The first successful operation of pig heart transplantation into the human body gave hope to patients with bitter organ transplants. Why do allogeneic organ transplants love "pig omnipotence"? How to solve ethical problems?
After 7 hours of surgery, a gene-edited pig heart bounced back in the body of 57-year-old David Bennett. This is also the world's first surgery for a pig heart transplant into a human body.
"It's a big gamble." David had received a pig valve transplant, and this time the heart situation worsened again, and after the consultation determined that he was not suitable for traditional heart transplant surgery, pig heart transplantation became his last choice to survive. After urgent authorization from U.S. regulatory agencies and patient consent, the University of Maryland Medical Center performed the procedure for him. During the most critical 48 hours after surgery, the patient did not have any abnormalities, but still connected to a variety of medical devices, and doctors are also closely monitoring the risks of infection, organ rejection, etc. that may occur at any time.
On January 7, 2022, doctors in Maryland, USA, transplanted the heart of a gene-edited pig to human patient David Bennett for the first time (Image source: Visual China)
Still, in the face of the reality of tight supply of human organs, this operation still brings new imagination space to xenotransplantation.
Whether xenotransplantation can be revived
There are two main branches of organ transplantation, one is "allogeneic organ transplantation", that is, the recipient and donor receiving organ transplantation are the same species, such as organ transplantation between people; the other is "xenotransplantation", such as transplanting animal organs into the human body.
At present, the vast majority of organ transplants performed in the clinic are allogeneic organ transplants, but due to the insufficient number of donors, many people cannot wait for a suitable organ until the last moment of life.
Experts estimate that about 300,000 patients on the mainland need organ transplants each year to save lives. In 2020, the ratio of donors to recipients in mainland organs will be 1:15. One for every 15 waiting patients has access to a life-saving organ, and although the condition has eased, a large number of patients are still waiting to leave.
In order to alleviate the contradiction of serious "short supply" of organ transplants, scientists have long begun to try animal organ substitution methods, and carrying out xenotransplantation has become an important way to solve the shortage of organs in the world.
Which animals can act as donors for organ transplantation? The first thing that comes to mind are monkeys, orangutans and baboons, who are closely related to humans. They belong to the same primates as humans, and their organ structure, physiological function, and metabolism are similar to those of humans.
▲ Illustration of people, monkeys and pigs under the X-ray machine (Image source: Visual China)
Back in the 1960s, surgeons tried to transplant organs from orangutans into humans. The recipient immune system quickly repels the transplanted organ, causing the transplanted organ to fail in a short period of time, leading to the death of the recipient of the organ transplant. The repeated failures of initial exploration have led to the realization that primate "close relatives" may not be ideal organ transplant donors.
The inclusion of primates as organ donor candidates also faces many problems, including technology and ethics. Most of the smaller species of primates, whose organ performance and size can not meet the needs of human metabolism, primates have a low reproductive rate, and the larger orangutans and baboons are themselves endangered and difficult to meet the human demand for organ transplants. They are "close relatives" with humans, and may also carry some viruses that humans are susceptible to infection, such as monkey immunodeficiency virus and Ebola virus, etc., once these organs are transplanted into the human body, recombination may produce more harmful viruses. Various unfavorable factors have dimmed the "aura" of primate candidates.
Scientists have turned their attention to animals whose external indicators are close to those of humans, such as body size, diet, and metabolic level. After layers of "screening", due to the advantages of organ size similar to that of humans, low risk of infectious diseases, and relatively sufficient quantity, pigs are considered to be the best choice for xenotransplantation at this stage.
From the performance parameters, the body temperature of pigs and humans is 36 ° C ~ 37 ° C, the size of the heart, the distribution of the pipes and the power output, and even the heart rate (the human heart rate is 60 ~ 100 beats / minute, the pig is 55 ~ 60 beats / min) are similar. The foreseeable scope of organ transplantation includes corneas, skin, islets, joints, tendons, ligaments, kidneys, heart, liver and many other aspects.
In the medical community, the heart valves of pigs implanted with human cells have been used for patient treatment, and the ligament tendon transplantation of pigs has also matured.
In September 2017, at the 14th International Xenotransplantation Society Congress in Baltimore, USA, the Emory University team in Atlanta announced that a macaque monkey in their lab had a rejection that occurred more than 400 days after receiving a transplant of a genetically modified pig kidney, several months longer than previously recorded. A team from the University of Munich in Germany performed a pig heart transplant on a baboon, and the graft persisted for 90 days.
German researchers transplanted the hearts of multiple baboons from pigs, and the baboons survived for 90 days (Image source: Nature)
At the same time, a small number of bioengineering companies use gene editing technology to improve the immuncompatibility of heterogeneous organs with human immunity by knocking out some pigs' genes and inserting human genes, and reducing the risk of infection of endogenous viruses in animals.
Genetic technology cracks some of the obstacles
Even though there are still many problems, with the blessing of gene editing technology, xenotransplantation seems to have opened a window for patients.
The main obstacle to all organ transplants is the behavior of the human immune system to "clear out dissidents.". Once a "foreign object" enters the human body, the immune system will attack and reject the "foreign object", and the transplanted organ may be destroyed within a few minutes. This ultra-acute rejection is not only seen in xenotransplantation, but also in interpersonal organ transplantation.
In response to ultraacute rejection, scientists have tried to perform animal experiments by removing the donor's antigen or using hemodialysis to remove antibodies from the recipient, but these methods have had little effect. With the development of gene technology, especially the advent of gene-editing technology CRISPR/Cas9, scientists can "knock out" a gene to achieve a more matching organ transplant donor.
At the same time, the researchers also added human genes to the pig body, so that after the pig organ is transplanted into the human body, it can produce normally functioning proteins, such as human thrombomodulatory proteins that inhibit blood clotting, and CD46, which can protect the organ from the attack of the host antibody immune response.
The potential risk of viral transmission from xenotransplantation is quite tricky. Studies have identified 26 pathogens at risk of interspecific cross-infection, including porcine endogenous retroviruses (PERVs). Although there are currently no reports of pervics causing illness in humans, PERV remains one of the main concerns of regulators worldwide.
New virus transmission cannot be "created" by allogeneic organ transplantation. To dispel concerns, scientists once again used the gene "knockout" method to achieve one-time knockout of pervic fragments hidden in the genome, and the viral infection rate dropped to one-thousandth of the original.
▲The organs of a pig can be widely used for the transplantation of human corneas, skin, islets, joints, tendons, ligaments, kidneys, hearts, livers and other organs (Image source: Nature)
In 2017, the team of Harvard University professor George Church and Luhan Yang published the results of the study in the journal Science. They bred the world's first pigs without endogenous retroviruses, fundamentally solving the risk that transplantation of pig organs into humans may lead to viral transmission. The following year, version 2.0 of the transgenic pig, which further solved the problem of immune rejection of xenotransplantation organ transplantation, was born. Since then, version 3.0 of the transgenic pig, which combines the advantages of the previous two generations, has gone one step further in the safety and efficacy of xenotransplantation.
▲Yang Luhan's team carried out gene editing and transformation of "Pig 3.0" (Image source: Nature)
Through known key gene loci in the pig and human immune systems, scientists can use gene editing to solve this problem. The world's first pig heart transplantation into a pig heart used in human surgery mentioned at the beginning has undergone 10 genetic modifications, including knocking out 1 gene for controller growth, 3 genes for human immune rejection, and inserting 6 genes that make pig hearts better adapt to the human immune system.
Of course, in order to obtain such an ideal organ transplant donor, it is necessary to maintain a completely sterile and virus-free "isolated" state in their living environment. It is conceivable that in an ultra-clean pig barn, they are monitored 24 hours a day, eating sterile and non-toxic feed and water, and undergoing quarantine inspection on time... All of this necessarily requires a great deal of financial and material investment.
An ethical challenge that cannot be avoided
Of course, from the perspective of solving the contradiction of "short supply" of organ transplantation, the technical and monetary problems should be solvable. So how to deal with ethical controversies?
Are humans transplanting pig organs considered "hybrids"? On this question, Professor Dai Yifan of Nanjing Medical University once responded from a personal point of view, he believes, "Just like a car has changed its engine, it is still the original brand of car, and the essence has not changed." If people replace pig hearts with pig hearts and become pig people, then patients with artificial devices in their bodies become robots? "Will the memories of animal organs be transplanted to people?" In clinical experiments, the elderly who transplanted the kidneys of young people, the hair would turn black, the heart of the grumpy person would be transplanted, and the temper of the gentle person would become grumpy... If organs do have "memories", how will xeno organs affect people's physiology and psychology?
▲ "Producing" organs like meat sausages for human transplantation! It's not a fantasy, the plots in those sci-fi films are becoming a reality (Credit: Nature)
In addition, the lifespan of different animals is different. The lifespan of general pigs is about 15 years, so will transplanted pig organs accelerate the aging of receptors? Where is the maximum amount of gene editing for xenotransplantation? Animal organs have a certain proportion of human cells, so should it be called "it" or "he"?
(Source of the article: Synthesized from the Intellectuals Zhihu Column, the Science Guild Zhihu Column, Xinhua Net)
Producer: Popular Science Central Kitchen
Producer: Beijing Science and Technology News | Beike Media
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