A spoonful of honesty in a barrel of molasses about regenerative medicine

Interview with Roman Deev

Denis Yatsutko, XX2 century

Roman Deev, Director of Science of PJSC ISKCH. / Drawing – Asya Hell.

On our recently published interview with Elena Gubareva on the state of affairs in regenerative medicine Director of Science Institute of Human Stem Cells Roman Deev reacted with a skeptical remark on his Facebook page. We decided to talk to Roman to find out his point of view on the prospects of tissue engineering.

XX2 CENTURY. Roman, when we had an interview with Krasnodar residents, you noticed so skeptically on Facebook that the statement that we are keeping pace with America and Europe is too optimistic. Why?

Roman Vadimovich Deev. In general, my Facebook wall is quite skeptical. Therefore, the statement of colleagues from Krasnodar is not the only case when I allow myself, rather, to speak ironically about some announcements, events and opinions in the field of regenerative medicine. To be precise, I wrote that I "dearly love my colleagues from Krasnodar, but why lose your head". There are some reasons to write like this for the simple reason that I was lucky enough to observe the process of creating this laboratory, its development, the work of this team. In addition, I have to be quite knowledgeable about what is happening in Russia in this field of science. I absolutely understand Elena and her motivation in this interview; of course, "to do science" – I pronounce these words in quotation marks; "to do science" – it's not a good phrase, but, nevertheless, it's difficult to engage in biotechnological developments in Russia. Moreover, in this case it happens within the framework of an institution subordinate to the Ministry of Health, with sufficiently reduced budgets, so working in such laboratories is a "feat in peacetime." This is understandable, and it commands respect. But there is one caveat: it is impossible to keep up with foreign colleagues if at the same time you work on foreign equipment, implement foreign thoughts, ideas, concepts, and so on. We can talk about a parallel course if we work with domestic equipment, with domestic reagents, because science is not just a thought and its implementation. This is actually an infrastructure created for conducting certain scientific research. Therefore, equipment, reagents, standards for the organization of the laboratory and research process, the very topic of tissue engineering in the form in which it is reproduced here – these are not our ideas, let's be honest!? After all, it was implanted, transferred to us, just as Peter the Great transferred some ideas, some formats from the West in his time. The same goes for regenerative medicine. Of course, we certainly have important discoveries, important achievements in this area, but if we talk specifically about the content of today, let's be honest and frank, we reproduce everything that was once done by someone in the West. Enriching, improving, but in fact there is not a single technology that is completely its own.

XX2 CENTURY. That is, a catch-up strategy?

R. D. Of course. Do you understand what the matter is: regenerative medicine (in its modern sense) – this is fifteen to twenty years of history and work; and laboratories in The Russian Federation, which could have been created within the framework of a certain innovation trend that was in the formation of the policy of innovative development, how many? Ten years? Eight? How do you want to keep up when we are two times behind purely chronologically? I'm not talking about the technological lag. There are no miracles. I don't want to say "catching up – not catching up", everyone has their own way; apparently, we are going our own way, but we must understand that this is "out of step", this opinion is self–deception.

With Elena, we did not discuss this interview with her… But, after all, people read it, and they can draw wrong conclusions from what they read. On the other hand, it was the opinion of one expert. I have a different opinion. I am not ready to act as a mentor or correct someone else's professional opinion.

XX2 CENTURY. And about Elena's statement that Asian countries, China, are ahead now, what can you say?

R. D. It depends on what... and we review that interview, right? Is this the format of our conversation?

XX2 CENTURY. Why not? At first. Another expert's point of view is interesting.

R. D. Good. It depends on what is considered a criterion, what is considered a measure. If the measure is the number of publications, then, of course, a billion Chinese, anyway, will write more of them. I say conditionally, but out of a billion, the sample of scientists is more than out of a million, even out of three hundred million in the European Union or the USA. There are just mathematically more of them. If you look at breakthroughs, it is not yet clear that the quantity turns into excellent quality. Cool works appear, but these cool works are still a creative rethinking and development of what has been done in the West. CRISPR/Cas9 was not invented in China. They were reproduced, they began to be used more boldly for a number of reasons, but they were not invented in Asian countries.

XX2 CENTURY. And actually this bolder use does not mean that China, maybe, is just overtaking?

R. D. No, of course not. I'll explain why. Because there is another criterion, which is called "broadcast to the clinic." One thing is technology, another thing is its research, fine–tuning, eyeliner, the third thing is preclinical research, the fourth thing is introduction into the clinic. And if we look at the history of biotech carefully, we will remember that there are two gene therapy drugs registered in China, and they are the first on the planet – Oncorine and Gendicine, 2003 and 2005, but these are American patents. It was just more convenient to register them in China. It was faster to conduct clinical trials there, apparently cheaper at that time. But it turns out that this is not a Chinese development.

XX2 CENTURY. Does registering in China make it possible to use them somewhere else?

R. D. No, of course it doesn't. Only within the framework of the regulator that registered. It was registered by the FDA (they also call it the FDA) of China, which means that they are used only in China if there are no other interstate agreements.

If you look at the technologies registered and approved by national regulators, be it genetic, be it cellular, then, of course, the Western countries are leading (maybe for now). If you look at the number of clinical trials – again, purely mathematically, quantitatively – then competition begins between the West and The East in this aspect. Is there an "exhaust" of this amount today? He's not here yet.

If you look at the legislation, apparently, the most meaningful, balanced and developer-friendly legislation in general is in little Japan.

Therefore, the answer to Your question cannot be unambiguous yet. From the point of view of the laboratory part, yes, probably, Asian countries are winning in number, primarily at the expense of China. From the point of view of quality and yield for medicine, it is premature to draw conclusions about Asian leadership in regenerative medicine. We have been hearing opinions for two or three years that the Chinese quantity is about to turn into quality. Probably, this happens in technology, but not in biotech yet.

XX2 CENTURY. And in terms of what quantity can turn into quality? What is expected from the Chinese?

R. D. Nothing special. Reproduction and rapid clinical trials of Western technologies.

XX2 CENTURY. Is that all?

R. D. This is my value judgment. Gene therapy was not invented in China, CRISPR/Cas9, genome correction was also not invented in China. When will the Chinese science industry really start generating technology? The devil knows. It is not generating yet. So far, only borrowing and creative development and rethinking.

XX2 CENTURY. In your opinion, when can I expect in In Russia or even in the world of actually used tissue-engineered organs for the treatment of people?

R. D. And why?

XX2 CENTURY. What does "why" mean? Aren't they needed?

R. D. You see, we have such a stereotype that it is very necessary.

XX2 CENTURY. Isn't it? Don't wait for a donor…

R. D. These are all beautiful journalistic fairy tales, in fact. They are very good for science, they are very good for receiving and implementing grants, but for life, as experience shows, they are far not only from implementation, but even from the meaning of this implementation. I'm becoming a skeptic here.

Yes, there are probably isolated applications where it makes sense, but I don't think humanity will go this way at all. This is an eternal journalistic funny story that originates, it seems to me, from the cartoons of the last (if not the century before last) century, when a doctor comes to a pharmacy and takes a liver, kidneys, spleen from the shelf… It's all not technologically advanced.

Do we understand the term "tissue engineering" the same way? Maybe we understand it differently? In the classical sense, tissue engineering is the use of a certain matrix, a kind of scaffold, synthetic or natural, on which we "planted" cells. And they, so smart, "sat down" there, multiplied and turned into what the patient and the doctor need. But we can see that it doesn't work. This does not work even for such qualitatively simple things as bone tissue. Simple – how simple a living tissue can be at all. And for such complex, multicomponent structures as the esophagus, trachea, lung, liver – this is not the way at all. From a scientific point of view, this is, of course, an interesting direction; and from a practical point of view, it is a way of disposing of banknotes, nothing more.

XX2 CENTURY. But they are trying to do something in this direction. Do you think that there is no future for all this?

R. D. They are trying to do a lot of things, but this does not mean that everything will work out of it. Of course, the vast majority of tissue engineering developments have no future. They will be replaced by much more effective and technological approaches even before the actual transition to clinical practice.

XX2 CENTURY. For example, which ones?

R. D. For example, an interesting technology, everyone is hearing about it, of course, bioprinting. There are a catastrophic number of problems there, and it is difficult to make predictions in this regard now, but in principle it looks much more interesting than tissue engineering. And what is called "cheap and angry" and what biotechnology really allows is, of course, the cultivation of humanized animals. Because it's understandable and it's relatively cheap.

XX2 CENTURY. Are humanized animals animals that have human tissues implanted in them?

R. D. Including. At the earliest stages of embryogenesis. However, genome correction technologies that are gaining momentum may struggle with the expression of antigens. To raise a pig with a non-immunogenic heart suitable in size, which can be taken and transplanted, may be much cheaper than to grow a pseudo-heart from pseudocardiomyocytes on a pseudo-frame, activate a pseudo-electric system of electrical coupling there for coordinated contractions of these pseudocardiomyocytes; launch pseudo-coronary vessels there, which will all supply blood... I say again: this is beautiful for scientific science fiction, it's very "cool" for sci-fi and it worked well in the last decade to receive grants. But by the end of this decade, even grants will stop being given for this, because it is already clear that this is a soap bubble.

XX2 CENTURY. In my opinion, a pig heart transplant to a human looks no less fantastic.

R. D. No, there are technologies, prototypes of humanized animals have been around for ten years, smart companies are working on these technologies, they will bring them soon, I hope.

XX2 CENTURY. And will not be rejected?

R. D. You're asking me how Grandma Vanga is. In theory, this property is inherent in the ideology of this technology, otherwise there would be no sense. Any animal organism is a much cheaper and much more effective bioreactor than all the technological bells and whistles that are used, all these tricks with half–industrial, half-basement-assembled bioreactors, all this, unfortunately, and this is also just a personal value judgment, is not technologically advanced. This is momentary, for very specific forms of near-scientific business.

XX2 CENTURY. And in this case, what are the promising areas for the use of stem cells?

R. D. We should always call a spade a spade. What kind of stem cells are you asking about? Because, for example, there are hematopoietic stem cells, and we cannot talk about prospects, since they have been widely used in the clinic for half a century. Their first allogeneic transplantation was in 1964-68, then in the 90th year – for this the Nobel Prize. Thank God, oncohematology, hereditary diseases with hematological syndrome are treated exactly like this – with hematopoietic cells of bone marrow and umbilical cord blood, to restore damaged or destroyed hematopoiesis. And, in general, there are no questions to this. There are various forms of improving this technique aimed at more effective suppression of the immune system before transplantation, methods of enriching the transplant with hematopoietic stem cells, growing these cells in vitro. It's all there, yes, but the concept is here; and it's been working for half a century.

But if we are talking about other types of stem cells, then the situation is different there, you can't consider them all "in a bunch". Therefore, if you can formulate which stem cells you are interested in, then I will try to answer.

XX2 CENTURY. I am not an expert, but I know that there is a lot of talk now, for example, about pluripotent stem cells.

R. D. You mean iPS, right? Cells with induced pluripotency. If you have noticed, even the initiated clinical studies using this material are devoted to the treatment of a genetic disease (a genetic defect of retinal pigment epithelium cells). This is the nosology that requires, on the one hand, the replenishment of dead or dying cells of the same organism, that is, they must be autogenic, on the other hand, the patient's cells must be genetically corrected, brought to the iPS stage by laboratory means, then they must be sent somewhere along the path of differentiation, in this case in the side of the pigment epithelium. But the niche of genetic diseases is a very small area of medicine; rare diseases. This means that the economic costs of developing such methods can be so great and unrecoverable that they can become a risk factor that it will not be possible to actually broadcast widely into clinical practice for routine use.

XX2 CENTURY. That is, do you think that they will simply stop investing in it?

R. D. Genetic diseases are not treated radically in any other way. They need to be treated by correcting genes and efficiently delivering the corrected genetic material. Here, this technology seems – I say carefully – seems really advantageous in comparison with all other possibilities. While there is no particular alternative, it seems that this should work. But each time it will be an individual and personalized approach. And who will pay for such treatment?

XX2 CENTURY. Is there no alternative? And CRISPR/Cas9?

R. D. Yes, but they must be delivered to their destination. You won't let him go through Vienna. It's not a systemic drug, you can't eat them like a pill and you won't go further. These structures need to be somehow delivered to the body, to tissues and cells. An elementary example is the hereditary pathology of muscle tissue, Duchenne myodystrophy, a terrible disease. We take CRISPR / Cas9, will you take it three times a day after eating a tablespoon? How do you get it into every muscle fiber? An adult has 40 kg of muscle tissue; okay, let a child have 10-15 kg. How do you put a mutation-correcting construct inside these hundreds of millions of fibers and correct the dystrophin gene in this way? We won't do it ourselves, we won't be able to. This delicate procedure must be performed by the helper cells we have mobilized. Let it be iPS, for example, which can be transplanted in a corrected form, hoping that they will convey the necessary information to the right place, modeling, forcing /training them to convey it. Of course, it's a matter of technology, how to implement it. And here such a technology is absolutely advantageous, because so far there are no alternatives that could replace it.

XX2 CENTURY. A few years ago, there was a lot of talk in the media and social networks that in expensive clinics where rich people are treated, stem cells are injected to everyone and from everything in a row. What is this about, which cells? What were they injected with?

R. D. I suggest asking the prosecutor's office about this. Because if everyone was stabbed with something in a row, I assume that dozens of volumes of criminal cases should be stored somewhere in the depths of the prosecutor's office. Have you heard of at least one criminal case on this topic?

XX2 CENTURY. Was it some kind of divorce, apparently?

R. D. Not a divorce, but such a fried topic. Why not write a couple of articles about it in some tabloid. It's fun.

XX2 CENTURY. So maybe there was nothing?

R. D. You know, of course, there are unscrupulous people in any business. There are unscrupulous trolleybus drivers, probably there are unscrupulous employees of the factory where rockets are made. Surely there are unscrupulous people in white coats, there is no getting away from this. Therefore, I fully admit that at one time there were organizations that were engaged in this, but I assure you: they never existed in such numbers as we were told about it, including officials of the Ministry of Health. I remember these quotes, I had to attend various meetings, hearings, in the State Duma, hell, where even representatives of the Ministry of Health, I won't name names, claimed that pluripotent cells were stabbed in almost every basement. Of course, there was no such thing, it's all nonsense. And if there were individual facts, then the materials of administrative and criminal investigations should have been preserved for them. Well, show me.

XX2 CENTURY. So if it was, it was more of a crime?

R. D. If the legislation is violated there, how else can it be qualified? Whether there was a crime or not, the court can probably determine, but, tell me – did something at least come to court? Was there at least one case at all, at least one trial? Guys, let's operate with facts. Where? Who! When?

Yes, of course, you can go online, Google, and you will find a clinic in Switzerland. This country is not a member of the European Union, so they allow themselves everything there. They, for example, treat many diseases, the clinic of Paul Nihans, with the cells of a mysterious black mountain sheep. That is, it is the use of xenogenic cells. They even have a Russian-language page. So, maybe they have a violation of the law there in Switzerland…

XX2 CENTURY. Sheep?

R. D. Sheep. Black, mountain.

XX2 CENTURY. How do these cells interact with the human body in general?

R. D. The way xenogenic cells should be. They must die. They should cause some kind of humoral and immune reactions. But then again, he's been using them for 50 years, Paul Nihans. Judging by what they write, many famous people were clients of this clinic, some popes, Charlie Chaplin. All this can be found in the available sources in Russian. And, in general, the clinic is working, as far as I understand, quite successfully.

XX2 CENTURY. But is this shamanism? The same as, for example, any perfume, as it happens, you know, it says on the package: "Cream with birch stem cells"? Just not "stem cells of the birch trunk".

R. D. Well, shamanism is partly, yes... as for cosmetic matters, it's marketing. "Birch stem cells", well, well, you never know what they will write. As for this clinic, here, shamanism is not shamanism, one cannot discount some non-specific effect on the recipient's body. Foreign cells get in, the immune system is invigorated, hormonal shifts begin, it works for some period… I'm guessing now, I'm not claiming. Because I have no research experience, I have not seen a single publication. To be honest, I didn't look carefully, but that's how I haven't come across publications on the systemic introduction of xenogenic cells from animals to humans in fifteen years. In my opinion, nothing good should come from this. But it is impossible to discount, once again, some kind of nonspecific reaction of the body, which can really change the status of the body in some situations, the balance of illness and health. How long, in which direction? But again, we haven't seen, in general, a single trial in these few decades.

XX2 CENTURY. Is everyone happy, apparently? It's amazing... damn, you cut it so much, I wanted to talk about tissue-engineered organs so much…

R. D. We can, of course, fantasize about this topic.

XX2 CENTURY. But after all, messages constantly appear: they have grown this, they have grown this, they have planted it on the frame…

R. D. Didn't grow anything. Nobody has grown anything anywhere, you know? The fact is that you read these messages in the interpretation of the press services of universities or Russian-speaking journalists, which is even worse. I speak impersonally, but it's just that very often when the same news is repeated/retold after three knees, and even with a bad English translation, the final result published in Russia is radically different from what actually happened. So don't just believe what you hear, that's all. No organ has ever been grown anywhere. As soon as he grows up, we'll celebrate, we'll open a bottle of champagne.

XX2 CENTURY. Just the other day there was news that the intestines were grown and even with nervous tissue.

R. D. It is possible to grow an organ only inside the body. It cannot be grown outside the body. You can create some kind of bioartificial equivalent. Not even an analogue. Where there will be an inanimate stroma, that is, a framework on which the "village" of cells is two-three-four-five orders of magnitude smaller than they actually are in a unit volume of any living tissue. These cells are in isolation from nervous regulation, in vitro – in isolation from humoral regulation, and there is no need to fantasize: they do not "sit down" qualitatively on the substrate offered as scaffolds; they do not build high-quality tissue, nothing happens.

XX2 CENTURY. What's going on?

R. D. At what point? At the moment in vitro? Or at the moment when they are injected into the body? Nothing happens in vitro. They live and live. Conditions are created for them, they are warm, humid, oxygen, vitamins – everything is there, they live for themselves. Cells can be cultured on the surface, in a cup, or in a three-dimensional system. For this purpose, for example, special membranes are used so that it is possible to increase the surface area and it is possible to grow more cells in one bottle. Naturally, in conditions of a more intensive exchange of media and gases. And instead of these complex sponge or membrane filters, on which large volumes of cells are grown, you can offer these cells a matrix and say: "And this is a matrix for tissue engineering." The essence will not change: some cells "sit down" and live. Well, maybe some reproduce, synthesize something somewhere. As a result, it turns out that on a three-dimensional inanimate frame there exists, sometimes in half a layer, sometimes in one layer, sometimes in several layers, a certain number of cells. As a rule, these are connective tissue cells, as a rule, multipotent mesenchymal stromal cells are used for this, those that we call MMSCs, or, as they sometimes say, MSCs – so what?

Imagine that there is such a medical device. You can layer epithelial cells on top, then some epithelium will crawl along the surface. And it's wonderful, and that's all that happens in vitro. Yes, it is also possible to act with some chemical or biological agents and induce directional differentiation. But there is no need to think that the bone will grow if we direct it to the osteogenic side. No, there will fall out small, small crumbs of mineral, crystals that are visible only under a microscope, microscopic precipitates of calcium phosphates. There will also be minor molecular signs of ongoing bone differentiation. That's what will happen in the vast, absolute majority of cases and the absolute number of such technologies.

What happens when such a product is placed in vivo? First, how to put it in vivo? Most often this is an operation. The operation is a trauma, it is a wound; the body reacts to it with inflammation, migration, aggression of leukocytes, oxidation, production of pro–inflammatory cytokines, that is, a good half of the transplanted material dies immediately. Then the question of blood supply arises – they, after all, want to eat. In vitro, they were fed a rich and expensive nutrient medium through a tube, and then they got into the operating bed, even there are no vessels. If this is an organ that should peristalt, or the heart, then the development of the autonomic nervous system, intramural nerve plexuses, is essential, integration with the nervous regulation system should occur. These fairy tales that cells are so smart and after transplantation they know what to do themselves, we all went through this in the 90s and early 2000s, in experiments when they were simply injected. There was such an idea that they themselves would come by the mechanism of roaming, by the concentration gradient of certain substances to the right place and do everything there... Yes, indeed, this effect of directed migration is shown in a huge number of articles that, by the cytokine gradient, cells, even after systemic administration, can migrate to where they smell delicious, where the concentration there are more attractants, some of them can really differentiate into something. Single ones! As a rule, at the organizational level, in the clinical picture of diseases, this "arrival" of cells does not affect at all. This is based on the fact that after transplantation of some tissue equivalents, even in animal experiments, if they are carried out correctly, most often either a complete, total death of the transplanted cellular material occurs, or subtotal.

How does the body react to this? All our pathomorphological reactions to such interventions are known and stereotyped; and have long been described in textbooks: resorption, encapsulation, germination by connective tissue, suppuration… The ideal case is when the process of resorption of the transplanted (implanted) material occurs simultaneously with the replacement of its tissues from the edges of the wound (surgical wound).

Let's say bone surgeons never fantasize about this topic. All developers of bone materials put this goal in the ideology of their developments and honestly talk about it: we want to create such a material that the rate of its resorption corresponds to the growth rate of a nearby bone, so that the process is balanced. The problem is that while chemists and technologists fail to do this, the mineral does not dissolve for too long, combinations are selected - mineral, mineral plus cells – not so that they become some kind of outstanding bone, but so that they contribute to this balance of the speeds of both processes.

In other areas of surgery, colleagues are not yet ready to admit (primarily to themselves) that the same principle applies in other tissues: all patches on bubbles, all patches on tubular organs (intestine) are also resorption with replacement. Yes, unlike synthetic materials that are used for this, in tissue engineering, the process can be more accurate, more synchronized in speed, on the one hand. On the other hand, there are materials of biological origin, they are used, they are on the market, meaning a variety of patches obtained from the pericardium, fascia, etc., they have been used for several decades, almost a century. They are actively used in surgical practice, both wonderful and good. Of course, there are some cases where it does not work, I am not ready to indiscriminately extend this to the whole body, there are complex areas where it is not possible to do it yet.

If it is not possible to germinate through, then the second stereotypical reaction of the body to the transplantation of a tissue–engineered structure is to bypass the obstacle, overgrow and encapsulate. This is the next option: to enclose in a connective tissue capsule. Therefore, when we restore some tissue elements, parts of organs where the epithelium is the functionally leading tissue, then with a successful combination of circumstances it just grows on top, that's all. These are not the cells that were in this bioartificial equivalent. These are the cells of the body, it's not like everything happens in a vacuum, there are always living tissues around the structure.

I am sure that for the vast majority of cases of tissue engineering, we will start talking about it soon. Right now we are shy. I regularly visit all forums, watch, listen. We haven't talked about it for ten years, but it feels like it's time. It's time to reveal the cards and stop fooling around.

This does not mean that these technologies have no future or there are no minor applications. There are some: there is an esophagus, there is a trachea; but, firstly, this does not mean that there are no alternatives, they are there. Yes, tissue engineering is an interesting approach; you can play, try, see – in preclinical research, first of all. But in principle, I don't see any powerful applications for tissue engineering yet.

XX2 CENTURY. It turns out that all reports about the same grown intestine with nervous tissue, that an artificial vagina was grown on a certain frame, should be treated as an empty boast?

R. D. Look here: they take a frame, sow cells there – smooth muscle cells; it turns out a tube. If it is sewn into the place of a removed or undeveloped vagina, there will be a tube replacing the vagina. Can we say that this is a vagina, or what? The longer this tube stands in this place, the more intensely nerves begin to germinate into it, connective tissue grows, its epithelium grows – so it's our own, it's not like we planted and sewed up some nerves… The vagina may not be the most successful example…

XX2 CENTURY. The press release said that this is for women with vaginal underdevelopment and that this is a fairly common problem.

R. D. Not often, far from often (1 case per 5000-20000 girls). In addition, plastic, reconstructive surgeons make vaginas from a fragment of the intestine and from other own tissue materials. To date, they have even learned to transplant the uterus, moreover, even to give birth after that. Therefore, the vagina, from the point of view of science, is interesting. From the point of view of practice – why?

XX2 CENTURY. I was warned that you are a skeptic…

R. D. But what is so much! (laughs)

XX2 CENTURY. It's amazing, actually. Every time I go to talk to scientists, I'm usually set up for something like this: "Let's talk about the future, about how everything will be fine." But no. In the anti–plague they say that the last strains of smallpox will never be destroyed; Alexander Kaplan says that the brain is too complex matter, and we will never reproduce it; You say that there will never be tissue–engineered organs - it's sad.

R. D. Well, you know: a pessimist is a well–informed optimist.

XX2 CENTURY. I would still like light notes. And what good is going on?

R. D. Yes, life is good. The sun is shining. The sky is blue. Doing your own thing is fine. To help the sick. Developing and implementing new methods is generally great.

XX2 CENTURY. And what interesting new methods are there in terms of using stem cells?

R. D. Which ones? I ask again: which ones? I (again, this is subjective) am waiting with great interest for the results of the treatment of genetic diseases using iPS technology. These are studies that began with the replacement of atrophied pigment epithelium in the retina. Extremely interesting. Here, as I have already said, there is no alternative, and for the first time we have obtained a molecular skeleton key for this problem. This could prove to be a very powerful breakthrough. Yes, there are few such patients. But yesterday they were sentenced, and today there is a technology that gives them light. In most other cases, there is no such critical difference "yesterday-today". They replace the trachea, but it was already replaced. Worse or better – we look at the statistics on the results and cannot say that the previous methods were much worse than tissue engineering. But in the case of the retina, there was nothing at all.

In general, when there is progress, it is immediately visible. For example, iPS technology, the first works – the sixth year (2006), then the eighth year, and, consider, in six years – the Nobel Prize! That is, it is obvious that technology has given us some serious new tool. Of course, this is not always the case with the Nobel Committee, very often the Nobel Committee is conservative, but, nevertheless, it is quite clearly visible here. And all this wonderful tissue engineering… Well, how old is she? Well, 20 years? Where are the breakthroughs? What problem has been solved in 20 years?

XX2 CENTURY. Are there any other inspiring examples? When yesterday is nothing, and today is a breakthrough?

R. D. ECO. In vitro fertilization. Nothing until '78, but from '78 – please.

XX2 CENTURY. And fresher?

R. D. Fresher, please, CRISPR/Cas9. This technology is two or three years old, in fact, exactly in the version in which it is now. And clinical trials have already begun, can you imagine?

XX2 CENTURY. In China, they are already trying…

R. D. There is even yes, already the correction of the embryo is being done.

XX2 CENTURY. An adult cancer patient is still being treated with CRISPR.

R. D. Fine. If it works out, great.

There was also an improved powerful technology for training lymphocytes, training them for malignant tumors. What we cannot do in other ways is the technology of chimeric antigen receptors.

XX2 CENTURY. CAR-T?

R. D. Yes, yes. And then clinical studies began. These are the most powerful things, they are always at the junction of the finest applied molecular biology and transplantology. And the cages on the frames can be grown for another 15 years. It will be quite suitable for student papers, well, for graduation papers – it's interesting.

XX2 CENTURY. But after all, a lot of laboratories are engaged in the cultivation of tissue-engineered organs all over the world.

R. D. So what?

XX2 CENTURY. Are they all, all these hundreds, probably, scientists engaged in nonsense?

R. D. Different laboratories work with different motivations. Someone got on his horse, someone does it well, grants are given - well, it's a sin not to use. Science is the same way of earning and bringing money to the family. Someone really sincerely believes that now we will grow something and sew it, and it will grow. Someone doesn't have enough imagination to come up with something else. Someone doesn't have enough experience. Someone wants to please the authorities. Everyone has different motivation.

XX2 CENTURY. I still want to be optimistic. It's not just that they are planted with cages. There are reports that vessels have sprouted there, nerve tissue has sprouted there…

R. D. I have been hearing such messages for ten years; to some extent I am in the subject. I've been an editor of a specialized scientific journal for eleven years, as you know, and I've been hearing this all these years. Surely this was all said before me, but I didn't hear it because I was small.

Well, listen, vessels have been grown in vitro since the beginning of in vitro research, that is, since the beginning of the XX century, when tissues, for example, connective tissue, were already systematically cultivated. Well, the vessels grew there, why shouldn't they grow? For a hundred years they have been growing the main vascular cells – the endothelium, a hundred and ten – to be precise; they grow in vitro – and what?

The first Russian monograph on the cultivation of connective tissue is one thousand nine hundred and sixteenth year. The first issue of the journal, which is called "Russian Archive of Anatomy, Histology and Embryology". The publisher is Professor A. S. Dogel, Petrograd University already, but still Imperial. Monograph of Professor A. A. Maksimov. And he has it shown there, and the endothelium is shown…

XX2 CENTURY. And expectations…

R. D. It is possible to expect. Wait.

XX2 CENTURY. But when they talk about bio–artificial organs, is it something else? There was also news recently: bio-artificial spleen, bio-artificial liver…

R. D. I don't know. This word is "bio–artistic" – by it you can mean the devil knows what. It is necessary to understand what is meant by this.

As for the spleen, do you understand what's going on… Look, a fairly common injury among young slightly sexually mature guys, especially conscripts, is the separation of the spleen or rupture of the spleen capsule. In these cases, it is necessary to remove it, because it is dangerous to leave or suture it, it is fraught with bleeding. The architecture of the spleen is such that it consists of three components: a framework (the so-called stroma), and then, in a certain three–dimensional order, lymphocytes are cells that do not build some kind of systemic tissue, they grow in nodules, here they multiplied – a ball, here they multiplied – a ball, and everything else is dying red blood cells. Just a bag of dying red blood cells. It is called the "Cemetery of red blood cells" because of this. There is no outstanding 3D structure on which the function would depend. What did the old doctors do before? I don't know if they're doing it now or not. It is believed that the spleen is needed at a young age – for the formation of lymphopoiesis, and so on, and so on. In a person of an older age group, it is simply removed, just you-bra-sy-va-yut. Into the basin. And they try to save young people. But you can't just leave it and you can't sew it up either. Because this is an organ without a clear internal structure, you can sew it up here, and then it will spread out. So what did they do? They took a kitchen grater, sterile of course, took the spleen, rubbed it, ground it, right on the operation, into minced meat. We took an oil seal, we have such a formation in the abdomen, a thin two–layer film where fat formations hang, bags were made from the oil seal in several places, just a thread was passed and, like a pouch, tightened - and this stuffing was inside. Minced meat is sterile. What's there? Dead red blood cells, dying, and lymphocytes, which gradually formed new small spleens there. As a result, the guy had not one large spleen in the left hypochondrium, but ten small spleens, and the lymphocytes continued to live and perform their function. So it's better not to even tell about the spleen. The spleen is generally a noodle about tissue engineering. Not serious.

With the liver, yes, the liver is a complex organ in terms of 3D architecture. Monstrously complex. Because hepatocytes, liver cells, are so non-standard polarized that on the one hand they must produce bile and release it into the bile duct, on the other hand, detoxify, on the third hand they must synthesize proteins and throw them into the blood, all this must be properly supplied with blood, that is, a very complex system of angioarchitecture. Plus, to all this, there should be connective tissue on which this whole complex structure is held. No one has ever reproduced this anywhere else and most likely will not. To grow a layer of hepatocytes and call it an artificial liver or to grow hepatocytes on a sponge or on balls and call it an artificial liver or a bio–artificial liver - this does not mean to reproduce a fragment of an organ, it is not true. No one, anywhere, and never by tissue engineering technology has done this, and most likely will not.

XX2 CENTURY. The Federal Center of Transplantology, which is located in the Oktyabrsky Field area, a couple of years ago announced the creation of a bio-artificial liver.

R. D. And you look more closely at what they were talking about. They publish works, as a rule, about extracorporeal artificial liver. These are hepatocytes that perform part of the functions, being in special columns outside the body. This is one option. The second option they worked with was taking a stroma, that is, a connective tissue framework, and hepatocytes are sown on it. Well, yes, they can live in three-dimensional space, but this does not mean that they function like a liver, that they produce bile at one end, produce proteins at the other, and detoxify at the third. No, of course not. Ordinary people tend to believe what we hear. We tend to think that if they talk about a bio-artificial liver, then it's, bam, a kilogram like that, and you can take it and sew it on. And journalists tend not to fully understand what they hear. And some scientists tend to exaggerate somewhat. And so the myth is born. This is a recipe for the birth of a myth.

Even the body does not know how to restore the liver normally. These are fairy tales that it is worth cutting off and ... Here the eagle flew, there, to Prometheus and pecked out, and everything grew back ... Yes, of course, it regenerates well in rodents, very well. It doesn't work that way with a person. You will cut off a piece of liver, and virtually nothing will happen afterwards. There will be some kind of hypertrophy after a while, a little hyperplasia, but in principle nothing will happen. Recall the situation with cirrhosis, when part of the hepatocytes, part of the liver lobules die, epithelial nodes begin to form in their place, that is, young hepatocytes or their precursors, a hypothetical liver stem cell that no one has yet found, identified, can develop, but the problem is – these nodes of young, newly formed hepatocytes, but even inside the body, vessels are not brought to them and bile ducts do not come out of them. And this catastrophe is called cirrhosis of the liver, people die from it. Because, although there are hepatocytes, they cannot perform their function with such a three-dimensional organization. No detoxification for you, no protein synthesis for you.

XX2 CENTURY. The picture is getting sadder and sadder.

R. D. It's time. It's time to pour a spoonful of honesty into this barrel of molasses, which we have been hearing for more than ten years.

Portal "Eternal youth" http://vechnayamolodost.ru  13.12.2016