In the 20th century, there were many advances in the treatment and control of diseases, but there were two, vaccines and antibiotics , that were a milestone because of the impact they had on public health and life expectancy. In the 21st century, the third of them, regenerative medicine , has emerged. Researchers and clinicians do not hesitate to qualify it as the third medical revolution , given the therapeutic possibilities of stem cells , capable of differentiating and forming any tissue in the body, as well as being able to divide to produce more stem cells. Hence, scientists believe that it is an ideal source to treat a multitude of ailments where cell damage has occurred, from diabetes to Alzheimer’s.
It still sounds like science fiction, but it hasn’t been for a long time. If Rafa Nadal performs now on the courts as when he was twenty years old, it is thanks to treatment with growth factors , a modality of regenerative medicine that he has resorted to in recent years to solve his knee problems, first, and those of back later. Dozens of centers around the world apply this method, the most widespread of regenerative therapies, which has also been used by many other athletes, such as Xavi Hernández, Victor Valdés, Joseba Beloki or José Manuel Calderón .
The wear and tear on the body of a high-competition athlete accelerates the erosion of the joints , and it is in them that growth factors have proven to be especially effective. These are proteins that are extracted from blood plasma and have the capacity to regenerate damaged tissues – ligaments, muscles – because they facilitate the production of blood vessels, as well as cell proliferation and differentiation. The result is the improvement of joint movement and the reduction of pain , since they also reduce inflammation. The therapy began being used in athletes, but its use has been extended to people with osteoarthritis, a problem that only in Spain affects almost 30% of the population, according to the Spanish Society of Rheumatology (SER).
The principle on which regenerative medicine is based, the body’s potential to repair itself, is no exception in nature. When a lizard or lizard loses its tail while escaping from the predator that stalks it, its life is not in danger of being amputated. Your body has the ability to manufacture lost appendix tissues, muscles, nerves, blood vessels one by one, and have a new tail in about sixty days. Is it risky, delusional, even to think that the human body can harbor a similar ability? Everything points to no. “When the heart is damaged by a heart attack, what regenerative medicine seeks is to repair the part of the affected organ, adding, removing and restoring tissue that has stopped working,” explains Josep Samitier, director of the Institute of Bioengineering of Catalonia.
In the Gregorio Marañón Hospital in Madrid, they have investigated in recent years with stem cells to solve a problem: the failure of the blood pumping function that occurs in the heart after a heart attack or heart failure. This disease, which affects 10% of the population over seventy years of age, is characterized by a progressive weakening of this organ, so that it does not pump enough blood to distribute it throughout the body. Every year, it produces around 20,000 deaths in our country, according to the Spanish Society of Cardiology (SEC), and it does not have a definitive solution, except for a transplant. However, only a minority of patients have it due to a lack of available organs.
The trials carried out on patients, both in the Madrid center and in the rest of the world, provide good and bad news, points out Francisco Fernández-Avilés, head of the hospital’s Cardiology Service and director of the research: “All the studies have agreed on two things, the positive is that the administration of cells is safe, something very important, and the negative is that the efficacy in the objective sought is very limited ”.
The reverse is an incentive for scientists, which forces them to review the processes and confirms, once again, an invariable law in science: knowledge is achieved by trial and error. In stem cell research, an apparent paradox occurs: the virtues they contain can be translated into therapy, but also cause harm or not have the intended effect. Its plasticity, its ability to become any specialized tissue, could generate a type of cell that is not the one that was sought. On the other hand, if the ability to renew itself gets out of control, it could lead to tumors . In that difficult balance, scientists move.
In the case of the heart, one of the objectives pursued is to repair the alterations in the electrical connections that produce sudden death. The challenge is to get the stem cells to understand each other so that they contract in a synchronized way when producing electrical activity. But that is something very difficult, as Fernández-Avilés points out: “If they do not act like this, short circuits can occur which in turn lead to lethal arrhythmias.”
So far, the use of stem cells in the heart has been shown to be safe , which is a big step. From there, what have researchers around the world done? “We have returned to the laboratory to find out how we can have more powerful cells than we have now and with what tissue engineering structures must be used on some occasions to facilitate their being properly organized,” Fernández-Avilés answers. In the heart, there are different types of cells –muscular, nerve, vascular–, and it has been seen that a single type of stem cells is not enough to generate them all as had been thought. On the other hand, it is necessary to ensure that they are integrated into the structure of the organ , which entails a difficulty, indicates this expert, “because the new ones do not have the same capacity as the original ones to colonize that structure and repopulate it adequately.”
One possible solution that is already being tested is to create tissue in the laboratory with stem cells and a matrix to implant in the heart. Japanese doctors from the University of Osaka used these patches of heart muscle tissue in early 2020 on 10 patients with ischemic heart disease, a disease caused by arteriosclerosis of the coronary arteries. The narrowing that it causes in the vessels prevents them from supplying the blood that the heart muscle needs. Researchers have used iPS cells, a type of stem cell with the ability to develop in most tissues, and are working on the hypothesis that they will repair damaged arteries.
It is known that, throughout a person’s life, at least 50% of the cells they have at birth are renewed. Until a few years ago, it was thought that the body’s ability to regenerate was limited to some tissues and that there were other particularly complex ones, such as the heart or the nervous, that could not do so. But that dogma has fallen, which has meant a radical conceptual change: medicine can now try to repair the deterioration that occurs in complex organs such as the heart and also to repair the central nervous system or the brain . Last year, Japanese neurosurgeon Takayuki Kikuchi of Kyoto University Hospital implanted reprogrammed stem cells in a patient in his fifties with Parkinson’s disease. They were cells capable of synthesizing dopamine, the brain substance that helps control muscle movement. In the intervention, they placed them in twelve places in the brain known to be centers of dopamine activity. Previously, experiments in monkeys showed that they improved the motor symptoms of the disease. Now it remains to know its effects in the short, medium and long term in humans, once the intervention is repeated in the chosen patient to implant more stem cells.
As we can see, the expected advances in regenerative medicine include diseases of great social, medical and economic impact, such as diabetes. In this pathology, an ambitious goal is pursued: to create a miniature pancreas with stem cells that can replace the damaged organ in patients and normalize the production of insulin , the hormone that regulates blood sugar levels. A closer goal is the American company ViaCyte, which tests 75 patients with type 1 diabetes a patch with pancreatic cells produced from pluripotent cell lines. It is already validated in mice and the results of human trials are expected next year.
Meanwhile, at the Salk Institute in La Jolla (USA), the Spanish scientist Juan Carlos Izpisúa and his team took a momentous step in April to achieve one of the great challenges of regenerative medicine: manufacturing organs and ensuring that all people who need it have access to a transplant .
To get a heart or liver ready for transplantation, two pathways are explored. The first consists of removing the cells from the organ from a cadaver or a donor that has not been able to be implanted and making a new one, from the matrix that remains, with the recipient’s cells. This would prevent immune rejection. The other alternative, the one explored by Izpisúa’s team, “consists in growing the organ compatible with that of the receptor in chimeras –a hybrid species between humans and macaques–, in which rejection is also prevented,” explains Fernández-Avilés. .
Numerous research groups have managed to decellularize organs from animals until they are left in a basic lattice. The difficulty is in successfully completing the opposite process, getting the cells to give rise to each of the tissues that make up that organ. The most complex thing is to vascularize the tissues . As Samitier affirms, “you have to ensure that they are irrigated, that they have blood vessels, to be able to feed themselves and receive oxygen”. In complex organs, with many cell types, this is an essential requirement, but the third medical revolution has started with more affordable goals.
“We are already regenerating bone, we are working with cartilage and tendons and, in the case of blood vessels, it has been possible in animal models to generate structures that serve to connect two vessels when one is damaged,” he points out.
One of the most unknown uses of regenerative medicine is the key role it has played in covid-19. Thanks to the so-called organs on a chip , the effect and potential consequences of some drugs have been known at record speed. These are small bioreactors made of plastic, with cavities and channels that allow liquids to be conducted in a controlled way. In these rooms, biological material is introduced that imitates a small organ with the same characteristics that a kidney or a liver can have, or with those of several organs at the same time, as if making a puzzle. Samitier explains that, in COVID-19, these organoids have been especially useful “because the infection affected several organs and this system made it possible to know simultaneously the efficacy or toxicity that the different drugs could have in all of them.” Furthermore, if these organoids include cells from a specific patient, “they serve to personalize treatment, something that is already beginning to be applied in oncology.”
Along the same lines, the development of regenerative therapies goes hand in hand with the appearance of new biocompatible materials and the development of 3D printers that have revolutionized industrial manufacturing and medicine.
For example, the international team led by Javier Llorca, at the Madrid Institute for Advanced Materials Studies (IMDEA), has developed a biodegradable 3D metal scaffold for bone regeneration . These structures are used after a serious break or after having had to remove a bone fragment by a tumor. Until now, they were made of stainless steel or titanium, but they remained for life in the patient. However, the Llorca team has managed to create this scaffold in magnesium, a biodegradable metal that the body metabolizes little by little once the bone tissue has regenerated.
One of the characteristics of the structures that are inserted into the bone tissue is that they must be porous, so that vascularization and cell growth can occur. The one designed by the IMDEA researchers combines these properties and, incidentally, the speed at which the scaffold degrades is adjusted to the time it takes for the bone to regenerate. This is an example of interdisciplinary collaboration making its way into science in general and medicine in particular. The specialists point out that a key factor in the future of regenerative therapies is the collaboration between experts from numerous specialties: researchers, engineers, clinicians, materials specialists … For example, “in hospitals, there is already talk of having next to the operating room rooms with bioprinters to be able to prepare the material that they have to implant later in a patient ” , points out Samitier.
Ever since Matthew Kaufman and Martin Evans grew stem cells in their laboratory at the University of Cambridge (UK) in 1981, researchers have been dreaming of their potential therapeutic uses. However, making that dream come true takes time. The first practical applications, the simplest, took more than two decades. The most complex, such as the manufacture of a heart or a kidney, will not arrive before thirty or forty years, according to the most optimistic. It must be borne in mind that the risks to avoid are as important as the benefits to be pursued. Fernández-Avilés is clear that “it is not necessary to generate false expectations.” In a society where the instantaneous prevails, time is measured in minutes or days. However, medicine and research take decades to deliver optimal results.
