‘We are building translational bridges’: St Petersburg University hosts a school of biomedicine for young scientists

How knock-out mice can help people

On the first day, Professor Raul Gainetdinov, the director of the Institute of Translational Biomedicine and the academic supervisor of the Pirogov Clinic of High Medical Technologies, spoke about the main areas of work and the infrastructure of the Institute of Translational Biomedicine. He also gave a lecture on trace amines and their receptors.

He explained how technology that ‘edits’ genome CRISPR/Cas9 has changed science. For example, switching off or knocking-out a certain gene of knock-out mice can make it possible to understand what exactly the gene is responsible for and how it influences functions of the body. Although knock-out mice first appeared in 1989, nowadays due to CRISPR/Cas9 the scope of work with transgene animals has greatly increased. ‘Nobody uses the old technology anymore,’ Raul Gainetdinov underlined.

Today, thanks to the unlimited capacity of CRISPR/Cas9 we can ‘knock-out’ a genome, or carry out various manipulations with a genome, in any animals, no matter if they are mice, rats or pigs. Of course, researchers are eager to experiment on primates, as they stand closer to humans in terms of evolution.

Professor Raul Gainetdinov, Director of the Institute of Translational Biomedicine   

He pointed out that in the vivarium of the Institution of Translational Biomedicine there are unique knock-out animals, both mice and rats. Their trace amine receptors are switched off (β-Phenylethylamine and structurally similar tyramine, tryptamine and octopamine), encoded by genes from TAAR1 to TAAR9. Also, there are animals with knocked-out dopamine transporter (DAT). Experiments on such animals will enable scientists to begin to understand brain functioning of humans with schizophrenia and parkinsonism. For example, studying of receptor TAAR1 in knocked-out animals has already resulted in developing a new class of antipsychotic medicine that is now being clinically tested.

Apart from this, though DAT knocked-out mice with blocked synthesis of dopamine are paralysed, they start moving in extreme circumstances, for example if placed in water. The same was observed in people suffering from severe forms of Parkinson’s disease and were totally immobilised. Studying the various mechanisms that have an effect on these mice will let the scientists work out new treatment for restoring mobility of people with Parkinson’s disease.

Three steps towards neuroprotheses

The same issue was tackled by Professor Pavel Musienko, Doctor of Science (Medicine). He is the head of the Laboratory of Neuroprosthetics of the Institute of Translational Biomedicine, head of the Laboratory of Clinical Neurophysiology and Neuro Rehabilitation Technologies of the Clinic of Paediatric Surgery and Orthopaedics, and leading research associate at the Laboratory of Pavlov Institute of Physiology of the Russian Academy of Science.  

He spoke about the three stages of research work in the field of neuroprosthetics. The first is studying neuron networks in experimental models, identifying mechanisms of their normal and abnormal operation. The most important is sensory-motor function: walking, swimming, grasping motions, etc.

Knowledge acquired at the first stage allows to go on to the next level of study: developing approaches of substituting and restoring of neural system functions. Then, having figured out where the problem lies and how to deal with it, at the third stage scientists create technologies for neuroprosthetics, synthesise biocompatible materials and produce neuronal implants from them. 

Only after going through all three stages can we get the instrument that is safe for the health and easy to use. Then, it should be clinically tested. This is what is called translational biomedicine.

Professor Pavel Musienko, Head of the Laboratory of Neuroprosthetics of the Institute of Translational Biomedicine of St Petersburg University, Doctor of Science (Medicine)

He also spoke about several projects he is currently working on in collaboration with Russian and foreign colleagues. One of the newest experimental projects deals with studying dopamine system and dopamine-associated diseases on knocked-out rats. This work allowed the start of understanding the possible influence of the dopamine system on locomotor function.

Zebrafish and their “human” brain

Not only rodents help researchers to solve complicated issues of functioning of a human body, Professor Allan Kalueff, head of the Laboratory of Biological Psychiatry of the Institute of Translational Biomedicine, spoke about experiments in the field of neurobiology on small zebrafish which are very likely to outnumber laboratory mice and rats in the near future.

These fish do in fact have a lot in common with humans. ‘Around 90% of different specimen that have an effect on fish, will have an effect on humans and the other way around. The genetic similarity between zebrafish and humans is more than 70%. However, looking at coding sequences, the level of similarity will be even higher. Biologically important homology between humans and zebrafish exceeds 80%,’ said Allan Kalueff.

According to Kalueff, zebrafish help the study of the reactions of the human body to stress, as well as to different substances (including narcotics), and to investigate their effects on brain functioning. However, the professor pointed out that zebrafish are not suited for some research, as it does not have cerebral cortex. Otherwise the zebrafish brain is amazingly similar to a human brain. Moreover, the professor added, compared to mice and medflies, which are mainly experimented on, zebrafish are much closer to humans given the overall combination of traits.

If applied to zebrafish, the relative capacity of chemicals continues, so we can use these fish as a sort of dose measurer. We can test unknown and known substances on fish and then extrapolate the data to humans and predict the influence of the substances on humans. It works almost like Mendeleev Table.

Allan Kalueff, Head of the Laboratory of Biological Psychiatry of the Institute of Translational Biomedicine

Among other advantages of the fish, Allan Kalueff named: longevity (zebrafish life expectancy is approximately five years, whereas mice’s is only around three); visibility of heart (even through the skin of fish); skin colour changing as a reaction to a different specimen; and cheapness. 

Finally, he said that the aim of translational biomedicine is to discover connections between species, which will allow to trace the origins of certain diseases. ‘In translational biomedicine we do not study humans, mice or zebrafish. We build translational bridges in order to understand better the evolution. If we manage to find any evolutionally conserved mechanisms of diseases, any old breakdowns, pertaining to mice, humans and fish, we will push the course of time a hundred million years away. And if we discover the breakdowns that can be fixed with dopamine or RNA interference, we will nip pathology in the bud,’ said the scientists.

The school for young scientists of the Institute of translational biomedicine was organised with the help of the Russian Science Foundation and the Council of young scientists of St Petersburg University. You can find the full programme of the School here.