— Eugene, how do you identify yourself? What do you call yourself when people ask you about your identity as a scientist? A biologist? A bioinformatician? A molecular biologist?
— I wear different hats. But I'm certainly not a bioinformatician. I prefer to identify as an evolutionary biologist. I guess it may sound silly in Russian. The correct term would probably be "evolutionist" or something.

— Here we go! Evolutionists, creationists...
— Exactly!

— Is it a trendy field of science?
— How should I put it... Generally speaking, it seems to be quite trendy now. In the last 20–25 years, things have really changed thanks to genomes, high-throughput sequencing, and experimental evolution, and this field of science became quite popular... But maybe it's just wishful thinking. Anyhow, this area of study has definitely become respectable. When I started out about thirty years ago or so, it wasn't like that at all. But now it definitely is.

— Ten years ago, my student Anna Lubetskaya and I compiled a list of all bioinformaticians, that is, everyone who published in journals with the word "bioinformatics" in the title. Then we collected all their articles, including those in non-bioinformatics journals, gathered all the keywords in those articles, and assigned a weight to each word for each given year based on their comparative frequency of use. We then assigned each bioinformatician the total weight of the words they used in their articles each year. If the resulting sum was positive, we called it vogue, and if it was negative, to avoid offending anyone, we called it vintage. And guess who turned out to be the most vintage author?
— Yours truly, of course!

— Exactly. So I guess it's not a trendy field of science after all.
— I'm not sure you would have gotten the same results now. I think that in the last decade this field has been coming to the forefront. I'm not saying that it has become literally in vogue, but it's nonetheless coming to the forefront.

— What's the balance between an inherent scientific agenda and certain opportunism in what you do? Say, a good collaboration comes up, so you act on it. Or you find use for a good piece of data or some interesting genome. Or, God forbid, a pandemic happens...
— That's a good question. Let's say it's fifty-fifty, so as not to offend anyone: I neither deny nor condemn opportunism.

— That's because you call yourself an evolutionary biologist. However, bioinformaticians are opportunists by definition.
— Yes, indeed. I hope that we also bring a fundamental component — evolutionary biology — into these opportunistic relationships. Since, you know, "nothing in biology makes sense except in the light of evolution". And we always try to follow that principle. So fifty-fifty is me being a bit flattering to myself. There might actually be 60% opportunism if you look more closely.

— What's the most interesting thing that has been happening in evolutionary biology lately? And what are you most pleased with? What were you best at?
— Let's start with things done by other scientists. Here, I'm most interested in experimental evolution. I'm talking, of course, about the works of Richard Lenski, but not only him. There are now many others. It's also incredibly fascinating to see how different phenomena — selection, fixation of something random and non-random, the so-called clonal interference, and replacement of one lineage by another — manifest in actual experiments. It's fascinating to observe.
As for my own field of study... Quite a lot has actually happened over the last five years, and I might sound a bit presumptuous here. As I said in my talk at a recent conference, I think that, to my own surprise, we've managed to basically figure out the history of viruses. How all the diversity that we see today evolved and how it is structured. Our understanding has clarified, which I myself was very struck by. Everything fits into place without falling apart. It's beautiful.

— Do you expect no fundamentally new viral polymerases to be discovered?
— I expect exactly that. I can predict which polymerases that the hosts already have could be hijacked and utilized by some fairly rare viruses (because if they weren't rare, we'd already know about it). But there are no fundamentally new polymerases, and there won't be any.
On the other hand, since we've touched upon the issue of diversity versus unity, there are all sorts of amazing discoveries in which we have participated... But not to boast too much, I should also mention the others. There is, in particular, Rotem Sorek from the Weizmann Institute. He is quite remarkable. He and I both study the diversity and evolution of bacterial immunity systems and defenses against viruses and other genetic parasites. And here we observe a number of absolutely astonishing phenomena. Combinatorial diversity is made up of a relatively small number of building blocks, which one might call elementary particles, while the number of combinations is incredibly large. It's like what happened in organic chemistry. Atoms are few, but together they make up a whole big world.

— You deal with the deepest evolutionary stories imaginable. Viruses are the most complete evolutionary reconstruction there is. The only thing deeper than that is the origin of the genetic code, which you have also touched upon.
— It's a complex but important issue. I'm thinking of speaking about something that goes even further back.

— Well, that's the deepest we can go. In normal, cellular life we can't go any further than LUCA. But with viruses you apparently do go further.
— That's not quite correct. You can look much deeper into history.

— On the other hand, you say the most interesting thing going on right now is evolutionary experiments, which study short-term and recent events. How can you be interested both in deep and shallow evolution?
— That's another excellent question. I can, and it's even much deeper than we discussed — up to theories that encompass evolution in general (not only biological). But I am interested in the entire spectrum of evolution. I like it. I intentionally live and act that way.

— On what exactly do you think we should focus our attention in evolutionary biology at the moment? What is the most fascinating point?
— It's the study of bacterial and archaeal diversity in connection with the origin of eukaryotes. The discovery of Asgard archaea, which are almost undeniably the closest known relatives of eukaryotes, is profoundly significant. And the story continues. It's entirely plausible that we'll find even closer relatives and gain some insight into how and when endosymbiosis occurred.
Metagenomics is equally fascinating. It's a quietly ongoing revolution from which an increasing number of ideas and knowledge are being drawn. Our understanding of all viruses and their evolutionary history is rooted in metagenomics. Of course, it's not solely based on it, but it is what leads us to believe that we are conducting a comprehensive sampling. There, key discoveries are made, such as a large number of bacteria and archaea that are now clearly symbionts or parasites of other bacteria and archaea. This was known but seemed incredibly exotic, and now it is quite clear that these things are exceptionally widespread but hard to detect.
It's fascinating to follow (this again relates to the field of diversity, but in a slightly different context) the discovery of various unicellular eukaryotes, which are so exotic that few would find them uninteresting. Bacteriophages, which are abundant in our guts and other places, have genes that are expressed in ways we don't yet understand. Some of the genes in these phages are fragmented beyond recognition. Sure, there are plenty of introns and inteins, but there is something else there too. Something incredibly peculiar is happening — some sort of pathways for expression and, so to speak, mRNA assembly. There is a level of molecular biology at play that we don't yet fully comprehend.

— Are there any areas of evolutionary biology or the aforementioned bioinformatics that you find uninteresting or difficult to grasp?
— The word "uninteresting" is inapplicable when discussing evolutionary biology. As for what I struggle to grasp, it's everything that falls under ‘evolution and development’, i.e., the evolution of multicellular organisms and particularly the details of their development.

— Why is that?
— It's really difficult to tell. There are factors at play like... continuity, history, and chance.

— Was there no one to perform omics research twenty years ago because you didn't find the right people, and then it just took off from there?
— Something like that.

— Evo-devo relies heavily on omics technologies.
— It didn't pan out for me. Not that I wanted it to. Besides, there was no data available. On the other hand, evo-devo involves understanding biology at a level of complexity that utterly intimidates me. I want to have at least some understanding of what we're doing. When I look at a book by Eric H. Davidson — may that remarkable person rest in peace — the diagrams I see there fill me with absolute dread. They can be drawn, but I don't believe they can be explained in understandable terms. I don't want to engage in that.

— Maybe you just don't like meat grinders.
— I'm not particularly fond of them either. On the other hand, what area of bioinformatics interests me? Frankly, there are almost no such areas.

— In this context, bioinformatics is a tool. It doesn't consist of areas, just like electron microscopy.
— I disagree. Both of them have areas of genuine, serious research. There are remarkable people who are interested in algorithms.

— Those remarkable people are doing a good job creating a new microscope for us.
— There are individuals who have rightfully earned their Nobel Prizes for creating new microscopes.

— What could a Nobel Prize in evolutionary biology or bioinformatics be awarded for?
— In evolutionary biology, probably for nothing, because it doesn't fit into Nobel Prize categories. It's neither medicine or physiology nor chemistry. As for what a Nobel Prize in bioinformatics could be awarded for, I have a very clear idea. I even have some specific insider knowledge. Without a doubt, it should be awarded for sequence similarity search programs... Sequence similarity database screening, FASTA, BLAST, and so on.

— About twenty years ago, Jim Fickett and I were debating what a Nobel Prize in mathematical biology could be awarded for, and we thought of protein structure.
— Yes, also for that to some extent.

— So should the Nobel Prize be awarded to Google?
— Michael Levitt has already been awarded the Nobel for some versions of structural modeling. Google and David Baker certainly deserve a prize too. But on the other hand, it's unfair because sequence comparison in practice, at least for now, is much more important. It's what the whole world relies on.

— Are Nobel prizes in biology actually necessary? Do they make sense? After all, it always turns out that, in addition to the two or three people who get the prize, there are half a dozen others who should also be awarded for the same discovery...
— With very few exceptions, that's how it usually goes, yes. And those exceptions happened a while ago. I think we need to be more relaxed about it. We should give prizes but not make a fetish of them. After all, it is clearly written in Nobel's will that they are given for specific discoveries or inventions. That's just the way it is. You shouldn't think that whoever got them is a great scientist and whoever didn't is not.

— Let's take CRISPR-Cas, for example. The award was given to the scientists who figured out how to use CRISPR-Cas for genetic engineering. However, prior to that, there were the remarkable people from Danisco who experimentally demonstrated that CRISPR-Cas is a form of anti-phage immunity. Before that, you and your colleagues had predicted it, and even before that, Francisco Mojica had spent a decade collecting repeats in bacterial genomes and even observed phage insertions in them. And even earlier, some forgotten Japanese researchers were the first to describe such repeats...
— Of course, all these people deserve some sort of reward.

— In other words, the award was given, as Alfred Nobel intended, not for a discovery but for an invention. However, adaptive bacterial immunity is a discovery, and it's as fundamental as it gets.
— Absolutely correct.

— So who is to be commended?
— Everyone! Certainly, another prize could be awarded for these discoveries in physiology and medicine. It's not entirely impossible for this to happen, but I find it highly unlikely. Both groups have done well. Once again, awards should be given as they stimulate progress rather than hinder it, but there is no need to fret over it.

— What should we fret over, then?
— We should fret over understanding of how the world functions.

— Is there something we will never comprehend in evolutionary biology?
— Of course! The answer is simple. We will never comprehend how life originated. We can construct a beautiful theory to some extent and develop good chemistry, but it's very challenging. Not only I, but even you won't witness it. But, theoretically, if everything goes well and humanity survives, then maybe in a hundred years we might create a functioning cell in a lab. I'm not completely ruling that out. But how it actually happened, that no one will ever find out.

— At the same time, if we manage to create a sufficiently large, autonomous, and not too erroneous RNA replicator, it seems we could consider this issue fundamentally resolved.
— That would be an enormous achievement, but who can guarantee that it happened exactly like that? Nobody. It's not like there is only one way you can make polymerase.

— You even wrote about the multiverse and the anthropic principle out of desperation.
— Not out of desperation! I did write about the multiverse, yes. I don't deny it.

— To me, this seems like a total capitulation.
— Well, I disagree... "Who says you should be happy?" Who says there is logic behind evolution? Nobody!

— As for who said that I should be happy, I can answer that. Grandpa Darwin did.
— He did say that... But if you dare to revisit the article about the multiverse, that's exactly what it says. There is one small condition, though, natural selection should have already started. A system where natural selection occurs — a replicator — has emerged. And these first replicators had to appear somehow. There are theories on how, and they might turn out to be fruitful. Some colleagues and I are trying to evolve them into a more mathematical theory about the emergence of selection before replicators.

— You've pulled me back into the RNA world again, and I'm trying to discuss the transition to the protein world. What about translation and the genetic code?
— Which is more terrifying is a matter of preference because both are almost infinitely terrifying.

— But that's exactly why the multiverse was theorized.
— Read the article, it will tell you a lot.

— Your interactions with physicists have corrupted you.
— Or perhaps improved.

— That's an interesting question, because when I contemplate something, I find the linguistic metaphor and pondering what's happening in comparison with what we roughly understand about language very useful. Incidentally, when it comes to language, there is the same unresolved question of how it emerged. And you, I believe, have never used linguistic parallels and metaphors...
— That's a bit harsh! We published an article about universal grammar a few years back. You probably haven't read it, have you?

— Eugene, you write more articles than I can read.
— Exactly! Honestly, I'm glad you haven't read it. The article, although published in PNAS is quite shallow. I won't say "bad", as that would be too self-deprecating, but it's extremely shallow. But it's a genuinely interesting topic for me. Due to my mindset or something else, and the love for literature I have, I've always been interested in linguistic analogies, metaphors, and hopefully, deeper analogies. But I've never gotten anything out of it.

— We understand that the only thing that could have come out of your love for metaphors is literature. The question is how you think, not what you write about.
— I find physical parallels to be extremely interesting. Moreover, I believe them to be not just parallels but rather foundations of the universe, if you'll forgive my choice of words. My physics colleagues and I are currently trying to construct a very general theory.

— Do you understand all the formulas in your articles written with Mikhail Katsnelson?
— That's a good question. So far, yes. But now it's heading somewhere where it requires serious effort.

— Do you have a grasp of thermodynamics?
— Do I grasp it? You know, I think I do. Including non-equilibrium thermodynamics, which is absolutely necessary.

— This year in the Bioinformatics Methodology course, I read your articles with my students. Philosophical ones. Articles about the genetic code. Articles about introns and splicing...
— Only my reviews can be called philosophical. All the other articles are very specific.

— I mean the articles that resulted from the scientific agenda, not opportunism. They wanted to pick easy articles, but I didn't let them.
— Was it a PhD or Master’s program?

— First- and second-year PhD students. From our discussions, about twenty proper tasks emerged ready to be done.
—That's excellent and wonderful. My book The Logic of Chance was largely good because quite a lot was taken from it and converted into specific research.

— Do you keep track of who took what?
— Only when it comes to my own work. I don't keep track of global literature.

— Do you have disciples? Those who have branched out and become independent.
— Yes, of course. There are few that I enjoy talking about, but they do exist.
King Jordan studies the evolution of transposons, which is thematically linked to the work he did with me. But he also studies human population genetics, which has no connection to my research. Liran Carmel, a physicist by training, is without a doubt my disciple when it comes to his work in bioinformatics and genomics. However, he has completely detached from my work and ventured into an entirely different field, reconstructing the epigenetic landscape of ancient, Neanderthal, and other genomes, achieving much success and making quite a name for himself in this area. This is very pleasing.

— What about Aravind L. Iyer?
— With Aravind, it's not that simple. From the very beginning, there wasn't much I could teach him as he already knew and understood a lot. Of course, I was able to teach him something, like the dos and don'ts of writing articles. But it would be somewhat self-congratulatory to claim that he is my disciple. The same goes for Kolya Grishin. He probably learned something from me, but not a great deal overall. And of course, Arcady Mushegian as well. Mart Krupovic was in my lab for a very brief period, just visiting. Despite this, I regard him as my disciple and take great pride and joy in it.

— I believe I know the answer, but still: if you wanted to share something with Vadim Izrailevich, what would it be?
— It may surprise you, but firstly, I recently discussed with him the virus system we talked about. In fact, he and I have just published together something closely related to it. Secondly, I talked to him about a somewhat deeper concept that I refer to as evolutionary entanglement. Like in quantum entanglement, you know...

— Yes, entanglement.
— So, I was telling him about the entanglement in the evolution of genetic parasites and mobile elements. In a way, I discovered it, and in another way, I came to a realization of it with the help of CRISPR. Defense systems are inherently formed from mobile elements or their fragments, and conversely, mobile elements recruit a lot from defense systems. This is a fundamental aspect regarding evolution as a whole.

— And what would you share with Darwin? Provided that he would understand it.
— Good question. I think he would understand everything. But what would I want to share with him? I don't think I'm ready to share anything yet. But if we manage to complete the theoretical work we are attempting with Misha Katsnelson and some others, and it would not be like spilling beer over a cat... On the other hand, I would also tell him about the theory of the origin of complexity, about Michael Lynch's work, and so on. I believe he would grasp that quite easily.

— Dousing a cat with beer?
— It's a joke, although rather important for understanding the essence of scientific work. A group of officers, including Lieutenant Rzhevsky, spends the entire day on horseback running difficult errands for the Emperor. It's hot, and the officers are all covered in dust. Generally speaking, it's tough. Finally, they complete all the errands, let out a sigh, and stop at an inn for dinner and overnight stay. Suddenly, Lieutenant Rzhevsky addresses the group, "Gentlemen, our horses have served us loyally all day. What do you think about buying ten boxes of Veuve Clicquot and washing the horses with champagne?" To which colonel replies, "Lieutenant, what a fantastic, brilliant idea. I completely agree with you. Our horses deserve it. The only issue is that we're low on money, and our salaries have been delayed. We'll be lucky if we can afford a single bottle." "...What a shame. Such bad luck. Well, let's at least spill some beer over a cat, shall we?"
By the way, it was Misha Katsnelson who told me that joke. If our work ends up being more akin to washing horses with Veuve Clicquot than spilling beer over a cat, then I'd like to tell Darwin about it.

This interview was initially published in the Troitsky Variant—Science newspaper, issue 343 of December 7, 2021.

*The media outlet has been designated as a foreign agent in Russia