"We need to be careful not to be overly optimistic and aggressive in cutting-edge medical research."
Written by | Ling Jun
Source | "Medical Community" public account
"The patient's survival of two months has exceeded expectations."
Today, after learning of the death of the first pig heart transplant patient, Professor Zhu Tongyu, vice president of Shanghai Medical College of Fudan University, director of Shanghai Key Laboratory of Organ Transplantation, and chairman of the Organ Transplantation Branch of Shanghai Medical Association, told the "medical community".
On March 9, the University of Maryland Medical Center (UMMC) announced that The world's first transplanted gene-edited pig heart patient, David Bennett, 57, died.
News of Bennett's death caused a sensation in the industry. On January 7, 2022, he received a swine heart transplant, and there was no ultraacute immune rejection after the operation, and the extracorporeal membrane oxygenation device (ECMO) was removed 5 days later, and the transplanted heart function was stable for the next few weeks, without any signs of rejection.
The exact cause of David Bennett's death is unclear. UMMC said Bennett's condition deteriorated a few days ago and was given palliative care, with other details pending further thorough examination by the attending physician before being published in medical journals.
Bennett with the attending physician
What are the possible causes of patient deaths?
"Although he eventually died, surviving for two months as a xenotransplant and transplanting a heart to maintain function has been a major breakthrough in the history of human transplant medicine." Professor Zhu Tongyu said.
In October 2021, David Bennett enrolled in UMMC for treatment due to end-stage heart failure due to complicated hereditary heart disease. A number of U.S. transplant centers have assessed that Bennett's arrhythmias are so serious that he is not suitable for implanting an artificial heart, but his underlying conditions are not eligible for human organ transplant waiting lists.
In accordance with the "compassionate use" requirement, on December 31, 2021, the US FDA approved the emergency authorization for surgery of "pig heart transplantation". The surgery was performed a week later, and the results are considered another brand-new milestone in the history of xenotransplantation:
There was no immediate rejection after the pig heart transplant, and the function lasted for more than a month. The previous time, in 1984, a baby in California received a heart transplant from a baboon and survived only 21 days after the operation.
In January, David Bennett underwent a swine heart transplant
One of the important reasons for the initial success of this transplant is that the corresponding pigs have undergone gene editing:
Knock out 3 rejection-related genes to reduce the aggressive rejection response of the human immune system;
Knock out 1 growth gene to prevent the pig heart from continuing to grow after transplantation;
Six human genes were edited and inserted into the donor pig's genome to make the pig's organs more tolerant of the human immune system.
Before David Bennett's death, according to information previously released by the hospital, his body was also slowly recovering. In February, the hospital also released a video of him watching a rugby game with a physical therapist.
Speculation about the cause of death, organ rejection, infection and other complications, and even the patient's underlying physical condition may be the cause.
Professor Zhu Tongyu speculates that the biggest reason may be the rejection reaction.
"Although patients have successfully survived the ultra-acute rejection after surgery, acute and chronic rejection remains a major obstacle in the transplant community." Professor Zhu Tongyu said, "Although the donor pig has undergone gene editing, the difference between it and the human genome is not on the order of magnitude after all, and we still need a long time to explore and optimize the scheme in the future." ”
At the same time, the presence of infection is not excluded. "As far as I know, the immunotherapy program after this pig heart transplant is much stronger than the conventional solution in humans and humans, and the use of these drugs may cause serious suppression of the human immune system."
According to UMMC, doctors used an innovative drug on Bennett after surgery to prevent rejection after organ transplant surgery. "It may also mean that we need to do more evaluations of the use of these drugs." Professor Zhu Tongyu said.
It is reported that overseas experts hope that the UMMC research team can publish David Bennett's body's response to pig hearts in medical journals as soon as possible, so as to provide more research data for the academic community.
On March 9, UMMC released its official tribute, and Dr. Bartley P. Griffith, clinical director of the Heart Xenotransplant Program, said that thanks to Mr. Bennett's unique and historic contribution to the field of human transplantation, we have obtained valuable information that the heart of a genetically modified pig can function properly in the human body while the immune system is fully suppressed.
Will it lower academic expectations for "xenotransplantation"?
Will David Bennett's death affect the course of clinical research in the field of xenotransplantation?
According to the World Health Organization, about 2 million people worldwide need organ transplants every year. Scientists around the world are trying to solve the shortage of transplanted organs in a variety of ways, and xenotransplantation is one of the most cutting-edge and promising ways.
Because pigs and humans are close in terms of food habits, metabolic levels, body temperature, heart rate, and the "performance parameters" of some organs are also similar to humans, it is often used as the best choice for xenotransplantation.
On January 20 this year, researchers at the University of Alabama's Birmingham (UAB) School of Medicine implanted the kidneys of a "genetically modified pig" in a brain-dead patient, and the kidneys worked successfully after surgery. "The hopes of millions of patients are pinned on this project." At the time, UAB said clinical trials in "living patients" would begin this year once it was approved by the FDA.
And because of Bennett's death, citing the Associated Press, according to recent cases, the question we face is what evidence there is to persuade the FDA to allow clinical trials, that is, even if the transplant fails, it will not cause the patient to die immediately.
The Associated Press said overseas experts believe Bennett's death should not slow efforts to study how animal organs can be used to save human lives.
"I think for FDA experts, the outcome of Bennett's death should be expected." Professor Zhu Tongyu told the medical community, "In fact, his survival for two months is already a very ideal result, and I don't think this will have a negative impact on further xenotransplantation research in the future." ”
"Instead, we need to be careful not to be overly optimistic and aggressive in cutting-edge medical research." Professor Zhu Tongyu said that the FDA emergency authorized surgery is based on "compassionate use", and patients have no way out, "and before really entering large human clinical trials, scientists need to further explore more ways." For example, is it possible to simulate the immune environment of a human in vitro to evaluate the results of xenotransplantation by different gene editors? ”
"At the same time, how many genes in pigs will eventually need to be edited?" Which genes are edited? How to further establish a sound zoonotic disease and immunological evaluation system? Further clinical research is required. ”
"We can't be too hasty, but we can't stay put, we need to act as soon as possible." Professor Zhu Tongyu concluded.
Pan Dengke, deputy director of the Organ Transplant Research Institute of Sichuan Provincial People's Hospital, told the "biological world" that the first human same heart transplant only survived for 18 days, but completely changed the old pattern of organ transplantation at that time. Today, the first genetically engineered pig xenocardial heart transplant in humans survived for two months, which can undoubtedly change the new landscape of this field.
Dr Griffith also said in his tribute: "As with any of the world's first transplants, this time brings valuable insights that promise to inform transplant surgeons and give more hope to future patients." ”
bibliography:
1.Patient in Groundbreaking Heart Transplant Dies，https://www.nytimes.com/2022/03/09/health/heart-transplant-pig-bennett.html
Source: Medical community
Editor-in-charge: Zheng Huaju
Proofreader: Zang Hengjia
Plate making: Xue Jiao