— Let's start from the beginning. How did you become a biologist?
— It runs in the family. Everyone in my family works in medicine. My father is a chief doctor. My mother is a deputy chief doctor of a children's clinic. One of my aunts heads a hospital department, while my other aunt is the chief pediatrician of Bashkiria. As for my uncles, one of them heads a department in a clinic, while the other is in charge of emergency services in Ufa. I was raised in that “medical family”. We always celebrated Medical Workers’ Day with great reverence, and from an early age, it was clear that I was destined for a career in medicine. However, I knew that I didn't want to simply sit in a clinic and treat patients. I was interested in conducting research. I couldn't put it into words back then because I didn't know such a thing existed, but it just felt right — medicine as a science.
Then I got lucky. I ended up enrolling in the biomedical faculty of the Pirogov Russian National Research Medical University in Moscow, where they specifically trained medical researchers. I graduated from it with a degree in medical biochemistry, but not a medical degree per se, I didn't have the right to practice medicine. I’ve achieved what I aspired to at 14. It was a robust education: five years of chemistry and biology, five years of math, five years of physics, and everything else a scientist needs in addition to medicine, which we studied for six years like all medical students.
After that, I immediately started working as a junior researcher at the Institute of Pharmacology of the Russian Academy of Medical Sciences, in Kirill Raevsky's laboratory. He was an extraordinary scientist. He worked on antipsychotics that block the D2 subtype of the dopamine receptor. At that time, it was the best dopamine lab in the country! I became fascinated by dopamine. I started measuring it in different situations and reading literature on the topic,  and it all took off from there. And I am just that lucky  – dopamine has been my main area of interest ever since, starting with my thesis, which involved measuring dopamine in different structures of the brain.

— So that lab was your goal from the start?
— Actually no, I ended up in that lab accidentally. I wasn't particularly knowledgeable in molecular biology, which was the trend at the time and the field of choice for the top students. That, and genetics, of course. Also, our Institute of Pharmacology wasn't too highly regarded, so, like my family, I chose something closer to medicine, the "boring" field of pharmacology.

— Why do you call it boring?
— It is generally considered less glamorous. It might seem that all your work consists of fairly routine pharmacological tests. The odds of you being the one to discover a substance that will be utilized by millions are slim. Citation rates in pharmacology are also lower. But I regret nothing. I found my true self when I started studying dopamine. It was fantastic. As a young man, I personally knew all the pioneers in the field, including Nobel laureate Arvid Carlsson, who unveiled the role of dopamine in the brain, and Oleh Hornykiewicz, who first suggested using levodopa for Parkinson's disease therapy . That drug has been the gold standard since 1958. I was acquainted with all of them even before my departure to the States thanks to Kirill Sergeevich [Raevsky], who took me to international conferences in those years. It was a tremendous source of knowledge and inspiration.
In 1992, I defended my PhD thesis and spent another four years fighting for the chance to conduct scientific research in Russia. The 1990s were quite an era. For three years, I sustained my lab on a "grant" money provided by MMM.

— Did Mavrodi actually provide you with a grant?
— No, it certainly wasn't Mavrodi who granted me funds for scientific research. I got involved in MMM quite early, took a risk, and managed to withdraw money. And it was that very money that I used to support my team and family for three years. By 1996, it was clear that working in Russia was no longer a possibility. My team disbanded, and I made my way to the United States, to Duke University, to work with a man named Marc Caron. To our great regret, he passed away last year. I considered him then, and still do, as the top expert in dopamine research (after Carlsson). He was an extraordinary scientist with a broad range of expertise, equally proficient in pharmacology, animal behavior, and molecular biology. At that time, there were no other experts like him. No one could talk about all those topics at a high level simultaneously. He would ask, "Have you conducted that particular behavioral test on animals?" while also discussing receptor mutations and their biochemical characteristics. I was greatly impressed when I met him at a conference, and I decided then that if I were to work with anyone, it would be with him.

— So you didn't send out dozens of postdoc applications like people do nowadays?
— No. Moreover, I have two amusing stories about my employment there. Marc was originally from Canada, but at that time he was entirely based in the States. Unaware of that, I wrote him a letter expressing my desire to work with him, but asked if it could be arranged in Canada instead of the US. I can only imagine how much he laughed at that — and here I thought that he had labs in both Canada and the US. His response was: come, but unfortunately, it has to be in the States.
And here's the second story. I sent him that letter in February, around the same time he published a groundbreaking article in Nature. That requires a bit of backstory. It was shortly after knockout animals had emerged: the first was created in 1989 by Oliver Smithies, who later received a Nobel Prize for this achievement. Scientists began to explore the potential applications of those animals in physiology and pharmacology. Immunologists were the first to join the knockout race. For them, conducting experiments was simpler, all they needed to do was take blood samples and perform lab tests. Hence, they were the first to utilize those technologies as disease models. Our approach is different. We need to study behavior and gather statistics, which is why neuroscientists were initially quite skeptical about knockouts... until Marc Caron's article in 1996. The article discussed mice with a knocked-out dopamine transporter, which resulted in an abundance of dopamine and made the mice behave as if they were on cocaine by eliminating the dopamine reuptake mechanism — exactly what cocaine and amphetamine do. So, Marc created his "genetically-high" mice, surprising all neurophysiologists and pharmacologists, who didn't know such a technology existed, and leading them to question Marc about the increase in dopamine levels. As you may recall, my specialty since my graduate thesis has been measuring dopamine levels. So when Marc received my letter, he assumed that I was interested in his mice and thought that he could use my skills. However, at that time, Russia was far behind the rest of the scientific world, so I didn't even know about his article! It was simply a lucky coincidence, or rather a very lucky one. I joined Marc, and we started working together on that very hot topic, eventually publishing over 100 articles featuring those mutants.

— It was a lucky coincidence, indeed!
— Yeah! I quickly became an Assistant Professor at Duke University. When I left 12 years later, Marc had 47 knockout lines in his lab. For comparison, I currently have nine in St. Petersburg, and I'm already full. And he had 47! Maintaining and caring for them is both expensive and challenging. It was pure bliss, a scientific paradise where any idea could be tested immediately. If you suspected that a certain protein was responsible for something, you could check it right away.
However, due to scientific inflation, the cost of maintaining so many lines had eventually become unbearable, even with the support of two or three grants. It wasn't a shared-use core facilities center, but his personal lab, and he bore the costs for its unique infrastructure. The maintenance cost was around $30,000 per month, and I believe it has doubled since then. That era was the golden age of using knockout lines in pharmacology, much like the Augustan Age of poetry.

— Are we talking about rats or mice?
— Rats are always preferable, but they are more difficult to work with. At that time, technologies for targeted mutations were only available in mice. Mutant rats only appeared later when the CRISPR-Cas method for genetic modification was introduced. Even now, few people have them due to inertia, as most equipment has been designed for mice. From a psychopharmacological perspective, rats are superior as they share many similarities with humans. Rats are highly intelligent creatures, which is crucial for our cognitive abilities research. Rats allow for the study of more nuanced behaviors, and their behavioral repertoire is significantly larger. Indeed, when knockout mice were introduced, many cognitive scientists argued that mice were too primitive for cognitive studies. Historically, cognitive experiments have always involved rats.

— It appears we've gotten way ahead of ourselves without giving proper definitions. What exactly is knockout and why do we need it?
— Good question. A knockout is a genetic technique used to deactivate a specific gene. The animal remains healthy and generally feels well, but one specific gene is eliminated, hence the corresponding protein is also absent. It enables us to use those animals as excellent models for certain human diseases and to test potential therapy techniques on them. Currently, such modifications are performed using the CRISPR-Cas method, although previously other techniques were used, all with the aim of deactivating a specific gene.

— So, knockout is the tool. But what is the ultimate goal?
— I personally need knockouts for a very specific task — to identify new targets for pharmacological interventions to alter brain states. I use knockouts as models for various disorders and diseases, such as schizophrenia and drug addiction, which are associated with high levels of dopamine. I'm searching for medications that can influence that target in mice. If it proves effective in mice, then it can be tested on humans. There are various models available. I have rats that produce high levels of dopamine, and some lack serotonin. My primary focus now is on trace amines.
I refer to them as the cousins of dopamine, with which they have similar structure. They were discovered before norepinephrine and dopamine, but their functional role remained unclear.
The picture became somewhat clearer when their receptors, which belong to the GPCR class, were discovered. The discovery was made by Bob Lefkowitz in his lab at Duke University, earning him a Nobel Prize in 2012. Marc Caron was his first postdoc and later opened his own lab nearby, but essentially the two labs operated as one. Bob and Marc shared adjacent offices throughout their careers. I had the privilege of working closely with both of them and consider them both my mentors. Caron was particularly renowned for his work with dopamine receptors, which also belong to the GPCR class. He cloned two of the five known receptors, but unfortunately never received a Nobel Prize. So, they discovered the first receptor — the beta-2 adrenergic receptor, activated by adrenaline — and boldly stated in their Nature paper that there would be many more such receptors. But there turned out to be more than 800!!! They could never have imagined, not even in their wildest dreams, that there would be so many. As much as 4% of the genome turned out to be GPCRs. What it means is that we have a total of 20,000 genes, and over 800 of them are GPCRs, which play a significant role in our body's functioning.
For instance, histamine GPCRs, opioid receptors, adrenergic receptors, serotonin receptors, dopamine receptors, and so on — they are all in charge of transmitting the signal from outside the cell to the inside of the cell. It is a vast field of knowledge, and it is reflected in pharmacological areas as well, — up to 40% of all compounds used in clinical practice either activate (agonists) or block (antagonists) some of the mentioned receptors. For instance, all known antipsychotics (more than 40 at the time) block dopamine D2 receptors.

— Is that where we get back to trace amines?
— Precisely. There is a great deal of research being conducted in the wake of interest in that topic. Notably, new GPCRs for trace amines — the cousins of dopamine — have been discovered. They were classified as so-called orphan receptors because the chemicals that could activate them were unknown at that time. In 2001, when they were discovered, Marc and Bob essentially handed that topic over to me, and I've been working on it for more than 20 years now. As it turns out, humans have six subtypes of those receptors. I began studying them and started getting some very intriguing data. And since ligands are future drugs, I started collaborating with several companies. In 2007, I decided to move to Genoa, where the Italian equivalent of Skoltech, the Istituto Italiano di Tecnologia (IIT), had opened, and I took that topic with me. Meanwhile, Marc couldn't find anyone willing or capable of pursuing that topic, so I completely moved it to Italy. At IIT, I started a partnership with Hoffmann-La Roche from Switzerland, who provided us with grants for five or six years. During that period, we jointly published around 20–30 papers detailing TAAR1, the first of the six receptors. The company initiated clinical trials on a TAAR1 agonist to manage psychosis in schizophrenia. That project was a success, but it ended once they started clinical trials and no longer needed me. That's the way it works — scientists conduct only fundamental research. In our case, we demonstrated that it was a viable target for such therapy. From there on, it was the clinicians' job.
Meanwhile, I continued my research on other trace amine receptors. However, unexpectedly in 2007, just as I had relocated to Italy, an article by Nobel laureate Linda Buck was published in Nature. Structurally, they're all roughly similar, and that article claimed that the other five trace amine receptors, apart from TAAR1, were purely olfactory. Linda Buck made a bold statement that they had analyzed and found those receptors to be only present in the olfactory epithelium and not in the brain. By that time, I had already begun to study those receptors quite intensively and had knockouts ready for that purpose, so I strongly disagreed with her assertion. Yes, those are olfactory receptors responsible for instinctive smells, like the smell of organic decay or pheromones, or the mechanism by which a cat recognizes a mouse or an antelope recognizes a tiger. But what are those smells? I have an interesting story about it. My colleagues from Harvard gathered urine from 400 different zoo animals, both herbivores and carnivores, and discovered a high concentration of beta-phenylethylamine in the carnivores’ samples. Beta-phenylethylamine is a derivative of the amino acid phenylalanine. It is plentiful in meat, so those who consume meat have a lot of it. It is one of the best known trace amines. Generally, trace amines are produced through the decarboxylation of amino acids. In other words, we are all made up of 20 building blocks — amino acids — and if you remove the acid part from an amino acid, you get an amine, which is a trace amine. As a result of that amino acid decarboxylation process, there should be at least 20 trace amines. It can be either an endogenous process, using the body's own enzymes, or exogenous one, managed through bacteria. Those amines are particularly prevalent in foods produced by bacterial fermentation, such as wine, cheese, smoked meats, beer, and sausages. So we have decided to study what we consume. It seems like a fitting choice for Bashkir-Italian researchers!

— So it's a recognition system of sorts?
— Among other things. Take the immune system, for example. We have different bacteria living on our skin that are determined by the type of immune system we have. Those bacteria break down amino acids, producing amines. There is a theory suggesting that we use the resulting smell to identify suitable sexual partners, essentially selecting an immune system for our offspring. At least it is what  has been demonstrated in bats. Instinctive smells also signal danger. I've mentioned predators and herbivores, but the smell of a corpse and rotten fish is also trace amines. They serve as a warning to keep us away from THAT.
That's how I ended up studying olfaction, even though I never thought I'd be involved in that kind of research. But I'm convinced that those smells are more than just odors. Linda Buck claimed that those receptors aren't found in the brain, but how did she ascertain that? She homogenized the entire brain and examined the RNA. But what if she simply diluted them in the large volume of the whole brain solution and probably failed to see that they could only be present in certain groups of neurons? What if? I've been trying to prove for years that she was mistaken: those receptors are expressed in the brain, and they represent a new target for pharmacology.

— Have you had any success with that?
— Absolutely. I've been living and working in St. Petersburg for the past seven years, and I have established the Institute of Translational Medicine at St. Petersburg University. We secured an infrastructure grant from the Russian Science Foundation and immediately opened five labs, the number that we now have doubled.  We have upgraded the vivarium to meet global standards. ThereI have knockouts of all six trace amine receptors. Some I brought from Italy, while others we purchased or created ourselves at the Transgenic Center at SPbU. Thus, we are leading the way in global science in that field, examining behavioral changes and the emotional state of mutants and gradually proving that those are new pharmacological targets. We are leaders here.

— Do you use artificial intelligence for ligand selection?
— No, we don't. We have chemists-partners who, in my opinion, solve those problems much more effectively. I had an exceptional colleague at the  SPbU Institute of Chemistry, Professor Mikhail Krasavin, who sadly passed away unexpectedly a few weeks ago. We were co-recipients of an RSF grant. He was an outstanding medical chemist. He and I discussed AI tools, and he too believed that human instinct far surpasses AI. He made predictions, identified patterns, and as a chemist, knew how to select the appropriate compound. He enjoyed taking time to sit, sketch, and ponder. He would then send us the compounds and optimize them after getting the test results back from us. Sadly, he is no longer with us, but we continue to work with his students.

— Which receptors have you managed to research and understand well?
— The first step is TAAR1. It is the most extensively studied. As I mentioned earlier, I studied one of its ligands for Hoffmann-La Roche. They invested five years in clinical trials, obtained very promising data, but unexpectedly discovered that the drug triggers a severe side effect in 17% of African-Americans. There was an issue with the enzyme that metabolizes that specific substance. They had to start from scratch. The target remained the same, but the substance was entirely different.That setback cost them five years.
However, I continued with my research. Once, I was at a conference in Quebec, Canada. I gave my usual presentation on trace amine receptors. Some attendees agreed with the statements, others didn't. It is a new research field, and not many people are familiar with it. After my presentation, I was very tired, jet lag had turned my day into night. As I was passing by the conference rooms, I noticed an open door where a speaker was discussing a new antipsychotic he referred to as a serotonin agonist. I found it hard to believe, as all pharmacological knowledge suggests that it's impossible. Moreover, he demonstrated the structure of a substance that closely resembled trace amines. I was surprised, indeed... but I went to get some sleep.
In the evening, I went to a bar with my Canadian friend Martin BeaulieuBallew. We were sitting there drinking beer when a stranger sat down next to us. As it often happens at conferences, which is exactly what makes them so great, the man turned out to be the CEO of Sunovion, an American-Japanese company valued at 4 billion dollars. We started chatting, and I asked him if they had been the ones reporting on the new antipsychotic, to which he replied affirmatively. So I told him explicitly that in my opinion it was not a serotonin agonist at all but a TAAR1 agonist. I also told him that Hoffmann-La Roche was stalling a little and that Sunovion could come out of that race victorious. He didn't believe me at the time, but three or four years later they did revisit the topic and found out that I was right, as his colleagues told me in 2019. That was when they published a paper about the new TAAR1 agonist in the New England Journal of Medicine, the most influential medical magazine out there. They ran phase II clinical trials for schizophrenia with excellent results, but most interestingly, no side effects.
They were so impressed with the whole thing that they invited me to work for them as a consultant. I helped them make a cartoon for doctors to explain what trace amines and their receptors are. I'm also involved in the making of informational materials. At every conference where they have a booth, even in our challenging times, they show a video of me talking about that receptor for the whole 10 minutes. Despite the fact that I'm from Russia, they're not afraid. I remain their primary TAAR1 consultant.
So there are now two drugs being tested based on the TAAR1 target, and I have had a hand in both. Both are still undergoing clinical trials, with Sunovion at phase III and Hoffmann-La Roche at phase II. Sunovion is currently trying to expand the range of indications: since there are no side effects, it can be given in case of depressive disorder. Sunovion has a total of 25 different clinical trials underway. Sometime last year, the official names for those drugs emerged. Hoffmann-La Roche called its drug ralmitaront, and Sunovion called its drug ulotaront. If you take the first two letters of both names, you get Raul, which is my name. That wasn't planned though, it was just a funny coincidence. I was the chief consultant to both companies.
Ulotaront is expected to receive FDA approval this year, and ralmitarone in three to four years. Ulotaront's sales potential is estimated at $5 billion over five years.

— Everything you've mentioned applies to TAAR1. And what about the rest of the receptors?
— Actually, that's what we're working on right now. I have all those knockouts, and I can see a major change in the emotional behavior of those mutants. We also have two breeds of mice for which we not only deleted the appropriate gene but also inserted a blue marker at the spot where it should be expressed. After that, we started looking for the receptors corresponding to that gene and found them — in the olfactory limbic brain. Those are the oldest brain structures responsible for emotions. So it's not just the olfactory system. The response is projected into the structures responsible for emotions, which convert instinctive scent information into emotional states. Those could be fundamentally new pharmacological agents, and that's what we're currently trying to prove.
Out of the remaining five, TAAR5 is the most extensively studied. It has been shown to be activated by trimethylamine, a substance that smells like rotten fish, and inhibited by timberol, an artificial terpene used in the perfume industry for its pleasant pine and cedar scent. And that combination fits quite well, so to speak, into the cultural aspects of humanity. Pine scents have always been used for purification. Consider funerals, Christmas trees, frankincense, myrrh, and eucalyptus in saunas, for instance. Those are all various types of conifer resins. We are deeply fascinated by that subject, and I am currently searching for other antagonists among terpenes.
We have already tested about a dozen terpenes. We found two that work, but there are thousands out there! There's such a potential! I would like to establish a conveyor system to better understand them. Again, intuition suggests that many of them are traditional remedies for a good reason. To feel better, people stroll through pine forests, along seashores lined with pine trees, and so on. It's soothing. Tar soap, resins — each plant has its own unique properties. And depending on the type, some terpenes are more prevalent than others. All of that needs to be systematized. So, the current status of our work is that we already have our own "Russian" active agonist for the TAAR1 receptor, and we are seeking an investor to develop our medication in Russia. We are still studying the other five receptors at a fundamental level, confirming their potential as therapeutic targets.

— Are you able to work at the same level as before?
— Generally speaking, yes. But of course, everything is complicated and expensive now. For instance, we are currently trying to purchase a test system that would allow us to test an unlimited number of terpenes for their activity against TAAR5. And it's proving to be incredibly expensive. The system costs €30,000 in Europe, but we are being proposed with the price of €90,000.

— What should the ultimate outcome look like?
— The hypothesis is quite simple. If we remove the rotten smell from your perception, your emotional state should improve. It could potentially be a new antidepressant, a treatment for anxiety, and much more.
It's like in that joke about Petka and Vasily Ivanovich.
Petyka says to Vasily Ivanovich:
- Vasily Ivanovich, take a bath. You reek of filth.
- But I took a bath just last week, Petka.
- Please take a bath, Vasily Ivanovich... It's unbearable...
Vasily Ivanovich goes to the store and returns with a pine-scented cologne. He sprays it on...
- Does it smell better now, Petka?
- How should I put it, Vasily Ivanovich... It smells as if... someone took a dump under a pine tree.
That's the essence of our groundbreaking discovery. The terpenes in the pine trees neutralize the smell of decay. You see, I'm preparing a speech for the Nobel Committee for when they award me a prize for that discovery.
I still believe that trace amines and their receptors offer immense potential to pharmacology and medicine. Do you remember how in Patrick Süskind's Perfume (and the namesake film adaptation), the perfumer collected the scents of deceased girls? He was actually amassing a bouquet of trace amines. That is what defines us. That is what will remain after we're gone. One day, we'll all just be a sack of skin filled with trace amines. That is what I sometimes tell my students and postgraduates...