13 April 2009

Biotech innovation stuck at the start

The star who didn't leaveGalina Kostina, Expert magazine.

Sergey Lukyanov, in difficult times, found a niche that allowed him to create research technologies in Russia that are in demand all over the world and use the proceeds for the development of fundamental science.

The names of Russian scientists Sergey Lukyanov and Mikhail Matts were mentioned in press releases dedicated to the winners of the Nobel Prize in Chemistry in 2008, who received an award for the discovery of green fluorescent protein: Osama Shimomura, Martin Chalfi and Roger Qian. Let the Russian names were still only nearby, but it's still nice. The discovery of the green fluorescent protein made it possible to obtain a unique research tool: it was possible to label biological objects important to scientists – various proteins, cellular organelles and cells, making them (thanks to the ability to emit light) available for observation in living organisms. But the researchers wanted to observe many objects at once, and for this, in addition to green, fluorescent proteins of other colors were needed. Russian scientists from the laboratory of Sergey Lukyanov (the Ovchinnikov and M. M. Shemyakin Institute of Bioorganic Chemistry of the Russian Academy of Sciences) were able to expand the palette of fluorescent proteins by solving a problem that many scientific groups of the world, including the Nobel Prize winners themselves, had unsuccessfully struggled with before them.

Lukyanov's colleagues say that he is one of the most cited Russian scientists in the world in his field. And they also call him the star who didn't leave. Many Russian biologists, who lost any opportunity to engage in expensive fundamental science during perestroika, were forced to move to more favorable places for this. Sergey Lukyanov stayed for several reasons. He was leaving for a while, but after three weeks he felt completely uncomfortable. It was clean, beautiful, rich, but I didn't like someone else's lifestyle and work, I didn't like talking in a foreign language all the time, I didn't like parting with family and friends for a long time. It seemed to him that he could achieve something at home if he was active. And he even figured out how to do it to survive in science. At a time when it was almost impossible to find funding for the study of the fundamental laws of the structure of the living (for example, for the study of the regeneration of planarian worms, which Sergey had been enthusiastically engaged in since his student years), it would be possible to create modern methods for studying the same worms and sell them to Western scientists. The money received, in theory, was supposed to support fundamental research, which, in turn, would also lead to the creation of new methods. The calculation turned out to be correct: now the Russian biotechnological innovation company "Eurogen", the creation of which was initiated by Sergey Lukyanov, sells its technologies and products to them all over the world. However, the turnover of the company is small, scientists cannot afford to buy equipment more expensive than a million dollars, necessary for those fundamental works for which they have swung. And these developments, as Eurogen hopes, could make a revolution in the creation of new approaches to the treatment of oncological and autoimmune diseases. The company could dramatically increase its own importance, and then its value, by proving that in Russia can create world-class innovations.

The unbearability of other people's schemesNow a corresponding member of the Russian Academy of Sciences Sergey Lukyanov clearly remembers that at the age of six he decided on a vocation.

He was fascinated by the magic of the living, which, from his point of view, did not correspond to the simplest physical laws in any way. The book will fall if it is swept off the table; the hand will move without any external influence on it. He used to crouch down to the anthills when his parents dragged him to the beach, and did not understand how you could lie on the sand for hours instead of watching the life of an entire state of living beings.

In the eighth grade, he moved to a school with a very strong biological class, which was led by Galina Anatolyevna Sokolova. As the winner of the Olympiads, he entered the Moscow State University at the biofac, where he specialized in embryology. Lukyanov dreamed of studying developmental biology. But because of the child's illness, he did not go to graduate school, where he could continue to study his favorite topic. He got to the Institute of Bioorganic Chemistry (IBH) by chance: he met a familiar graduate of the biofac on the tram, who persuaded him to try to get a job at this institute in one stop. Lukyanov was taken as an embryologist to Andrey Zaraisky's group, which was engaged in the study of genetic sequences, gene cloning, and their analysis, and research technologies played a very important role in this. "Since it was a laboratory of molecular biologists, at first I didn't even understand what language the employees spoke among themselves," Lukyanov recalls. "But I was hired on the condition of mastering genetic technologies, and I began to learn quickly." He studied quickly, but he felt with horror that a physical intolerance of other people's technologies was maturing in him. "I started getting angry because the schemes seemed imperfect to me: some stages were superfluous, some were completely wrong, and I started rewriting the protocols on the go." Lukyanov laughs: new techniques burst out of him like poems from a poet. At first they scolded him: the experiments had to be reproduced according to standard protocols, then they began to listen and look closely, then to consult. And he corrected and composed everything. The love of childhood and youth for building various theoretical models of development in comparison with the poetry of methods began to seem to him pure graphomania. "They say Moliere wanted to be a tragedian most of all, but he turned out comedies," says Sergey. – I dreamed about developmental biology, but I started inventing technologies. Maybe the genes of the parents who designed the rolling mills have manifested themselves?"

After some time, academician Evgeny Sverdlov, the head of the laboratory where Sergey worked, allocated him a group, and later agreed to create a separate laboratory. It was not only a gesture of support for a budding scientist, although the academician always tried not to clamp down on the young, but also a necessity. Densely occupied positions of middle managers in the early nineties began to be vacated when biologists left the country in packs. There were a lot of vacancies. Looking at the rapid exodus of scientists, Lukyanov at first thought that this was a disaster, but, as it turned out, it was also a chance for the young: "In three or four years, my remaining colleagues and I have gone through a career path that would have taken thirty years earlier. The point, of course, was not so much in positions as in freedom, which made it possible to implement their ideas." However, the euphoria evaporated quite quickly. The new democratic government announced that science should be self-supporting. But there was some benefit in this: "Since we were not funded, they did not ask us anything. Freedom is freedom. And we were free to choose directions and topics. However, when messengers were sent to the government with timid questions about money, they were only surprised that there was still someone left in the institutions."

Lukyanov believes that in In the nineties, he found a very correct solution: "If I studied the genetic abilities of a planarian worm to regenerate, and someone else studied the development of a fly or a frog, then hundreds and thousands of scientific groups in the world were doing the same. It is clear that success will come more likely to those who are better equipped for such research." In modern biology, a high flight of thought is not enough, it is often impossible to test this idea without powerful tools. So Lukyanov decided that it was possible to win in competition with stronger players by becoming their ally and a welcome assistant, offering them advanced technologies to study the structure of the living world. And the sale of these technologies will allow us to somehow support the laboratory.

"As scientists, we knew what our colleagues around the world needed," says Lukyanov, "and began to offer them simple and convenient methods we developed for finding the right genes, analyzing and comparing them. Now these methods are already included in textbooks."

The first publications appeared, demand began to form. We thought about creating a company, but we didn't know how to do business, and when we began to explore the possibilities, we realized that they simply wouldn't be enough to overcome all the barriers. Therefore, Lukyanov and his colleagues gladly jumped at the opportunity to cooperate with the American company Clontech. She gave grants for technology, received rights, and was already engaged in the implementation of both technology licenses and products. American money allowed us to continue working. But that wasn't the only benefit. Our scientists became more and more famous, and during trips to American partners, they not only advised them, but also accumulated scientific information. From there, by the way, they took out the idea to work on multicolored fluorescent proteins: Clontech, and other groups, did not succeed with this.

And the E. coli shoneIt was a kind of scientific race, started by the discovery of a green fluorescent protein, which was first isolated from the jellyfish Aequorea Victoria by Osamu Shimomura.

Much later, Martin Chalfi showed that it was possible to make genetic constructs with the genes of this protein and, by introducing them, for example, into his beloved worm Caenorhabditis elegans, observe the glow. And Roger Qian significantly improved the quality of natural proteins and conducted a lot of experiments with them, showing the possibilities of their widest application. Luminous proteins were known before this green, but to generate the glow they needed other low-molecular substances with which they were combined. Accordingly, they were difficult to use as a tool for studying cells. The green squirrel was unique. It turned out that he did not need additional factors, only molecular oxygen. The green protein catalyzes itself, forming a chromophore molecule inside that can absorb light and fluoresce. Therefore, it was easy to use it in genetic constructs. Qian, who experimented for a long time with the replacement of amino acids in green protein, was able to obtain only varieties close to green – bluish, bluish, yellowish. But he could not get the red scale in any way. Red, on the other hand, was very important: it would become a wonderful tool for observation, since red light shines well through living tissue and allows you to observe cells in whole organisms without destroying them.

Lukyanov's laboratory was also interested in this problem: "An excellent scientist with an encyclopedic education, evolutionist Yuli Labas, gave us a hint. He advised looking for glowing proteins not in glowing organisms, where all other scientists were looking, but in brightly colored, for example, in corals." At first glance, this was a strange proposal: after all, until now everyone believed that pigments, and not fluorescent proteins, give color to corals. But Lukyanov himself was inclined to non-standard approaches. Why not check it out? On a tip from Labas, the scientists got acquainted with the famous Moscow aquarist Andrei Romanko. At first he supplied them with corals, then corals began to be bought in Moscow pet stores for 10-20 dollars apiece. By isolating matrix RNAs from coral proteins, Russian scientists tried to catch molecules similar to the chromophore molecule of a unique green protein. The experiments could have been delayed, since there were as many chances as searching for a needle in a haystack. But the scientists were lucky. In the first experiment, Mikhail Matts managed to "catch" a similar gene. It was a real celebration when the cloned gene was planted in the genome of E. coli and it shone! Even if it was also a green light, but it said that their almost adventurous experiments would lead to luck. They were convinced that non-luminous organisms also have fluorescent proteins similar to green. And they are also autocatalytic, which means they are convenient for research. Possessing excellent genetic technologies, proteins of different colors – green, blue, yellow, red – were "caught" and cloned in the laboratory in just a month from corals and anemones, and in subsequent years similar proteins were found in marine oarfish. Sergey Lukyanov demonstrates the possibility of using these proteins on the example of a frog, a photo of which was published in the journal Nature at the time: one half of the frog is red, the other is green. In the two-cell phase, a red protein was injected into the left embryo in the laboratory of the Institute of Bioorganic Chemistry, and a green protein was injected into the right embryo. The frog grew up, and in the dark, under ultraviolet light, it became a colorful shining princess.

Russian scientists continued to work with the found proteins. They played with them like a Rubik's cube. By making point changes to the gene, they got a fluorescent timer protein that produced green light for a while, and then red. With its help, it was possible to study the change in the production of various genes over time. Scientists made various modifications from fluorescent proteins, which obtained a variety of properties under irradiation. One of the proteins was even turned into a killer: when irradiated with light of a certain wavelength, it could purposefully kill cells or inactivate proteins in a living system. And this is essential not only for research, but also for a new direction in oncology.

The first fluorescent proteins were also sold by Clontech. Along with the advantages of such cooperation, Russian scientists received other kinds of experience. They saw that too rapid modifications of technologies or proteins with new properties do not always please American partners. It was often unprofitable for them to make significant technological changes in production. In addition, it became a pity to give away the rights to their high-tech products. Once again, scientists thought about their own company.

Brains need toolsAbsolutely absurd organizational and financial problems in science also pushed for the creation of the company.

One of them was related to personnel. Since the strong outflow of scientists in the early nineties, vacancies have been filled. And in the heat of the beginning of the reform of science, the Presidium of the Russian Academy of Sciences in 2006 developed a new system of remuneration for researchers, according to which the reduction in the number of employees was to be 20% by 2010 in order to raise the salaries of the rest. It was assumed, apparently, that the institutions would "ask" pensioners and inefficient workers, but this did not happen. "As a result, we got into a completely idiotic situation," Sergey states. – Students study at universities, graduate students write their dissertations here, and then we tell them: I'm sorry, but we don't have any bids, we can't take you in any way, although we would like to. Where should young people who want to do science go? That's right, abroad. I think it's immoral both in relation to them and in relation to those who prepare them. Besides, it personally offends me to train high-class professionals for Western companies and universities." When Russian grants appeared, it became possible to accept temporary employees. But our grants, unlike, for example, three- to five-year American or European ones, have strict annual budgeting, and even a five-year grant obliges to spend the allocated funds by the end of the year and dismiss all employees who can be accepted only next year. But not at the beginning of the year, but in May or August, when funds will be allocated with great delay. And while the employee gets settled, while he starts working, it's time to fire him again. Ragged financing does not allow us to work normally: for six months there is nothing to buy reagents, go to a conference, pay salaries to employees. The purchase of tools and reagents with such financing was carried out in a hurry – just to have time to buy before the end of the reporting year, even if not the best. The rules dictated how to accept employees: not the one the supervisor wants, but the one who will win the tender: "And I don't need a winner. I need a friend, a person whose scientific abilities and personal qualities I know, who will harmoniously join my team."

The creation of a company based on a laboratory could solve some of these problems and even out the flow of funds. "However, all our calculations were sad," says Sergey Lukyanov. – No matter how we turned it, the company could not help but be unprofitable. The situation changed only in the late nineties with the adoption of sparing legislation for small businesses with a simplified taxation system. And in 2000 we registered the company "Eurogen"." First of all, we invited designers and created the company's website. Timofey Panfilov, a graduate of the chemical faculty, who had worked in business and was able to work with personnel and accounting, was invited as a director. Then we learned how to work with clients, how to sell licenses, how to get money, how to organize the shipment of developed samples and technologies. "At first we tried to work with each client individually, but we realized that it was unrealistically expensive, and we started working through distributors," Lukyanov recalls. – Almost at every step we stumbled and gained experience. They began to participate in competitions for grants, to lose, to learn again to write what an official wants to see, although sometimes his logic seemed incomprehensible and even absurd. For example, a negative answer to the question “Do you need foreign partners to complete the project?” he was rated with the lowest score. And why do we need a foreign partner if we are the best?" We learned how to win.

So money began to flow from various sources – from sales, services for companies, grants. Now fairly even funding allows scientists to make technologies like candy. "They are exclusive," Lukyanov says. – Largely because no one in the West can afford to gather specialists of this class in one team. And we have excellent guys working here. By the way, many of them are graduates of the same 520th school that I myself graduated from. Not without pathos , I will note: it seems to me that such an opportunity to raise talented scientists from childhood is priceless. Here in Russia."

Although the technologies are exclusive, although they are sold all over the world, they do not bring millions of profits. The research market is quite narrow. There is enough money for inexpensive equipment, reagents, some business trips, and most importantly - for personnel: "I was glad to see with what pleasure young specialists start working in the company. They don't need to look to the West, although salaries are higher there. They see an opportunity to realize themselves without parting with their relatives and without spending efforts on adaptation in a foreign country." As planned, part of the money is directed to basic research. In principle, within the framework of one company, applied science could do without them, it would be possible to take on the side. "But if we look beyond the horizon for more than five years, we need to dig into science in order to improve our technologies and be the first to invent new ones," Lukyanov believes. Ideas are growing faster than turnover, and the company is acutely aware of these limitations. Sometimes, because of this, you have to part with talented personnel who are clearly outgrowing the company. Someone went abroad, someone went to a larger company…

"Fundamental science requires colossal investments,– Lukyanov says. "To compete with Western scientists, we need not only sharp brains, but also devices that cost from a million dollars." One of the promising directions of the company is the search for new approaches to the treatment of autoimmune diseases. These diseases are associated with the fact that some cells of the immune system, designed to attack external enemies (viruses, bacteria), transform into auto-aggressive and attack certain cells of their own body. Modern means are aimed at destroying the communications of these pathological cells, at their disorientation and, as a result, at stopping their activity. But when the drug leaves the body, communications resume, and the cells of the immune system can attack the body again. These drugs are very expensive, the course of treatment costs 30-40 thousand dollars a year with a constant need for medicines. Sergey Lukyanov believes that it is necessary to get close to the attacking cells themselves. This requires fundamental research to begin to understand the populations of immune cells and the mechanisms of their work. "To do this, we need a tool such as a cell sorter, which allows us to sort cells into various functional groups at a tremendous speed,– says Lukyanov. – We are not able to buy it, it costs more than a million dollars. But the state can do this if it decides that it needs modern science."

Now the state allocates significant funds for science. With all the effort to do it effectively, it is not very successful yet. According to Lukyanov, it would be fair to send part of this money to innovative companies that, like Eurogen, combine applied and fundamental science and have achieved some success. Lukyanov is convinced that his company, armed with the modern expensive devices it needs, would have a real chance to make a revolution in biomedicine and take a leading position in the development of new approaches to the treatment of oncological and autoimmune diseases. He knows other quite successful companies that could "jerk" if not for financial constraints.

Portal "Eternal youth" www.vechnayamolodost.ru13.04.2009

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