Regenerative medicine in Russia: through the thorns…

Features of national regeneration

Candidate of Biological Sciences Larisa Aksenova, "Science and Life" No. 2-2012
Published on the website of the Skolkovo Foundation

The famous American industrialist Henry Ford, trying to protect the workers of his factories from injury, decorated the workshops with posters: "Worker, remember: God created man, but did not create spare parts for him." What has changed since then? If Ford (and he died in 1947) had managed to live at least ten years longer, he would have tried to avoid categorical statements, because he found the birth of a new field of science – regenerative biomedicine.The last century has left us a legacy of many amazing scientific discoveries in various fields of science.

In the XXI century, humanity is called upon to solve the most important intellectual task – to find an application for these achievements, to create the latest technologies that will help improve the quality of life, make it more comfortable and convenient. This applies not only to computer technology, communications, household amenities, but above all – health. At the end of December 2011, a meeting was held for the first time in the editorial office of the journal "Science and Life" within the framework of the media club "High Technologies". A series of five meetings jointly with the Moscow Institute of Physics and Technology (MIPT) is dedicated to the achievements of the biomedical industry. Regenerative medicine is not randomly chosen as the first topic, it is one of the most actively developing biomedical technologies. At the moment, there are examples of the creation and successful use of artificial organs and tissues obtained by cell therapy and tissue engineering in the treatment of people: cartilage tissue for repairing the knee joint, bladder, urethra, heart valves, artificial trachea, cornea, skin. The easiest to grow are cartilage tissue, skin. The next level of difficulty is vessels. The third level is the bladder, uterus. And finally, the most difficult ones are the heart, kidneys.

A lot is expected from regenerative medicine and at the same time it is questioned, it causes a lot of controversy and discussion: moral and ethical, medical, regulatory. But, as always, our Russian reality gives a unique and completely unexpected flavor to any scientific developments. And why do we need regenerative medicine if residents of the Kostroma region, for example, have to wait several months for the opportunity to get to a routine examination using ultrasound? The latest expensive equipment is brought to the clinics, but they do not pay money to the specialists who have to service it.

Why, with the huge demand for tissue and cell therapy methods, and, according to experts, the market for "stem cell treatment" in our country is, according to conservative estimates, $ 2 billion and is mostly "gray" and "black", there is no legislation regulating the use of these methods? And, of course, a question that does not require an answer: but why, despite all the difficulties and difficult circumstances, do our scientists work at the forefront of science, saving people's lives? During the three-hour discussion, the participants sought answers to these and other questions related to the formation of a new field of medicine in Russia. There is a video on the website of the journal "Science and Life" (section "Video"), but here we will touch on the most relevant topics discussed during the meeting.

One of the most pressing problems of regenerative medicine is the cultivation of the skin epidermis from a person's own stem cells. According to statistics, 450-500 thousand people in our country need such an operation every year. In case of extensive skin lesions, donor tissue is needed immediately after the burn, since it covers the exposed surface and produces physiologically active substances necessary for "repair" – growth factors, cytokines. But the donor tissue does not always take root: it is rejected by the patient's immune system. Therefore, sometimes it is necessary to use not only the donor tissue, but also the epidermis of other parts of the patient's body. In the laboratory of the Deputy Director for Science of the N. K. Koltsov Institute of Developmental Biology of the Russian Academy of Sciences, Doctor of Biological Sciences Andrey Vasiliev, they have been conducting research on growing a skin flap for transplantation for many years. The first successful transplants using skin epidermis grown from the patient's own cells were carried out by scientists back in 1988 at the Military Medical Academy of St. Petersburg. Then it was possible to grow and successfully use a flap of skin with an area of 400 ^cm2 in the treatment of the patient.

The method of Russian scientists allows you to increase the area of a piece of skin with a size of 1 cm ² by 10 thousand times. It was successfully used both at the N. V. Sklifosovsky Institute of Emergency Medicine and at the Republican Children's Clinical Hospital, where a child from Chechnya was taken who received a burn of 65% of the body surface. The operations were carried out in two stages: first, donor tissues were transplanted, and after a while their own autologous, grown in vitro from the patient's stem cells.

Andrey Vasiliev's laboratory has also developed other effective methods of therapy using cellular technologies, which have been successfully used in medical practice for many years. For example, artificial cornea transplantation. More than 60 such operations have already been performed at the Helmholtz Moscow Research Institute of Eye Diseases. At the request of the P. A. Herzen Moscow Cancer Research Institute, a technology for restoring the larynx after surgery to remove it has been developed, more than 50 such operations have already been performed. But it is extremely difficult to reach the production level.

There are stem cells in every person's body. The bone marrow is a reservoir of stromal stem cells-precursors of blood cells (hematopoietic cells); bone tissue (osteoblasts), cartilage cells (chondrocytes), adipose tissue cells (adipocytes) and stromal cells (fibroblasts). It is possible that progenitor cells of liver cells (hepatocytes) and skeletal muscle cells (myocytes) will be found in the bone marrow.

"We have no illusions that it will be easy to do this in a year," says Yuri Sukhanov, Doctor of Biological Sciences, President of the association "Association of Experts in Biomedical Cell Technologies and Regenerative Medicine". "But we hope to complete clinical trials by the end of 2012 and receive registration for three biomedical cell technology products: artificial living skin, artificial cornea and mesenchymal equivalent – a stem cell preparation that can be used to close scars and fistulas after surgery and in cosmetology."

"Until now, the methods have not been implemented and are used as laboratory experiments, as an initiative, as a charitable contribution," Andrei Vasiliev said at the meeting. The reason for this situation is the lack of legislation. "And how can we guarantee the appearance of a product on the market if there is no licensing system in the Ministry of Health today?" – he explained.

Yuri Sukhanov confirmed: "The product of biomedical cell technologies, as well as any drug, must undergo full testing and have a passport confirming its biosafety and effectiveness, the stem cell donor must give informed consent. But at the moment there is no legal basis for this."

Researchers have learned how to reprogram ordinary cells from the patient's skin using special substances (transcription factors) into induced stem (pluripotent) cells. The resulting cultures of the patient's stem cells can be directed along the path of transformation into progenitor cells and further specialization into various autologous cells and tissues: neurons, skin tissues, blood and liver cells. According to experts, these technologies will be available for clinical use in three to five years, and for exclusive use - in one and a half to two years.

The Ministry of Health is familiar with the problem and plans to adopt a whole set of biomedical laws in 2012, in particular on cell and tissue therapy, donor blood and organ and tissue transplantation. The association "Association of Experts in Biomedical Cell Technologies and Regenerative Medicine", in fact, was created a few months ago in order to attract leading specialists – doctors and biologists – to the development of these standards. There are other reasons why there is an urgent need to adopt such a law. Currently, stem cells in Russia are used virtually uncontrollably, and this creates not only moral and ethical problems, but also, as experts warn, risks to the life and health of patients. The process of developing legislation in this area requires huge joint efforts of lawyers, doctors, and scientists.

In 2000, Dr. Anthony Atala, director of the Wake Forest Institute of Regenerative Medicine in Winston-Salem (North Carolina, USA), performed the world's first organ transplant operation obtained by tissue engineering methods. This organ became the bladder. In total, seven similar operations were performed in patients aged 4 to 19 years between 2000 and 2005.

In 2002, Dr. Sergey Chebotari from the Medical School of Hanover grew a heart valve using autologous endothelial progenitor cells and transplanted it to a patient.

In 2003, Dr. Christian Biancosino, also from the Medical School of Hanover, managed to create a tracheal flap – a piece of tissue that corresponded to all the characteristics of normal human tissue and recovered after irradiation, that is, it was suitable for restoring tracheal defects in cancer patients.

Between 2004 and 2007, Dr. Anthony Atala performed five transplants of artificially grown urethras to boys aged 10 to 14 years.

In 2008, Dr. Paolo Macchiarini performed the first tracheal transplantation at the Hospital Clinic in Barcelona (Spain), created in the laboratory on a donor frame using the patient's cells. At the moment, more than 10 similar transplantations have already been performed, in the last two, a nanocomposite framework created in the laboratory was used, not a donor one.

But, according to Andrey Vasiliev, "it is better to have a bad law in this area than the absence of it." Scientists do not tire of explaining that pluripotent cells, which are valuable as the primary material for regenerative medicine, which include embryonic and induced stem cells, are not at all the same as abortive and fetal material.

Pluripotent cells are able to "transform" (specialize) into any of the 210 (!) types of cells in our body. In a healthy adult (postnatal) body, there are no such cells anymore. But they are not present in both abortive and fruit material, in which cells have already specialized, and they have acquired properties characteristic of various types of tissues: muscle, bone, nervous.

"Pluripotent cells arise at the earliest stage of embryo development in the internal cell mass of the blastocyst and can only be obtained from the so–called residual blastocyst after in vitro fertilization – IVF," explains Andrey Vasiliev. – We are working with cells of an adult organism that have multipotent properties. Such cells in the adult body include resident tissue stem/progenitor cells and circulating (hematopoietic and mesenchymal) stem cells."

Multipotent cells have the ability to differentiate into many, but not all, cell types. The simplest example is hematopoietic stem cells, which are "stored" in the bone marrow and give rise to all hematopoiesis cells. Resident tissue stem cells are present in all types of tissues – in the liver, spleen, lungs and even in the heart.

Under certain conditions, they are able to specialize into tissue cells of the organs in which they are located, are the "cellular potential" of the body, but often it is almost impossible to get them.

"There are cases when they take abortive or fetal material and pass it off as embryonic stem cells. But this material has nothing to do with embryonic pluripotent cells. And such a confusion of concepts has largely discredited cellular technologies in our country," Vasiliev emphasizes. – Why can't abortive cells be used? From a biological point of view, this is absolutely meaningless. There are cells in the postnatal body that have exactly the same properties, and it is not necessary to destroy the embryo for this, taking someone's soul."

There is another reason for the ban on the use of abortive material, which in European laws is formulated as follows: "... if cells from abortive material are introduced into medical technologies, it commercializes the female reproductive sphere, which is unacceptable." There is another extremely important issue of the use of stem cells in regenerative medicine. This is the biosafety of their use. As mentioned above, there are no pluripotent cells in an adult healthy body. But they can spontaneously occur with sarcoma and teratocarcinoma. Accordingly, the opposite is also true: if pluripotent cells or cells with induced pluripotency are introduced into the body (and since 2006, the procedure for obtaining them from ordinary cells, thanks to the work of Japanese researcher Yamanaka, has become routine), they can induce cancer. Pluripotent stem cells often serve as the primary material for cellular technologies, but doctors must be absolutely sure that they are not in the biomaterial that is eventually transplanted to the patient. Currently, technologies are being developed that allow directly obtaining cells of another tissue from cells of one tissue, bypassing the state of pluripotence, but such procedures will become available in seven to ten years. So, in order to preserve the health of patients, strict control and testing of the transplanted biomaterial is required.

But "there is not a single laboratory in the country that could control the quality of grown stem cells or donor material. There is not a single industrial site where these products could be produced," explains Yuri Sukhanov. "We need to create an entire industry from scratch."

In the laboratory of Professor Helen Heber-Katz at the Wistar Institute (Philadelphia, USA), it was possible to "turn off" the p21 gene that blocks regenerative abilities in mice of the MRL genetic line. As a result, mice gained the ability to repair damaged tissues: if you make a hole in the ear of such a mouse, it will completely tighten. All types of tissue will be formed around the injury – cartilage, skin, blood vessels – without scar formation. This amazing quality helps mice get rid not only of holes in their ears, but also from the consequences of a heart attack. Their heart muscle is completely restored after a heart attack.

Mikhail Batin, president of the charity foundation for the support of scientific research "Science for Life Extension" and head of the laboratory of regenerative medicine at MIPT, is even more categorical: "Regenerative biomedicine requires attention, money, and the creation of a scientific school. But the general trend in the development of regenerative medicine in Russia is such that scientists are experiencing incredible difficulties. It's not that they don't get support, but they are in a struggle… We are looking for the best specialists in Russia and abroad. We offer to work together and create projects, we try to bring modern biomedical technologies to Russia." So, thanks to the efforts of Mikhail Batin, the famous Italian surgeon Paolo Macchiarini was invited to Russia, who has already carried out a series of successful organ transplantations created by tissue engineering methods.

The scheme of the world's first successful transplantation of the bioengineered equivalent of the trachea created in vitro
(2008, Macchiarini).

In December 2010, he spent at the Russian Scientific Center of Surgery named after B.V. Petrovsky in Moscow transplantation of trachea artificially grown from the patient's own cells in a bioreactor. The professor continues to improve the technologies of regenerative medicine for tracheal transplantation and is going to extend them to other organs: lungs, heart and esophagus. In 2011, Macchiarini became one of the 39 winners of the Second Open public competition for a mega grant from the Government of the Russian Federation (based on Resolution No. 220 "On Measures to Attract Leading Scientists to Russian Educational institutions of higher professional education"). At the Kuban State Medical University (Krasnodar), where Dr. Macchiarini was invited, a Research, educational and clinical center for Regenerative Medicine is being created under his leadership, where cell therapy methods will be developed, and university staff and students will be able to learn from the invaluable experience of an outstanding world-class specialist.

Maria Konovalenko, Project Coordinator of the Science for Life Extension Foundation, spoke about the latest domestic and foreign scientific and practical achievements in the field of regenerative biomedicine. In particular, about the unique operations for transplantation of artificial bladder and urethra grown by tissue engineering methods by Dr. Anthony Atala from the Institute of Regenerative Medicine Wake Forest, USA, in 2000-2005. It is hoped that this scientist can also be invited to our country and thereby contribute to the development of domestic science. The MIPT staff plans to create a laboratory that would develop technologies for restoring the bladder, urethra and heart valves from patients' own cells.

At least regenerative biomedicine in Russia now has its own "road map". More than two dozen domestic and foreign specialists took part in the development of the development plan for this young and promising area. Among the scientific aspects are therapeutic cloning, restoration of regenerative abilities, technologies for monitoring, diagnostics and storage of stem cells, cell therapy and tissue engineering. The task of such a "roadmap" is the formation of cooperation, the creation of uniform standards, the setting of clear tasks and deadlines, the formation of orders for structures that provide financing.

Portal "Eternal youth" http://vechnayamolodost.ru08.02.2012