— Many have heard the term “regenerative medicine”, but few understand what it actually means. So, let's begin at the beginning — what principle lays at the root of regenerative therapy?
—Let us start with the most well-known term, stem cells. It is often used as an umbrella term for any type of cell therapy. Those cells are undifferentiated cells in our bodies that, like back up soldiers, can be activated while  healing injuries. Normally, they play a constant role in the body's natural regeneration process as our bodies age and cells require renewal. In medicine, they are used in several ways.
The primary application is precisely in regenerative medicine. Unlike lizards, we can't regrow parts of the body, but theoretically, we can introduce stem cells at the site of an injury to enhance the body's natural regeneration process. This is the fundamental concept of regenerative medicine. Stem cells also can migrate to problem areas, essentially acting as a repair team. In areas of trauma or other degenerative processes, specific biomolecules are released that signal the stem cells. Once they receive the signal and "sense" the biomolecules, stem cells "follow the scent" to get to the affected area.
This makes them useful for both systemic treatment and targeted delivery of chemical and gene therapy drugs. In the latter case, we can minimize systemic impact by increasing concentration only where needed, enhancing therapeutic potential.

— How is this type of therapy used in cancer treatment? What drugs are currently being developed and which are only theoretical?
— Antitumor therapy would be the  most advanced therapy as of today. However, it doesn't involve stem cells per se, but rather genetically modified T-lymphocytes. It is known as CAR-T therapy. In this case a chimeric receptor that recognizes a molecule found on tumor cells is introduced into T-lymphocytes through genetic modification.
That way, we can reprogram any T-cell to target and destroy tumor cells by hacking its "friend or foe" recognition system. This has proven to be an effective therapy for certain types of cancer, primarily those affecting the hematopoietic system, such as B-cell lymphoma. Currently, scientists try to adapt this technology for other types of tumors.
Other similar technologies exist as well. The dendritic vaccine method, for example. It’s like training a dog to sniff out a criminal's clothing and locate them by scent. Similarly, dendritic cells are initially trained using isolated tumor antigens. Then they are introduced into the body where they begin to attack tumor cells.
In replacement therapy, induced pluripotent stem cells (iPSCs) are differentiated into necessary cells and introduced into the body to treat specific diseases, like those of the retina or spinal cord.
Stem cells can also be useful in cosmetology. Injecting them into the skin enhances collagen production and skin vascularization, generally producing a rejuvenating effect. They are used in reconstructive lipofilling procedures where fat is transferred from one area to another to add volume. Over time this fat gets absorbed, but introducing stem cells at the place of its injection preserves it much better.

— That seems to be the most hyped use of stem cells, which has generated a lot of conflicting messages in the media...
— There are some concerns about stem cells potentially transforming into tumor cells, as both can divide multiple times. There exists a theory that tumors actually appear as a result of a genetic malfunction in a stem cell, which then begins to divide uncontrollably. The existence of so-called cancer stem cells has also been proven. These cells are responsible for metastasis and resistance to anti-tumor therapy. So the main concern is a stem cell "malfunctioning" and transforming into a cancer cell.
These fears have to do with the use of poorly differentiated, or very young stem cells like embryonic or induced pluripotent stem cells. In the early days of cell therapy, scientists even considered using fetal stem cells derived from living embryos.
Indeed, such experiments sometimes resulted in teratomas, benign tumors where a cell begins to divide and transforms into various things at the injection site: teeth, hair, and other body tissues. Therefore, undifferentiated cells are no longer used in their pure state. We only utilize differentiated and pre-differentiated cells – those that have already begun the process of becoming specific cell types. Their likelihood of transforming into a tumor is extremely low. With that in mind, from an oncological perspective, such therapy can be considered safe.

— Has the coronavirus pandemic changed the direction of your research?
— When I was working in the U.S., we were studying viruses that cause hemorrhagic fevers. After returning to Russia, our group continued this research. So by the onset of the pandemic, we had extensive experience with infectious diseases, and I had a prototype of a coronavirus vaccine ready as early as February 2020. Unfortunately, we were unable to find an industrial partner interested in implementing it. Nevertheless, we applied our experience in developing immunological tests and by spring 2020 we had developed an enzyme-linked immunosorbent assay (ELISA) for antibodies to SARS-CoV-2, which we used to test samples for the plasma bank of recovered patients in the Republic of Tatarstan.
The first Russian patients infected with coronavirus were brought to Kazan, and some of them actually became the pioneer donors of anti-COVID plasma, which contains antibodies against SARS-CoV-2. Transfusing it to sick patients could potentially improve the course of the disease. That's how our research on other viral diseases proved useful for a rapid response to the new pandemic.
We also began studying biomarkers of inflammatory response, or “cytokine storm”, to understand the effectiveness of anticytokine therapy, plasma transfusion, and the use of immunoglobulins. Additionally, we researched which biomarkers could indicate a severe disease progression or the need for a specific therapy. Indeed, treatments are often chosen empirically, through a method of "scientific trial and error", which is associated with significant risks for the patient. By the time the appropriate therapy is identified, it could already be too late.
We also conduct research on vaccine efficacy. For instance, in the fall of 2021, we published a study on the effectiveness of the Sputnik V vaccine, demonstrating that it indeed induces a robust immune response, both humoral and T-cell. The immunity stays high for seven months post-vaccination. Currently, we are continuing to investigate immunity levels over a longer period of time and the effectiveness of booster shots.

— It seems cell therapy and similar methods are pushing “traditional drugs” — molecules synthesized by chemists in labs or extracted from living organisms — out of medical practice. What's causing this shift?
— To answer this question we need to take a brief look at the history of drug design. Initially, it was believed that simply screening large libraries of chemical compounds could directly solve the problem of discovering new drugs. Unfortunately, this approach didn't work out and in fact led to the current crisis in the pharmaceutical industry. After all, for pharmaceutical companies to prosper, they constantly need new drugs, effective and sellable, the so-called blockbusters. However, finding such drugs is becoming an increasingly difficult task.
Molecular docking, or rational drug design, partially addresses pharmacology issues. Using this method scientists shift screening to a computational level or create new chemical compounds for specific targets using artificial intelligence algorithms. The problem is that not all discovered compounds are highly selective, leading to severe side effects. It's like curing a headache by beheading. This has led to a renaissance of gene therapy, where it's possible to “hack” genetic information within a cell and correct a genetic defect or reprogram the cell to adopt a more "healthy state". However, this approach is also not perfect. Almost anything can be cured in a test tube, but curing an organism is an entirely different matter.
The pandemic has indeed accelerated the practical implementation of this method. In essence, almost all of today's vaccines against SARS-CoV-2 are variants of gene therapy. Vaccines like Sputnik V deliver the virus's genetic information in the form of cDNA to the body's cells, prompting them to produce the viral antigen and trigger an immune response. It's also possible to deliver information about the viral antigen directly into the cell using messenger RNA. This means nearly everyone on the planet will receive gene therapy However, pharmaceutical companies don't emphasize it to avoid alarming the public.
It’s crucial to understand that scientists have found this approach to be safe and effective, and believe it can be used to develop other drugs. Also, while drug design used to take many years, it is now obvious that with enough desire and political will, a drug can be created in just a few months and clinically tested within half a year. So this is how the pandemic has accelerated the development of new drugs, particularly gene therapy-based ones.
Gene therapy is one of our primary focuses for treating rare inherited diseases, also known as orphan diseases. We use the mentioned trends to streamline drug design and work on dozens of drugs simultaneously. This approach also significantly reduces the cost of each specific drug and makes it more accessible to patients.

— Looking further into the future of your research, what appears most promising?
— I’d say so-called multi-omics medicine. Disease analysis here isn't based on one or a few parameters, but rather on a a comprehensive "portrait" — proteomic, genomic, transcriptomic, metabolomic, transcriptomic, and other data. Essentially, we are creating a digital model of a person, not a static, but dynamic one. This is beneficial for early disease diagnosis, as even minor changes we observe could signify the onset of a pathology, even though the parameters are still within the normal range. Moreover, the norm varies from person to person, which enables us to tailor therapy to each patient's needs. Additionally, we work with a variety of wearable devices — sensors and gadgets that monitor the patient's health status.

— When can we anticipate mass adoption of such technologies?
— We are already providing 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 challenges to mainstream use are, as we discussed earlier, primarily cost and legislative issues.

— Looking back, which of your developments are you most proud of?
— We have some fascinating projects in regenerative medicine, specifically related to peripheral nerve and spinal cord injuries. For instance, we're involved in patient motor rehabilitation, developing neuroregeneration technologies that enhance nervous system recovery.
We have recently succeeded in attracting significant business investment for gene therapy projects targeting hereditary orphan diseases. We're hopeful that this year will mark a turning point for us, allowing us to finally move these projects towards implementation — getting the drug licensed and into clinical use.

— Which of your projects would you say are the most unconventional?
— I can name many fascinating projects. One notable area is regenerative veterinary medicine, where we're developing species-specific drugs for treating animals, such as racehorses. In theory, we could also provide treatment for rare animals in zoos.
Another unique project involves developing artificial microvesicles (membrane coated microcontainers — Editor's note) for use in regenerative medicine and as carriers for vaccine design. The concept involves creating biosimilar microvesicles from human and animal cells. Unlike natural microvesicles, which are produced in very small quantities ("a teaspoon per bucket of cells"), making them difficult to use in biotechnological production, our methods significantly increase the yield of these microvesicles and allow us to program their properties.
In the future, drugs developed using this approach could form a new sector within biotechnology. Currently, the most exciting research is happening at the intersection of different scientific fields. When biologists and medical professionals work separately, the results are usually not very exciting. However, when they collaborate and also include chemists, physicists, and IT specialists, the projects become groundbreaking and competitive.

— Summing up, is regenerative medicine and stem cell treatment already a practical field or, like omics technologies, is it still more of a fundamental science?
— Everything has been working smoothly in the lab for quite some time now. However, getting the product to the end users is still a challenge. The main hurdles are cost, logistics, and issues with certification. Creating a drug that is suitable for everyone is quite a complex task. If we take the so-called allogeneic cells (donor cells – Author’s note) from a person, multiply them, and use them to treat others, we solve the problem of obtaining and producing such cells in large quantities but have to face the issue of immunological compatibility.
Currently, the most prevalent technology involves working with mesenchymal stem cells. These cells have lower immunogenicity than, for instance, hematopoietic stem cells, so there is no need for strict donor-recipient matching. However, there are concerns regarding transportation, preparation, and administration. Like all cells, stem cells are transported at extremely low temperatures of up to -80 degrees Celsius.
A possible approach here is autologous transplantation. You need to take material from an individual, cultivate stem cells from it, and then use those cells to treat that specific patient. However, the medical facilities suitable for such treatments must be equipped with advanced laboratories and skilled staff. Hence arises the high cost of such therapy. Moreover, this often doesn't appeal to pharmaceutical companies as autologous application is more of a treatment method than an actual medication. They prefer to build a large factory, manufacture some sort of unified product, and then sell it.
There is also a legal dilemma. If it's considered a drug, how should it be tested? Since an everlasting cell source is unattainable, each batch essentially becomes a slightly different drug. And if it's autologous, how can preclinical and clinical trials be conducted for this unique drug? In the case of orphan diseases (and it’s the case when the patient is certain to die without treatment) we lack the legislative framework that would permit us to test drugs on them as part of individual clinical trials.
Such experimental therapy exists outside of Russia because the alternative is the patient's death, sometimes a terrible one — both for the patient and their loved ones. Our healthcare system isn't ready for this yet. It operates on the "The Lord giveth and the Lord taketh away" principle out of fear of making mistakes. In my opinion, this matter should be addressed individually, offering a chance to both the incurably sick person and the medical field in general.