Conversation with Albert Rizvanov

Olga Fadeeva, "Biomolecule"

Albert Rizvanov — Professor, Ph.D., Doctor of Biological Sciences, Corresponding Member of the Academy of Sciences of the Republic of Tatarstan, Director of the Scientific and Clinical Center for Precision and Regenerative Medicine of the Institute of Fundamental Medicine and Biology, Head of the OpenLab laboratory "Gene and Cell Technologies", Head of the Department of Exploratory Research of the Research Center of Pharmacy of KFU. Honorary Professor of Fundamental Medicine, University of Nottingham, UK. Honored Scientist of the Republic of Tatarstan. The field of scientific interest is regenerative medicine, gene and cell therapy.

— Albert, good afternoon! Is regenerative medicine and treatment with stem cells already a practical branch, or, for example, omix biology, rather a fundamental science for now?

— Everything has been working fine in the laboratory for a long time. But it is still difficult to bring the product to consumers. The main problems are cost, logistics and certification issues. It is not easy to make a drug that is suitable for everyone. If we take the so—called allogeneic (donor - author's note) cells from some person, multiply and use them to treat other people, the problem of obtaining them and working out in large quantities is removed, but the question arises of the immunological compatibility of such a drug in other people.

The most common technology today is working with mesenchymal stem cells . They have less immunogenicity than, say, hematopoietic stem cells, so matching a donor-recipient pair can be avoided. But there are issues of transportation, preparation, introduction. Stem cells, like any other, are transported at ultra-low temperatures, at least at -70 C.

You can approach the matter from the point of view of autologous transplantation, when a material is taken from a person, stem cells are grown from it and used to treat this particular patient. But medical centers, within the walls of which such treatment takes place, must have high-tech laboratories and qualified personnel. Hence the high price of such therapy. And it is often not interesting to pharmaceutical companies, because autologous use is more a method of treatment than the actual drug. They want to build a big factory, produce something uniform and then sell it.

And moreover, there is a legal problem: if this is a drug, then how to test it? After all, an eternal source of cells is impossible, respectively, each batch is a slightly different drug. And if it is autologous — how to conduct preclinical and clinical trials of this single drug? If we talk about rare (orphan) diseases, when a patient is guaranteed to die without treatment, then we do not have a legislative framework that would allow testing drugs on him as part of individual clinical trials.

There is such experimental therapy abroad, because the alternative is the death of the patient, and sometimes terrible — both for himself and for others. Our healthcare is not ready for this yet, acting on the principle of "God gave — God took", because it is afraid of making a mistake. In my opinion, this issue should be approached individually, giving a chance to both terminally ill people and medicine in general.

— Describe the principle of regenerative therapy.

— The term "stem cells" is often used as a general term for any cell therapy. Stem cells are non—specialized cells in the body, which, like reserve soldiers, are activated, mobilized, and take part in the healing of some injuries, if necessary. And normally they are always involved in the natural regeneration of the body, because our body is constantly aging, and cells need to be renewed. Stem cells are responsible for the natural processes of growth and renewal. In medicine, they are used in several directions.

The main thing is regenerative medicine. Unlike lizards, we cannot grow a new tail, but in theory, if we introduce stem cells into the injury site, we will get an additional acceleration to regeneration. This is the basic concept of regenerative medicine. Stem cells also have the ability to migrate to the foci of the problem, because, in fact, it is a repair team. In the foci of injuries or other degenerative processes, special biomolecules are isolated that "feel" stem cells and go there "to smell".

Therefore, they can be used both for systemic treatment and for targeted delivery of drugs, chemical or gene-therapeutic. In the latter case, we can reduce the systemic impact by increasing the concentration only where necessary, and thus strengthening the therapeutic potential.

— How is this therapy used in the treatment of cancer? What is already under development, and what still exists only in theory?

— The most advanced therapy to date is antitumor therapy. But this is not really about stem cells, but about genetically modified T-lymphocytes. This is the so-called CAR-T therapy, when a chimeric receptor is introduced into the cells of the immune system — T-lymphocytes — with the help of genetic modification, which recognizes a molecule found on the surface of tumor cells.

So we can "rewire" any T-cell so that it destroys tumor cells. It turns out that we are "hacking" her identification system "friend-foe". And this is a fairly effective therapy for some types of oncopathology, first of all, tumors of the hematopoietic system, for example, B-cell lymphoma. Today, this technology is actively trying to adapt to other types of tumors.

There are other similar technologies. For example, the method of dendritic vaccines. Its principle can be compared to the training of a dog, which is given a piece of criminal clothing to smell, and it finds it by smell. So dendritic cells are first trained on the example of isolated tumor antigens, after which they are injected into the body, and they begin to attack tumor cells, recognizing their antigens.

There is also substitution therapy, when induced pluripotent stem cells (iPS cells) are transformed into the necessary cells by differentiation and injected into the body for the treatment of a particular disease, for example, the retina or spinal cord.

Another application of stem cells is cosmetology: if you inject stem cells into the skin, collagen production improves, skin vascularization, that is, they generally have a rejuvenating effect. They are used in reconstructive surgery, in the lipofilling procedure, when fat is pumped from one zone to another to give volume; over time, this fat resolves, and if you insert stem cells there, it is preserved much better.

— It's just that there is a lot of contradictory information about stem cells in the media...

— The possibility of turning stem cells into tumor cells is of concern, because the first, like the second, can divide many times. There is a theory that the origin of the tumor is based on a genetic malfunction in the work of some stem cell, which begins to divide uncontrollably. The existence of so-called stem tumor cells has also been proven. These cells are responsible for metastasis and resistance, resistance to antitumor therapy. Therefore, the main fear is that the stem cell may "break down" and turn into a tumor.

These concerns were primarily related to the use of low-grade, that is, very, very young stem cells, such as embryonic or induced pluripotent. At the dawn of cell therapy, the use of fetal stem cells obtained from living embryos was even considered.

And indeed, in these experiments, teratomas sometimes developed — benign tumors when a cell begins to divide, turning into literally everything at the injection site: teeth, hair and other body tissues. Therefore, no one uses low-grade cells in their pure form today. Only differentiated and predifferentiated cells are involved, that is, those that have already begun to move towards becoming certain types of cells. The probability of transformation into a tumor in them is extremely low. Therefore, such therapy from an oncological point of view can be considered safe.

— Has the direction of your research changed in connection with the COVID—19 pandemic?

— When I worked in the USA, we dealt with viruses that cause hemorrhagic fevers. After returning to Our group continued these studies in Russia. Therefore, by the beginning of the pandemic, we had extensive experience working with infectious diseases, and already in February 2020, I had a prototype of a vaccine against COVID—19 in my hands. But, alas, we could not find an industrial partner who would be interested in its implementation. Nevertheless, we applied our experience in the development of immunological tests, and in the spring of 2020 we developed an enzyme immunoassay (ELISA) for antibodies to SARS-CoV-2, which was used to test samples for the plasma bank of COVID—19 patients in the Republic of Tatarstan.

The first Russian patients infected with coronavirus were brought to Kazan, and some of them just became donors-pioneers of antikovid plasma — the one that contains antibodies against SARS-CoV-2. Transfusion of it to sick patients could improve the course of the disease. So our developments on other viral diseases were also useful for a very prompt response to a new pandemic.

Now we are studying biomarkers of the inflammatory response, that is, the cytokine storm, in order to understand the effectiveness of anti-cytokine therapy, plasma transfusion, as well as the use of immunoglobulins. And we are also investigating which markers could indicate an unfavorable course of the disease or the need for a particular therapy. After all, treatment is often selected by the method of "scientific poke", empirically, which carries great risks for the patient: by the time the right type of therapy is selected, it may be too late.

We are also conducting research on the effectiveness of vaccines. In the fall of 2021, for example, they published a paper on the effectiveness of the Sputnik V vaccine and showed that after vaccination with this drug, a very good immunity is really formed — both humoral and T-cell. Immunity remains high for seven months after vaccination. Now we continue to investigate its level for a longer period, as well as the effectiveness of revaccination.

— Recently, in an interview, you talked about molecular docking. I was hooked by your expression: "Archimedes said: "Give me a fulcrum, and I will turn the Earth over," chemists say: "Give me a target, and I will select a chemical compound that will act on a certain protein according to the key-lock principle."" Is docking really so all-powerful, and with its help you can invent a cure for any disease? Why then do we need to explore other approaches to therapy, and does molecular docking have weaknesses?

— Initially, it was believed that a simple screening of large libraries of chemical compounds could solve the problem of finding new drugs "head-on". But, alas, this did not happen, and this is what now lies at the heart of the crisis in the pharmaceutical industry. After all, in order for pharmaceutical companies to flourish, they constantly need new medicines — effective, marketed, so-called blockbusters. And today it's getting harder to find them.

Molecular docking, that is, rational design, helps to partially solve pharmacological issues by transferring screening to the computational plane or creating new chemical compounds for specific targets using artificial intelligence algorithms. The problem is that not always found compounds have high selectivity, so they have severe side effects: roughly speaking, we can treat migraines by cutting off the head. In this regard, gene therapy is undergoing a renaissance today, when you can "enter" a cell and correct a genetic defect, or reprogram the cell to lead a more "healthy lifestyle". But even here there are huge difficulties, because anything can be cured in a test tube, but how to cure the body is a big question.

However, there is an interesting nuance related to the coronavirus pandemic. Almost all of today's vaccines against SARS-CoV-2 are, in fact, gene therapy. Vaccines such as Sputnik V deliver the genetic information of the virus in the form of cDNA to the cells of the body, forcing them to produce a viral antigen to trigger an immune response. It is possible to deliver information about the viral antigen to the cell directly, using matrix RNA. It turns out that almost all people on the planet will receive gene therapy, it's just that pharmaceutical companies do not focus on this so as not to frighten the population.

Scientists, however, see that it is safe and effective, and that this type of platform can be used to create other medicines. Moreover, if earlier the development of drugs took many years, now it suddenly became clear that if you really want and have the political will, you can create a drug in just a couple of months, and in six months to test it. Therefore, the pandemic has accelerated the process of developing new drugs, primarily gene drugs.

Gene therapy is one of the main directions of our work for the treatment of rare hereditary, so—called orphan diseases. We apply the above-mentioned new trends for the development of medicines in a conveyor way and can simultaneously develop dozens of medicines, thereby significantly reducing the cost of each specific one and making it more accessible to patients.

— What other promising areas are there in your work?

— There is a so-called multimix medicine, when the analysis of the disease is not done according to one or more parameters, but its expanded "portrait" is immediately compiled — protein, genomic, proteomic, metabolomic, transcriptomic, etc. It turns out that we are, in fact, creating a digital model of a person, and not static, but dynamic. This is useful for early diagnosis of diseases, because even small changes that we observe may indicate the development of pathology, although the parameters are still within the normal range. Not to mention the fact that the norm is different for everyone, which allows you to select individual therapy for patients. Plus, we work with various wearable devices — sensors and gadgets that register the patient's condition.

— When can we expect the mass introduction of such technologies?

— For example, we already offer diagnostics to our patients at the Scientific and Clinical Center for Precision and Regenerative Medicine at the Institute of Fundamental Medicine and Biology of Kazan Federal University. The problem of mass application is, going back to the beginning of our conversation, firstly, cost, and secondly, legislation.

— If you look back, which of your developments are you most proud of?

— We have very interesting work in the field of regenerative medicine, namely injuries of peripheral nerves, spinal cord. We are engaged, for example, in the motor rehabilitation of a patient, developing neuroregeneration technologies that enhance the recovery of the nervous system.

Right now, big business has managed to attract interest in financing projects on gene therapy of hereditary orphan diseases. And we hope that this year will be a turning point for us, and we will finally launch such projects on the rails of implementation — bringing the drug to licensing and clinical use.

— Which of your projects are the most unusual?

— There are a lot of interesting projects. We can single out regenerative veterinary medicine, where we develop species-specific drugs for the treatment of animals, for example, sports horses. Theoretically, we can also treat rare animals in zoos.

Another unique project is the development of artificial microvesicles (synthetic microcontainers — author's note) for regenerative medicine and as a carrier for the creation of vaccine preparations. The bottom line is that we create biosimilar microvesicles from human cells in animals. And unlike natural microvesicles, whose yield is very small ("a teaspoon per bucket of cells"), accordingly, they are extremely difficult to use in biotechnological industries — our approaches allow us to increase the yield of such microvesicles by orders of magnitude, as well as to program their properties.

Drugs based on this approach could develop into a new branch of biotechnology in the future. In general, the most interesting research is now taking place at the intersection of sciences. Therefore, when biologists and doctors work in isolation from each other, nothing good usually comes out. But if they join forces, and also attract chemists, physicists, IT specialists, then projects become breakthrough and competitive.

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