Lung transplantation is the most risky and difficult of all organ transplants. In a simulated transplant, the scientists used two special enzymes to change the blood type of the lungs.
Among the various types of organ transplants, lung transplants are a type of considerable or even the most difficult. Every year, many patients who are waiting on the waiting list die because they can't find a matching lung in time. Part of the reason for this lack of transplantable lung numbers is a mismatch between the donor lungs and the patient's blood type. Canadian scientists recently published a study in the internationally renowned medical journal Science Translational Medicine, using a "molecular scissors" method, they turned the lungs of the original A blood type into type O, which can theoretically be transplanted to patients of various blood types. The significance of this method is not limited to lung transplantation, and may also be used for blood group modification of other transplanted organs in the future.
It's not too late to start
Compared with liver, kidney and other organ transplants, the medical community is not late to explore lung transplantation, but it is much later to succeed for the first time in humans.
On April 3, 1933, Soviet doctor Yuriy Vorony performed the world's first kidney transplant, but the operation was unsuccessful, and the transplanted patient died two days later. But 17 years later, the medical community's exploration of kidney transplantation has paid off. On June 17, 1950, American physician Richard Lawler performed a kidney transplant for a patient with a genetic disease of polycystic kidney disease. The transplanted kidney allowed the patient to live for 5 years.
Liver transplants started much later than kidney transplants, but were quickly successful. On March 1, 1963, Thomas Starzl, a doctor at the University of Colorado in the United States, performed the world's first human liver transplant, but the operation was unsuccessful. However, the first successful liver transplant only waited 4 years. On July 27, 1967, Staz performed a liver transplant for a 19-month-old baby girl with liver cancer. The surgery allowed the baby girl to live more than 1 year longer, but the cancer metastasis eventually took her life. For his outstanding contributions to liver transplantation and other organ transplantation, Staz is also known as the "father of organ transplantation" by the medical community.
In fact, the exploration of lung transplantation started only 3 months later than liver transplantation, but the road to success is much bumpier. On June 11, 1963, three months after Thomas Staz performed the world's first human liver transplant, James Hardy, a doctor at the University of Mississippi in the United States, performed the world's first human lung transplant, but the patient who received a single lung transplant survived only 18 days. Although the medical community has subsequently made many attempts at lung transplantation, all of them have failed. The success of the first lung transplant will not come until cardiopulmonary bypass (temporarily taking over cardiopulmonary function through cardiopulmonary bypass, keeping the blood circulating during surgery, removing carbon dioxide from the blood and providing oxygen) and some immunosuppressive drugs. Countless patients and their families have to wait for 20 years: it was not until 1983 that the medical community successfully achieved the first single lung transplant, and 3 years later, the first double lung transplant was successful. Both "firsts" were created by Joel D. Cooper, a physician at the University of Toronto in Canada.
The most difficult
Although nearly 40 years have passed since the success of the first lung transplant, to this day, lung transplantation is still more difficult than liver, kidney and other organ transplants. This can be seen in part in the number of medical institutions with lung transplant qualifications. According to the "List of Medical Institutions with Human Organ Transplant Practice Qualifications" released by the National Health Commission of China in 2021, a total of 180 medical institutions across the country have organ transplant qualifications, of which 109 and 143 can carry out liver transplantation and kidney transplantation, respectively, while only 49 can carry out lung transplantation. There are even more institutions that can perform heart transplants than there are 66 institutions that can perform lung transplants. According to Dr. Yang Jun, The Department of Thoracic Surgery of Shanghai Chest Hospital, in an interview with Chinese media, "the lungs are always exchanging gas with the outside world, the difficulty of the operation itself and the infection control after the operation, the postoperative chronic rejection reaction, etc. Lung transplantation is more serious than other organ transplants", so "lung transplantation can be said to be the most difficult and risky of all organ transplants."
In addition to technical and other reasons, the lack of eligible lungs for transplantation also makes lung transplantation more difficult. According to the latest data that can be found (2019), a total of 5818 cases of organ donation were completed nationwide in 2019 (some types of organs can be used for transplantation of more than one patient), of which only 489 cases of lung transplantation. In the United States, where statistics are more comprehensive and open, liver and kidney donations completed in 2021 were 9236 and 24670, respectively, while lung transplantation was only 2524 cases.
As with other organ transplants, one obstacle to a patient getting a matched lung is that the donor does not match the patient's blood type. The effects of this condition appear to be more severe in the case of relatively few donated lungs. This can be seen in the waiting time on the organ transplant waiting list for patients of different blood types: patients with the highest requirements for blood group A, B and AB blood types have longer waiting times on the waiting list and a 20% higher risk of death during the waiting period than patients of other blood types.
There is no doubt that if this blood group matching problem can be solved, then the waiting time for patients may be greatly shortened. The study, published in Science translational medicine, is trying to solve this problem. The researchers hope to start with lung transplants, which are the most difficult to transplant and have relatively few donated organs, to convert lungs that could not be used for transplantation because of blood group mismatch into lungs that can be transplanted by specific patients. In this study, the scientists turned the lungs of the original type A blood into the lungs of the O blood type that could theoretically be used in all patients. The scientists leading this innovation come from institutions with a well-known reputation for lung transplantation and an excellent tradition: like Joel Cooper, who successfully completed lung transplants for the first time, they are from the University of Toronto in Canada (and collaborators are from the University of British Columbia, Canada).
A、B、H
In the familiar ABO blood group system, people's blood types are divided into four types: A, B, AB and O. These blood types get their name from the antigens that "stand" on the surface of red blood cells. There is an A antigen on the red blood cells of type A blood, a B antigen on the red blood cells of type B blood, and both A antigen and B antigen on the red blood cells of type AB blood. There are B antibodies and A antibodies in the blood of the two blood types A and B, respectively, and there is neither A antibody nor B antibody in the blood of the AB type. If blood types are incompatible at the time of blood transfusion — such as the infusion of type A blood into a person with type B blood — the corresponding antibodies in the blood react with antigens on red blood cells, causing red blood cell agglutination to block capillaries and red blood cell rupture and hemolysis, a series of chain reactions can be life-threatening. Since people with the AB blood type have neither A antibody nor B antibody in their blood, they can receive blood of any blood type in an emergency (but the amount cannot be large, and the principle of blood transfusion is always homotype blood transfusion).
In the public perception, many people mistakenly believe that there is no antigen on the surface of the erythrocytes of type O blood. But as far as the ABO blood group system is concerned (there are other independent blood group systems, each with its corresponding antigen), there is an H antigen on the surface of the red blood cells of type O blood. This H antigen does not react with A and B antibodies, which is why blood type O can be transfused to people of any blood type in an emergency. In fact, H antigen is also the basis of A and B antigens: the human body takes the H antigen as the "base", adds additional elements to it, and produces A antigen and B antigen (there are indeed a few people who do not even have H antigen on the surface of red blood cells, and the blood type of these people is the so-called "Mumbai blood type", which is often called "panda blood"). If you remove these extra elements on the A and B antigens, then theoretically you can transform the red blood cells of type A and B blood into red blood cells of type O blood.
The research team at the University of Toronto adopted exactly this strategy: using two "molecular scissors," they "cut" off the excess antigen elements on the red blood cells of type A blood lung, leaving behind the H antigen.
On July 21, 2020, after 166 days of hospital treatment and 92 days of lung transplantation, Cui Zhiqiang, the first patient with end-stage lung transplantation of new coronary pneumonia in Hubei, was discharged from wuhan university people's hospital. (Visual China/Photo)
"Molecular Scissors"
This H antigen on the surface of erythrocytes is a sugar chain consisting of 4 (3 in total) sugar modules. When synthesizing H antigens, the body uses enzymes to add these sugar modules one by one to a "skeleton" on the surface of the cell. The synthesized H antigen not only provides an identity for O-type erythrocytes, but also provides a "base" for A, B, ab-type erythrocytes to produce their own antigens. Using different enzymes, different blood types of the body add two sugar modules to the H antigen. Adding one of the sugar modules produces an A antigen, and adding another sugar module produces a B antigen, corresponding to A and B blood groups, respectively. On the erythrocytes of AB blood, the body adds a sugar module to some "skeletons" and another sugar module to other "skeletons".
In 2019, using a stool sample from a man with type AB, the team's scientists screened nearly 20,000 genes in his gut microbiota and found two special enzymes. These two enzymes act like scissors in two steps to "snip" the excess elements on the A antigen and convert it into the H antigen.
In the new study, the team explored whether it was feasible to use these two enzymes to engineer the blood type of transplantable organs. The researchers first tested the effectiveness of these two enzymes at a lower level. Since previous studies have shown that these two enzymes can convert the A antigen on red blood cells into the H antigen, these tests in the new study are based on the shallow and in-depth demonstration of whether subsequent experiments on the lungs are feasible.
The scientists first examined whether these two enzymes were able to efficiently function in the perfusion fluid of the ex vivo lung perfusion system. By perfusing and ventilating the lungs at room temperature, the system is able to mimic the internal environment of the donor lungs and is used to preserve, evaluate, and treat the lungs (including various treatments for the donor lungs prior to transplantation). On the other hand, the exploration of the final stage of this new study was also carried out on the lungs perfused in vivo. Therefore, it is very necessary to first test the effectiveness of these two enzymes in the perfusion solution. Their tests found that by simply adding a small amount of the enzyme to the perfusion solution containing type A RBCs and standing for 30 min, all the excess elements of the A antigen on the surface of the erythrocytes were "spliced" by these two enzymes, thereby converting the A antigen into an H antigen.
Previous studies have found that in addition to being distributed on the surface of red blood cells, antigens that determine blood group may also be distributed on the surface of some other types of cells. The researchers of this study used the staining method to observe, and they found that on the surface of some cells in the lung, there are also antigens that determine blood type. In view of this, the researchers explored at the tissue level before trying to change the blood type of the lungs. They used the aorta of people with blood type A to verify the effectiveness of both enzymes. Like red blood cells in the perfusion fluid, they found that with only a very low dose of the enzyme, the A antigen on the aorta could be converted to the H antigen in a very short time (within the time that the donor perfusion system processes the donor lung before transplantation).
"Cut" out the O-shaped lungs
Finally, the researchers tried to convert 8 pairs of blood type A lungs on an ex vivo lung perfusion system (all of which were pre-evaluated and used lungs that could no longer be transplanted). These lungs are connected to an ex vivo perfusion system, simulating the state of the environment within the body. The scientists then added these two enzymes to the perfusion fluid and tested the antigens in the lungs 1 h and 3 h after perfusion. The test found that after only 1 hour of perfusion, more than 97% of the A antigen had been removed, and more and more H antigens appeared. In addition, the researchers observed neither significant changes in the state and physiological function of the lungs nor signs of an inflammatory response. This method of using "molecular scissors" to change the blood group of an organ does seem to be feasible.
Undoubtedly, the most direct test of the effectiveness of this method is the use of blood group-converted lungs for transplant experiments. But because of the lungs used in the study that could no longer be used for transplantation, and the risk of preliminary experiments, the researchers were unable to actually use these lungs that changed their blood type for transplantation. So they conducted a simulated transplant study using 3 other pairs of lung types of blood type A.
In a simulated transplant study, the researchers first split a pair of lungs in two, connecting each side of the lungs to an isolated perfusion system. In both perfusion systems, one adds these two enzymes to the perfusion solution and the other does not. Since the lungs of the two systems come from the same donor, the two can be compared to each other. After being fully treated by the enzyme, the scientists added plasma of type O blood to the two systems, simulated the process of the lung being transplanted into a patient with type O blood, and tested the various indicators of the lung in the next 4 hours. The study found that after enzymatic treatment, the lungs converted to type O blood did not have an immune response to the A antibodies in the type O blood added to the perfusion system. Without enzymatic treatment, the lung that serves as the control will soon bind the A antibody in the perfusion fluid to light. This means that the A antigen in the lung tissue produces a significant immune response with the A antibody in the perfusion fluid. Correspondingly, after adding plasma of blood type O to the perfusion system, the function of the lungs without blood type conversion and some other indicators show abnormalities due to the immune response, while the side lung that has converted blood type does not have and can perform functions normally.
This series of results initially proves that with this "molecular scissors", the lungs of blood type A can be converted into type O for transplantation by patients of various blood types. From the perspective of the similarity of principle, if the right enzyme can be found, there is no reason why the lungs of type B blood cannot be converted to type O. In addition, if the blood type of the lungs can be converted, then the blood group of other organs such as the liver, kidneys, and heart can theoretically be changed with this strategy. Therefore, the most significant significance of this study is to provide a possible strategy and method for modifying various O-type , that is , general-purpose — transplantable organs.
Next
While the results of this study are encouraging, it seems premature to apply it to the clinic. One problem the researchers in this study were aware of was that there was always an enzyme in the body of blood type A responsible for adding an A antigen element to the H antigen. This means that if the modified lungs are really transplanted into the human body, these enzymes may re-add these elements to the H antigen, converting the original "cut" H antigen back into the A antigen, which may trigger the body's rejection of the lungs.
Therefore, along the direction of this study, the next more plausible exploration is to change the blood type of the laboratory animal organs in this way, transplant them into animals of other blood types, and observe the animals' responses. Among all kinds of experimental animals, the baboon is the closest animal model to humans, but for many reasons (such as time-consuming, costly, etc.), the team at the University of Toronto believes that it is not the best choice to use baboons to conduct research now, so they intend to use mice to further verify the feasibility of this method. If the validation is successful, they believe this approach will dramatically shorten the time patients spend waiting for transplantable organs in the future.
Southern Weekend contributed to Chen Bin