Medicine of the future is on the threshold

"Regenerative medicine is not a new technology, but a different medicine"

Olga Belenitskaya, "In the World of Science" No. 1-2, 2020
Published on the portal "Scientific Russia"

Growing new organs from stem cells, gene therapy, genome editing, cloning, genetically modified organisms... Probably, there are no hotter and more relevant topics today than these. At the same time, it is difficult to find topics that would be accompanied by as many myths as the above. We asked the academician to clarify this complex and interesting problem Vsevolod Arsenyevich Tkachuk, Dean of the Faculty of Fundamental Medicine, Director of the Institute of Regenerative Medicine of Lomonosov Moscow State University.

– Vsevolod Arsenyevich, this year the Federal Scientific and Technical Program for the Development of Genetic Technologies for 2019-2027 was approved. The same topic arose in connection with the creation of the scientific and technological valley "Vorobyovy Gory". Why is there such an interest in genetic technologies now? Is it only here or all over the world?

– There has always been an interest in genetics everywhere. A special rise was caused in the middle of the last century by the discovery of Watson-Crick, the creation of a model of the double helix of DNA and the postulation of the mechanism of transmission of hereditary information: one gene – one protein – one trait. For half a century we thought that the structure of proteins was recorded on the entire DNA molecule. But it turned out that everything is much more complicated. In the human genome, only 2% of the DNA structure is responsible for the structure of molecules in our body. Most of the DNA structure contains information that we have read, but have not yet understood.

– Are there any hypotheses?

– Someone thinks that this is a memory of evolution. genetic archives; someone - that this is the memory of some epidemics; and someone. including me, believes that the main percentage of this non-transcribed part of DNA contains information about long regulatory RNAs and short microRNAs. For microRNAs, it has already been shown that these are small molecules consisting of 20-22 nucleotides that can reprogram cells, make an undifferentiated cell differentiated or return it back to an undifferentiated state and even reprogram some mature cells into other mature cells. This is a very important discovery, fundamental for many branches of biology and medicine.

The possibilities of cloning human tissues have significantly expanded. A new and very effective method of genome editing has also appeared in the arsenal of science. With its help, mutations can be corrected and eliminated, and mutations can be introduced into the genome of an animal, a bacterium, a virus, or a particular human cell. There is a chance in this way to find out which DNA structures are responsible for certain signs. It became possible to change these signs by manipulating the structure of DNA.

The program for the development of genetic technologies is a very serious support for genetic research. Three centers have won grants, but I hope that support will be given to other teams to carry out these works.

– Is the Vorobyovy Gory Scientific and Technological Valley being created for these studies?

– Including. As for the technological valley, all the great universities of the world create such an innovative environment for themselves. And now a site has been allocated on the territory of Moscow State University, it is tens of hectares, on which scientific and production clusters will be created. One of them is biomedical, in which we will also participate. The construction of laboratories and offices will begin in order to attract business and private companies to cooperate with the university. Here we need to learn to hear each other. A scientist is passionate about fundamental science, he is not obliged to think about how to implement the knowledge he receives in solving momentary social needs. And business knows the market, needs, but does not know how it can respond to this request. We need to communicate, hold joint conferences so that mutual understanding arises. On this site there will be some preferences for firms that will be engaged in high-tech products. The state has provided for their exemption from taxes. I know that there are students who aim to find a good job right after graduation, drive a good car, wear the "right" ties and watches. And there are students who are set up for some kind of romantic action, their goals are on the horizon or beyond it. They are most often engaged in fundamental research, about which you never know how they will end. You won't guess which of the scientists will be lucky, who won't. Discoveries come by chance, but not to random people. They need to be seen, heard. My late teacher, Academician S.E. Severin, said that luck comes to every scientist at least once in his life. We must wait patiently for her, do our business and "be at home when she comes." These people need government support.

This combination of specialists will work in the space of the technological valley of Moscow State University. This is a very good decision made by our rector. V. A. Sadovnichy started talking about it 15-20 years ago. And now the law has finally been passed.

– Will the Academy of Sciences participate in this?

– Yes, of course. In fact, we are interpenetrating organizations. Several hundred academicians, corresponding members of the Russian Academy of Sciences work at MSU. This year alone, more than 25 MSU employees were elected members of the Academy of Sciences. It is a tradition that the first persons of science are invited to give lectures at Moscow University. And that's why we are united, we work together.

– Many people perceive regenerative medicine as an opportunity to regularly change their organs, print them on a 3D printer, endlessly rejuvenate the body. What is regenerative medicine? What are its capabilities?

– Regenerative medicine is a completely new field of medicine. This is not a new technology in medicine, but a different medicine. Modern medicine is aimed at regulating living cells. Medications slow down or accelerate some processes in the cells that make up our body. And regenerative medicine is a direction that involves the cultivation of organs and tissues that have died or for some reason have not formed in the body. It began to appear at the end of the last century and is now developing rapidly. There is such a phenomenon – the renewal of our body. This is a very powerful process. During the lifetime of the human body produces tens of tons of cells. We are updating all the time. And for a long time we didn't know how to manage this process. There are dozens of cell killing mechanisms that are evolutionarily embedded in every living organism. These are special ways to remove old cells, instead of which new ones are formed. Health, harmony, and well–being are when these two processes, the death and formation of cells in the body, are balanced.

Only in recent decades have we begun to understand how the processes of cell death are triggered. New opportunities have also opened up to regulate cell formation. In the XIX century. it was believed that cells are formed only from mature cells, that is, two daughter cells, its exact copies, are obtained from the mother. And that's right. But these tons of cells (only 3 tons of blood cells are formed during the lifetime) cannot arise due to the division of only differentiated cells. There is a biological limit – a mature cell cannot share more than 50 times.

But there are stem cells – hematopoietic, which are capable of unlimited division and differentiation into blood cells, and mesenchymal, which give rise to cell lines of muscle, fat, cartilage and bone tissue. This was discovered in Russia at the beginning and in the middle of the last century, which marked the beginning of regenerative medicine – it became possible to grow artificial organs outside the body with their subsequent implantation. This is a promising direction, because there will always be a shortage of donor tissues. The better medicine copes with diseases, the longer we live, the more it will be necessary to transplant worn-out, broken structures in the body.

With age or during illness, stem cells are consumed. They learned to isolate them from different tissues, grow, multiply and return them back. It started back in the last century. And literally in recent decades it has become clear that in the body some mature cells can turn into others. Little by little, we began to understand the role of regulatory RNAs. which are recorded on the non-transcribed part of DNA, and a new opportunity has appeared to regulate the processes of repair, regeneration, and cell renewal in the human body. There is a prospect of a new therapy that will be aimed not only at regulating living cells, but also at growing new cells, tissues, structures in our body.

– You said that these discoveries were made in Russia...

- Yes. Russian histologist, professor of the Military Medical Academy A.A. Maksimov in 1908 discovered hematopoietic cells, from which all other blood cells are formed. Thanks to this discovery, when the Chernobyl disaster occurred, bone marrow transplantation was used very effectively in the Soviet Union. And this was actually a hematopoietic stem cell transplant, which restores the recipient's entire immune system, as well as red blood cells that carry oxygen to all organs and tissues.

Another histologist, A.J. Friedenstein, discovered stem cells in the 1960s. from which muscles, fat, connective tissue, bones are formed. He died without receiving a decent recognition. 15 years have passed and he has become the most cited scientist in Russia.

– And what other organs can be grown?

– It is possible to grow blood vessels, nerve fibers, skin, and other tissues. You can, for example, the bladder, the ureter. It is not yet possible to completely recreate such complex structures as the heart and kidneys outside the body.

– And the brain?

– There is such a complex network of intercellular connections that we don't understand it yet. we can't grow it, of course. Unfortunately, many more diseases, such as Alzheimer's and Parkinson's, are at the stage of experimental attempts to restore function by improving blood supply, some other techniques, and not restoring the structure. But the goal of regenerative medicine is to completely restore the structure, to make it new, with the same properties, the same function. It is not possible to do this with the brain yet. But the nerve endings are being grown. After transplantation of a finger or hand, it is possible to accelerate the germination of nerve fibers, to achieve the full functioning of these limbs. In science, everything does not develop along a linear trajectory. We are at the beginning, and then a rapid rise is possible. And if we can't do something now, it doesn't mean we won't do it in a few years. Regenerative medicine is a serious, science–intensive medicine. Thousands of clinical trials are now coming to an end in the United States, Japan, and China. Such studies are also being conducted in Russia. But this is a very serious caliber weapon. This can be as dangerous as it is effective.

Therefore, the main focus now is on not doing any harm. The same is true in the case of genome editing. We can correct the right gene, but we cannot guarantee that we will not interfere with the genome somewhere else and will not do what we did not expect and what is undesirable. We cannot predict that this is a completely safe method – both cell therapy and gene therapy, when we grow tissues, restores functions. This requires many years of preclinical, clinical trials to make sure that this remedy is not only effective, but also safe.

– What are biomedical cell products? A number of countries have a multi-stage control system that guarantees the quality and safety of the use of the cellular product. Does the law "On Biomedical cell Products" adopted in Russia concern the medical industry?

– We have called biomedical cell products cell therapy products. These are the cells that are injected to restore some kind of structure. They can be autologous, taken from the patient's body. When a person gets sick, gets old, stem cells are consumed, they can be multiplied hundreds of times outside the body and returned to the right place. But in the body, these cells can change their phenotype. They have a constant ability to transform into other types of cells. And this is determined not only by their genome, the structure of genes, and not only by epigenetic influences, but also by the microenvironment of the cell. Therefore, we can introduce a stem cell, but we are not sure which cells it will be next to and what kind of sprout it will give, what it will begin to turn into. It is necessary to secure her transformation, for example. into a fat cell or cartilage, which is undesirable when treating the brain or heart. Therefore, it is necessary to work out the technique of differentiation directed in one direction, which is desirable for us. And only then enter into the body. This is the law adopted by the State Duma, signed by the President. He suggests that therapeutic cells should undergo preclinical animal trials, and then full-fledged clinical trials, as is done with any new drugs. The law regulates under what conditions and who can produce these cellular therapeutic drugs.

– Editing the human genome opens up incredible prospects, and there is no stopping it. But the ethical side of such interference is actively discussed in international organizations. We recently interviewed Academician A.G. Chuchalin, who heads the bioethics committee. He said that there is an ambiguous attitude towards genome editing in the world. How to be here?

– I have the deepest respect for A.G. Chuchalin, we have been friends for many years. In the Ministry of Health, I head the Commission on ethics of biomedical drugs. We meet with him, discuss emerging issues, hold conferences. This is an interdisciplinary problem. In addition to doctors and biologists, philosophers, sociologists, journalists, etc. should participate in this work. There should be an agreement between society and specialists.

As for genome editing specifically, I have already said that we know how to correct the right gene, and in some cases it is reasonable to do so. But humanity has no experience of using this method.

We don't know what will happen to a person in 10-20 years. Therefore, it is necessary to conduct research on animals. If you apply this in a clinic, then only when there are no other means of salvation, when suffering is so hard or death is so inevitable that there is no other way to help. But in the coming decades, it is necessary to apply this method so as not to affect the germ cells, so as not to transmit these genomic changes to the next generations.

– What about genetic diseases?

– It seems obvious that this technique should be aimed at curing genetic diseases. But caution is also needed here. The great physiologist I.P. Pavlov said 100 years ago that diseases are not the punishment of the Lord, it is the laboratory of the Creator. This is the formation of biodiversity, which will allow your family, clan, tribe, humanity to survive in some other critical situations. Therefore, we need to weigh a lot and make a decision with great care, so as not to harm either the patient or our kind-tribe. That's my position. It seems to me that all serious scientists have a balanced attitude to this. There are, of course, some enthusiastic people who are ready to do it even now. At the level of genome changes in the human embryo, there are also ethical and religious problems. I don't think anyone in our country is ready to decide on such work with embryos. This is both unsafe and will require an agreement in society, a firm knowledge of what we can afford and what we should not afford.

– Should international agreements be concluded?

– They should be, but different nationalities and religions have their own peculiarities. For example, among Christians, from the moment of conception, an embryo is considered an individual with whom one should act according to the same rules as with a born person. And the Chinese have an embryo before birth – not an individual, not a person. You can experiment with it. Judaism has its own interpretation of the embryo, Islam has a different one. And we have a multi-confessional state, and it is very difficult to adopt an ethically impeccable law that suits everyone. And how to do it at the international level? Therefore, UNESCO, and academician A.G. Chuchalin represents our country on bioethics there, develops uniform principles. Now in all countries, philosophers, religious figures, politicians, scientists have agreed to ban human cloning. Our country has also signed this convention. You cannot multiply copies of the same person, even if he is the most brilliant or beautiful. This will end badly for society, for the population, for all mankind. We don't know how these clones will behave decades later. Even the usual medications that we use for the disease have a 20-year delay. After 20 years, every drug is tested, and if a survey of thousands of people showed that it shortens life, the drug is withdrawn by a directive decision. This is done all over the civilized world. And what will happen to altered genes, clones or chimeric organisms cannot be predicted. And if it gets bad, where will we put them?

Great discoveries have been made in this area in recent decades. I think it is appropriate to compare them with the detection of radiation at the beginning of the XX century. Then it was discovered as a kind of useful property of matter, and even for a while French ladies powdered themselves with radium, because the skin became clean, but then they suffered from radiation sickness. Everything that a person has discovered, he sooner or later applies. It cannot be stopped, but a certain caution is needed. The specialist's duty is to warn society about this.

– In our country, in 2016, the use of GMOs – genetically modified organisms was banned, and now they are going to edit the human genome. Is there no contradiction in this?

– An analogy is appropriate here. I know that this may not meet the understanding of those who have a firm negative point of view on GMOs. but here's the problem: people can't do without genetically modified plants. All over the world, the rules regarding GMOs are the same as for medicines. If a store sells such a genetically modified potato that does not rot or a weevil does not eat it, then it is not harmful to a person, because it was tested according to the same protocols as new medicines are tested, and came to the conclusion that there is no harm. In our country, unfortunately, in the 1990s there were no conditions for conducting such studies. And many people were scared of GMOs, and rightly so. It is necessary to monitor agricultural technology. There are norms of herbicides that will kill all weeds, but will not kill the plants we need. However, if these norms are significantly exceeded, then an excess of herbicide can accumulate in the food product. This is no longer the problem of the geneticists who introduced these genes. No one has ever proved that the introduced gene harmed the person who consumed this food. Although this also needs to be checked every time. I say this because I am very afraid that the same misunderstanding may occur with the use of gene-cell methods in medicine. It is necessary to educate both medical specialists and society about these methods.

Now in the United States, parents pay an amount for children's insurance that takes into account their survival to 100 years. They say that someone who was born in the XXI century will live 100 years. Why? Because of regenerative medicine. There is hope for the creation of "spare parts" for the human body. Growing organs and tissues can have the same effect of prolonging life as it was with antibiotics in the middle of the last century.

– These are very expensive technologies, aren't they?

– Dear ones today.

– Won't it turn out that only the richest people will be able to use them and thus a kind of selection of humanity will take place?

– Your concerns are perfectly reasonable. Therefore, I say that a public agreement is needed in this area so that it does not create social tension. It is necessary to take into account both the possibilities of medicine and the readiness of society.

– If it is possible to get rid of the most terrible diseases with the help of this medicine, what will people die from?

– If people don't die, it will be the end of life on Earth. It is necessary to free up space for new generations, and they must evolve taking into account the changing conditions on Earth. It's obvious. But it seems that there is a certain program of life embedded in us. The Bible says that a person can live 120 years. Apparently, it is. In some regions, there are old people who are 110, 115 years old, but there are no 200-year-olds. Probably, there is some time limit when defects accumulate in the body, which the update system can no longer cope with. Maybe medicine will extend this limit a little, but it will not eliminate it completely.

Life is so arranged that the care of the body is provided by evolution. In addition to the biological clock, epidemics are probably involved in this selection, and maybe social conflicts. I don't want to speculate on this topic, we don't know much yet. So far, we know only one life-limiting law: a human cell is capable of dividing no more than 50 times, because with each division, DNA is shortened, vital genes are lost.

– Please tell us about the congress on regenerative medicine, which is currently taking place at Moscow State University.

– This is the fourth congress. More than 1.4 thousand people from all major cities of Russia gathered for it. They came from 18 foreign countries – the USA, England, France, China, from CIS countries – Kazakhstan, Belarus, Ukraine. This is a very hot, relevant and interesting scientific field. Live communication and conversation about successes and failures are no less important than just information about the results. We have interesting reports here, contests of young scientists, memorial symposiums in memory of those. who was at the beginning of this science. Young people who go into science should know them. But society should also know about us. Scientists should not be offended. No one knows from which research something necessary and great will grow. Maybe this will be the salvation for humanity. Or is it the future glory of our country. Therefore, it is necessary to treat very respectfully those people who work in laboratories and honestly develop their science. Inspires that. that there are not a few of us, but hundreds. And very decent world-class work is being done now, as it was in the last century.

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