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Ten milestones of transplants

This report published in number 10 of Muy Saludable has been awarded for its rigor, impact and informative clarity in the VI edition of the ASEBIO Awards for Communication and Disclosure of Biotechnology.

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risky is open heart surgery

Since the first successful operation of this kind took place in 1954, outstanding advances have been made. Today we investigate how to regenerate organs from the patient’s own cells.

Legend has it that in the thirteenth century the sacristan of a church suffered terrible pain because he had a gangrenous leg. Curiously, the temple was consecrated to the saints Cosme and Damian, two medical brothers of the third century who had died martyred. One night of great suffering, after praying vehemently, he dreamed that both presented themselves before his bed and replaced his diseased leg with that of a man who had just passed away.

The story does not stop being an anecdote, but, in a certain way, it shows that the purpose of the transplants has been planned for us for centuries.

In Frankenstein (1818), we find how this idea is concretized, even in the creation of a body from parts and organs of corpses.

However, transplants, as we understand them, are relatively recent interventions. Next, we explain its evolution from ten major advances that in recent decades have saved millions of lives.

1. Microsurgery allows joining arteries

If we had to choose a year and a character to define the beginning of the era of transplants, it would undoubtedly be 1902 and the French doctor Alexis Carrel, who would obtain the Nobel Prize in Medicine ten years later. Until then only skin grafts and tooth tests had been done, with little success, and a technique to implant a kidney or a heart had not yet been developed.

“At that time a war surgery based on the extirpation was practiced,” says Antonio Román, coordinator of the Pulmonary Transplant Program at the Vall d’Hebron Hospital in Barcelona and president of the Catalan Society of Transplants.

“What prevailed was speed,” he adds. It was not sought to repair, but to retire. In part, this was because anesthesia was much less effective than today, but also because it was not known how to connect the blood vessels and the best that was aspired was to cover them to avoid bleeding.

However, in 1902 Carrel succeeded in describing the technique of triangulation, a way of performing the pangs that allowed arteries and veins to be legated. It was the beginning of microsurgery and, by extension, that of transplants, since it made it possible to link the donor and recipient vessels. The road was thus open, but it would not be free of difficulties.

2. The first kidney transplant, between twins

first-successful-kidney-transplant
first successful kidney transplant

The vast majority of initial attempts were made with kidneys. “In theory, they are easier to transplant than other organs, and we also have two, so the vital commitment is less,” says Dr. Roman.

In 1906, the French surgeon Mathieu Jaboulay made two tests. In the first, he tried to implant a pig kidney in the fold of a woman’s elbow. It seemed to work, but on the third day he had to remove it. The same happened months later, in this case with a goat.

In 1933, the first transplant of an organ from a human corpse was tried, but it did not work either. Although the technique was ready, something prevented it from falling; the key seemed to be in the immune system, which rejected the foreign organ.

But how to know if it was true?

The answer came in 1954, when the team of the American surgeon Joseph Murray practiced the first renal transplantation between twins. In essence, the defenses of the brother who received the transplant recognized him as his own. For the first time, an intervention of this type was successful in the long term, and similar operations were repeated throughout the world. However, there were still many limitations and we would have to wait a little longer for the step that would revolutionize this field to take place.

3. The revolution of immunosuppressant’s

The objective was clear, but complex: to devise a strategy that would allow reducing the own defenses without compromising the life of the patient. The first achievement came in the early 1960s with azathioprine, a drug that hinders the division of lymphocytes, the main cells of the immune system.

Its use allowed many more kidney transplants to be done, since it was no longer necessary to practice between twins. But its effectiveness was not the best: the organ ended up failing and half of those intervened died during the first year.

The breakthrough took place in the late 70s, thanks to cyclosporine. Instead of hindering the division of lymphocytes, this prevents them from functioning, so it ended up being the immunosuppressant hinge with which almost any type of transplant could be addressed. It proved so effective that the deceased in the first year became less than 10%. Then there would be new medications and combinations that allow lower doses and side effects.

“Today the acute rejection that kills has been solved, but in the vast majority of patients there is a chronic rejection, that is the true executioner,” says Dr. Roman.

In this process, the irreversible deterioration suffered by the implanted organ forces many people to go through a new transplant.

Stem-cell
Induced pluripotent cells are capable of differentiating into two hundred types of adult cells, which give rise to lung, liver and other tissues.

Despite the advances, this expert regrets that there have been hardly any developments in twenty years. “This is where we should concentrate our efforts,” he says.

In this coincides Rafael Matesanz, founder and director of the National Transplant Organization, a model that has led Spain to head the global lists in this type of operations? “Generating new molecules is expensive, and since they do not have as much market potential as other areas, there seems to be little enthusiasm among manufacturers,” says Dr. Matesanz.

4. First heart transplant

One of the great events in this field took place in 1967 at the Groote Schuur Hospital in Cape Town, South Africa. Christiaan Barnard’s team transplanted the heart of a young woman, who had died in a hurricane, to Louis Washkansky, 56, who had already suffered three heart attacks.

“It was a giant step, involving the combination of different advances in anesthesia, in the fact that a cardiac arrest was caused by hypothermia – that is, by cooling the patient’s blood to minimize the damage – and in the use of the extracorporeal circulation, which allowed him to survive while they extracted his heart,” says Dr. Roman.

However, although the intervention passed to posterity as a major milestone, the results were not as expected. Washkansky died at eighteen days of pneumonia, and the vast majority of the following attempts failed, in general due to problems due to rejection of the implanted organs. In fact, there was a break and during the 70s, we hardly tried anything like that again.

Dr. Roman does not doubt: “The great jump was, again, cyclosporine.” Its introduction allowed heart transplants to resume in the early 1980s.

Today, approximately 85% of the operated patients survive the first year.

5. The first partial face transplant arrives

With the improvement of surgical techniques and immunosuppression, the operations multiplied: the lung transplant -and the double lung transplant-, the liver transplant, the heart and lung transplant…

In 2005, a surprising event took place: in the Hospital Complex of Amiens, in France, the first partial face transplant was carried out. The recipient was Isabelle Dinoire, a French woman who had fainted at home and had been hit by falling furniture.

When he regained consciousness he found that his dog, trying to wake her up, had ripped part of his nose, lips and chin.

The surgery was complex: for hours it was necessary to implant and join muscles, vessels and nerves of a donor. And there was also the psychological component: the risk of the woman rejecting her image.

But it was a success.

When the journalists asked him how he could accept his new face, Dinoire replied that he could smile, gesture and express him. The patient died last April, as a result of complications that arose after experiencing a rejection in the affected area, but in recent years there have been new developments in this regard.

Thus, in 2010 the first total transplant of a face was practiced. It took place at the Vall d’Hebron Hospital in Barcelona. The operation lasted twenty-four hours.

Organ-transplantation
Organ transplantation

In addition to chronic rejection, the shortage of organs hinders many transplants. More and more patients can enter the waiting lists, and these do not stop growing. Some experts believe that the ideal solution would be to manufacture them on demand from the patient’s own cells, which, in addition, would prevent rejection.

In 1998, James Thomson, of the University of Wisconsin, in USA described the human embryonic stem cells, able to differentiate and give rise to any type of tissue.

But its use raises certain ethical problems, because it is necessary to take them from embryos in their early stages of development, which are destroyed in the process.

Would it be possible to design them and avoid this inconvenience?

The Japanese doctor Shinya Yamanaka, from the University of Kyoto, and Thomson himself demonstrated in 2008 that from adult cells, even if they were fat or skin, induced pluripotent stem cells could be built. Today they are one of the great hopes of transplants and regenerative medicine.

They have been tested in some clinical trials, but on them they plan questions. “At the moment there is more noise than reality,” says Dr. Roman. “It is a promising field, but still in very early stages, its safety or effectiveness are not sufficiently proven, so much more research is required,” says Dr. Matesanz.

7. A biomolde for new organs

In any case, if we want to make an organ we will need a kind of scaffolding on which the cells can grow In 2008, researchers from the University of Minnesota, USA. In the US, they took rat hearts and washed them with special detergents that remove all the cells but leave the structure intact. They turned them, so to speak, into a mold. Then, they planted them with cardiac cells from newborn babies. These, in some way, followed the instructions that the matrix dictated to them to develop.

After a few days of cultivation, they managed to beat. Now similar techniques are being tested with human tissues, and although the heart is difficult to recreate, fragments of it could be fabricated to, for example, recover infarcted areas. In fact, important steps have already been taken in other cases.

Also in 2008, a new transplant was carried out in which the trachea of the donor had been cleaned and its structure covered with cultured cells of the recipient, a young woman with respiratory tract damaged by tuberculosis. It was at the Hospital Clínic in Barcelona, and the woman is still alive eight years later.

However, the controversy plans on this type of interventions: apparently, the communication of the results by the responsible surgeon, Paolo Macchiarini, was too optimistic and not as transparent as it should be. In fact, the patient has been reoperated periodically because the duct tends to close, in addition to suffering other complications. “I think there are risks and that it has gone too fast,” says Dr. Román. We are touching the future, but we must move forward safely.

8. Bladders and intestines printed in 3D

If filling cadaver organs seems a promising way, it would be even more possible to directly manufacture these biomoldes. For this purpose, 3D printers have already been used, which are not only capable of reproducing designs of different materials, but could be used to inject cells of different types, each one in its corresponding place. However, it is difficult, because many organs have varied cell populations , in superimposed layers, and need numerous and efficient blood vessels to nourish themselves.

As in the previous case, it has already been tested in humans, with a last of material similar to plastic and with Macchiarini also as the protagonist.

However, the results have been worse than expected – and from what were reported at the beginning – and most patients have died. In fact, the Karolinska Institute in Stockholm, where Macchiarini worked, has not renewed the contract.

Even so, Dr. Matesanz is optimistic. “What apparently Macchiarini did, even with all the doubts that arise with everything related to this surgeon, seems a clear way in the transplants of hollow organs, such as the trachea, the bladder and fragments of the intestine. Other complex organs I do not see clearly. “For that there are other strategies, which recover in part some old ideas, such as xenotransplantation, that is, those that occur between different species.

9. Pigs, the human spare parts factory

When Jaboulay implanted kidneys of pig and goat in humans, they only lasted a few hours. Today we know that the failure was due to rejection. Despite this, the use of animal organs continues to be explored. Pigs are, in this sense, very interesting.

Not only are they easy to breed, but the functioning and size of their organs are similar to ours. Of course, they contain retroviruses that can be reactivated when they are passed on to humans, but even this problem could have been solved: last year it was discovered that the new technique of genetic clipping- CRISPR -words in English of short palindromic repetitions grouped and regularly interspersed- allows solving it . “There are several teams that work in this type of transplants, but the future will probably not happen here,” says Dr. Román.

Instead, pigs could be used as if they were incubators of human organs, a more interesting alternative. The biochemist Juan Carlos Izpisúa works at the Salk Institute in California. Its approach is overwhelming: it consists of suppressing the animal’s genes that give rise to a certain organ to create a kind of niche, a virtual hole.

Then, when it is still an embryo, human stem cells will be injected to fill it, which gives rise to an essentially human organ. However, “there are still no published studies, we do not even know exactly the methods they are using,” Dr. Román points out. Of course, “this is a very suggestive initiative,” says his colleague Matesanz. And, in this way, feeling the future, we definitely jump towards it.

10. Organs repaired and reimplanted

“In the coming years we will continue to make progress in the manufacture of organs from stem cells and almost certainly in chimera animals, such as pigs,” says Dr. Román, but it is also possible to speculate on advances in other fields.

For example, some researchers work in the development of immunotolerance, a technique that avoids the use of immunosuppressant’s. It has been speculated that in a short time you can carry out head transplants (Italian neurosurgeon Sergio

Canavero wants to try it in 2017), although many experts, like Dr. Román, consider that, for the moment, it is mere fiction. On the contrary, he is more convinced of the use of devices that replace organs. “There we have dialysis. In addition, there are already many patients who live years with machines that act as the heart, “he says.

Perhaps one of the greatest advances will be related to prevention. “There are diseases that not long ago implied the need to carry out a transplant, but now we can stop,” says the specialist of the Clinic.

Repairing instead of replacing organs represents another of the most realistic objectives. “We are already able to keep lungs alive outside the body, that’s an opportunity to fix them,” explains Dr. Román. For example, in the event of a tumor being given, we could remove them from the body, subject them to doses of chemotherapy that are unthinkable at present and, once the problem is solved, reintroduce them.

Hence, to the answer of what we can expect in the exciting career of transplants, Dr. Román responds without hesitation: “No need.”

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