Since the first successful operation of this type took place in 1954, outstanding progress has been made. Today we are investigating how to regenerate the organs from the patient’s own cells.
Legend has it that in the 13th century the sacristan of a church suffered terrible pain due to a gangrenous leg. Curiously, the temple was dedicated to Saints Cosmas and Damien, two medical brothers from the 3rd century who had died martyred. One night of great suffering, after having prayed vehemently, he dreamed that they would both appear at his bed and replace his sick leg with that of a man who had just died.
The story is still an anecdote, but, in a way, it shows that the purpose of transplants has been hanging over us for centuries.
In Frankenstein (1818), we find how this idea is specified, 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 based on ten great advances that in recent decades have saved millions of lives.
1. Microsurgery allows arteries to be joined
If we had to choose a year and a character to define the beginning of the transplant era, it would undoubtedly be 1902 and the French doctor Alexis Carrel, who would win 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 that would allow implanting a kidney or a heart had not yet been developed.
“At that time a war surgery based on extirpation was practiced”, comments Antonio Román, coordinator of the Lung Transplant Program at the Vall d’Hebron Hospital in Barcelona and president of the Catalan Transplant Society.
“What prevailed was speed,” he adds. It was not intended to repair, but to withdraw. In part, this was so because anesthesia was much less effective than today, but also because it was not known how to connect the blood vessels and the maximum that was sought was to cover them to prevent bleeding.
However, in 1902 Carrel was able to describe the triangulation technique , a way of making the punctures that allowed arteries and veins to be ligated. It was the beginning of microsurgery and, by extension, that of transplants, since it made it possible to link the vessels of the donor and the recipient. The way was thus open, but it would not be without difficulties.
2. The first kidney transplant, between twins
The vast majority of the 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 lower,” says Dr. Román.
In 1906, the French surgeon Mathieu Jaboulay did two tests. In the first, he tried to implant a pig kidney into the crook of a woman’s elbow. It seemed to work, but on the third day he had to remove it. The same thing happened months later, in this case with a goat.
In 1933, the first transplant of an organ from a human cadaver was tried, but it did not work either. Although the technique was ready, something was preventing it from falling; the key seemed to be in the immune system, which rejected the foreign organ.
But how do you know if it was true?
The answer came in 1954, when the team of American surgeon Joseph Murray performed the first kidney transplant between twins. In essence, the defenses of the sibling who received the transplant recognized it as their own. For the first time, such an intervention was successful in the long term, and similar operations were repeated all over the world. However, there were still many limitations and we would have to wait a little longer for the step that would end up revolutionizing this field.
3. The immunosuppressant revolution
The objective was clear, but complex: to devise a strategy that would reduce one’s defenses without compromising the patient’s life. 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 they no longer needed to be performed between twins. But its effectiveness was not the best: the organ ended up failing and half of those operated on died during the first year.
The big breakthrough took place in the late 1970s, thanks to cyclosporine. Instead of hindering the division of lymphocytes, it prevents them from functioning, which is why it ended up being the hinge immunosuppressant with which almost any type of transplant could be approached. It was so effective that the number of deaths in the first year dropped to less than 10% . Then would come new drugs and combinations that allow reducing 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 real executioner,” says Dr. Román.
In this process, the irreversible deterioration suffered by the implanted organ forces many people to undergo a new transplant.
Image: Induced pluripotent cells are capable of differentiating into two hundred types of adult cells, which give rise to lung and liver tissues, etc.
Despite the advances, this expert regrets that there has been hardly any news in twenty years . “This is where efforts should be concentrated,” he says.
Rafael Matesanz, founder and director of the National Transplant Organization, agrees on this, a model that has led Spain to top the world charts in this type of operation. “Generating new molecules is expensive, and since it does not have as great a market potential as other areas, it seems that there is not much 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 been run over, into 56-year-old Louis Washkansky, who had already suffered three heart attacks.
“It was a giant step. It involved the combination of different advances in anesthesia; in the fact that a cardiac arrest was caused by hypothermia -that is, cooling the patient’s blood to minimize the damage-; and in the use of the extracorporeal circulation, which allowed him to survive while the heart was extracted, “says Dr. Román.
However, although the intervention passed to posterity as a great milestone, the results were not as expected. Washkansky died within eighteen days of pneumonia , and the vast majority of subsequent attempts failed, mostly due to rejection problems of the implanted organs. In fact, there was a hiatus and during the 70s something like this was hardly tried again.
Doctor Román does not doubt: “The great leap was, again, cyclosporine.” Its introduction allowed heart transplants to resume in the early 1980s.
Today, approximately 85% of operated patients survive the first year.
5. The first partial face transplant arrives
With the improvement of surgical techniques and immunosuppression, operations multiplied: lung transplantation – and double lung transplantation -, liver transplantation, simultaneous heart and lung transplantation …
In 2005, a surprising event took place: the first partial face transplant was carried out at the Amiens Hospital Complex in France. The recipient was Isabelle Dinoire, a French woman who had fainted at home and hit a piece of furniture when she fell.
When she regained consciousness, she found that her dog, trying to wake her up, had torn off part of her nose, lips and chin.
The surgery was complex: for hours you had to implant and join muscles, vessels and nerves from a donor. And then there was the psychological component: the risk that the woman would reject her image.
But it was a success.
When journalists asked him how he had been able to accept his new face, Dinoire replied that because he could smile, gesture and express himself. The patient died last April , as a result of the complications that arose after experiencing a rejection in the affected area, but in recent years there have been new advances in this same direction.
Thus, in 2010 the first total transplant of a face was performed. It took place at the Vall d’Hebron Hospital in Barcelona. The operation lasted twenty-four hours.
In addition to chronic rejection, organ shortages make many transplants difficult. More and more patients can enter the waiting lists, and they continue to grow. Some experts believe that the ideal solution would be to manufacture them on demand from the patient’s own cells, which, in addition, would avoid rejection.
In 1998, James Thomson, from the University of Wisconsin, in the USA, described human embryonic stem cells, capable of differentiating and giving rise to any type of tissue.
But their use raises certain ethical problems , since they must be taken 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 induced pluripotent stem cells could be built from adult cells, even from fat or skin. Today they are one of the great hopes of transplants and regenerative medicine.
They have been tested in some clinical trials, but questions hang over them. “At the moment there is more noise than reality,” says Dr. Román. “It is a promising field, but still in very early stages. Its safety or efficacy has not been sufficiently proven, so much more research is required,” says Dr. Matesanz.
7. A biomold for new organs
In any case, if we want to make an organ we will need a kind of scaffold on which the cells can grow. In 2008, researchers at the University of Minnesota in the US took rat hearts and washed them with special detergents that remove all the cells but leave the structure intact. They made them, so to speak, into a mold. Then they seeded them with heart 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 got them to beat. Similar techniques are now being tested with human tissues, and although the heart is difficult to recreate, fragments of it could be made to, for example, recover infarcted areas. In fact, important steps have already been taken in other cases.
Also in 2008, a novel transplant was carried out in which the donor’s trachea had been cleaned and its structure covered with cultured cells from the recipient, a young woman with airways damaged by tuberculosis. It was at the Hospital Clínic de Barcelona, and the woman is still alive eight years later.
However, controversy hangs over this type of intervention: 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. Roman. We are touching the future, but we must move forward safely.
8. 3D printed bladders and intestines
If filling corpse organs seems like a promising avenue, it would be even more promising to be able to directly manufacture these biomolds. For this, 3D printers have already begun to be used, which are not only capable of reproducing designs of different materials, but could also be used to inject cells of different types, each one in its corresponding place. However, it is difficult, as many organs have varied cell populations , in overlapping layers, and need numerous and efficient blood vessels for nourishment.
As in the previous case, it has already been tested in humans, with a last made of a material similar to plastic and with Macchiarini also as the protagonist.
However, the results have been worse than expected – and than was initially reported – and most of the patients have died . In fact, the Karolinska Institute in Stockholm, where Macchiarini worked, has not renewed his contract.
Still, Dr. Matesanz is optimistic . “What Macchiarini apparently did, even with all the doubts that everything related to this surgeon raises, seems a clear path in the transplants of hollow organs, such as the trachea, the bladder and intestine fragments. In the heart, the kidney or other complex organs I don’t see clearly. ”For that there are other strategies, which partly recover some old ideas, such as xenotransplantation, that is, those that occur between different species.
9. Pigs, the human spare parts factory
When Jaboulay implanted pig and goat kidneys in humans, they only lasted a few hours. Today we know that 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 their organs function and size are similar to ours. Of course, they contain retroviruses that can be reactivated when they pass to humans, but even this problem could have been solved: last year it was discovered that the new CRISPR genetic cutter technique – acronym in English for short palindromic repeats grouped and regularly interspersed – allows to solve it . “There are several teams working on this type of transplant, but the future will surely not pass through here,” says Dr. Román.
Instead, pigs could be used as human organ incubators, a more interesting alternative. The group of biochemist Juan Carlos Izpisúa is working on this at the Salk Institute in California. His approach is overwhelming: it consists of suppressing the genes of the animal 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, resulting in an essentially human organ. However, “there are still no published studies; we do not even know exactly what methods they are using,” says Dr. Román. Of course, “it 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, progress will continue 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 with advances in other fields.
For example, some researchers are working on the development of immune tolerance, a technique that avoids the use of immunosuppressants. It has been speculated that head transplants could be carried out in a short time (Italian neurosurgeon Sergio
Canavero wants to try it in 2017), although many experts, such as 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 for years with machines that act as the heart ”, he indicates.
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 that we can now tackle,” says the specialist at the Clinic.
Repairing rather than replacing organs represents another of the more realistic goals. “We are already able to keep lungs alive outside the body ; that is an opportunity to fix them,” explains Dr. Román. For example, in the event of a tumor, we could remove them from the body, subject them to doses of chemotherapy that are currently unthinkable and, having solved the problem, reintroduce them.
Hence, to the answer of what we can expect in the exciting race of transplants, Dr. Román responds without hesitation: “That they are not necessary.”
