Pharmaceutical medicine is not always able to cope with severe chronic diseases. Often she offers patients drugs that, although they help to improve their well-being, do not cure the disease itself. If you stop taking them, then the problems return. In other words, medicine fights the manifestation of the disease, but not the cause. And the cause of a chronic disease is almost always some kind of breakdown in the cell. Fortunately, in the twentieth century, another, so to speak, engineering approach was discovered: to find and fix this breakdown.
One of the directions within this approach is the use of stem cells. Stem cells are a kind of biological reserve of youth and health of any living organism, including humans. Their task is to reproduce other cells in the body. Unlike other cells, stem cells can either divide very many times, reproducing their own kind, or turn into specialized tissue cells. Another amazing property of stem cells is that they themselves can find breakdowns in the body and rush there to fix them – a kind of “ambulance” of the body itself. They are present in the human body until death. True, their quantity and quality over the course of life is significantly reduced. That is why the older a person is, the slower any damage heals.
Every new organism starts with a single stem cell. After fertilization of the egg by the sperm, the first full-fledged cell of the body with a double set of chromosomes, the so-called zygote, is formed.It is rapidly dividing, giving rise to new and new cells, which are organized into tissues and organs, in accordance with the genetic program recorded in them. At the same time, the potential of new generations of stem cells decreases. The very first stem cells, “first order” cells, can give rise to any tissue, but subsequent stem cells, “second order” cells, give rise to only certain types of tissues. After birth, various types of stem cells are already present in the body. Some of them are constantly working. These are hematopoietic – they are responsible for blood, mesenchymal – they are responsible for bones and cartilage, and tissue-specific stem cells, for example, skin and intestines.
And separately we should talk about the placenta and the umbilical cord. They are necessary while the baby is in the womb, as they connect the fetus to the mother, and after the baby is born, they are treated as “biological debris” and thrown away. However, the stem cells that are in these tissues are of great value, because they have a very great potential for the treatment of diseases.
The very idea of stem cell therapy at first glance is very simple. When some mechanism at the cellular level is disturbed in a person, healthy stem cells need to be transplanted into the patient’s body, which, having multiplied, will replace the diseased cells with healthy ones. The idea is simple only in theory, and stem cell therapy is still quite narrowly applied, although it is seen as having great potential in other cases.What options for solving problems can cell therapy offer today and what prospects it has in the future, clarified scientists involved in the study of the potential of stem cells for the treatment of diseases: Professor of Stony Brook University (USA) Grigory Enikolopov, whose laboratory studies brain stem cells an adult, and the founder of the Mediland group of companies, which researches and implements advanced cellular technologies, Yaroslav Isakov.
What are the most common diseases that can be treated with stem cells today?
Ya.I.: The whole topic of stem cells began with the transplantation of bone marrow cells in order to treat blood diseases. Basically, we are talking about various types of cancer. This treatment was used already in the second half of the 20th century, even before the boom in stem cells began. And so far only it is the standard and generally accepted method. Interestingly, such transplantation makes it possible to cure some concomitant chronic diseases. If it becomes obvious that a bone marrow transplant is necessary, then a donor can be selected whose stem cells will have certain properties and will fight the concomitant disease. A striking example are two patients who were cured of HIV in this way. The first, a patient, Timothy Ray Brown, was cured in 2007 and is referred to as the “Berlin patient”. And the doctors announced a complete cure for the second, “London patient”, recently, at the beginning of 2019. Their cure stories are very similar: in addition to HIV, both patients developed additional blood cancers that required a bone marrow transplant to treat. Both of them underwent transplantation of donor hematopoietic stem cells. At the same time, they picked up not just donors whose blood stem cells suited them. They were matched with donor cells containing a certain mutation: unlike normal cells, the mutated cells lacked the traitor protein. The virus uses a Trojan horse protein to infiltrate lymphocytes.Accordingly, if this protein is absent, then the virus will not take root in the body, since it cannot get inside the cell. As a result, both patients were cured of HIV.
– The recovery of a Japanese patient from schizophrenia, which, like in the first two cases, was the result of transplantation of hematopoietic stem cells of the bone marrow during the treatment of blood cancer, made no less a sensation. Moreover, in the latter case, it was a side effect that turned out to be a surprise for the doctors themselves.
Ya.I.: But it should be understood that neither for HIV nor for schizophrenia such a method of treatment is standard. It is standard for the treatment of various forms of blood cancer, and the positive side effects are still a bonus, the result of successful experiments. Nevertheless, these experiments prove that such a way of healing is possible and, accordingly, it is necessary to continue work in this direction. In addition to blood oncology, there are a fairly large number of diseases for which the method of stem cell transplantation can work and is now in the stage of clinical trials. After all, stem cells are found in all organs, even in the brain.
– For a long time, we were guided by the concept that nerve cells in an adult organism are not formed and we gradually exhaust the reserve that was formed during embryonic development. For example, Alzheimer’s disease is just associated with the degradation of neurons. This disease was considered incurable. After the discovery of human neurogenesis, that is, the formation of stem cells in adult nervous tissue, more than thirty years ago, the concept changed.We now know that nerve cells can regenerate. We study neurogenesis in the adult and aging brain.
Is it possible to find a treatment that will make neurons recover? What are the ways?
G.E.: In an adult, neurogenesis – the birth of new neurons – occurs only in a few areas of the brain, but these areas are especially important. For example, new neurons are being formed in the hippocampus, an area that is responsible for memory and emotional state. It turns out that in Alzheimer’s disease, the already existing hippocampal neurons are especially sensitive and die first, and the production of new neurons that could replace the dead ones is greatly suppressed. Together, this leads to a sharp decrease in the number of working hippocampal neurons and, as a result, to memory impairment, the development of depression, and a decrease in the ability to rejoice and empathize. Since it is clear that the cause of these changes is associated, among other things, with a lack of neurons in the hippocampus, it is also understandable that one can try to solve the problem or at least slow down its development by correcting the process of neurogenesis. And there are two possible ways to do this. One, and our laboratory is working on it, is to spur the formation of new neurons from the stem cells left in the brain. There are several possible solutions to this. For example, many studies have shown that, oddly enough, exercise and new experiences cause brain stem cells to multiply more actively. Although most of these results have been obtained in animals, there is confidence that it is also suitable for humans. The solution is simple and accessible to everyone – to move more and learn new things. So the saying “a healthy mind in a healthy body” is now acquiring a scientific basis.
The second way that you can try to use is cellular medicine.You can try to transplant stem cells or neurons into damaged areas of the brain in the hope that healthy donor cells will replace and crowd out the recipient’s diseased or already dead cells. True, here it must be taken into account that in addition to the direct expected effect, there may also be a side positive effect. It consists in the fact that during stem cell transplantation, a general physiological reaction of the body occurs, which can sometimes lead to tangible progress, albeit temporary.
For which diseases of the nervous tissue do you think cellular technologies are promising?
G.E.: For example, there is a lot of effort being put into alleviating the symptoms of Parkinson’s disease, in which one specific type of neuron dies. Therefore, there are many attempts to plant in the brain either ready-made neurons of this type, or stem cells that could generate such neurons.
Another very attractive area for cell therapy is the treatment of macular degradation. The macula is the central part of the fundus of the eye, the retina. It is located opposite the lens and is responsible for central vision and its clarity. Very often, with age, the neurons of the macula die or worsen their work. In this case, a person loses central vision and reading, and other fine work becomes very difficult or even impossible. At the same time, the region of the macula, which is the most critical for clear vision, contains only from several tens of thousands to hundreds of thousands of neurons. By comparison, the brain contains hundreds of billions of neurons.Therefore, much effort is being made to inject neurons and stem cells into the macula in the hope that even a partial restoration of the macula can halt vision loss.
What other diseases can be treated with stem cells?
Ya.I.: With the help of stem cells, many blood diseases, some orthopedic diseases and eye diseases are treated, in addition, stem cells are used in recovery after a myocardial infarction. Both for the first and for the second case, the methods have already been developed. In addition, they try to treat rare and incurable diseases with stem cells, in which classical therapy does not work and conventional pharmacological preparations cannot cope. And recently, cellular technologies are being tried as tools to combat aging of the body.
– In all these cases, cellular medicine uses donor stem cells. In this case, donor blood can be taken from an adult donor, or you can use cord blood. What are the benefits of donating cord blood?
Ya.I.: The concept of using donated cord blood originated in 1988, when a five-year-old American boy, Matthew Farrow, who suffered from a severe incurable hereditary disease, Franconi anemia, was transplanted with the cord blood of his newborn sister. As a result, the boy was completely cured, now he is an adult man who has his own family and children. And from that moment on, specialists began to improve the method of introducing cord blood stem cells to the patient and expand the range of application of this method in relation to serious diseases.
Cord blood consists mainly of hematopoietic stem cells. Although it also contains some other types of stem cells. Cord blood cells are more likely to take root in a foreign body than adult cells.The fact is that the adult body is well prepared to meet with foreign cells. He perceives them as a potential enemy and tries to destroy them. This is called an immune response. The immune response protects us from various infections. But in transplantation, in 80% of cases, transplanted cells from an adult donor attack the host cells. And the immune response of cord blood cells is much lower than that of the cells of an adult organism, because the child has not yet been ill with anything, and the placenta was protected from the mother’s organism, and his immunity has not yet developed. Therefore, there is a high probability that cord blood transplantation will do without serious consequences.
Ya.I.: Creation of cord blood banks began in 1992. The first such bank was created on the basis of the New York Blood Center. Now there are about 550 cord blood banks in the world. Even then, banks were divided into public and family. In private banks, parents store the cord blood of their newborn child as a genetic reserve, providing him with some kind of “biological insurance” for his whole life. This means that if necessary, for example, if the owner of these stem cells at some point in his life encounters a serious disease that can be cured by stem cell transplantation, then he will be able to use his own genetic reserve. Cord blood stem cells have a genetic potential that was given by nature and remained unchanged and free from subsequent mutations, and mutations in any organism occur continuously, and some of them can be fatal.In addition, the stem cells of one family member with a high probability can be suitable for his relatives: for brothers and sisters, the probability of a match is 25%, for parents – 10% probability, for people of the third degree of kinship – 2-3%. In our practice, there was a case when the umbilical cord blood of a newborn girl helped her sister get back on her feet after a serious injury.
We are talking about a girl from the Khmelnytsky region (Ukraine), who survived cerebral therapy at the age of 2 years. A few years later, the girl’s parents decided to conduct an experimental therapy – an infusion of umbilical cord blood. According to the testimony of the parents, immediately after this therapy, the girl’s condition began to improve rapidly. Here is what Natalia told her mothers:
“I was seven months pregnant when my two-year-old daughter Sophia fell through the ice. She stopped breathing and her heart failed. In intensive care, the heartbeat was restored, after a while the respiratory function was restored, but they said that they could not do more, because the brain had died. Sophia did not react to anything, they fed her through a tube. After I gave birth to my second daughter, my husband and I decided that we would take Sophia home. I am a doctor, so I was able to master the techniques of care. We saved the umbilical cord blood of our newborn daughter, although at that time we had no plans for this blood. A few months later, we received a call and were told that one of the clinics was transfusing cord blood as part of the Ukrainian-German clinical research program. We checked if Sophia’s sister’s umbilical cord blood was suitable, and fortunately, it turned out to be compatible. This blood was transfused to Sophia, and literally a week later we saw an improvement in her general condition: food began to be digested, her skin turned pink, the infections that endlessly tormented her receded. In a word, a miracle happened. And after the second transfusion, her body strengthened so much that we were able to start rehabilitation programs. Sofia is now thirteen years old. She goes to a regular school, copes with the school curriculum. We are happy.”
– Saving cord blood stem cells in a private bank is a paid service. Not every family decides to save the cord blood of their baby.
Ya.I.: If the family does not want to use this service, then the parents of the newborn can donate his cord blood to a public bank for donor purposes. At the same time, it should be understood that cord blood is “biological garbage”, which, if not donated to the bank, is subject to destruction. Now in public banks around the world, in the aggregate, about 800 thousand samples are stored.- In addition to the use of donor or – in the case of preserving one’s own cord blood – one’s own healthy stem cells, another approach has emerged in cell medicine, even more engineering. They take his own cells from the patient, turn them into stem cells and implant them in him.
Ya.I.: The technology is called “obtaining induced pluripotent cells”, that is, cells are converted into stem cells of the “first order”. This method was developed by the Japanese scientist Shinya Yamanaka, who received the Nobel Prize for it in 2012. This technique makes it possible to reprogram the cells of the body and return them to an embryonic state, and then turn them into the cells necessary for the body. So far, this is a very expensive technology that is under development. The production of one line of such cells costs an average of approximately 50 thousand euros. For example, the European Induced Cell Bank currently has only 316 induced cell lines.
At the moment, cell medicine is still not mass-produced. Surely there are serious problems in this area that have not yet been resolved.
Ya.I.: Speaking about the use of umbilical cord blood, the biggest problem is that there is too little of it. The umbilical cord contains a small amount of blood, and therefore this method is well suited in cases where a small number of cells can be dispensed with. Otherwise, it takes a long time to grow enough cells in the laboratory for transplantation.
G.E.: Indeed, it is the small number of required stem cells that is often a serious deterrent. Theoretically, any organ can be grown from stem cells or damaged cells of this organ can be replaced. But in reality, today there are limits to both multiplying a lot of cells and getting them to work correctly. Imagine if we are trying to restore the liver – and this is a huge volume of cells, about 300 billion, then how long it will take to replace diseased cells with healthy ones. Therefore, the example of macular degeneration is especially attractive, not only because vision is the most important thread connecting a person with the world, but also because, perhaps, even a few tens of thousands of properly functioning cells can change the lives of millions of people for the better, especially in old age.
Today, there is another poorly predictable factor that worries me a lot. This is the clonality of transplanted cells. In the process of cultivation, cells inevitably appear that either divide better than others, or have some other properties that help them survive. And we unwittingly select such cells: if a cell reproduces only 10% faster, then in a few generations its descendants, its clone, will prevail over the rest. As a result of this involuntary selection, we select some traits that may be useful.
– And besides the complexity of the techniques, what else hinders the development of cellular technologies?
Ya.I.: Oddly enough, this is an undeveloped legal framework. When it is not about standard treatment, but about experimental treatment, then it should not contradict the law. Therefore, countries with more flexible legislation in this regard have a huge advantage in the development of cellular technologies. The undisputed leader today is, if we talk about Europe, then this is Ukraine. Thanks to flexible legislation, about 3,000 techniques based on cell therapy are now being used. Often, patients who have recovered from serious diseases as a result of the use of cell therapy on an experimental basis become fierce propagandists of these methods.
– Is it possible to imagine that cellular technologies will eventually replace some areas of pharmacological medicine? And in the future, will we be going to doctors for cells, not pills?
Ya.I.: Yes, of course. The pharmaceutical industry may well switch to this method.So far, the routine use of cellular technologies for therapy is a very expensive pleasure. But as the methods of obtaining and growing stem cells improve, the cost of treatment using cellular technologies will decrease.
From this point of view, a good example is DNA sequencing, that is, the decoding of the genome. Twenty years ago it was a very new and expensive technique. Steve Jobs, this procedure cost 270 thousand dollars, and today it costs three orders of magnitude less. It is quite possible that cell lines will cost hundreds of dollars in a few years, and not tens of thousands, as they are now. And then the attending physicians will turn to these methods quite standardly, and the organs for transplantation will be printed in the district departments of hospitals.