnard received a heart from a young woman who had just died in a car accident and transplanted it into a 54-year-old heart patient. However, due to severe rejection, the patient died 18 days later.
In the following half century, with the continuous advancement of surgery, anesthesia, critical care medicine and nursing technology, the advent of various immunosuppressants, and the improvement of organ donation and transplantation norms, the number and quality of various organ transplantation procedures have been rising.
For example, China's first heart transplant was completed at Ruijin Hospital in 1978, and 149 heart transplants were completed nationwide in 2010, and in 2018, this number has risen to 490 cases, and the survival rate of one year after surgery has reached 90%, higher than the international average, and patients have been reported to have survived for more than 20 years after transplantation.
After years of development, in many heart centers at home and abroad, heart transplant surgery technology has matured, to the current mainstream in situ heart transplantation as an example, the main steps include the establishment of cardiopulmonary bypass, removal of the patient's diseased heart, the donor's heart and the patient's left atrium, upper and lower vena cava, aorta, pulmonary artery and other parts of the suture connection.
Schematic diagram of vascular connections in heart transplantation
(Source: Mayo Foundation)
In heart transplant surgery, not only the surgical technique itself, but also the preoperative and postoperative procedures also face many difficulties.
Let's talk about the postoperative period, postoperative complications are an important cause of surgical failure and even patient death, early complications often occur within a few days after surgery, including primary graft dysfunction (PGD), ultra-acute rejection and infection, etc., and delayed complications will occur months or even years after transplantation, including cardiac graft vascular disease and immunosuppressive drugs related side effects.
However, compared to the various difficulties after surgery, the biggest difficulty in heart transplantation comes from preoperative - insufficient donors.
More precisely, it is a serious deficiency.
For patients with end-stage heart disease, heart transplantation is one of the most effective treatments. About tens of thousands of people in China need a heart transplant every year, but only more than 400 surgeries have been performed in the country this year.
Organ donation volume and organ donation rate (PMP) of all provinces in China (including municipalities directly under the central government, excluding Hong Kong, Macao and Taiwan) after their deaths in 2019 Wang Haibo, Shi Ying, Zhou Zhiye, et al. Analysis of the current situation of organ donation and transplantation in China in 2019[J] . Chinese Journal of Organ Transplantation, 2021, 42(6): 324-325.
The same is true in other countries, where about 4,000 heart transplants are performed each year, but there are more than 100,000 patients on the waiting list, and the average waiting time for every patient in the United States who needs a heart transplant is 6 months, and many people die before they can wait for the heart.
In addition, heart transplantation faces the same dilemma as other organ transplants: current human medical technology has not yet been able to "make" a heart with complete physiological functions.
Why Pig Hearts?
Faced with the severe shortage of transplanted organs, many scientists have begun to turn donor research to animals, especially pigs.
When it comes to heart transplantation, pigs have many unique advantages: it is an animal that has been domesticated for thousands of years, and we know very well the habits and feeding methods of pigs; in terms of size and anatomy, the heart of a pig is very similar to that of a human.
But whether it is a pig heart or the heart of other animals, the biggest obstacle to successful transplantation comes from immune rejection.
Our immune system is extremely complex, it can effectively recognize a variety of foreign pathogens (including bacteria, viruses and fungi, etc.) and actively attack, as far as possible to avoid us from being infected or severe.
But when confronted with a transplanted organ, our immune system also recognizes it as a foreign body and attacks it. In the early days of organ transplantation in the middle of the last century, rejection became the most frightening thing for doctors, and many patients died of various rejection reactions after transplantation. Thanks to the later invention of various new immunosuppressants, the problem of rejection began to be greatly alleviated.
Compared with same-species organ transplantation, it is more difficult to transplant the organs of heterogeneous animals (such as pigs or baboons) to humans, mainly because pigs and human vascular endothelial cells express different antigen epitopes, in which the α-Gal epitope (α-galactose) carried by the pig heart will interact with human anti-Gal antibodies to mediate immune rejection.
To solve this problem, as early as two years before this pig heart transplant, the FDA approved the breeding of a genetically modified pig that removes the α-gal sugar on the surface of pig cells through transgenic technology, which can reduce rejection by about 85%.
But the final situation is more complicated, the pig heart for transplantation modified 10 genes through CRISPR-Cas9 technology, knocked out 3 key sugars (which may cause rejection), added 2 human genes to prevent blood clotting, 4 were modified to reduce inflammation, and 1 growth-related gene was also turned off to prevent pig hearts from growing too large (for humans).
So we can find that when David Bennett, 57, became the first patient to receive a pig heart transplant at the University of Maryland Hospital due to heart failure, the preparations had already begun.
Because of his serious condition (he had been using ECMO for more than fifty days at the time) and a long waiting period, the FDA gave him the green light to urgently approve this historic operation in the name of "compassionate use".
David Bennett underwent the surgery smoothly
(Source: YouTube screenshot)
An innovative moment in a historic attempt
Although David Bennett is still dead 2 months after transplantation from today's point of view, this pork heart transplant is still a very huge step forward.
We can compare the first xeno heart transplant in humans in 1984. Doctors transplanted the baboon's heart to a baby girl with a serious congenital heart disease, but the baby girl died of severe rejection 21 days after the transplant.
David Bennett, who was fine in the weeks after the transplant, was out of ECMO 5 days after surgery and started walking the next day without finding a serious rejection, and even watched the Super Bowl live with his doctors.
The pig heart transplant extended his life for 2 months, allowing him and his family and friends to stay for 2 months longer. The specific reason for his death has not been revealed, but his family is still grateful for the transplant at University of Maryland Hospital, as his son said in a statement issued at the hospital.
「We are grateful for every innovative moment, every crazy dream, every sleepless night that went into this historic effort. We hope this story can be the beginning of hope and not the end. We hope that this story is not the end, but the beginning of hope. ）
Bennett and his doctors in postoperative recovery
(Source: dicardiology.com)
From the perspective of the bystander, we found that this operation is far from moving the pig's heart into the human chest cavity, behind which is the progress of transplant surgery, the improvement of immunosuppressive drugs, the increasing understanding of various gene functions and the invention of new gene editing technologies, etc. It is the comprehensive progress from basic medicine to clinical medicine in decades to complete this 9-hour xeno heart transplant.
Over time, xenocardial transplantation and suppression of other xeno organs will save the lives of countless patients from waiting for an organ day after year.
Medical progress has not always been smooth sailing, and finally, I would like to conclude with a quote that Thomas Starzl, the father of liver transplantation, said in 1982: "The history of medicine is that what was inconceivable yesterday, and barely achievable today, often becomes routine tomorrow."
The history of medicine is often something that was thought impossible yesterday, and it is difficult today, but tomorrow it has become a routine.
Acknowledgements: This article has been professionally reviewed by Wang Meng, attending physician of cardiovascular surgery at Sun Yat-sen Memorial Hospital of Sun Yat-sen University
Image source: Youtube video screenshot
Curated by: Gyouza