— Olga Anatolyevna, what was your upbringing like? Did it leave you any chance not to become a scientist?
— I don't think it did, really. My father was a famous chemist. He contributed to the theory of heterogeneous vulcanization development, which made it possible to use vulcanization processes in the tire industry. My father passed away too early. He was always passionate about science. I was three when he taught me how the world around functions. My father and I were very close. He spent lots of time with me, took me out for walks. He used to narrate Strugatsky Brothers' science fiction to me as my bedtime stories. Science and science fiction have been part of my life since childhood. My mother was the head of our family and a prominent figure in her own right. She was the Soviet Union's No. 1 chemist for plastic film, including special-purpose film. What choice did I have as a child? I went to School No. 171. I had a B in essay writing and a C in my behavior report just because I didn't like wearing skirts. I wore pants instead.

— When you applied to university, did you have a clear idea of what you wanted to do?
— I just wanted to understand things about life processes. I read a lot. The most important book in my life was The Double Helix: A Personal Account of the Discovery of the Structure of DNA by James Watson. It had a tremendous impact on me. The School of Biology was not an option as I didn't know the first thing about biology. Although, the School of Chemistry, Enzymology and Chemistry of Natural Compounds seemed right to me. I joined the department during my freshman year. I came there and I've stayed there ever since.

— For years, you've studied the ribosome, which is responsible for protein synthesis, and you've been searching for new antibiotics. What's the most interesting part of your research?
— The most fascinating aspect of my field is that by doing it, you occasionally stumble on some entirely new and unusual processes. Just recently, Petr Sergievand his Skoltech grad student Tinashe Prince Maviza discovered a new way of how bacteria fight toxins by disrupting the RNA chains. This strategy allows bacteria to dodge toxins attacks and survive. This is an interesting, completely new piece of research. The first article reporting its findings came out earlier this year. Researchers are now working to further advance this area.

— What's the biggest issue with the development of new antibiotics?
— The problem with new antibiotics is, we don't know where to source them. The obvious sources have been depleted. We are now seeking scientists who explore unconventional sources like marine microorganisms, Kamchatka thermophiles, soils, and so on. I wouldn't say we've found lots of really new antibiotics. Typically, we deal with antibiotics that are already in the database but their mechanisms of action were not clear before. We've figured out the mechanisms of a few such antibiotics. Very occasionally we get lucky and discover new, previously unknown molecules. We figured out how one similar compound binds to the ribosome, revealing a completely different mechanism of action, unlike any other antibiotic.

— How exactly does that mechanism work?
— The ribosome has numerous sites where these antibiotics will disable one or another stage of translation. One of our antibiotics disabled a translation stage that no other molecule had blocked before. We singled it out as its forte. But later it turned out that this antibiotic destroys human cells along with bacterial cells. The real challenge regarding antibiotics is that once we discover something, an experienced team of organic chemists needs to step in. They will use our findings to build libraries in order to identify the best compound to be developed into a drug. For now, this is beyond our capabilities. But I believe we'll get there eventually. Right now, we're working on a completely new antibiotic. Everything about it is new: its formula, the mechanism of action, and the ribosome binding site.

— Is it synthesized or derived from a natural source?
— The latter. I'm not at liberty to talk about it yet for legal reasons (publication patent, and such). Although, this example shows that there is always room for discovery, even in a well-researched field such as antibiotics. It still has potential.

— How prominent was antibiotics and ribosome research when you started your scientific career in the early 1970s?
— The topic was as relevant then as it is now. In the U.S., the researchers who won the Nobel Prize for their work on ribosome structure have pioneered a company whose business is in new antibiotic development based on structural design. They've made some progress, but it's not as simple as it seems. The problem remains. I guess we've demonstrated some appreciable success, too. There are graduate and undergraduate students at Skoltech who are working on a variety of ribosome-related research tasks.
This topic itself goes way back in history. Our mentors Alexei Bogdanov and Alexander Spirin made a tremendous contribution towards understanding ribosome structure and the process of translation. It's a fascinating and sufficiently researched field. Yet young researchers are those who are responsible for its development.

— Despite the extensive research effort, isn't it strange that the last time a new class of antibiotics was discovered was in 1984?
— Discoveries are made, but very few make it to clinical trials. There are a lot of issues associated with this process.
First of all, we have to make sure the new drugs kill what they're supposed to kill. We don't want them to kill us instead, I mean our cells, do we? Secondly, toxicity of the compounds must be taken into account. It is worth mentioning that most bacteria utilize the same platforms, albeit with some modifications. The compound may seem new, but if the platform is the same, the mechanism of antibiotic resistance will recognize it. What would make a real difference is a completely new medication. One interesting strategy is to create cocktails of compounds with multidirectional action. There are many different types of antibiotics out there. For instance, it is more difficult to develop resistance to ribosome-targeting antibiotics, which is why these drugs are easier to work with. However, those medications have their own set of issues. Cell walls can be a piece of work. They're just more complex technologically speaking. Anyways, it is important to be equipped with a variety of strategies. I think that certain once-forgotten antibiotics may be about to come to the fore. They might yield promising results in combination with other ingredients.

— What are some of the recent success stories in this field? I mean people, certain researchers, not countries. Who are our trailblazing molecule explorers?
— Actually, many of them are our collaborators and alumni. For example, Alexander Mankin is an alumnus of ours. To tell you the truth, antibiotics research isn't a highly rewarding job. It's too expensive to start a business, and the drugs end up costing pennies anyway. That is the reason why even promising innovations sometimes fail to make it to clinical trials. In the current context of COVID-19, complications caused by hospital infections, and superbacteria horror stories, it's time for private businesses to take the lead. Our job is to deliver the foundation. Someone else, not scientists, should take it from there.

— U.S. biotech companies had this tradition in the 1960s: every employee was supposed to bring back a lump of dirt from whatever exotic destination they had traveled to on holiday.
— We are doing the same thing now. The Citizen Science project led by Dmitry Lukyanov in partnership with Novosibirsk has volunteers who travel to different parts of Russia to collect samples. Then they study this material, isolating unusual viruses and bacteria that may potentially serve as a basis for further research. They pay attention to the routes in the north, the south, and the mountains.

— It seems that we know pretty much all there is to know about the ribosome. But that's probably an amateur’s perspective. What is your current research focus?
— We do know a lot, it is true. We know of the fundamental principles. My current focus includes regulation, unusual factors and situations, stress environment for bacteria or humans who are being exposed to bacteria, mechanisms of stress relief, and so forth. Regulatory science is so not what it used to be 20 years ago.
Once I received this amazing grant, positively the grant of my life, all thanks to Howard Hughes. It was a substantial amount for its time, almost equal to a regular RSF[1] grant for a whole research team. The only mandatory condition of the grant was to publish articles and spend the money on research. That grant enabled us to start working on the telomerase from scratch. We published many insightful articles on telomerase, the yeast model, and the structure of telomeres in the yeast model. These latest articles appeared in eLife.
I find the work of Professor Maria Rubtsova particularly interesting. Her work sets an example of courage in science. Telomerase RNA is a component of telomerase, the enzyme that extends the ends of telomeres. It's active in stem cells but gets deactivated in human somatic cells. However, it turned out that only the catalytic subunit synthesis is deactivated, while RNA is always present. Maria began wondering what exactly RNA does there. She found out that there is an open reading frame, which means that protein encoding can take place. Maria decided to research if this protein really exists and, if so, what its purpose might be. Incidentally, we pitched this idea to Nobel Prize winner Thomas Cech at some conference, and he opined that it was an exercise in futility. That notwithstanding, Maria decided to proceed. She successfully synthesized this protein on its own, obtained antibodies in collaboration with her colleagues, and procured evidence of the protein's important role. I believe it takes a great deal of courage to persevere in what interests you when everyone around is telling you to drop it.

— How did this work advance our understanding of how a cell functions?
— If you begin to pour something nasty on the cell to induce its death – apoptosis – then the heightened expression of telomerase RNA will aid in the cell's defense. RNA itself is useless, it's the protein that matters. The protein, encoded by telomerase RNA, helps the cells survive an aggressive impact. This protein, as we found out from later research, regulates the process of autophagy. We don't have all the answers yet, but we can state with certainty that this proliferating cell uses telomerase to extend telomeres, and the signaling molecule from a key component of the telomerase complex is there to synchronize this process with environmental conditions. Accordingly, if you knock out the protein, this will have a major impact on cell components, including the mitochondria, which indicates that this protein may be acting as a major regulator. I think this is one of our most intriguing studies in recent years, and it's still ongoing.

— Okay, let's talk telomeres now. When they were first discovered in the 1970s, we thought we were about to take control of the human lifespan and thus make a difference in the human quality of life. Why didn't it happen?
— Active telomerase is a double-edged weapon. You have stem cells with active telomerase, they reside in niches, they're protected, and their activity diminishes with age. Now imagine that telomerase is activated in a regular cell, giving it the ability to divide infinitely. It's exposed to sunlight and a bunch of other factors, leading to mutations that let the cell ignore the body's orders to stop dividing. What this means is that the probability of cancerous growth rises by orders of magnitude. Telomerase activation must be severely restricted. Such research has been conducted. For example, in Spain, a research team created an adenovirus containing a telomerase protein gene. When it enters a cell, it activates telomerase for a while, because the virus can only survive in the body for a limited time. In mice infected with this virus they observed a 25% increase in life expectancy. A similar study was performed with two female volunteers, but the results are still pending.

— When did that happen? I don't recall this being reported in the media.
— It happened fairly recently. Experiments on humans raise logical ethical questions. It's one thing when we're dealing with a disease in a critical stage. But when you get a relatively healthy person, I wouldn't risk exposure to a potentially harmful experiment. We can't predict the possible repercussions 5-10 years from now. Stem cell research slowed down dramatically when things got out of hand with their ubiquitous use, leading to tumors. This greatly undermined the credibility of stem cell research, despite its enormous potential. With stem cells, one can use their own cells for regeneration. I think this field holds great promise for the future.

— For a while, the telomere length test was on the list of compulsory tests required to obtain health insurance in the U.S. Is this still the case?
— I think they've stopped, having realized that the correlation is nowhere near 100%. Your somatic cells rarely divide, they have enough telomeres obtained through differentiation. The main issue is with the clonogenic potential of stem cells. It is illustrated by how elderly people experience weight loss when regular fibroblasts are replaced by fatty tissue. This signifies a decreasing clonogenic potential. The telomeres become shorter, telomerase activity drops, and the population of differentiated cells diminishes. But there's a host of other adverse developments involved: the repair processes work poorly, mutations build up, and the cells are not in good shape. Our aging process is not associated exclusively with telomeres and telomerase. There are a multitude of other factors at work, having to do with regulation of different processes, translation, accumulation of all kinds of nonconforming molecules, and so on.

— What are some notable recent papers on the subject? Where are things heading at the moment?
— The general trend is heading towards a healthier lifestyle. Avoid sweet foods, do plenty of exercise, and try to avoid unhealthy habits. Since we mentioned sweet foods: EFKO has this project promoting sweet proteins, which can be added to ice cream or soda as a sugar substitute. You need 1000 times less of this stuff than you'd need sugar. And it's just as sweet as sugar and digests like meat. Mental activity also plays a role. No wonder Russian Academy of Sciences members have the most longevity. These people are mentally active all the time, they never lounge on couches or wander aimlessly, their mind is working tirelessly on scientific problems, and they have goals to aspire to.

— A substantial portion of your work is related to non-coding RNA. What is it and why does it seem to be such a hot research topic worldwide?
— Non-coding RNAs are their own universe. In and of themselves, they regulate pretty much everything. This is indeed a substantial part of our work. At Skoltech, this branch of research is represented by Olga Burenina who has discovered a bunch of new non-coding RNAs that can be used to obtain accurate cancer diagnosis. As we demonstrated with telomerase RNA, many RNAs are able to encode peptides. Sometimes encoded peptides influence regulation.
Skoltech grad student Nikita Shepelev, teaming up with our former grad student Pavel Baranov, who is now a bioinformatician in Ireland, has searched for unusual peptides in the non-coding regions of mRNA, the new area we are now currently exploring.

— How did RNA become such a hot topic in the first place?
— The traditionally recognized non-coding RNA is structural RNA. Over the past decade, however, evidence has surfaced suggesting the existence of other RNAs, and those RNAs regulate practically everything. The classic example of a small non-coding RNA would be microRNA, which regulates translation, and which you can harness to selectively kill or block a specific matrix. This is now a potential strategy for treating all kinds of diseases, especially cancer. Often, the attachment site for these microRNAs is not just one, but a whole class of RNAs that control a particular function in the cell.

— Is it possible to target cancer cells without affecting healthy tissues?
— It's possible. An array of such RNAs can selectively destroy cancer cells while causing minimal harm to healthy cells around. RNA technology is currently on the rise, and we owe this partly to the COVID pandemic. The mRNA vaccines were a triumph for RNA research, and this triumph has far-reaching implications. Essentially, you can program your immune system in a sense.

— How does it work in real life? How do you get it to function?
— You take the mRNA you have synthesized. You encapsulate it in the appropriate particles that go into the cells. The mRNAs then leave the particles, get translated, and the proteins encoded in them are left to degrade inside the cell. Every cell has histocompatibility arrays that bind the peptides and start to manifest them on the cell surface. The immune system then realizes something is amiss in the cell when foreign peptides appear on its surface, triggering a response to identify the foreign peptides. In theory, you can alert the immune system in a special way to specifically recognize these “wrong” cells. This is a cross functional platform designed to eliminate diverse pathogens. There's research in progress worldwide to perfect this strategy to a level where it can be deployed to treat a broad range of diseases. These are the discoveries that await us in the near future.

— Do such experimental drugs exist?
— I believe they would exist in the companies that have produced mRNA vaccines. At least I would do such a thing. They have forward-thinking people working there. We'll read all about it in the media in the next couple of years.

— Does Russia have an mRNA vaccine research program?
— Oh, absolutely! The Institute of Bioorganic Chemistry of the Russian Academy of Sciences is implementing a Ministry of Education and Science project on mRNA vaccines, coordinated by the aforementioned Maria Rubtsova. Novosibirsk has some tried and true strategies, concentrated in the company run by Vladimir Richter. It's actually a collaborative effort. They've developed the processes to synthesize all the required components. Now it's a question of funding. Speaking of the furtherance of vaccine science, we will certainly need it going forward. This goes beyond merely addressing the COVID problem. A cross functional platform is needed to be developed for eliciting a specific immune response in an individual person. This is something that Russia really needs, it's absolutely essential.

— How many research teams do we have working on this?
— Very few.

— What are the priority areas for investing research resources, technology, and hardware?
— For starters, there has to be someone who needs all this. Projects of this nature never come alone, as an isolated initiative. The creators of mRNA vaccines had to work long and hard to prove their product is important and much needed. Then the pandemic came, and suddenly everyone demanded vaccines. The technology itself is quite unique. It delivers mRNA to the cell, but any RNA can similarly be delivered, and you can change the vesicle composition. This opens up entirely new opportunities. We could deliver microRNAs, blocking RNAs, and so on. There are plenty of excellent solutions in need of a solid delivery system, the more specific, the better. I have to admit that epidemics give a powerful impetus to similar technologies. RNA technology is a vast domain. We've only seen the tip of the iceberg, with the rest of it yet to surface.

— What did RNA do for the emergence of life on Earth?
— RNA has what it takes to nurture life into existence. But frankly, I suspect we owe life on Earth to the accidental infiltration of some alien bacteria. The transition from DNA to RNA to protein is just so prohibitively complex. I get it all, but I just can't wrap my mind around the translation process. I get a much clearer picture with bacteria and evolution.

— What groundbreaking scientific discoveries do you look forward to?
— The regulators complex. When you get into it for real, you realize it's a vast domain with numerous subdomains. You have intercellular signaling, passage of nerve impulses to their destination, and you have RNA, proteins, and vesicles involved in all of this. Perhaps we could find out how cells communicate with each other. From a practical standpoint, it's more RNA technologies. The two recent success stories are CRISPR/Cas and the mRNA vaccine. I'm positive that they are our future. I don't just mean the ones already mentioned. Many new RNA application concepts are on their way.