— You graduated from the School of Biology at Moscow State University in 1995, then earned your PhD at the University of Illinois, worked at the Max Planck Institute... I'm curious why, in the early 1990s, amid such turbulent times, you chose to enroll in a faculty that implies a career in fundamental science? I'm a biology graduate myself, albeit from years later. My older colleagues shared stories about salary struggles in the early 1990s, and how cafeterias gave away free pickled cabbage and brown bread to keep the faculty alive...
— To tell you the truth, I simply had no idea what was going on. It never even crossed my mind that things could change so drastically.

— Why did you choose biology?
— I was never particularly good at math, so mathematics or physics were off limits to me. I wasn't into the liberal arts, either. Chemistry seemed too hard. So, it was either medicine or biology for me. I was terrified of medicine: it's a huge responsibility to work with people. You're responsible for whether they live or die. Essentially, I had no other options.

— Why did you focus on the brain?
— I decided to do brain research after grad school. And once you get into something upon graduation, it is hard to radically change the direction later because of the competition. Actually, it was my last chance to pick a field that I would pursue for the rest of my life. Also from a non-specialist point I’d say the brain is one of the most fascinating topics there can be.

— In popular science literature, I often come across the assertion that the brain is so forbiddingly complex that even the conscious mind, a product of the brain, is powerless to understand it. Do you agree with the statement?
— Such questions can be posed in philosophical discourse, but I prefer to take more of a pragmatic approach. All biological systems are complex. The brain, particularly the human brain, is among the most complex ones. But tools keep coming into our hands with which to investigate it, and it would be unwise of us not to try.

— Could we say that the brain is the most complex system?
— It wouldn't be far from the truth. Our other organs and tissues are also complex, particularly the more vital ones like the liver, kidneys, and lungs. But the brain stands on its own. It has a lot more functions. The brain's mission is to manage our body's interaction with the external environment and with other individuals of its owner's species.

— As I understand, your job is to study the brain at its most basic organization level, the molecular level, with additional emphasis on gene activity regulation in the brain, is that correct?
— We try to study a bunch of different aspects. But, as always with biology, our limits are set by the tools we have. When the microscope was invented, a whole new universe opened up for biologists. Then we learned to decode the genome. Now we have the tools to assess gene expression. Our team investigates the molecular composition of the brain. But we never deal with a living brain, we study a brain that is no longer active.

— A dead person's brain?
— That's right. We examine the building materials it is composed of.

— Like archaeologists at the ruins?
— Exactly! It's as if we've unearthed a building and are trying to reconstruct what went on in the building by inspecting the pipes, the layout, the forgotten tools...
To understand the dynamics of the brain, it is necessary that we compare its different states. There are three key areas of the work we do. The first is development and aging. Our brain is not endowed with all its functions to begin with: those functions develop as the brain develops. With aging, the process is reversed: some functions fade away.
Related to loss of function is the second area, the medical sphere. We can compare a healthy person's brain with that of a person with schizophrenia, depression or autism spectrum disorder, and then try to figure out which markers pertain to these disorders or which molecular irregularities could be their cause.
The third area is evolution related issues. This is where we compare the human brain with that of a chimpanzee or a more distant relative. In one of our research projects, we combined the ontogenetic and evolutionary approaches, gaining more insights into what makes the human brain different. And this wasn't about a fully formed brain. We looked at what makes the development of the human brain different.

— Elena, you became a successful scientist pretty early on in life. I know you went to Harvard in the 90s to pursue your scientific interests in a country where science is organized better than it is in most other places. Why didn't you emigrate?
— It would have been only natural for me to emigrate, and it probably would have been the best choice in the given circumstances. To stay was a very sentimental thing to do.

— There are some 30 trillion cells in an average human body. They all carry the same genetic information, yet some become, for instance, liver cells, while others become neurons. What's special about brain cells?
— If measured by cell number, the human brain is not the largest in the animal kingdom, but it is unrivaled in terms of structural complexity. If we get down to brass tacks, the difference between liver cells and brain cells is in the pattern of their active genes. They are supposed to branch out from the basic, embryonic level, activating the gene set that pertains to their tissue type.
Then there is also the splicing mechanism. Cells barely use it during the early stages of embryogenesis. Kidney and liver tissues hardly ever use splicing even in adult organisms, which means they maintain the same gene structure they had in the embryo.
But it looks like the brain could never become so complex without alternative regulation. The brain starts to use splicing early on in embryonic development. Most likely, this alternative splicing act enables brain structures to evolve more rapidly. Compared to even our closest relatives, the apes, human brain cells use more versatile forms of splicing.

— The methods your team uses in brain study gained mass application quite recently. These are technologies known as "omics". These disciplines include genomics (study of gene activity) and transcriptomics (tracking mRNA remnants in cells to determine what genes were active there and what they did). What could these methods reveal if applied, for example, to my brain? Would they diagnose me with a mental disorder if I had one?
— They could reveal quite a lot. But normally it is impossible to take a brain tissue sample from a living person.
Just think about it! We have studied such common mental disorders as schizophrenia, depression, and autism for over a hundred years, and we're still none the wiser about their molecular mechanisms. When something goes wrong, we don't even know why or how it happened.
Once we had high hopes for genetic research. We thought it would shed light on those very mechanisms, given that all these disorders have a large hereditary component. If a twin gets diagnosed with a disease, there is a likelihood of about 50% that the other twin will get the same diagnosis. This is a really high heritability rate. Although schizophrenia research has been conducted on over half a million people, the cumulative genetic effect that could be linked to the risk of schizophrenia accounts for a mere 7% or so of the risk. That's nothing!
This 7% does not signify the extent of the risk of developing schizophrenia when you have a genetic marker. It signifies that the person's chances of getting schizophrenia are 7% higher than the average for the given population.

— Researchers have identified many genetic markers for schizophrenia, haven't they?
— That's exactly the problem. There are too many. If we add them all up, the cumulative effect will amount to 7%. But if you consider an individual marker, even the most salient one, it will account for about 1% or even less. This is unfortunate for two reasons. On the one hand, it hinders our ability to diagnose early and help people. On the other hand, it prevents us from understanding the primary causes of the disease.

— A cheek smear will make everything clear at once...
— But this is not only about diagnosing. We want to understand how to treat the disease, how to prevent it, and what precautions to recommend that people practice from an early age in order to stave off the disease.

— So genetics appeared to be little help. How about molecular research?
— In genetic research, it isn't a problem to take half a million cheek smears. The genome is identical in all cells, so we can match and dig for markers. But when it comes to molecular research, you can't harvest half a million brains and fully study the billions of cells in each one... When you're not looking at genetic data, each cell looks different. This instantly complicates the task, and not by orders of magnitude, but times billion.

— What if one relies on some mean value, say, studies a piece of cortex?
— That's exactly what has been tried to be achieved. The existing research, and there are quite a few of them, zoom in on very specific regions of the brain, such as some parts of the prefrontal cortex, just because, from a psychiatric perspective, those areas are most likely to play a dominant role in the progression of schizophrenia.
And that's another problem. To compare it to geographical discoveries, let’s imagine Europe and let’s say it has been thoroughly explored and mapped in meticulous detail. But other parts of the world? Everything is uncertain there. For all we know, they're inhabited by monsters. That's more or less the current state with the study of psychiatric conditions. The brain works as a system. It is hardly possible to figure out what's wrong with the brain by studying a little piece of it. That's why we've been trying to broaden our research geography, perusing many different regions of the brain.

— It's like working on a jigsaw puzzle, isn't it? A piece here, a piece there...
— It's a fitting comparison. We have examined the lipid composition of the membranes in 75 brain regions, and observed gene activity in 35 regions. After that, I believe we are starting to notice the changes that come with schizophrenia.
There are neuronal and glial cells in the brain. Their balance changes markedly in schizophrenia patients. We assume that the imbalance may be triggered by a specific combination of regulatory factors. This is merely an assumption. But since we register coordinated changes across many regions of the brain, we are equipped to analyze and identify the key players that appear to be the regulators. If the changes look coordinated, there must be a coordinator. We can sift through the regulatory factors to identify the suspects and make a list of them. It's too early for an indictment, but at least we have a list of suspects.

— What are some other diseases we can make similar lists for?
— We plan to study the brains of persons with depression. We worried at first, thinking that maybe depression doesn't involve any obvious molecular changes in the brain, unlike schizophrenia. But our preliminary findings indicate that the brain undergoes significant changes in depression as well, so our next task is to compare the two diseases.
And at this point we run into yet another problem. There are no molecular or other biological diagnostic tools in psychiatry. It's talk therapy, and sometimes it is difficult to state conclusively whether one person has schizophrenia while another has depression. It's always a set of symptoms. People with schizophrenia will also manifest depression symptoms, and possibly auditory hallucinations as well. Huge tomes are written to aid with diagnosis. It's kind of like identifiers in botany: the leaf is this shape or that, five petals or six.
But in botany, at least those attributes lead to unequivocal identification. Here, you might have six petals but the leaf will be a completely different shape. Go and classify that! Perhaps the molecular research we are doing and planning to do will help us understand just how different those diseases are.

— So what about my brain? What can you say about its molecular composition?
— In this case, we should try to analyze not the brain, but some other data we can collect. As we have noted before, a cheek smear won't be much help. Fortunately, our blood plasma is teeming with metabolites, including lipids, which are the key component in the brain membranes. The lipids go through the blood-brain barrier and end up in the plasma. They may be able to tell us more about physiological states.
The current blood work — cholesterol, triglycerides, sugar — is far from comprehensive. You can't say that the doctors and biologists have tested all the compounds found in the blood, identified those that are indicative of something important, and discarded all the rest as irrelevant. That is not the case. It makes sense to screen your blood plasma for compounds that can tell you something about your brain.

— So this wouldn't be a targeted search, but rather a screening and comparison?
—That's just one of possible strategies. Well, blood plasma is a questionable source of data on the brain as it reflects what goes on elsewhere in your body, not just your brain. A lab in Pennsylvania has found out that specific lipids start to cross the blood-brain barrier in the event of a critical brain hypoxia.
So it's more of a police line, really, than a wall. And sometimes the officers there feel disgruntled, perhaps their salaries have been delayed or the food was crap in the local station cafeteria. And this begins to tell on their performance. And then all sorts of things can sneak in that aren't supposed to cross the blood-brain barrier. Hypoxia markers are already used in practice. In the event of severe brain damage from drowning or suffocation, you can see it in the blood. This way you can figure out how badly the newborn's brain has suffered from hypoxia, which sometimes accompanies childbirth. There are specific markers, cardiolipins, that only appear in the blood plasma when the brain is severely damaged.

— Do similar markers exist for the disorders or other manifestations of higher mental functions?
— Some 20 labs are working on this, which isn't so many for the entire world. Our team has recently joined this research effort. We have studied a number of disorders characterized by distinct manifestations, certain malfunctions in the brain. Those disorders were schizophrenia, depression, and bipolar disorder. We've filled a panel with a few dozen potential markers that can help detect a risk, not specifically of schizophrenia, but of any mental disorder, with an accuracy rate of over 90%.

— So, in theory, when I go to my local outpatients' clinic to do my blood work 25 years from now, the doctor might tell me to go into psychiatric therapy, right?
— It may come sooner. I'd give it five to ten years at the most. But the presence of a marker will never be tantamount to a diagnosis. Because it cannot be ascertained with 100 percent accuracy. To my regret. Try telling any of us to go see a therapist or a psychiatrist, who's really going to go? It's another thing if markers of schizophrenia have been detected, so one would better get checked.
This is not to identify some potentially socially dangerous individuals. Schizophrenia doesn't show symptoms every day, and in some instances, the acute phase can be kept fully under control. However, the condition of many schizophrenics deteriorates over time, eventually degenerating into full disability. This poses a problem for the person, their family, and society overall. We end up losing a healthy, active member of the community.

— You've studied the human brain most of your life. You know several orders of magnitude more about the brain than an average person ever will.
— That's a disputable statement. I know a thing or two about some aspects of the brain functioning.

— Has your knowledge of the brain ever helped you in managing your own life? Any life hacks to share?
— My work to date has been somewhat far removed from practical advisory. The important point to keep in mind is that our brain is part of our body, not an isolated system. If we want our brain to remain in good shape, we ought to take care of our general health.
The other aspect is that our brain is a dynamic, constantly changing system. Its raison d'etre is to adapt our behavior to the necessity of interacting with the world outside and other people.
However, the brain lacks the ability to distinguish between the actual external environment and illusions. To our brain, what it sees on the TV screen is just as real as what happens in real life. The more tenuous the ties between our vision of the world and the actual reality, the less sound our reactions will be to the real world.
The same goes for abstract thinking, for instance. If we fail to give the child the right information at the right time, or we don't let the child manifest the appropriate activity that would get inside their brain and form a skill, it will be too late after a certain age. For instance, kids older than 7 or 8 will never learn to speak a foreign language without an accent. That's because a different department of the brain is responsible for this.
When we are born, our brain is essentially a tabula rasa. The intake of external information triggers a cascade of skill-shaping processes. If no information arrives, no cascades will be triggered. These aspects cleared up for me when I started studying the brain. I have to say, there's a lot more that we need to learn about the brain before we're able to tie molecular aspects to behavior.

— I meant to ask you something. I happen to fall in love recently and at times my brain feels just like cotton candy. I can't think. What's going on in there? Is it the proverbial oxytocin doing this to me?
— If science could get inside your brain, maybe it would figure out what goes on in there during your different states of mind. Molecular neurobiologists lack methods to do that. CT scanners have too many limitations, like poor spatial resolution, for instance. As for oxytocin and serotonin which you mentioned, what we know about these molecules we know from studies on rats and mice…

— Elena, you get so many things done. Is there anything you don't have time for?
— The pandemic left me no time to feel lazy, I even only had time to read on weekends. Frankly, my favorite thing to do is to do nothing: just lie in bed, reading or daydreaming. Gelfand told me he owed his most notable discoveries to laziness. More than once, feeling too lazy to get up from the couch and grab a reference book, he would start reconstructing some formula only to stumble on a new solution. I, too, think it's important to know how to be lazy. It's probably the best thing in life!