Rafael Mañez: "We talk about the illusion of man by transplanting pig organs"
Rafael Mañez: "We talk about the illusion of man by transplanting pig organs"
What are xenotransplants?
In short, they are transplants of interspecific cells, tissues or organs. In our case, due to its clinical interest, it can be said that the objective is to provide human beings with animal organs.
And what has been its evolution?
Research on organ transplants among species began in the 1960s. In the history of transplants, what popularized the issue was the heart transplant performed in 1967 by surgeon Barnard. But this was not the first heart transplant ever. Three years earlier, a very serious U.S. patient received the heart of the chimpanzee. With this I mean that the idea of xenotransplants is quite old.
The development of xenotransplantation took place in the 1960s, when humans began to place the kidneys of monkeys, especially chimpanzees and baboons. And the results were not at all bad. For example, in 1964 a patient received the chimpanzee kidney and was well for nine months. Human organ transplants that took place in those years were no better, as the problem of rejection became clear. The real breakthrough occurred in the 1980s. By then surgeons were technically prepared to perform transplants, but they could not overcome the problem of rejection. The detection of cyclosporine helped to avoid the problem of rejection, as it caused the drugs to lose the level of body defense in a balanced way.
In any case, during those years there was no stop in transplants?
In general, it can be said that there was a stop. For many years only kidney transplants were performed, and the results were not very good either, since one year after receiving the kidney the number of survivors was 50%. Therefore, for some years few transplants were performed. There was no effective system to deal with rejection. Therefore, the proper functioning of the chimpanzee kidney for nine months should be considered a great achievement.
In the 1980s, cyclosporine existed to overcome rejection in human organ transplants, a single xenotrasplante was performed in humans. In 1984 a girl of a few days was crowned by the baboon, with a 20-day operation. It was very difficult to find organ donors for that age, and that is why it became the xenotrasplante. The organ shortage caused the issue of xenotransplantation to resume in the 1990s. In 1992 we performed two xenotransplants at the University of Pittsburgh in the United States. We put a baboon liver to two patients, one survived 70 days and the other 21. Then we realized that we could overcome the problem of rejection at least for a while.
Did these xenotransplants have repercussions?
We had to hear a lot. Ten years ago, AIDS appeared, probably an evil produced by monkeys retroviruses. Faced with the risk of infection we had to rethink the issue. As for the closeness of the species, we begin to look for species far from the human being, since closeness increases the risk of infection. But the problem of rejection worsened. We started working with pigs, because physiologically it resembles man and there is a history: to combat diabetes has been used swine insulin, skin and heart valves... Well in this sense, but the problem of rejection worsened; if with the organs of the baboons the rejection appears at 4 or 5 days, the total rejection with the pig occurs half an hour after the transplant.
We only had to approach the pig to the man. With genetics techniques, we decided to put human genes into the pig so that the immune system could get closer. Thanks to this, we are currently reaching a duration exceeding one month and have managed to overcome the initial absolute rejection.
Was that the only reason to start working with pigs?
No, of course. It should be noted that many species of monkeys are protected and the demand for such existing organs could not be addressed. Ethical vision also has its importance because we consider monkeys as close. However, if trials with monkeys had had a good result, most of society would be in favor. Finally, the fact that the tests performed on pigs were effective and worked in some way also played an important role in making this decision.
However, pigs have a retrovirus called PERV. In the xenotransplants that have been done so far it does not seem to have caused problems, but will it not create them from now on?
When we chose the pig we didn't know it was that PERV. We know that pork products have been eaten in human history, that pigs have many infections that we control, such as trikinosis, but from there there is much room to transplant pork organs. As for the PERV, the truth is that we do not know much. That is why we cannot despise.
Retroviruses are actually endogenous, they do not become viruses. All mammals have some endogenous retroviruses in the genome, between 5 and 10% of our genes are endogenous retroviruses. Pigs have that PERV, but it doesn't affect them, like ours. This is whether or not it can be transmitted. In this sense, we know that in vitro tests carried out in laboratories, under very special conditions, the retrovirus has been transmitted, something that has not happened in live trials. Can it happen? I don't know. So far no one has been contaminated, we cannot say that this will not happen or happen.
Why should pigs used in xenotransplants be transgenic?
Otherwise, we could not overcome the body defense mechanism, sudden systematic rejection. Rejection occurs because all humans have antibodies against pigs, like those we have against human blood groups. The blood group of the pig is very different from ours. When we introduce a pig organ, the body considers it enemy and provokes rejection. Just as it is impossible to carry out blood transfusions between incompatible blood groups, transplanting pork organs to humans is impossible. Those responsible for the rejection are the antibodies against the pig and the proteins we call ingredients. When these proteins perceive something strange, without distinction, they destroy everything. Of course, the body stops boosting additional proteins, as it should only destroy bacteria and viruses and not their cells. All cells release other proteins that stop the starting of the accessory. These proteins belong to each species, that is, the proteins that control the complement of pigs stop the complement of pork, but not that of humans, and vice versa. Therefore, we include the pigs genes that are able to synthesize this type of human proteins, so that in organ transplantation consider them closer when they meet human supplements.
And how is it done?
Like any other transgenic product, by microinjection into fertilized eggs.
We have looked at the evolution of xenotransplants, but what are you currently doing?
With regard to the practice of xenotransplantation, no complete organ transplantation is currently performed on humans, or any other, except for experiments with non-human primates. The truth is that since 1992 they have not been done with human beings. There are rumors that a Polish surgeon has done some with pork organs, but officially it is not admitted.
Cell transplants are something else. Research is currently underway that is transplanting cells from other species. However, these types of transplants have not been successful, except for bone marrow cell transplants. Neuronal transplants with negative results have been performed to cure Parkinson's disease. Boxer Cassius Clay was made in Mexico and, obviously, it was very beneficial. Cells capable of producing insulin have also been tested, and so far insulin treatment has not been eliminated. Very recently a Canadian research group has presented patients who have received the cell transplant and have been able to quit insulin treatment, but it is still early to say nothing. From this point of view, if interhuman transplants have not obtained good results, it is clear that in xenotransplants it will be more difficult.
Others have been done. That is, until the human organs appear, have the organs of animals been more than once put on the sick?
Yes, temporary transplants have been done, but rarely. The aim is to extend the lives of the dying to the appearance of the transplant organ. Such systems can hardly last more than a week. In Spain, this does not make much sense, because in those cases the organs appear up to date, and may be in other places, such as the United States.
You are researching xenotransplants and doing xenotransplants. Remove heart from pigs and put it on baboons. You are getting the average baboon to stay alive for 30 days. Based on this, what would you say about the future of xenotransplants?
I know nothing of the future. If I said something now, it would be only speculation. The value of research is measured by its potential usefulness or relevance in the future and not by its own research work. I think that's a mistake. Something similar has happened with pigs, overcoming the sudden rejection, it seemed that in a couple of years we were responding to the problem of organ shortage; 4 or 5 years have passed and we still have no magic solution. We are always working on a line and you will see where we got there. Right now we need to know why an organ fails and how to deal with it. According to the results we have, soon we could have the illusion of getting a pig organ transplant to humans, but we could not say more.
If they were ever held, would there be ethical debate?
Deciding what is ethical and what is not is a difficult issue. If specially bred animals were used and there was no danger in transplantation, most would agree. The balance shall include benefits and risks. It is clear, for example, that PERV can be contaminated in the laboratory. Knowing this, according to current experimental models, what benefit is obtained from life-prolonging treatment for 2 months? The risk would be greater than the benefit, but if the duration were years and we made sure that no infections were transmitted, things would change a lot because the lives of many people would be saved.
Yes, okay. In any case, quoting the ethical debate did not refer to it. I wanted to try to get all the research into the hands of private companies. And if the organs that can be produced in the future have ownership, it is clear that they will come to market and have price.
Yes, in studies that are being done in the world with xenotransplants private money is being used, that is so. Research has a huge cost. Companies have put in all this a big risk, a lot of money, so it seems normal to me that then we want to get something out. I would like everything to be taken over by public institutions, but in the world there is no public health organization that can afford it. As there is no, companies have taken the risk and got involved, put money... and maybe nothing comes out.
Hey, make no mistake, but what surprised me most was knowing that this type of transplant is performed in A Coruña.
Galicia is one of the three historical autonomies of Spain and each one wants to have its place. Here the transplant issue was already weighted. Liver, kidney, heart, lung, and pancreatic transplants were performed. The truth is that it is not easy to find so many transplants in one place.
I am Catalan and after five years in the United States, in Pittsburgh, the most advanced place in the world in number of transplants, I came to the hospital of Belvitge in Barcelona with the idea of getting something like this forward. We couldn't do it there, but they called me from the Juan Canalejo hospital in A Coruña because they wanted to reinforce the transplant area. After reaching an agreement with Imutran, we opened a xenotransplant research unit to investigate with pigs and baboons.
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