At the beginning of 2022, the University of Maryland Medical Center in the United States conducted the world's first human multigene-edited pig heart xenotransplantation.
Recently, the patient tragically passed away after 2 months of living.
Such results let everyone understand that xenotransplantation is still far from real clinical application, but in scientific research, this is already a great progress.
Xenotransplantation is expected to solve the problem of difficult organ sources to a large extent, but it has led to more discussions. Why choose pigs as organ donors?
Cross-species transplantation, can people still be called people?
How far is xenotransplantation technology from us?
Why choose pigs as organ donors
Organ transplantation is the only way to fundamentally treat organ failure.
After decades of development, the transplantation of clinical human organs (such as liver, kidney, heart, etc.) has matured and saved tens of thousands of lives.
However, there is a severe shortage of donor organs, resulting in a large number of patients dying because they cannot receive timely treatment.
Taking my country as an example, according to incomplete statistics, less than 20,000 patients undergo organ transplants every year.
The number of patients waiting for organ transplants is as high as 1.5 million, and the number is increasing by about 300,000 cases every year.
The same is true worldwide.
To address the shortage of clinical organ donors, scientists have turned their attention to animal organs, known as xenotransplantation—the transfer of organs from one species to another.
So why was the pig chosen?
This starts with the history of xenotransplantation research.
Xenotransplantation research has been carried out for decades. Scientists first selected primates such as chimpanzees and baboons, which are closely related to humans, for clinical application exploration—for patients on the verge of death due to organ failure, early Xenotransplantation.
Back in the 1960s, American scientists xenotransplanted a chimpanzee kidney into a patient who lived for nine months.
In the 1980s and 1990s, American scientists transplanted the heart and liver of baboons to a newborn and a 35-year-old patient, respectively, and achieved 20-day and 70-day survival records.
However, with the deepening of research, scientists found that primates are not suitable as xenogeneic organ donors.
The main reason is that most of these primates belong to wild animals, which may transmit microorganisms in nature to humans.
At the same time, the organs of animals such as baboons and monkeys are small and difficult to use for adult transplantation; while chimpanzees are endangered animals and are not suitable as donor objects.
In comparison, miniature pigs weighing around 80 kg have significant advantages in several respects.
As one of the first animals domesticated by humans, pigs have coexisted with humans for millions of years, with less risk of transmitting natural microorganisms to humans - pigs that meet the "specified microorganism free" (DPF) standard have been approved by the US Food and Drug Administration. Approved by the Bureau for clinical application.
More importantly, the organ size, physiological function and other indicators of miniature pigs are close to those of humans.
For example, the size, structure, and heart rate of pig hearts are similar to those of humans; if a small pig heart and a human heart are put together, it is difficult for ordinary people to distinguish them.
In addition, pigs are multi-littermate animals that are easy to breed and genetically modify.
Therefore, miniature pigs are currently recognized as the most ideal donors for xenotransplantation.
Is clinical application still far away?
Although xenotransplantation has solved many problems and brought hope to more patients.
But there are also many insurmountable bottlenecks.
For example, human rejection of xenogeneic animal organs is much stronger than that of human-derived organ transplantation, and is accompanied by complex side effects such as microthrombosis.
This rejection cannot be effectively overcome by medication alone, which is the main obstacle restricting the clinical translation of this technology.
To this end, scientists have prepared gene-edited pigs suitable for xenotransplantation by modifying the immune, physiological and other genes that lead to xenotransplantation.
In previous animal experiments, primates transplanted with gene-edited pig kidneys and hearts, respectively, have survived for more than 499 days and 180 days.
It is precisely based on these studies that scientists believe that the time for the transformation and application of pig organ xenotransplantation is becoming more and more mature, and the first human transplant of gene-edited pig heart that we have seen today.
So, can all vital organs be provided by gene-edited pigs?
the answer is negative.
Different organs have different immunological and physiological properties, which lead to different organ rejection characteristics after different organ transplantation.
At present, pig kidneys and hearts can survive long-term after transplantation in primates.
However, organs such as liver and lungs of pigs will still be rejected in a relatively short period of time after transplantation in primates, and have not yet reached the standard of clinical transformation.
Therefore, the most promising candidates for clinical xenotransplantation in the short term are porcine hearts and kidneys.
However, in general, the current technological maturity of xenotransplantation has not yet reached the standard for rapid and large-scale clinical application.
In the aspect of gene-edited pig kidney xenotransplantation, primate-based organ transplantation evaluation is the main yardstick for measuring the maturity of xenotransplantation technology. At present, many teams have achieved long-term survival after primate transplantation.
However, the success rate requirements that can meet the clinical trial have not been obtained, and further exploration is still underway.
In terms of xenotransplantation, only the research team in Munich, Germany has achieved a survival of more than 6 months after orthotopic porcine heart transplantation.
However, the team of Dr. Mohiuddin, University of Maryland School of Medicine, previously publicly reported that the longest survival time of porcine heart transplantation in primates was less than 2 months, which did not reach the technical maturity of clinical translation application.
Even if a major breakthrough has been made in primate experiments and transplanted to humans, there is still a long way to go - there are still many differences between humans and primates, and the transformation and application of this technology still needs to undergo strict procedures. tested in clinical trials.
Therefore, it should be pointed out that this world's first gene-edited pig heart transplant is not a real clinical trial, but a specially approved operation by the relevant US administrations out of "compassionate use" for patients. 1 patient cannot be sustained by a mechanical pump, does not meet the criteria for an allogeneic human heart transplant, and will soon face death without surgery.
The technique used in the clinic needs to be cautious and cautious.
It should be acknowledged that, as a new technology, xenotransplantation still has many limitations.
Although scientists can currently edit dozens of pig genes and prepare complex gene-edited pigs, which gene editing is necessary and which gene introduction may be harmful, these questions are still unanswered and need a lot of research to confirm .
What questions still need to be answered
Even if xenotransplantation can overcome technical barriers such as immune rejection, can you rest easy?
Maybe, it can't.
People still have a lot of concerns.
As researchers in this field, we are often asked a lot of questions by our friends and relatives, and the following two are more concentrated.
Question 1: Will xenotransplantation change human habits?
It has been reported that after receiving human organ transplantation, the patient's temper, habits and personality will change greatly, and he is close to the organ donor.
Scientists do not yet have a clear explanation for this phenomenon.
We know that the brain is the main organ that regulates human emotions and judgment. Therefore, there is no need to worry that transplanting animal organs will affect human behavior or personality.
Question 2: Will xenotransplantation cause people to contract new diseases?
The risk of microbial transmission that may result from xenotransplantation is one of the key concerns for scientists.
As mentioned above, pigs coexist as livestock and humans for a long time, and the probability of carrying microorganisms that seriously harm humans is relatively small.
In addition, pigs for xenotransplantation need to be raised in a special clean environment and meet strict microbiological testing standards.
In fact, porcine islet xenotransplantation has been used clinically for many years, and no single case of cross-species transmission of pathogenic microorganisms has been found.
Therefore, the international scientific community generally believes that the risk of cross-species transmission of pathogenic microorganisms brought by pig organ xenotransplantation is very small.
Of course, scientists will still carry out long-term and rigorous tracking of pig organ xenotransplantation patients that have been carried out or will carry out, and their contacts, to minimize risks as much as possible.
The results of the world's first clinical xenotransplantation of a pig heart show that the gene-edited pig heart has the potential to maintain human life activities. The xenotransplantation scheme can better avoid super acute transplant rejection, but it also indicates that the clinical application of xenotransplantation technology is still Many challenges need to be overcome.
my country started relatively late in the field of xenotransplantation, and has not yet realized the long-term survival of pig organs after primate transplantation. However, many research institutions have successfully produced multi-gene edited pigs suitable for xenotransplantation, and they have been used in the transplantation of pigs. Preclinical studies of porcine organ transplantation have been carried out on long animals.
It is believed that in the near future, Chinese scientific research teams will make more original breakthroughs in the field of xenotransplantation and promote the clinical application of xenotransplantation.
The future is bright, but the road is tortuous.
The faster, better and safer benefit of xenotransplantation technology is inseparable from the solidarity, assistance and joint efforts of all walks of life.
It is expected that in the near future, xenotransplantation will become a routine treatment, and organ shortage will no longer be a problem.
(Authors: Hu Zheng and Yang Yongguang, both are professors at the First Hospital of Jilin University)