English translation by Logrus Global: https://logrusglobal.com

"And the question is: is it a world of microbes or a world of humans?"

Sergej Netesov, a molecular biologist, speaks about who actually rules humankind. He knows what he speaks of. He managed the research department of Vector for 17 years.

April 19, 2020

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Author: Sergej Mostovshchikov

Source: https://novayagazeta.ru/articles/2020/04/19/84983-i-vstaet-vopros-eto-mir-mikrobov-ili-lyudey

A tiny creature rules humans today, a creature which most people in the world had almost no awareness of earlier in this same year. Something intangible affects that which is most essential — it deprives us of our money, habits, boundaries, politics, peace and loved ones. It forces us to hide, to be afraid, to argue and to fight. Finally, it turns out that almost everything depends on it, our life in itself, which, as it seemed, we were able to independently manage just the other day. What is this thing?

We talked about this with Professor Sergei Netesov, a molecular biologist, head of the laboratory for biotechnology and virology at the Department of Natural Sciences of Novosibirsk State University. The Professor's opinion is particularly interesting because he was director of science for 17 years at Vector, a famous and once very secret Center of Virology and Biotechnology. The main secret that we discussed with Sergei is as follows: to understand what is happening, we will have to think about the fact that the world which we used to live in is actually not a world of humans.

Fig. 1. Sergei Netesov and Sergei Mostovshchikov. Self-isolation interview

— Sergei Viktorovich, how did it happen that molecular biology has become the focus of your live?
— It was like a set of zigzags. First of all, we had a very good chemistry teacher at school. I have been wearing glasses since I was five, and these glasses have always served as a kind of excuse for me: I was interested in all sorts of interesting things like that. Chemistry at school didn't only give interesting information, but we also performed experiments. I was very interested in these experiments, I solved problems, and well, I first participated in the city academic competition and took second place there. Then I got to the regional competition and also took second place. As a result, I got to the Physics and Mathematics School of Novosibirsk University, again for chemistry. And when I entered the university, I had my first motivational push.

The fact is that in 1969, James Watson’s Double Spiral, a book describing the discovery of the DNA structure, was published. I saw it in a store, bought it, and I immediately read a quarter right there, I was even kicked out from the store. Then I bought two more such books. You see, before it was believed that there are some cells of which the body is composed of, but it was not clear how they worked. They were a kind of biological black boxe with half-way supernatural miracles occurring inside. And then suddenly these guys take it, and based on pure logic and radiographs create a completely believable model — how it all can actually work. And I just was struck by it.

I met several more people, students and graduate students, who were about five years older than me, who were also infected with these preoccupations. And when I did my graduate work in my fourth year, I was already an accomplished fanatic. We spent all night at work in armchairs so as not to miss the right moment in our experiments. At that time, I worked on a chemical-biological task: the reaction of adenosine triphosphate (ATP) with the formation of cyclic triphosphate at the end. This triphosphate was then linearized, and due to this we could obtain all sorts of ATP derivatives with interesting biological properties.

— Why did you find this important? Did you seen yourself as a kind of a master of the world?
— You see, when you face some things not in your imagination, but in a test tube, and their result is logically clear, you of course feel yourself not the master of the world, but rather a person who at least can control something in biology.

— And did you exert control?
— Well, regardless of the amazing things which could be controlled, reality is always present. For example, what slowed me down at that time in the Academy of Sciences was difficulties with reagents. It was necessary to order them six months or a year in advance, and funding for this was rife with uncertainty. I had to act informally: call friends and strangers in other institutes, ask what they have got, jot some notes, and do similar kinds of exchange. And then suddenly the All-Russian Research Institute of Molecular Biology (the future Vector) — a completely closed center — was set up in Novosibirsk, but it was already clear that it will deal with molecular biology and virology. An entire town had been built around it. And it had nigh unlimited funding for reagents. Of course, I went there. Moreover, I just got into all kinds of manipulations with RNA and DNA, and I became really interested to try them out on viruses, because they are the simplest, sort of half-living creatures.

I began my scientific life at VNIIMB by learning how to purify, i. e. isolate, one of the viruses which was completely safe; the mouse encephalomyocarditis virus which I could work with on a table, with no biosafety accessories. I isolated it, saw via electrophoresis that all the proteins are pure, isolated the nucleic acid and provided experimental evidence that it can be obtained in a homogeneous, pure form.

Eventually, I learned to purify viruses very well.

Then I took up a topic related to the flu virus. It was necessary not only to isolate it, not just to decompose it into its constituents, but to sequence its genome (read the nucleotide sequence.Ed.). This was one of the first such projects in our country. Of course, I didn’t do all this work myself, by that time I had my own informal team, and we eventually found out that the flu virus is really evolving, and even determined the sites where changes are taking place. Moreover, we found something interesting. It turned out that the main protein of the flu virus that binds to the cell forms trimers on its surface, and their tops look like a clenched human fist with five knuckles, and these knuckles are the sites where the main evolutionarily significant amino acid substitutions occur. There were other interesting works. Have you heard about reverse genetics? It turns out that you can work with DNA almost like a construction kit, by disassembling and reassembling it. In the 80s, it didn’t work well with RNA viruses, but we converted the RNA virus genomes into DNA, cloned, disassembled, reassembled them, and finally obtained a living virus. The first such study in the world was performed with the polio virus, and the person who did it got the Nobel Prize. At that time we experimented with other viruses, like the second line, but for these we had calculated and synthesized some reagents which did not exist in our country at that time. And by the way, we succeded: first we “revived” the virus based on its RNA synthesized on DNA copy, and then inserted another gene into the DNA copy of this virus genome, and the RNA obtained from it began to produce the hepatitis B virus protein.

That is, we actually created a live vaccine for hepatitis B with our own hands in 1991.

— Correct me if I'm wrong: was it the creation of a life with your own hands?
— Well, that's rather overstated. In fact this was the reproduction of a living virus using recombinant methods.

Fig.2. Photo: Kirill Kukhmar/ TASU

A black hole in statistics

— Since 1990, you were the Science Director of "Vector" for seventeen years. Can you list the most interesting projects that have been implemented during this time?
— In the nineties, when we still had the reagents, we managed to be the first in the world to sequence the Marburg virus genome (causes Marburg hemorrhagic fever.Ed.) and the second in the world with the Ebola virus genome. That is, our work was published second, but in fact we worked independently.

Then the reagents in our country ran out. Three quarters of my colleagues went abroad.

And only 4–5 years after that, we obtained foreign funding, grants. With incredible efforts, our General Director, Academician Lev Sandakhchiev, together with us, leading scientists, made Vector open for international projects. Thanks to this, we made a number of very useful things for Russia. For example, my largest grant was to study the prevalence of viral hepatites in Siberia. Generally speaking, there were no such large-scale monitoring works, neither before us, nor, as it turns out, after us until recently. Our data had shown how much hepatitis vaccines were needed, what was the territory coverage, who was in largest need of vaccination.

By the way, this is exactly what is currently lacking in Russia to understand the situation with pneumonias and, in general, with respiratory diseases. This isn't big data after all, it’s not worth tens of billions. But why does no one do this? Look here. Goskomstat is publishing an online "Healthcare in Russia" annals. It describes how many formally reported cases of respiratory diseases we have per a year. You won’t believe it — about 50 million. Next.

Every year, all respiratory diseases cause 60,000 to 94,000 deaths in Russia. This is a large number.

But you go deep into these statistics and suddenly discover that there is a black hole! There is no information on case specifics. What caused them?

A month ago, my grandson had a rather severe case of bacterial pneumonia. Do you know how they identified that it was bacterial? They began to use antibiotics urgently, and on the second day he responded and his condition improved. In parallel, they made a culture and got a result on the fourth day, identifying a particular bacteria. A week later, he was discharged and now he is healthy. But they didn't record any of this in his diagnosis!

And it turns out that we have an unnamed pneumonia in Russia.

And now, when the people say they already had this coronavirus in October or November, what should we do with this speculation? How can it be evidenced?

But, by the way, there is a paid test for six agents causing acute respiratory viral infections that can have a sequela as a pneumonia. It costs about five thousand, but insurance does not cover these expenses. Since this is not an insurable event, such a test will not be done in 99% of cases, and people aren't even told about the possibility of a paid test. On the other hand, when they are talking about a diagnosis of the specific virus based on computed tomography, I do not understand — how is this even possible? Tomography shows whether there is pneumonia or not, what is the level of lung injury. But it can't show, for example, which of the six pathogen viruses or which bacterium caused this. A virus or a bacterium do not leave their signatures seen on the CT.

Alright, well, let's take the Sklifosovsky Institute in Moscow as an example for this method of monitoring. Anyway, they don't have 100 thousand patients with pneumonia there. It's realistic to test at a minimum 500 people for six viruses and five to seven bacteria. At least it will be clearer what is the ratio of the causative agents of these pneumonia, which drugs are most preferred in Russia, and, most importantly, what vaccines should be made first.

We know that China, Korea, Germany, Italy have such data. And we do not. Why?

Do we consider computed tomography sufficient?

Fig. 3. A Russian kit for COVID-19 coronavirus detection. Photo: RIA Novosti

— To be clear, you propose that we are making a mistake and going in the wrong path?
— No, we're on the right path, but we're doing a plenty of mistakes. And it’s interesting that here we are always condemning America, but are making exactly the same mistakes. First we, like America, said that the test kits will be manufactured by only state companies. We missed the window to let commercial companies make their own tests. We decided first that only symptomatic patients should be tested, but now it becomes clear that there is an order of magnitude more asymptomatic individuals, that they are not isolated, which means they are able to infect many more people.

Finally, an antibody test showing the ability of a particular person to withstand coronavirus, has only just been approved.

But this almost begs the question: what degree of immunity does the wider population already have?

After all, this is nuanced: there are four types of coronaviruses infecting humans for decades, and in most cases they cause mild or moderate diseases. And two of them, the so-called beta-coronaviruses, share some antigens with the current coronavirus. There is a small chance that people who have been ill with two ordinary beta-coronaviruses still have some kind of immunity. That's why we have the scientific challenge of determining whether this is the case or not. Such an assessment was just made in California. And it turned out that about 3% of population have antibodies to this virus right now. But they had a very serious outbreak more than a month ago.

— And are we now able to solve serious scientific problems in Russia?
— I will say this. Of course, now is not the time where our virologists, epidemiologists and vaccinologists are considered one of the best in the world. In the past, there were was a time when we could do everything on our own territory, we didn't need Americans and Europeans to make discoveries and solve all our problems. Now we don't have this. To catch up to global standards, we need a lot of engagement with the wider world. Look here. During this coronavirus epidemic in Russia, about 1800 bases were sequenced in China. Yet Russia has only sequenced a couple dozen.

But look at the specialists we are training! I’ve been teaching virology at Novosibirsk University for twenty-five years. I met students with incredible potential. They reach PhD degree here and obtain results close to the global level. And then they are already 35. They can't get any more grants aimed at young scientists. They won't just get their own laboratory. This would require purchase of a wide array of equipment:

it's not like computer science, you can't get by with just a laptop here. Standard molecular biological laboratory equipment costs about five hundred thousand American dollars here. ?

Plus reagents. And what do we have? The salary of these specialists in Russia is 500 dollars, and they goes to Germany as a post-doc and immediately get six times more. And they've already got all the equipment and reagents needed. And on top of that, they are eligible for grant proposals there.

Of course we can become a leader in the field of virology. But for this, biologists must not be considered in the same category as IT specialists, and should be offered more grants, with more money.

— I may be mistaken, but it seems that not only scientists, but viruses themselves should be considered differently?
— Currently, molecular biology allows the study of microbial communities. And such study brought surprising data: if you count all the bacteria that live on our skin, in our mouth, intestines, and so on, their number will be several times higher than the number of cells in our body. A second point. It turns out that an adult human cannot live without them at all, because our existence is a symbiosis between a human and at least 50–70 bacterial species. An keep in mind: about half of these bacterial species cannot grow on a Petri dish at all because they live in a special way, only in a community. Moreover. Microbes living in our intestines include very pathogenic ones, for example, a bacterium that causes tetanus. It lives there without harming us. But if it gets into our bloodstream, it becomes deadly. And there are several such species.

The question is: where do we live? Is it a world of humans or a world of microbes? I am being absolutely serious here.

A human is not an independent, isolated entity, but a useful system convenient to live in for entirely different creatures.

Finally, a little about viruses. For example, there is a great variety of viruses and bacteria in our intestines. It seems they play a regulatory role there. That is, when the population of one bacterium exceeds a certain threshold, a dedicated virus destroys it, and its population drops. In fact, this is the element of protection which some bacteria have against other bacteria. That is to say, this whole idea that viruses are these parasites which should only be fought against, is, to put it mildly, not quite true. It turns out, for example, that viruses carry genetic information, and the exchange of this information between bacteria is impossible without plasmids and viruses.

It is likely clear that we, as humans, probably do not want to consider ourselves as simple vectors for the reproduction of bacteria and viruses.

But we can at least reassure ourselves that we have a brain, that we are somehow able to comprehend the situation and to accept the fact that we do not live alone, but that we live in a certain community that operates according to laws which we do not entirely comprehend.


— Could you give an example of one such incomprehension?
— Well, let's look at the tick-borne encephalitis. In the past, it could not be found in European Russia. It was discovered in 1937, and studies of its dispersal began only towards the end of the 80s. Three sub-types, Siberian, Far-Eastern and Central European, were found. It was determined that these sub-types began to expand. Now our Siberian sub-type is found near Moscow, in the Czech Republic, and in Germany. There were even conspiracy theories that we brought it there. Investigations were initiated. And what was the result? Germany, for one, had become such a very green, humane country, that instead of killing deer, they spared them and even installed feeders for them. But these animals are the food supply of ticks, and ticks are carriers of encephalitis.

Thus, it can be said that ticks regulate the level of humanism.

And how can we reduce tick populations, if we don't touch deer?

Fig. 4. Sergei Netesov

Another point. After SARS, the Chinese began their studies with bats. They began to sequence any and all bat viruses. They compared them with samples of the long-known human coronaviruses discovered back in the 60s. And it turned out: bats carry close relatives of these viruses. This suggests that transition of viruses from wildlife to humans has been going on for a long time. And it continues now. We just now saw this transition firsthand. This is one of the results of our interaction with nature.

— Well, considering the origin of the novel coronavirus, China interacts with nature either more closely, or somehow specifically.
— When I give lectures, I give a simple example. There is a province of Guangdong in China, from which the coronavirus which caused the SARS outbreak arose. This province is the size of the Novisobirsk Oblast [comparable to Oklahoma]. 2.9 million people live in Novosibirsk, and 115 million in Guangdong. To feed the entire Novosibirsk region with chicken, we need to grow about seven and a half million broilers every year. It takes 300 million chickens to feed Guangdong. Plus pigs, ducks and cows.

This is a kind of a huge Noah's Ark. The probability of a viral exchange between humans and animals is incredibly high under such population density.

Plus, they imported palm civettas, which are a distant relative of mongooses. They have interesting fur, tasty meat, and they contributed something to traditional Chinese medicine as well. They were kept in open enclosures with roofs, and in these roofs — bats. So, we can say that the Chinese made the SARS virus with their own hands. Something similar may have happened with the coronavirus at the market in Wuhan. Nature didn't so much as take revenge on us, rather it found a way to break through the thin barriers we had.

— One way or another, it broke through. And what should humanity do in this regard?
— We have three ways.

  • The first is to quarantine the virus, as China did and as Korea ended up doing. Interestingly, the only big country where this might not work is the United States. Everything became too serious there, too quickly.
  • The second way is to eliminate the coronavirus with a vaccine.
  • There is a third way. Large countries may not be able to maintain their current course there's still a long way until a vaccine, and due to democracy, they will not be able to organize quarantine properly. As a result, a large number of people will suffer through the illness, receive immunity, and when this proportion reaches about 50 percent of population, the epidemic will die out by itself. It's like pouring water on firewood — and the fire goes out by itself. Apparently, this scenario is now becoming relevant for a number of countries. We will come to understand this soon.

Fig. 5. Photo: RIA Novosti

In any case, we should take a closer look at the experience of Germany, where people are now being tested for antibodies and will receive certificates.

Their immune status is their pass to work, in fact, to a new life. With this pass, they will go to save humankind, because many more people can die from the economic downturn than from the disease itself.

— Regardless, nature has already changed the world of humans and will change it even more. How exactly?
I think that finally the people who control us will understand that they are looking for the enemy in a wrong place.

The authorities will finally pay attention to the vital need to monitor infections in wildlife, not only in humans. Humans must change their attitude towards nature, not only to plants and animals, but also to microorganisms.

And those who do not want to learn will at least remember that they need to wash their hands more often and have hygiene products ready. So that such people may find themselves in a new world as soon as possible, I propose to conduct a little experiment. Watch yourself for twenty minutes. How many times do you touch your face with your hands? What places do you touch with your fingers outdoor? Maybe this will teach something, lead to some visible changes in cities and in everyday life. There will be many more motion-activated taps, self-opening doors, and so on.

It is possible that this epidemic will influence us to get sick less, and think more. And not only about ourselves, but about the wider world which we actually inhabit.