Recently, a number of foreign media reported that the New York University Langone Medical Center has just conducted a special experiment - a medical team in the United States successfully transplanted a gene-edited pig kidney into a brain-dead female patient with renal insufficiency, and let the patient's blood creatinine return to normal, and the new kidney currently has good function of filtering waste and producing urine.
If the surgery is successful, this will show that the pig's organs can be safely used to save human lives. This makes one wonder: What is the point of this surgery? Why are pigs so powerful? When can it be used in the clinic for the majority of patients to use?
At present, the reason why this surgery has attracted attention is that it has a certain innovative significance - it verifies that knocking out α-gal xenozoan organs does not cause ultra-acute rejection in the human body, and the development of xenograft transplantation technology is further.
Image source: eGenesis.com
In general, organ transplantation may cause rejection, and some rejection reactions occur very quickly and violently, and organs often die in a few hours, and patients will die quickly. This is hyperacute rejection, which is common in cases of blood group inconsistencies and pre-existing antibodies in xenotransplantation and allogeneic organ transplantation.
However, in the eyes of the professional medical community, this operation is not enough to solve all the problems of xenotransplantation, and there is a certain amount of flattering and showy ingredients.
Specifically, the first recipient is a brain-dead woman, after the consent of the family, the doctor transplanted the pig kidney to the blood vessel of the recipient's thigh, rather than transplanting it to the internal iliac artery and vein like a normal organ transplant, which only facilitates the appearance and functional state of the kidney from the outside, not to prolong the life of patients with kidney failure.
When asked in the follow-up, "how long has this kidney survived in the patient", the chief surgeon only secretly stated: "The effect exceeded our expectations", "the amount of urine you expected", "the creatinine returned to normal", and "the pig kidney took effect almost immediately".
According to foreign media reports, the experiment ended after only 54 hours of continuous observation — and the recipient, the life support facility of the brain-dead woman, was also removed, and the experiment was over. If the experiment continues, the body's acute rejection may destroy the pig kidney, the experiment will fail, and the so-called "era of xeno organs for human transplantation is coming" will be falsified.
Why is xenotransplantation so popular? At the beginning of life, the human body functions intact, like a newly bought new car; but as we age, the new car becomes an old car, and it may need to be "repaired".
But to repair the "parts" of the human body, it is also necessary to have real "organs". It may be artificial organs (such as artificial joints and artificial hearts), it may be autologous organs (such as skin), or it may be allogeneic organs and xeno organs, so there is also the procedure of "organ transplantation".
Human exploration of organ transplantation began hundreds of years ago. In the 17th century, some people tried to use animal blood to transfuse human blood with large blood loss, and the result was that the patient died on the spot; at the beginning of the last century, doctors also increased the exploration of xenomorph organs, transplanting rabbit kidneys to children with underdeveloped kidneys; subsequently, other doctors also began to look for the source of human organs from goats, pigs and primates, but because of the strong immune response of the human body to xeno organs, it was enough to cause their death.
Humans finally realized that xenotransplantation can cause a very serious rejection reaction; since then, people have focused on human organ transplantation experiments, and in 1954 completed the first successful kidney transplant in human beings, because the donor and recipient are identical twin brothers, so there is no rejection at all.
However, not every patient is so lucky, follow-up human organ transplantation is more dependent on allogeneic organs, and solving rejection is the key.
It is reported that the main solution is to conduct ABO blood group, HLA matching, and lymphocyte toxin cross-coordination tests before surgery to select those with the mildest rejection between donors and recipients for transplantation. However, patients undergoing organ transplants also need to take lifelong immunosuppressants (such as cyclosporine, corticosteroids, azathioprine, etc.) to suppress the rejection of foreign organs by the immune system. The cost is that infectious immunity is reduced, making it susceptible to disease.
Nowadays, such a set of "matching - lifelong medication" allogeneic organ transplantation method has become a clinical organ transplant routine.
But far more patients now need to undergo organ transplantation than can be transplanted each year. According to data, about 300,000 people in China need organ transplantation every year, and only about 10,000 people can receive transplant surgery every year due to the limitations of organ sources, economic conditions and medical conditions; there are about 120,000 patients waiting for organ transplantation in the United States every year, and fewer than 30,000 people can successfully carry out transplantation. This has also given birth to a certain extent to the black industry of "organ trading".
How to solve the problem of organ donor loss has become a concern of the academic community and industry, and everyone will return to the perspective of xenotransplantation again.
Why are pigs the "best" source of donors?
It is reported that after a round of failed experiments on goats, baboons, rabbits, and dogs, pigs have received people's attention and are regarded as an ideal source of organ donors, because pigs have abundant sources, and many organs on the body, such as hearts, kidneys, etc. are about the same size as people, and their functions are more similar.
Comparing the size of organs in humans and pigs, the picture comes from nai500.com
However, even if the transplanted pig organs, there are still two problems: first, or immune rejection, if the transplanted organs are not immune homologous, it is easy to cause the killing of our own immune cells, which eventually leads to the failure of organ transplantation; secondly, the transplanted organs may have viruses, causing immeasurable harm to the recipient.
To solve these problems, scientists have tried to use gene editing technology to "remove" many biological barriers between pigs and humans and promote xenotransplantation.
It is reported that the United States took the lead in breeding medical pigs, in 2003, the United States Revivcor company created the world's first knockout α-gal cloned transgenic pig (GTKO pig), and now the United States heterogeneous skin graft has been approved by clinical trials, GTKO pigs have become the world's recognized donor base. The pig reported in this news for organ transplantation is from Revivicol.
Image source: IC Photo
However, this is only the basis of xenotransplantation, and there are still many problems to be solved. At present, α-gal knockout can evade ultra-acute rejection, but it is only one of the ultra-acute rejection targets, and there are many other targets, such as CMAH gene, β4GalNT2 gene and ASGR1 gene, if they are all knocked out, the possibility of xenograft ultraacute rejection may be minimized.
CMAH gene: N-hydroxyacetyl neuride (Neu5Gc), an enzyme encoded by this gene, is an important non-galactose antigen that plays a rejection reaction for xenografting. The presence and expression of the CMAH gene can cause xenotransplant immune rejection;
β4GalNT2 gene: The enzyme encoded by the β4GalNT2 gene can catalyze the Sd(a) blood group antigen, when the organ of the pig is transplanted to primates, the Sd(a) blood group antigen can be bound by immunoglobulins and cause immune rejection;
ASGR1 gene: THE ASGR1 protein is expressed in pig vascular endothelial cells, which can be recognized and attacked by the recipient's immune cells, causing acute intravascular coagulation, resulting in rapid inactivation of pig organs. At the same time, it can also induce thrombocytopenia in receptors after xenotransplantation.
In addition, pigs can also introduce some human genes, such as CD55, CD59 - are important human complement inhibitors, which can reduce the occurrence of ultra-acute rejection and inflammatory reactions, which can be understood as natural inhibitory immunomodulators.
However, in addition to ultra-acute rejection, pig organs may also face acute rejection based on ABO blood group and HLA complex, which may cause severe endothelial thickening, damage, ischemia and thrombosis after transplantation, and to avoid these reactions, more genes will be knocked out; in addition, there are cell rejection, chronic rejection; and the problem of some physiological functions of organs between different species is not clear; and the various known or unknown pathogens carried by pigs are not clear. At present, only part of it has been solved.
Judging from this operation, it is reported that the donor gene editing pig only knocked out the α-gal gene, and has only taken the "first step of the long march", which is still far from being able to completely avoid various rejection reactions in the human body.
In addition to these, there are complex ethical issues: even if humans receive xenotransplant studies, if used clinically, it is unpredictable that xenografts may be infectious and carried to xenograft recipients and widely spread to society, causing disaster.
As mentioned earlier, combined with the cost of organ transplant surgery of 300,000 yuan to 400,000 yuan per patient, this is a huge and unmet market. Xenotransplantation has a broad stage, and some companies have entered this blue ocean field.
For example, in September 2020, Hangzhou Qihan Biotechnology Co., Ltd., co-founded by Professor George Church and Dr. Luhan Yang, a pioneer in the field of gene editing, announced that it has made the first generation of heterogeneous organ transplant prototypes that can be used for clinical practice - "Pig 3.0", which has better immune compatibility and eliminates the endogenous retrovirus (PERV) of pigs.
Founded by Dr. PanDenko, the leader of the first cloned pig experiment in China, Zhongke Auger has bred more than ten kinds of genetically modified humanized pigs through gene editing and cloning technology for the research and development of xenotransplantation, solving the shortage of clinical transplant organs, and is currently preparing to build an ultra-clean pig facility (DPF) medical grade xenotransplantation medical donor base after recently completing financing to prepare for clinical trials.
As for overseas markets, eGenesis, a sister company of Kaihan Biologics, completed a $125 million Series C round in the first quarter of this year, is currently creating models of three pigs, and is also testing the efficacy and safety of genetically engineered organs, with clinical trials expected to begin in 2022.
In addition to the development of GTKO pigs for heterogeneous skin grafting, the gene-edited pig "GalSafe Pig" developed by The aforementioned Revivcor also received approval from the U.S. Food and Drug Administration (FDA) late last year for both edible and medical products.
In addition, Miromatrix Medical, which focuses on the use of pig organs for human xenotransplantation, went public on the NASDAQ in June this year, becoming the first xenotransplantation company to go public, and it is expected that by the end of 2022, it will begin human clinical trials of its bioengineered liver supported by an external liver assist system.
It is foreseeable that this news will more or less lead to a sharp rise in the stock price of Miromartix Medical and an increase in the valuation of many companies in the secondary market. However, objectively speaking, combined with the current research and development and the current situation of the industry, the new era of organ transplantation of xenomorph organs to replace human organs is far from coming, and scientists still need to continue to explore.
<h3>Read more</h3>
Knowledge | Change the body for a "part" and use artificial organs to "continue life"
<h3>bibliography</h3>
How long do we have to go to transplant pig organs to humans? A section of ginger;
Xenograft milestones! People have successfully transplanted kidneys from pigs, why are pigs the ideal source of organs? Popular Science China;
The world's first human surgery for pig kidney transplantation: it cannot bring a new era of organ transplantation, but only a surge in related stocks, Dr. Philip.