Artificial organs: Russian gasoline, Italian ideas

Organs for growth

Lyudmila Shapovalova, "Expert South" No.1-4/2012; photo: Elena Sineok

On the basis of the Kuban Medical University, Italian surgeon Paolo Macchiarini is deploying a laboratory of regenerative medicine as part of the development of a megagrant. It is assumed that in two years in Krasnodar they will learn how to grow human organs

The level of fuss raised at the Kuban Medical University by the arrival of Professor Paolo Macchiarini is such that it is immediately clear: the future has come here suddenly. The employees responsible for submitting the application say that they did not know until the last day that the university would be among the winners, and even the dissertation projects of 2011 submitted before October 1 did not have time to send them to the channels necessary for upcoming research. On September 21, the university learned that they had become the owners of 150 million rubles – an unprecedented amount for Russian science, which will have to be mastered in two years, making a big leap and, possibly, placing Kuban medicine on the scientific map of the world. Macchiarini himself admits that the university, despite having a solid clinical base, is "not big enough" for such a level of research, and in order to achieve significant results in two years, "it is necessary to accelerate very much," the professor warns with icy calm.

It seems that at such a speed, the purchase of equipment, selection and training of specialists have never been carried out before, not like in Kubmed – in any university in the South at all. In September, the winners were announced, in early November, the scientist conducted the first interviews, in December, the first specialists who passed the selection were sent to study in Moscow and Stockholm. Macchiarini's actions give rise not only to a feeling of extreme time compression, but also to the formalization of processes without drowning them in the bureaucratic sea: it is fundamentally important for him to demonstrate that it is possible to work openly and legally in the Russian region, without ties and pressure.

The project is all the more significant for the South because it is the only one here. Applications for mega–grants were submitted by a number of Southern Russian universities, among them - the Research Institute of Physical and Organic Chemistry, the Research Institute of Physics and the Research Institute of Biology of the Southern Federal University, Volgograd Medical University. However, Kuban has won another convincing victory – now on the field of science. Someone is inclined to explain the success of Krasnodar residents with a strong administrative resource of the region, but representatives of the university assure that they have tried themselves. Whatever the source of victory, it is important that the region has the opportunity to achieve outstanding results in the shortest possible time in an area in which the Kuban has hitherto been little known to anyone.

A new word in organ cultivationRegenerative surgery is one of the newest areas of medicine, he is no more than twenty years old.

If we simplify the essence as much as possible, then we can say that the purpose of this direction is to grow organs. Professor Macchiarini focuses his efforts in thoracic surgery – operations in the chest area, more specifically– on the trachea. This is one of the most difficult to transplant organs of the human body, firstly, because of the huge number of small blood vessels, without which the trachea is not viable, and secondly, because of its proximity to the aggressive environment of the outside world and the high risk of infection. The success in heart, liver, kidney and lung transplantology is largely due to the fact that when transplanting these organs, the task of attaching one major artery and one major vein is solved, and the organs are to a certain extent fenced off from the outside world. The trachea is a rather vulnerable zone of the human body: it can be affected as a result of cancer, complications after tuberculosis, external influences – burns, mechanical, and it is difficult to replace it. The first tracheal transplant operation was performed only in 1998 in Cleveland (USA), and the patient was doomed to take immunosuppressive drugs for the rest of his life so that the rejection of the donor organ would not occur.

At a public lecture for university students, Paolo Macchiarini promised to learn Russian in two years,
with the condition that Krasnodar students will master English in order to have access to the international scientific community

Regenerative surgery is designed to overcome two fundamental obstacles to the development of transplantology: firstly, the availability of donor organs, and secondly, their survival in a new organism. Macchiarini has been working for more than fifteen years to achieve the results that have been achieved now: his methodology has overcome three major stages. At the first stage, the trachea of the deceased donor served as the trachea frame for the patient. It was purified from the cells of the previous owner using an enzyme solution and the stem cells of the future owner were introduced into it, after which they were placed in a bioreactor. Stem cells, thanks to special treatment, formed a tissue shell on the frame, and after some time a successful transplantation was carried out in Barcelona.

At the second stage, Macchiarini abandoned the use of a bioreactor, deciding to develop a more advanced method and grow a new trachea inside the patient's body. The skeleton, as before, was taken from a deceased donor and also cleaned of his cells. Bone marrow cells and epithelial cells from the nasal sinuses were taken from a patient who had a trachea transplant and applied to the skeleton. A group of researchers led by Macchiarini discovered that the cells of the connective tissue of the body, fibroblasts, have receptors for the perception of erythropoietin, widely used in transplantation. This substance awakens the stem cells sleeping in the body and encourages them to divide, so that all stages of the formation of the necessary tissues took place inside the patient. Two months after the operation, the trachea created its own blood supply system, became viable, and the patient was able to speak for the first time in many years. A similar transplant was performed in Moscow in 2010, under the guidance of an Italian scientist.

Today, this is not the last word in regenerative medicine. In early November 2011, Macchiarini published the results of work that does not provide for the presence of cadaveric donor organs at all – and this is a huge breakthrough in medicine in general. A 36-year-old patient who suffered from tracheal cancer and underwent radiotherapy was implanted with a so-called bio-artificial organ. The frame of the trachea this time is made of nanocomposite materials, that is, it was not originally a carrier of aggressive cells of another organism. This opens up the widest opportunities for transplantologists, firstly, removing many issues of bioethics, and secondly, making the operation more accessible. The preparation of a donor trachea takes quite a long period, and for children, for example, there are practically no donors. A laboratory for further research in the field of nanotechnology and regenerative surgery should now appear in Krasnodar.

Not only an administrative resourceThe main obstacle – the difficulty of adopting a new one – Macchiarini has already overcome by now.

While preparing the very first operation in Barcelona, he was forced to finance almost the entire process on his own. Different stages of the work were carried out in different cities, and when it was necessary to transport cells cultured by local scientists from Bristol, they had to hire a private plane: they refused to take a liquid with a volume of more than 100 ml on board a passenger flight. "When I presented this technology at a master class in Moscow," Macchiarini continues to recall, "Russian scientists almost tore me apart: they did not believe that such a transplant could be performed without vascularization (formation of blood vessels. – "Expert SOUTH")".

The scientist, according to him, was ready for the fact that months and even years would pass before the technology would be accepted: "But if you compare the current situation with the one that was a few years ago, you can see that a lot has changed: now people are actively interested in cooperation with me. When you do something new, you always meet criticism, this is normal. I'm not afraid of misunderstanding: only stupid people don't change their minds."

The grant allocated to the university is 150 million rubles, the validity period is 2011-2013 with a possible extension for 1-2 years. In addition, according to the terms of the competition, the university provides co-financing of the project, which will be carried out from extra-budgetary funds in the amount of 43 million rubles. Rector of the Medical University Sergey Alekseenko believes that the key role in obtaining the grant was played by the presence of a good clinical base – the Regional Clinical Hospital No. 1. "The medical care that can be provided in the conditions of KKB No. 1 is at a high European level, and the scientific contacts of its specialists helped us in drafting the project. Within the framework of the Regenerative Surgery Center, it is planned to create two laboratories – fundamental research, which will be based at the university, and applied, which will be located in the regional hospital, – comments Mr. Alekseenko. – On the areas transferred by the hospital under the joint activity agreement, we deploy part of the equipment purchased with the grant funds. The governor of the region provides enough opportunities to maintain this clinical base at the highest level."

Some believe that the notorious administrative resource played a crucial role in the extraction of grants. However, the university itself was not quite sure of its victory, and did not even imagine by what parameters the application would be evaluated. Strictly speaking, none of the applicants knew these parameters: only after the fact, following the results of the second wave of awards, the Ministry of Education and Science published a methodology for identifying winners, which, after masterly explanations, still remained vague. In any case, whether an administrative resource was involved in the person of the knocking out, it seems, absolutely everything he aims at, Governor Alexander Tkachev, or not, it would not be very smart to judge the winner. Moreover, Tkachev's influence on Macchiarini can only be zero: everything that the professor is aiming at lies exclusively in the field of science, and he gave consent, assessing his personal prospects as a scientist. "I was interested in working on this project precisely because there is an opportunity to use the capacities of both the university and the clinic," Macchiarini explains his consent to participate in the application. – The experience of Professor Vladimir Porkhanov, who runs the hospital, was very important: the volume of transplants carried out here is one of the largest in the country, and the people who work at the clinic are open to everything new. I don't have much experience working in the Russian education system to judge whether it is good or bad. But I think that now is just the moment that can be used to change the attitude towards her, especially among young people. This is a great opportunity for students to use new technologies, gain new knowledge, and become more open intellectually."

Laboratory for the futureAccording to the vice-rector for Research, Professor Andrey Redko, more than 30 applications were submitted for participation in the study.

At the moment, 16 specialists are involved in the project, who have already started training at the A. I. Burnazyan Federal Medical Biophysical Center of the FMBA of Russia in Moscow and at the Karolinska University of Switzerland, where Macchiarini himself is based. Mr. Redko notes that during the selection of future colleagues, the Italian surgeon concluded that the Krasnodar young scientists were quite competent. "Our task," says Macchiarini, "is to give them the best education, to make them high–class scientists. They can go to the West or stay here to work. My name is highly respected in the scientific community, and if they say they studied with me, all doors will be open for them. I am confident that the program will be completed successfully, and the laboratory that will be deployed in Professor Porkhanov's clinic will subsequently work for the clinic."

The issue of further employment of specialists involved in research is not uninteresting. On the one hand, there is a risk of migration of well-trained scientists (although their supervisor does not consider this something negative). On the other hand, even if they decide to stay in Krasnodar, where can they go without the guardianship of the luminary? The rector is not afraid that after two years of work he will get confused specialists. According to the university's plans, in two years, at the end of the planned work, the university will become a platform for fundamental research of regeneration mechanisms and the development of advanced innovative technologies in the field of regenerative medicine and a center for scientific and educational exchange in the declared direction not only in the Southern Federal District, but also in Russia. "Within the framework of this grant, the researchers involved in it receive a decent financial reward comparable to the salary of a professor of medicine," explains Andrey Redko's optimism. – We hope that the laboratory infrastructure and organization of research activities developed as a result of the project will show young scientists that the country values their work and they have the opportunity to find research niches of an innovative nature, take part in competitions and grants of international level. For us, this project can become the core around which other scientific directions will develop – not only clinical. Representatives of fundamental sciences can subsequently join it – specialists in the field of molecular biology, morphologists, immunologists, biochemists, pathophysiologists and others who will have access to unique equipment. Without a megagrant, the university would not have such an opportunity."

Rector of Kuban Medical University Sergey Alekseenko (left) hopes,
that a joint project with an Italian surgeon will convince young specialists: there is no need to leave the country

In addition, in the wake of the implementation of the megagrant at the university, another relevant topic in the international scientific community has become more active – bioethics. In Russia, research and practices related to stem cells are just beginning to develop, and this issue is not as acute as in Western countries. But this is one of the most damning questions of medicine, and the head of the study insists on intensifying its development. "Different countries have different positions on bioethics," explains Paolo Macchiarini. – There are Catholic countries, Protestant, Muslim. There is a Pope in the south of Europe, and stem cell surgery is prohibited there. There is no Pope in the north, and they are allowed there. But the industry certainly needs regulation, it is necessary to protect us from those who just want to do something first, to carry out transplantation without having scientific research. Patients suffer from this first of all: they usually die. I am convinced that bioethics should be actively implemented in the field of medical research."

On the Krasnodar side, the head of the scientific and organizational Department of the University, Elena Kondratieva, is in charge of bioethics issues, who has been dealing with them for several years. The task of the relevant committee is to check all research conducted on the basis of the university for compliance with bioethical norms. "Medicine faces a lot of ethical issues, and regenerative medicine solves some of them, since it does not use donor organs. Another advantage of it is the use of stem cells from the patient himself, and not from a donor and not embryonic," concludes Ms. Kondratieva. The work on the grant is no exception, and Elena Kondratieva and Paolo Macchiarini published an article in which this new topic for Russia is being developed.

The head of KKB No. 1, Professor Vladimir Porkhanov, is convinced that in Krasnodar it will be possible to grow not only the trachea

Now the Kuban Medical University has to run very quickly in different directions: to purchase equipment (this is when the Federal Law-94 is problematic for science), to prepare a clinic, to consider bioethics issues. But the supervisor of all these procedures seems to have nerves of steel, and the shortness of time for the grant does not frighten him. "Western scientists criticize these projects, they believe that Russia wants to return to the world of science by buying high–class scientists," says Macchiarini. – One article in the journal Nature says that Russia is a country of corruption, in which nothing can be done legally. Here, on the basis of the Kuban Medical University, we compiled a research protocol, met with a woman who is likely to be the first candidate for transplantation. We want to reassure everyone who criticizes these projects by showing that employees here are able to act according to a formal protocol and there is no need to do anything illegal to implement the project." Answering the question about what results of two years of work will say that the project has been successfully implemented, the scientist calmly lists three parameters. The project will be successful if, firstly, the regenerative medicine laboratory starts working, in which dedicated employees will work. Secondly, if all clinical activities are carried out under the auspices of bioethics. Thirdly, if several transplants are carried out in two years.

reference
Paolo Macchiarini
Surgeon, specialist in tissue engineering and stem cells. Born in 1958 in Basel (Switzerland). He completed his residency at the University of Pisa (Italy), postgraduate studies at the University of Alabama, Birmingham (USA). Currently, he holds the positions of Professor of Regenerative Surgery at the Karolinska Institute in Stockholm (Sweden), Director of the European Respiratory Tract Institute at the Carreggi University Clinic (Florence, Italy), Head of the Thoracic Surgery Department at the University Clinic of Barcelona (Spain), Professor at the Medical School of Hanover (Germany), head of the Research Clinical and Educational Center for Regenerative Medicine Kuban State Medical University. His research interests include molecular and cellular biology, biotechnology, regenerative medicine, thoracic surgery, tissue engineering and cellular therapy of the respiratory system. Author of 41 book chapters, 18 scientific reviews and more than 100 publications in the world's leading medical journals. Winner of honorary scientific awards, Knight of the Order of the Italian Republic "For Merits in the field of science".
MegagrantsOn April 9, 2010, the Government of the Russian Federation adopted Resolution No. 220 "On Measures to attract Leading Scientists to Russian Educational institutions of higher professional education", according to which grants of up to 150 million rubles each were allocated on a competitive basis for scientific research.
It was determined that decisions on the allocation of funds will be made by the Grants Council of the Government of the Russian Federation. The Council, in turn, listed the priority scientific fields for state support: astronomy and astrophysics; nuclear energy and nuclear technologies; biology; biotechnology; information technology and computing systems; space research and technology; mathematics; machine science; medical sciences and technology; mechanics and control processes; nanotechnology; Earth sciences; sciences about materials; psychology, cognitive research; radio electronics; construction and architecture; physics; chemistry; ecology; economics, international studies, sociology; energy, energy efficiency and energy conservation. According to the results of the first vote, 40 projects were declared winners instead of 80. During the so-called "second wave of mega-grants" on September 21, 2011, the Council identified 39 more names of scientists. The Ministry of Education and Science plans to carry out an interim assessment of the results of the work on the projects, after which it is likely that some of them will be extended for another year or two.

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23.01.2012