Russian Science Foundation: Neuroscientist Raul Gainetdinov: ’The Foundation’s support helps us work at the world level’

Professor Gainetdinov, could you please explain what the brain is from a neuroscientist’s perspective? How well-explored is it?

The brain is, first of all, chemistry. Neurochemistry, to be more exact. It is an incredibly complex system with billions of chemical molecules that relay signals from one neuron to another. Then, all is transformed into impulses and physical processes begin, so a vast combination of natural sciences is involved in the study of the brain. I would say that it is completely unexplored. We are lucky if we know at least two percent of what the brain is. This is maximum. In recent years, approaches to the study of the brain have changed. In the process of the genomic revolution, the most powerful genetic methods for studying processes in the brain have appeared. Due to the fact that it became possible to turn genes on and off, and to express some markers of specific neurons in specific places, we have developed new tools that enable us to reach a new level of understanding of such an intricate mechanism of work. Yet our brain still keeps many secrets.

You are studying brain diseases associated with dopamine neurotransmission. These include Parkinson’s disease, schizophrenia, bipolar disorders, and others. What is the reason for their high prevalence in the present-day world?

Neurodegenerative disorders are mainly diseases of the older generation. As life expectancy is increasing worldwide, there are more older people and the more brain diseases such as Alzheimer’s, Parkinson’s, and so on. The stressfulness of life has also increased significantly. This causes nervous breakdowns, depression, and anxiety. For example, the COVID-19 pandemic has caused a surge in psychiatric illnesses worldwide. And the latest geopolitical events do not reassure people at all either. Unfortunately, the trend shows that the situation with the incidence will only get worse.

Did you start exploring dopamine with a purpose of defeating these disorders or just by chance?

After graduation, I came to work at the Institute of Pharmacology of the Russian Academy of Medical Sciences and was employed by a laboratory led by Kirill Rayevsky. He was engaged in the development of new antipsychotics, which were called neuroleptics then. I immediately joined the work on the creation of drugs for the treatment of schizophrenia. Every day, I measured the level of dopamine in experimental animals in different states. I grew fascinated with dopamine and gradually became an expert in these measurements.

Kirill Rayevsky was an internationally recognised person. He began to take me on business trips with him. As a result, at quite a young age, I met the leaders in this field, the scientists who had discovered dopamine receptors. I knew Arvid Carlsson, a Nobel Prize winner who had discovered the role of dopamine in the brain. He became one of the first scientists to prove the link between dopamine deficiency and Parkinson’s disease. I knew Oleh Hornykiewicz who had proposed the most effective anti-Parkinsonian medication titled levodopa.

I finally ended up at a laboratory of Duke University in the USA and became a student of a man who was an undoubted authority in the study of dopamine. His name was Marc G Caron and he was an outstanding scientist. Caron passed away last year, but he is still number one in dopamine. Marc G Caron combined work in biochemistry and work with animals. Such people are rare. I came to Caron’s laboratory as an animal expert, but over the years I mastered many biophysical, biochemical, and molecular biology approaches. My second teacher at Duke University was Robert (Bob) Lefkowitz, who was awarded a Nobel Prize in 2012 for the discovery of the G protein-coupled receptors, GPCRs. Those two laboratories worked as one. Bob and Marc discovered the first such receptor together, and now there are more than 800 ones known. Unfortunately, Marc was not awarded a Nobel Prize which he by all means deserved.

You are developing fundamentally novel drugs for the treatment of neurodegenerative and mental diseases. What is the point of your research?

A research team led by me is looking for new antipsychotics. These drugs are used to reverse psychoses. All antipsychotics that are currently used in clinical medicine block the dopamine D2 receptor responsible for positive emotions. However, they often cause severe side effects. Such drugs do remove psychosis, but at the same time people lose the pleasure of life, or such therapy may lead to obesity. We are looking for a drug with no side effects, which will become a game-changer in psychopharmacology. The key concept here is trace amines. These are analogues of dopamine that are present in our body in small concentrations, which is why they are called so. Although scientists have known about these substances since the 19th century, they could not understand their role in the brain for a long time.

The key to trace amines was found when their receptors were discovered. These are sensitive molecules that you can influence and thus regulate the level of dopamine. The human being has a total of six trace amine receptors. For more than twenty years, I have been studying the capabilities of this influence, first in the USA, then in Italy, and now in Russia at the Institute of Translational Biomedicine of St Petersburg University. Our institute has been created using a grant from the Russian Science Foundation.

The most studied receptor is TAAR1 (Trace Amine-Associated Receptor). As an antipsychotic, we are promoting TAAR1 agonists. These are chemicals that stimulate this receptor. We use mice and rats with turned off genes responsible for different receptors. We injected TAAR1 agonists into model animals that had a lot of dopamine, and they immediately calmed down. It was very convincing. So, with the help of an agonist substance, psychosis can be prevented. By affecting TAAR1, we change the function of the D2 receptor. This is not a direct path, but a very elegant one. We "approach" from the side and remove severe side effects. Now, we are working to ensure that the knowledge gained at our scientific laboratory could help people as soon as possible.

Is this "as soon as possible" a matter of the coming years or the distant future?

It is a matter of the coming years. The last stages of clinical trials are now underway abroad. They are carried out by two pharmaceutical companies, namely Sunovion, an American one, and La Roche, a Swiss one. I act as an advisor for them. By the way, our Swiss colleagues named the drug "Ralmitaront", while the American ones use the name "Ulotaront". If you add the first two letters of these titles, you get "Raul". What a funny coincidence!

There are very high expectations from the new drugs. For example, the American company is conducting 26 clinical trials of "Ulotaront" for depression, psychosis, parkinsonism, and anxiety. That means the list of indications is expanding, because there are no side effects. So, you can try to treat other diseases. At the second stage of the clinical trials of "Ulotaront", such convincing data were obtained that it was recognised as a breakthrough drug. This leads to a significant acceleration of the launch of the drug on the market in the United States. It is expected that "Ulotaront" may be approved for use as early as this year, while our Swiss colleagues fall three to four years behind. It is generally accepted in the United States that the creation of a new drug takes about thirteen years and two billion dollars.

And what about Russia?

It is much faster and cheaper, fortunately. In Russia, it takes seven to eight years and up to one billion roubles to create a new drug. Within the framework of the Russian Science Foundation grant, we are cooperating with the Russian company "Accellena". They decided to develop this scientific direction together with us. We have found an active compound and made some serious progress in it, as we see a very convincing effect on animals. If everything goes well, in eighteen months to two years we will enter clinical trials of a TAAR1-based drug in humans. In the coming years, a drug may appear in pharmacies that will radically change the quality of life of patients. However, there are also some challenges. In particular, it is quite difficult to obtain long term funding of such level in Russia. This is one of the difficulties of translational medicine. The longer our path to people is, the more expensive our research becomes.

Could you please tell us more about translational medicine. It is a relatively new concept. What value do you put into it as Director of the Institute of Translational Biomedicine?

Translational biomedicine is a term introduced in the United States some 15 to 20 years ago, when a network of institutes in charge of clinical research funding appeared. The point is to promptly introduce the developments of fundamental medicine into clinical practice. This implies the fastest possible creation of diagnostic methods and medications. Acceleration is achieved through the use of new technologies and the synergy of experts working in different fields of science.

Pharmacologists have always been translational biomedical scientists in fact, because they developed chemically active substances, and then tested them on animals, and then on people. For example, today it is possible to quickly transfer the results of fundamental research to animals using transgenic technology. In our animal facility, there are nine genetically modified breeds of mice and rats with changes in the monoamine transporter system. There is no other laboratory in the world working in this area that can boast such a number of breeds. With the help of directed gene mutation, we reproduce pathological mechanisms in animals. Having such a model, it is much easier to find and work out new principles of treatment.

After scientists find a working substance, it needs to be characterised very finely. It is necessary to study the pharmacokinetics, general and specific toxicity in animals in so-called preclinical studies. As the preclinical phase of the development of the drug progresses, the pharmaceutical development of production, and quality control of the active pharmaceutical substance and the finished dosage form are underway. And only after that the substance will be allowed to be tested on a small group of people in order to assess safety. Then, with a larger group, it will be necessary to select the dose and prove the effectiveness of the drug in the treatment of the relevant disease. And so on and so forth. It sounds simple, but in fact it is a very long and difficult process.

Unfortunately, in present-day Russia there are very strict requirements for experimental research of new methods of treatment. In the USSR, it was relatively easy to introduce a new drug or treatment into clinical practice. About 15 to 20 years ago, the requirements were tightened enormously by issuing a tough law in accordance with the US and EU standards. One would think it was correct. However, in the West, they still left loopholes to speed up the translational process. If people are severely suffering from some kind of disease, paralysed or in the last stage of cancer, pharmaceutical companies or clinics can easily conduct research on them if the person agrees. Everything is more difficult in Russia. There are many talented scientists here with many ideas, but difficulties arise when introducing them into clinical practice. Even just to try new experimental treatments, you need to conduct full-fledged toxicological and pharmacokinetic studies, which is very expensive and time-consuming. At present, I am also Academic Supervisor of the Pirogov Clinic of High Medical Technologies at St Petersburg University. My colleagues and I often discuss this issue and sign appeals to change the situation, at least for major research centres. If the laws are adapted, and such trends have recently emerged, then translational medicine will have good prospects, since there are motivated young people with a serious level of training in Russia.

The main condition for translationality is close cooperation of specialists from different fields of science and different countries. Do you feel such a team spirit?

I spent twenty years in the West and I know all the experts in the field of dopamine and trace amines. I am the chairman of the subcommittee on dopamine receptors of the International Union of Basic and Clinical Pharmacology (IUPHAR), the largest association of pharmacologists. The committee includes all the world experts in the field of dopamine. I am on friendly terms with them and we are in touch. We publish articles devoted to our joint research. I do share a team spirit with outstanding scientists. It has not been affected by the recent geopolitical events.

In our institute, we actively interact with each other. We are testing methods for screening new drugs; developing genetic methods for genome editing; conducting pharmacological studies on Danio rerio fish; developing new methods for treating spinal cord injury; and conducting a number of genomic and bioinformatic studies. Within the framework of the grants from the Russian Science Foundation, I formed an excellent tandem with Professor Mikhail Krasavin from the Institute of Chemistry of St Petersburg University. Unfortunately, he has recently passed away unexpectedly. He was a wonderful person and world-class scientist. Now, we will continue to work with his students.

Professor Gainetdinov, you are at the forefront of translational biomedicine in our country. Is it easy to be the first?

Being an innovator is fun. You feel as follows: here it is, the limit of knowledge, no one knows more than me in this area. I told you about only one TAAR1 receptor, but in general, there are so many new things in trace amines! It gives me pleasure to be the first in the knowledge of some area. Especially as a doctor. For me, the Hippocratic Oath is not empty words. What I am inventing now may become a new medicine or method of treatment in 20 or 30 years. It is very important to feel that you are not doing your job in vain.

What does the support of the Russian Science Foundation bring to you?

We have been fruitfully cooperating with the Foundation for several years. In fact, the Institute of Translational Biomedicine at St Petersburg University landed on its feet thanks to a mega-grant from the Russian Science Foundation. It lasted from 2015 to 2018. Initially, it was supposed to establish five laboratories, but gradually we grew up to create ten. Thanks to funding from the Russian Science Foundation with the support of St Petersburg University, we equipped a modern animal facility and were able to transport a collection of genetically modified animals from Italy in compliance with the international standards. We have also published several hundred articles, including those in Nature and Science. In 2019, I started my second Russian Science Foundation grant related directly to trace amine receptors. The support of the Foundation helps us work at the global level. In 2022, I published 24 articles. This is my personal record in terms of the number of publications. In the United States and Italy, I was not as productive. It seems to me that interaction with grant recipients in the Russian Science Foundation is very well developed. I would not like to change anything here.