For a rainy day

Stem cells: is it possible to replenish the health reserve?

Evgenia Candiano, Radio Liberty

Pharmaceutical medicine is not always able to cope with severe chronic diseases. She often offers patients medications that, although they help improve their well-being, do not cure the disease itself. If you stop taking them, then the problems come back. In other words, medicine struggles with the manifestation of the disease, but not with 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 of the body. Unlike other cells, stem cells can either divide very many times, reproducing their own kind, or turn into cells of specialized tissue. Another amazing property of stem cells is that they can find breakdowns in the body themselves and rush there to fix them – a kind of "ambulance" of the body itself. They are present in the human body until death. However, their quantity and quality decrease significantly over the course of life. 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 an egg by a sperm, the first full-fledged cell of the body with a double set of chromosomes, the so-called zygote, is formed. It divides rapidly, generating new and new cells that 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 tissues, but subsequent stem cells, "second-order" cells, give rise only to certain types of tissues. After birth, various types of stem cells are already present in the body. Among them there are those who work constantly. 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 we should talk separately about the placenta and the umbilical cord. They are necessary while the child is in the womb, as they connect the fetus with the mother, and after the birth of the child they are considered as "biological garbage" and thrown away. However, the stem cells that are found 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 treatment at first glance is very simple. When a person breaks some mechanism at the cellular level, it is necessary to transplant healthy stem cells 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 used quite narrowly, although it is considered to have great potential in other cases.

Radio Liberty asked scientists studying the potential of stem cells for the treatment of diseases: professors of Stony Brook University (USA) about what solutions to problems cell therapy can offer today and what prospects it has in the future Grigory Enikolopov, whose laboratory studies adult brain stem cells, and the founder of the Gemafond 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?

I.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 oncological diseases. This treatment was already used in the second half of the twentieth century, even before the boom in stem cells began. And so far, it is the only standard and generally accepted method. Interestingly, such a transplant makes it possible to cure some concomitant chronic diseases. If it becomes obvious that bone marrow cell transplantation is necessary, then you can choose a donor whose stem cells will have certain properties and will fight the concomitant disease. A striking example is two patients who were cured of HIV in this way. The first patient, Timothy Ray Brown, was cured in 2007, he is called the "Berlin patient". And doctors announced the complete cure of the second, "London patient", recently, at the beginning of 2019. Their healing stories are very similar: in addition to HIV, both patients developed additional blood oncological diseases, for the treatment of which a bone marrow transplant was needed. They both underwent transplantation of donor hematopoietic stem cells. At the same time, they were picked up not just donors whose blood stem cells were suitable for them. They were given donor cells containing a certain mutation: unlike normal cells, mutated cells lacked a traitor protein. The virus uses such a protein as a Trojan horse to penetrate 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.

– No less sensational was the recovery of a Japanese patient from schizophrenia, which, as in the first two cases, was the result of transplantation of hematopoietic bone marrow stem cells during the treatment of blood cancer. And 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 is this method of treatment standard. It is standard for the treatment of various forms of blood cancer, and the 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 working in this direction. In addition to blood oncology, there are quite a large number of diseases for which the stem cell transplantation method can work and is currently in clinical trials. After all, there are stem cells in all organs, even in the brain.

– For a long time we have been guided by the concept that nerve cells are not formed in an adult body and we are gradually exhausting 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 human neurogenesis was discovered more than thirty years ago, that is, the formation of stem cells in adult nervous tissue, the concept changed. Now we know that nerve cells can regenerate. Grigory, you are studying neurogenesis in the adult and aging brain. Is it possible to choose a treatment that will make the 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 formed in the hippocampus – the area that is responsible for memory and emotional state. It turns out that in Alzheimer's disease, existing hippocampal neurons are particularly sensitive and die first, and the production of new neurons that could replace the dead ones is strongly suppressed. Together, this leads to a sharp decrease in the number of working hippocampal neurons and, as a result, to memory deterioration, the development of depression, a decrease in the ability to rejoice and empathize. Since it is clear that the reason for these changes is connected, among other things, with the lack of neurons in the hippocampus, it is also clear that you 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 engaged in it, is to spur the formation of new neurons from the stem cells remaining in the brain. There are several possible solutions to this. For example, many studies have shown that, oddly enough, exercise and new experiences make brain stem cells multiply more actively. Although most of these results were obtained on animals, but there is confidence that this is also suitable for humans. The solution is simple and accessible to everyone – to move more and learn new things. So the saying "in a healthy body – a healthy mind" is now acquiring a scientific basis.

The second way that you can try to use is cellular medicine. You can try to plant stem cells or neurons in damaged areas of the brain in the hope that healthy donor cells will replace and displace sick or already dead recipient cells. However, it should be borne in mind that in addition to the direct expected effect, there may also be a side positive effect. It consists in the fact that when stem cells are transplanted, a general physiological reaction of the body occurs, which can sometimes lead to tangible progress, albeit temporary. For example, during the experiment, drosophila cells were transplanted to a rat, and the rat became more active and smarter. But, of course, not because the drosophila cells have taken root – this is the result of that very side physiological effect, and we cannot yet explain its mechanism.

– Grigory, and for what diseases of nervous tissues do cellular technologies seem promising to you?

G.E.: For example, huge efforts are being made to alleviate the symptoms of Parkinson's disease, in which one particular 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. However, when it comes to real patients, so far there are not so many successes – cells either do not take root, or do not turn into the right type of neurons, or begin to work so actively that it only exacerbates the disease. But progress in this direction is constantly happening, albeit in small steps.

Another very attractive area for cell therapy is the treatment of macular degradation. The macula is the central part of the fundus, the retina. It is located opposite the lens and is responsible for central vision and its clarity. Very often, with age, macular neurons die or worsen their work. In this case, the person loses central vision and reading and other delicate work become very difficult or even impossible. At the same time, the most critical area of the macula for clear vision contains only from several tens of thousands to hundreds of thousands of neurons. For comparison, the brain contains hundreds of billions of neurons. Therefore, a lot of effort is being made to introduce neurons and stem cells into the macula in the hope that even partial restoration of the macula can stop vision loss.

– Yaroslav, what other diseases can be treated with stem cells?

I.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 myocardial infarction. Both for the first and for the second case, the methods have already been developed. In addition, stem cells are being used to treat rare and incurable diseases in which classical therapy does not work and conventional pharmacological drugs do not cope. And since recently, cellular technologies have been tried as tools to combat aging of the body.

– In all these cases, cellular medicine uses donor stem cells. At the same time, donor blood can be taken from an adult donor, or you can use umbilical cord blood. Yaroslav, what are the advantages of donor cord blood?

I.I.: The concept of using donated umbilical 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 umbilical 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 severe diseases.

Umbilical cord blood consists mainly of hematopoietic stem cells. Although it also contains some other types of stem cells. Umbilical cord blood cells are more likely to take root in someone else's 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 during transplantation, in 80% of cases, transplanted cells from an adult donor attack host cells. In the worst case, such a reaction can lead to death. And the immune response of umbilical cord blood cells is much lower than that of adult cells, because the child has not been ill yet, and the placenta was protected from the mother's body, and his immunity has not yet developed. Consequently, there is a high probability that cord blood transplantation will do without serious consequences.

– There are cord blood banks. So, the idea of creating banks was born back in 1988 after the cure of Matthew Farrow?

I.I.: The 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 umbilical cord blood banks in the world. Even then, banks were divided into public and family banks. In private banks, parents keep the umbilical cord blood of their newborn child as a genetic reserve, providing him with a kind of "biological insurance" for his entire 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, he will be able to use his own genetic reserve. Umbilical 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 disastrous. In addition, stem cells of one family member are highly likely to 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 to get back on her feet after a serious injury.

We are talking about a girl from the Khmelnitsky region (Ukraine) who survived a coma at the age of 2. A few years later, the girl's parents decided to conduct experimental therapy – an infusion of her sister's umbilical cord blood. According to the parents, immediately after this therapy, the girl's condition began to improve rapidly. Here 's what the girl's mother Natalia told Radio Liberty:

– I was seven months pregnant when my two-year-old daughter Sofia fell through the ice. Her breathing stopped and her heart failed. In the intensive care unit, the heartbeat was restored, and after a while the respiratory function was restored, but they said they could not do more because the brain died. Sofia didn't react to anything, they fed her through a probe. After I gave birth to my second daughter, my husband and I decided that we would take Sofia home. I am a doctor, so I was able to master the methods of care. We kept the umbilical cord blood of our newborn daughter, although we had no plans for this blood at that time. And a few months later we got a call and were told that one of the clinics in Donetsk was carrying out cord blood transfusion as part of the Ukrainian-German clinical research program. We checked whether her sister's umbilical cord blood was suitable for Sofia, and fortunately, it turned out to be compatible. Sofia was transfused with this blood, and literally a week later we saw an improvement in her general condition: food began to digest, her skin turned pink, the infections that tormented her endlessly receded. In a word, a miracle happened. And after repeated 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. Radio Liberty failed to find scientific studies that would unequivocally confirm that in this case it was stem cell therapy that proved effective. We emphasize that stem cell therapy in most cases is an experimental and potentially very dangerous method for health, which should not be used without the decision of the attending physician.

– Preservation of cord blood stem cells in a private bank is a paid service. Not every family decides to keep their baby's umbilical cord blood.

I.I.: If the family does not want to use this service, 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 umbilical cord blood is "biological garbage", which, if not donated to the bank, is subject to destruction. Currently, about 800 thousand samples are stored in public banks all over the world.

– 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, even more engineering, has emerged in cellular medicine. They take his own cells from the patient, turn them into stem cells and give them to him.

Ya.I.: The technology is called "production of induced pluripotent cells", that is, cells are converted into "first-order" stem cells. This method was developed by 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 the embryonic state, and then turn them into cells necessary for the body. So far, this is a very expensive technology under development. The production of one line of such cells costs on average about 50 thousand euros. For example, the European Induced Cell Bank currently has only 316 induced cell lines. And this is the result of the work of the last seven years, despite the fact that the Japanese are willing to share their best practices.

– At the moment, cellular medicine has not yet become mass. Surely there are serious problems in this area that have not yet been solved.

I.I.: If we talk about the use of cord blood, the biggest problem is that there is too little of it. The umbilical cord contains a small amount of blood, and, accordingly, this method is well suited in cases where a small number of cells can be dispensed with. Otherwise, it takes a lot of time to grow enough cells in the laboratory for transplantation.

G.E.: Indeed, it is the small number of stem cells required 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 how to multiply a lot of cells, and to make them work properly. Imagine if we try to restore the liver – and this is a huge volume of cells, about 300 billion, then how long will the process of replacing diseased cells with healthy ones take. 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 several tens of thousands of properly functioning cells can change the lives of millions of people for the better, especially in old age.

– And what are the dangers and risks associated with cell therapy? I do not mean outright adventurers, when a doctor or a scientist quite consciously commits a crime by falsifying facts. Such things are marginal, but, unfortunately, they exist in traditional medicine too.

G.E.: First of all, there is always a danger that donor cells may not take root in the recipient's body or take root, but work poorly or uncontrollably, without brakes, so that treatment becomes worse than the disease itself. In addition, it must be remembered that even perfectly matched imported cells can trigger an immune response aimed at getting rid of these cells.

There is another serious danger – this is the possibility of developing cancerous tumors. It may happen that among the cells selected for transplantation there will be those that can turn into cancerous. It is almost impossible to predict this in advance, since this potential cannot always be recognized. In addition, uncontrolled cell growth depends not only on the cells themselves, as well as on the immune system, which must eliminate the wrong cells, but also on the environment, the so-called niche into which these cells have fallen. One niche can restrain the cancer potential of a foreign cell that has got there, and the other, although similar, will stimulate it.

To date, there is another poorly predicted 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 involuntarily 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 such involuntary selection, we select some signs that may be useful, but may also be harmful.

– And besides the complexity of the techniques, what else is holding back the development of cellular technologies?

I.I.: Oddly enough, this is an undeveloped legal framework. When it is not a standard treatment, but an experimental one, then it should not contradict the legislation. Therefore, countries with more flexible legislation in this regard have a huge advantage in the development of cellular technologies. The undisputed leader today is Japan, and if we talk about Europe, then this is Ukraine. In Japan, thanks to flexible legislation, about 3,000 methods based on cell therapy are now used. Often, patients who have been cured of serious diseases as a result of the use of cell therapy as an experiment become fierce propagandists of these methods, as happened, for example, with Timothy Ray Brown, who advertises these methods in every possible way and created a fund for the development of cellular technologies.

– Is it possible to imagine that cellular technologies will eventually replace some areas of pharmacological medicine? And in the future we will turn to doctors for cells, not for pills?

Ya.I.: Yes, of course. The pharmaceutical industry may well switch to this method. So far, 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. This procedure cost Steve Jobs 270 thousand dollars, and today it costs three orders of magnitude less. It is quite possible that cell lines will cost tens of dollars in a few years, and not hundreds of thousands, as now. And then the attending physicians will use these methods quite standardly, and organs for transplantation will be printed in district departments of hospitals.

G.E.: And by doing sports and constantly striving to learn new things, you help the stem nerve cells to multiply and, perhaps, you yourself carry out the prevention of severe brain diseases.

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