The success of biologists will save cells from death

Yuri Drize, "Search" No. 42-2015

Photo provided by D.Andreev

Dmitry Andreev, a senior researcher at the Belozersky Research Institute of Physico-Chemical Biology of Moscow State University, Candidate of Chemical Sciences, recently returned from Ireland. Together with colleagues from the University College of Cork (the second largest city in Ireland), he studied the so-called neural cells, similar to neurons. Scientists around the world use them as a kind of "guinea pigs", trying to understand what is happening in them – how they survive in the most adverse conditions. The new knowledge obtained by the researchers will help to develop promising methods of combating ischemic diseases, primarily stroke.

Dmitry Andreev has made great progress in these studies. During the relatively short time that he studies the regulation of protein synthesis, the scientist has published more than 20 works in leading foreign publications. Note, however, that neither these articles nor the progress in the development of an extremely promising scientific direction could have been. According to Dmitry Evgenievich, he actually became a molecular biologist by accident. During his studies at the chemical faculty of Moscow State University, he was not at all eager to study molecular biology, he was more attracted to organic chemistry. But in the third year, as part of the Soros program, Dmitry went to listen to lectures given by famous scientists. Among them was Professor Ivan Nikolaevich Shatsky, who devoted his report to the regulation of protein synthesis...

– At that time I didn't have a very good idea of what molecular biology was, but the topic seemed so interesting to me that I decided to go to work in the laboratory of protein synthesis regulation headed by Ivan Nikolaevich (it was in 2001), – Dmitry Evgenievich recalls. – At first I was on probation, and in the fifth year I became a full-time an employee of the laboratory. Together with colleagues (Sergey Dmitriev and Ilya Terenin), he was engaged in the regulation of broadcasting, conducted experiments, published several articles in well-known foreign journals, participated in conferences. Once, at the RNA Society conference in Japan (2011), I made a report and met Pavel Baranov, a graduate of the chemical faculty, who once worked at our institute, and now headed a laboratory in Ireland. 

It turned out that we both highly appreciate the promising, but very time-consuming method of ribosomal profiling, which allows us to get, as it were, a snapshot of the entire process of protein synthesis in the cell. It's like, say, looking through a microscope and seeing how stem cells turn into some kind of tissue, and at the same time all the changes in the synthesis of matrix RNA (mRNA) and proteins that occur during the transformation process. 

We agreed to master the tricky method together, for which I had to come to Ireland. Thanks to the fame of our laboratory abroad and our publications, which our Irish colleagues have carefully studied, I received an invitation to work in Cork. And all three months that the first business trip lasted, I worked out the conditions of the experiment – I wanted not only to copy the well-known technique, but also to improve it. It was only the second time I was in Ireland that I conducted experiments, and based on their results we published two good articles (in eLife and Genome Biology).

Now about the essence of our research. It is known that during a stroke, blood vessels become clogged or burst, a certain area of the brain does not receive oxygen and nutrients – and neurons die. But if you come to their aid very quickly, some cells can still be saved. The so-called therapeutic window for stroke is 3-6 hours, at this time it is still possible to influence the cells located in the "zone of ischemic penumbra". Neural cells are similar to neurons in many ways, and if we understand what happens at the first moment when cells are deprived of the most necessary (oxygen and nutrients), how they rebuild and adapt to an unexpected and fatal condition so that at least some of them can survive, then it will be possible to develop a treatment strategy that reduces the destructive effect stroke. We study how gene expression is regulated in the absence of oxygen and glucose, and how an amazing natural adaptation mechanism works. In the future, if it is possible to find out that a certain protein begins to be synthesized for the sake of saving the cell, you can try to influence the cell so that it "turns on" in advance. Or, conversely, to suppress certain genes that trigger cell death. To better understand the initial stages of the development of ischemic disease, we took "snapshots" of protein synthesis 20, 40 and 60 minutes after stress. And we saw not only early changes in protein synthesis, but also how the whole process develops dynamically. Very subtle mechanisms of protein synthesis tuning were also discovered, which could not have been seen before without the use of ribosomal profiling. As well as changes in the synthesis of important regulatory proteins, which, apparently, determine the fate of the cell in ischemia. But there is still a lot to do to understand the essence of the regulation that we are observing.

We have seen from our own experience that the ribosomal profiling method has a huge potential, helps to solve a variety of tasks. You can find out, for example, how new drugs act on a cancerous tumor; which specific targets are affected by drugs and which are not; why some cells are sensitive to chemotherapy and others are not. The answers received will allow pharmacists to improve new drugs. The selective effect of drugs on cancer cells will accelerate the development of personalized medicine, when drugs are selected based on the nature of the disease of each patient. It is already quite possible to do ribosomal profiling of a particular patient's tumor in order to study the features of this tumor and, based on the results, select a suitable treatment strategy. However, our group is primarily interested in the regulation of protein synthesis. What happens with certain effects on protein synthesis? Which proteins are activated and which are suppressed under stress and why is this possible?

We have already studied two stressful effects: when the cell is deprived of oxygen and glucose – I talked about this, and how the cell responds to oxidative stress. We acted on the cells with a certain toxic compound to understand what happens in it when the most important regulatory protein that provides protein synthesis is turned off (this is the initiation factor of protein synthesis, which is called eIF2). It is worth noting that the same factor is turned off with many other stressful effects, such as a viral infection or exposure to radiation. Obviously, understanding how protein synthesis is regulated by this factor is very important. 

As expected, we saw that protein synthesis is almost completely turned off during this exposure. This is not surprising – the cell is not up to the synthesis of new proteins, it saves resources (protein synthesis is one of the most energy–consuming processes). Some proteins have been known before, but others we have discovered for the first time. Now one can only guess how important they are for the survival of the cell (now their function will be closely studied). We have found certain common features in the mRNAs encoding these regulatory proteins, but we have not yet fully understood how these features regulate protein synthesis under stress.

All living things are armed with such special programs to combat adverse factors – otherwise they will not survive. Scientists have known about this for a long time, but only the particulars were known, and the overall picture could not be drawn up in any way. Ribosomal profiling in this regard is almost a universal method, because it allows you to look not only at protein synthesis, but also at changes in the number of corresponding matrix RNAs. 

– And what's next?

We will continue to use ribosomal profiling, since the possibilities of its application are almost limitless. You can consider a variety of effects on the cell, because there are countless of them. In order to implement all promising projects, it would be good to attract a dozen more employees – they will have a wide field of activity. 

– Do they use ribosomal profiling in our country?

– In our laboratory, the method has been set and is actively used, I don't know about others, there are no published works yet. It is known that many research groups show great interest in it. 

– What did you like about Ireland that you would borrow from colleagues?

– I liked the working atmosphere prevailing in the laboratory. I liked the people: friendly, open, interested in science. They go to the cinema together for the premieres of new films, go out into nature on weekends – it's customary there. And they also have no bureaucracy (at least it spares researchers). You don't have to spend hours going through the instances explaining why you need a reagent, you don't need to issue invoices and invoices, or even go to supplier companies to push, speed up... Here, all this takes a lot of time and effort. And colleagues should contact a special employee – and they will have the reagent in a week or two. With us, if we are lucky, then in a month, and if not, then in six months. It is strange that in such conditions it is still possible to compete with colleagues.

– Have you met any Russians in Cork besides your co-author?

– Yes, I know about five people who have been working there for a long time, settled down, as I understand, quite well, many have received Irish citizenship. 

– When are you going on a business trip again?

– I don't know yet. I've got a lot to do here, too. There are several articles in the work, I want to finish them soon and return to the experiments. And I communicate with my Irish colleagues by e-mail.

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21.10.2015