Fusion of Academic Science and Practical Medicine of the Tomsk NRMC RAS. Interview with RAS Corresponding Member V. Stepanov

Tomsk National Research Medical Center (Tomsk NRMC) RAS is the largest academic medical center in Russia. It deals with issues of oncology, cardiology, mental health, genetics, pharmacology. What advantages does the “fusion” of academic science and practical medicine give? What is the role of genes in our lives? Do they manifest themselves immediately, or do they need time? Does our lifestyle affect the health of our future generations and what is the role of genes in our encounter with infectious diseases such as COVID-19? Read about this in an interview with the Director of the Tomsk NRMC, Corresponding Member of the Russian Academy of Sciences Vadim Anatolyevich Stepanov.

– Vadim Anatolyevich, tell us about the research directions of the NRMC RAS.

As you noted, the Tomsk NRMC RAS is a multidisciplinary research center. We present the main directions of modern clinical medicine and some areas of fundamental science, in particular: cardiology, oncology, mental health. Perhaps these are the main and significant diseases that a person faces in the first place. These are the problems that require study and rapid transfer of knowledge to the clinic to help patients.

Our center has three clinical areas that are implemented in structural divisions – the Institutes of Oncology, Cardiology, and Mental Health, and two fundamental areas that we are developing – genetics, in particular medical genetics, and pharmacology. Such a bundle of clinical and fundamental directions gives us, firstly, the opportunity to approach the problem of human disease and health in a versatile, interdisciplinary manner, and secondly, to carry out a close connection of fundamental research with clinical practice. We are a research, scientific center, but, at the same time, we are also a medical organization with more than a thousand beds (this is how it is customary to measure the capacity of medical institutions). This allows us to quickly translate fundamental knowledge into practice.

We carry out a variety of approaches to medical care, ranging from emergency care: for example, when a patient with a heart attack arrives by ambulance and ending with high-tech medical care, highly specialized, expensive types that are available only in leading clinical research centers.

Genetics is one of the main links between different medical disciplines, because disorders of the hereditary apparatus genetically, in a broad sense, underlie many groups, forms of diseases, nosologies, diseases. This allows us to penetrate deeper into the mechanisms of disease development. In addition, modern technologies are largely based on the technologies of genetics, molecular biology. Accordingly, genetics is the technological basis for interdisciplinary research of fundamental and clinical medicine.

Why are these areas represented in our Center? In addition to the above, it is also a historical continuity. Our Center turned 5 years old in 2021. Before that, each of the Institutes existed separately as an independent research institution, first in the structure of the Academy of Sciences, then the successors of the Academy.

Our institutes were established about 40 years ago, when there was an active expansion of science to the East, to Siberia. First, there was the Akademgorodok in Novosibirsk, where fundamental science was developed, then medical science was developed. These five institutes were established in Tomsk; at first, they were created as branches of Moscow, after a few years they became independent. It was then that it was decided that these leading areas should be developed first. And the history of development has shown the wisdom of those leaders of the Academy of Medical Sciences who made this decision. In part, the interdisciplinarity of our center was laid many, many years ago.

What are genetic diseases and what is their danger?

Genetic diseases are a fairly broad term. We can talk about at least several groups of genetic diseases, each of which has its history of occurrence. And, accordingly, its characteristics and dangers. Although any disease is a danger to health.

Genetic diseases are diseases that are inherited. As a rule, these are violations of one specific gene. The danger of these diseases is that they lead to serious consequences. If a newborn is born with a genetic, monogenic disease, it means that they have quite severe disorders, and, as a rule, this is a sharp reduction in life expectancy. With most genetic diseases, children die in early childhood, including in the first years after birth, sometimes even months, rarely living to reproductive age.

There is another group of diseases – chromosomal disorders. As a rule, they occur during cell division due to a violation of the divergence of chromosomes or some major rearrangements. As a rule, they appear immediately after birth as multiple birth defects. This condition is disabling, leading to early death, high costs of treatment.

The next group of diseases to which genetics is also related is multifactorial diseases or diseases with a hereditary predisposition. Unlike strictly genetic, monogenic diseases, there is no unambiguous connection between a change in the gene and the possibility of disease manifestation. As a rule, these genetic factors are implemented in a complex. There are many genes at work, sometimes hundreds, and sometimes thousands in combination with environmental factors. The environment here is a trigger that causes the realization of a predisposition to a disease that a person has in the body. This group includes all frequent and common diseases: heart attacks, strokes, bronchial asthma, schizophrenia… These are the most frequent groups of diseases, and they also partly have a hereditary nature. Although genetics alone is not enough for these diseases to be realized. The danger of these diseases is obvious: for the patient – a violation of the quality of their life. If genetic diseases are not treated, they eventually lead to death. This is a huge burden for society as well. The entire healthcare system deals with these diseases, a significant part of the state budget is spent on the treatment of these diseases.

There is another group of diseases where genetics plays an important role: the disruption of somatic cells – cells of the body of an adult. In some cases, for some reason, sometimes environmental, there are disruptions of the normal operation of the genetic apparatus. This leads to the fact that cells acquire an extra ability to reproduce or lose the necessary abilities. As a rule, this is one of the causes of cancer.

“Almost any disease has genetic mechanisms”

Even if we talk about completely non-genetic diseases, for example, infectious diseases, including COVID-19. It would seem that there is a completely external agent here – a virus that has nothing to do with a person, with their genome, but even in such acquired diseases, genetics plays a certain role. And indeed, there are certain genes, factors that affect the activity of the immune system, the mechanism of recognition by human cells of virus cells. In this regard, these diseases also have a certain genetic component in the composition of the host organism – in humans.

Can a person’s lifestyle affect the future generation in such a way that it will have some kind of disease? For example, do many hours at the computer form myopia in future generations, or does a bad environmental situation cause any diseases?

Giving an unequivocal answer, perhaps not. But if a person is exposed to some environmental factors: risk, stress, and others, then this affects, first of all, the health of the person itself. At the same time, their genes do not change. With which genes a person entered life, they live on with those. Accordingly, they will pass on to their descendant the genes that they inherited. This is not directly related to the lifestyle or risk factors faced by the person itself. Unless, of course, these risk factors suddenly affect the germ cells – gametes, which will be passed down from generation to generation. For example, if, say, a person lives in a zone of increased radiation, or has been exposed to radiation, this, among other things, can lead to effects not only on somatic tissues, but also generative ones, which further transmit their genetic material by inheritance.

If we talk about myopia, by and large, this disease is a phenotypic multifactorial sign. A person may have a certain predisposition to myopia. Naturally, parents can pass this predisposition to children. Specifically, it can be realized in a person if there is a large load on the eyeball – frequent sitting at the computer, looking at gadgets at every moment of your life. But this does not mean that because of this, a person has transmitted this disease to their children. They can only pass on their genes.

To be sure that a healthy child will be born, is it enough to maintain a generational connection, find out from grandparents what diseases were in the family, or are there other, more accurate methods that are necessary?

Of course, it’s wonderful to know your ancestry. And any consultation of a geneticist begins with a description of the pedigree to understand what was in the family. This will greatly help to predict what will happen to those who seek medical advice themselves, or when planning a pregnancy. But that alone is not enough. You can be completely healthy phenotypically, externally, while giving birth to a sick child. This is due to the peculiarities of the transmission of genetic information. There are a huge number of hereditary, monogenic, diseases, more than seven thousand of them are known. Potentially, there are even more of them. We have about twenty-two thousand genes in the body that encode proteins. And the breakdown of each gene can potentially lead to disease. Hereditary diseases are very rare. The most common in our country are such hereditary diseases as cystic fibrosis, phenylketonuria. They occur with a frequency of one child per several thousand newborns. At the same time, this disease is realized when both dad and mom have transferred the “sick chromosome,” a chromosome with a mutation. In the language of genetics, this is autosomal recessive inheritance. Nature, on the one hand, does not like to make unnecessary movements, waste energy. On the other hand, it lays down in advance the need for a certain variability. Genetics is the science not only of heredity but also of variability.

It is laid down by evolution that mutations occur constantly. With any cell division, gametogenesis, a mutation occurs. Otherwise, no movement would be possible. We wouldn’t have formed as a species if nature hadn’t been changing. Initially, mutations are a payment for the possibility of change, a normal function of nature. But nature also provides for certain insurance mechanisms. For example, for the disease to manifest, two recessive mutations must converge in one person. Mom may be perfectly healthy, but one chromosome is normal, and the other has a mutation. Dad can also be perfectly healthy, but there is a mutation on one of the chromosomes. They may not even see it. Themselves, they don’t need any medical procedures. If they form a family, according to Mendel’s Laws of Inheritance, the probability of their having a sick child becomes ¼. Where ½ is the probability of transmission of the “sick chromosome” from mom, and ½ is from dad. And such a mutation has never appeared in this family before.

Therefore, in addition to knowing and studying your pedigree, special attention is also needed. For example, if there were cases of hereditary diseases in the family, in this case seeking medical and genetic counseling is mandatory. The family should come to a geneticist, they will determine by pedigree, maybe make appropriate analyses of the genome or part of it from mom and dad and prompt further actions. You can make a prenatal diagnosis: during pregnancy, take the material of the fetus, see what probability it has realized.

Does this intervention harm the fetus if you take tests at such an early date?

This is a standard medical procedure, it is associated with some risk, but if such a procedure is done, it covers the possible negative consequences from the birth of a sick child. Not doing this procedure [for those to whom it is assigned] carries a much greater risk.

This is not recommended to everyone. In general, if we talk about such approaches, then medical genetics is trying to solve the issues of preventing hereditary diseases at different stages. The first is to prevent the conception of a sick child – primary prevention. And the spouses’ consultation and genetic analysis are aimed at this. The next step is to prevent the birth of a sick child if the pregnancy has already taken place.

In this case, all pregnant women necessarily undergo several stages of screening. First, ultrasound and biochemical screening in the first and second trimester of pregnancy. If necessary, invasive diagnostics, including DNA diagnostics. The third stage – if the child is born, then you need to try to correct the manifestation of the disease with special therapy.

If the people themselves who are getting married are healthy, and they have no assumptions about the presence of a hereditary disease, then this does not mean that they are fully safe. Again, according to the laws of genetics, with a very low frequency of such diseases – one in several thousand, each of us is a carrier of at least a dozen mutations. We have seen this, including when sequencing complete genomes. These are the mutations that, when encountering the same mutant chromosome from another parent, will lead to the disease. I repeat, we have at least a dozen of them, and maybe more. And even with such low frequencies of rare genetic diseases, the frequency of heterozygous carriage, when a person has one chromosome normal and the other mutant, but they do not know it and do not see it, this frequency is very high, up to 1/30 and 1/40 of people in the population. Accordingly, there is definitely a chance of encountering a mutation.

How can the “broken gene” be fixed?

This is a very important and interesting question. This is what genetics is trying to do. Firstly, it may not be necessary to correct the gene. This is not always necessary. It is possible to correct the consequences of the action of the “wrong” gene. There is a mutation, it leads to something, there are some consequences. In some diseases, it is enough to correct the actions of the mutant gene in fairly simple ways. With the already-mentioned phenylketonuria, a disease associated with a disruption of the metabolism of one of the amino acids, it is enough to conduct appropriate diet therapy: a person should adhere to a certain diet all their life, excluding phenylalanine precursors in their food. Of course, it’s not very easy. This requires certain expenses, but it is the easiest way to avoid illness.

In some cases, it is possible to correct not the gene, but to carry out substitution therapy: if an enzyme or hormone does not work, its gene is broken, we can periodically add this enzyme or hormone in the form of injection, inhalation, or something else. This is also not always possible. This also requires a high frequency of interventions. Therefore, of course, it would be better to correct the gene itself.

But in an adult and even a newborn organism, we cannot do this in all cells of the body, or even cells of the organ or tissue where this gene manifests itself. With gene therapy, we can inject copies of a normally functioning gene into the body, which is sometimes embedded in the genome and can partially compensate for copies of a non-functioning gene. You can edit it using genetic engineering methods. But, as a rule, this is done in cellular systems, in a test tube, and not in the body. In the body, it is difficult and almost impossible to do this because of the large number of cells.

Although, there is an example of successful attempts when the gene was corrected not in a test tube, but already in the body itself. For example, there is Hunter syndrome– a rare hereditary disease associated with impaired metabolism of mucopolysaccharides. This leads to the accumulation of a complex of proteins, fats, carbohydrates in cells. A few years ago, in the US, the first work was carried out on genomic editing of a fragment of the gene that is responsible for the disease in the human body itself, or rather, in liver cells – the organ where this gene is primarily expressed. They were able to edit only a small fraction of the cells there, but it was enough to get some effect. It is still unclear how lasting it will be.

I want to say that interference with the genome of somatic cells is potentially permissible. We are not harming the next generations. Theoretically, it is possible to correct the embryo’s genome by genomic editing or other technologies. Then a person should be born with the absence of a mutation towards the correction of which we directed our efforts. But so far it is difficult to implement and unacceptable for ethical reasons because, in fact, we do not know what consequences it may lead to. Genome editing technologies are becoming more and more accurate, but we are not immune from making damage that for this person can lead to other problems. And if we have corrected a gene at the stage of one or two cells, then the whole body bears traces of our corrections. And if the organism survives to reproductive age, it will pass on these altered genes to subsequent generations. So far, we have no grounds and confidence that a person can so easily interfere with the genome of a particular person so that they pass it on to the gene pool of humanity. Until we have learned to be insured against the possible negative consequences of this.

And in the case of the most dangerous diseases, is such a correction carried out?

It is carried out, but not on an embryo, but in an adult. There are other ways to try to do so, so as not to harm either the descendants of man or nature as a whole. For example, if we take monogenic diseases, then theoretically and practically we can already guarantee the birth of a healthy child to a family that has a suspicion of a hereditary disease. Not through editing, but through the selection of the right embryos. This can be done using assisted reproductive technologies, for example, with IVF – in vitro fertilization.

This is usually done by couples who have problems with pregnancy: miscarriage, infertility. If a family has a hereditary disease in the pedigree, they, in principle, can have a child in a normal way. At the same time, it is not guaranteed that the child will be healthy. All the things I mentioned earlier are required: screening, testing, possibly prenatal diagnosis. We and world science are developing technologies of preimplantation genetic testing for monogenic diseases. This means that when artificial insemination occurs, before the embryo is implanted into the mother’s body, we take one cell from it to see what has been realized there: two mutant chromosomes – then there will be a sick child, two normal ones – healthy, one mutant, the other normal – a heterozygous carrier – healthy, but can pass on the genes. This can be done, and our Center is doing it, among other things.

We have protocols for preimplantation testing of a dozen and a half diseases that have been tested and used. And we already have the first cases of healthy children being born after such a procedure. This is a guaranteed way to get a healthy baby, but difficult. Because IVF is required, maybe even several cycles. In any case, it is completely painless for future offspring and is guaranteed to give a healthy child. This is not possible for all diseases. Theoretically – for any monogenic disease. But each time this procedure requires some effort. This is a personalized procedure when a system should be developed for each specific family.

Does the presence of medical ethics somehow inhibit the development of genetics?

I would not say that this does not allow us to develop further. Rather, it gives an opportunity to develop further in the right direction. Any science should consider not only the interests of scientists but also the interests of society. The generation of new knowledge should not harm either humanity as a whole or a particular family. Therefore, ethical aspects in medical genetics are extremely important. Where does it start? With medical and genetic counseling. The duty of a geneticist who advises a family is, first of all, to deal with a specific family, a specific case, to convey information as objectively as possible, talking about the consequences of possible actions. At the same time, for ethical reasons, a geneticist has no right to prescriptively assert something, demand something. If, after a set of procedures, it is discovered that a sick child will be born to the family, then the decision to terminate the pregnancy or give birth to a child remains with the family.

This applies to any interventions at the stage of diagnosis, treatment, therapy. Everything is done with the consent of the patient or family. And gene therapy is also carried out with informed consent that the person is informed about the need for therapy, about the risks and other things, same as with any medical procedure.

If we talk about more general points, then globally, the problem of genetics is that you need to do something useful to the patient, while not harming nature and the genetic health of future generations. In particular, that’s why there are many restrictions, moratoriums on experiments on genomic editing on embryos.

There are also ethical issues in this regard. For example, personal genomes. Now it is becoming real when everyone can sequence the genome and find out all their genetic variants. What to do about it? Often, we and other geneticists are faced with the fact that when making a diagnosis of a hereditary disease, we do not always know what we have obtained. As I said, sometimes it is necessary to decipher almost the entire genome and we find some other, unknown variants that could theoretically be pathogenic. What to do about it? Should we inform the patient about this or not? If we are not sure that they are pathogenic, due to insufficient information about them, methods of treatment, or something else. This is a debatable issue.

There are other ethical issues, for example: who can be granted access to the genome? Of course, with the consent of the person. For example, insurance medicine can be largely based on genomic data, hiring or discrimination for some things in society is potentially possible for genetic reasons. Theoretically, a new QR code with our genetic variants can be “glued” onto each of us. What to do about it? Who has the right to know about our genes? Does the state have the right? The person itself has the right, but the layman will not figure it out, they will not know all the risks. Does the scientist who performed the sequencing have a right to know? Yes, but not the right to disclose information. Do pharmaceutical companies have the right to use personal genomic information for their purposes? There are a lot of ethical, legal, and economic issues that are not fully resolved here.

Can a person find out all the information about the gene, or is there some part of the gene that cannot be deciphered?

In fact, we still know very little about our genome. It’s like reading a book in an unfamiliar language. Each person can get a printout of “their book” and there will be letters that they could read. Using the example of French: if a person knows only a few phrases, they will be able to make out something in this book, but they will not know all the subtleties. Our genome is a genetic text written in the form of a thick book with thousands of pages and three billion letters. The part that we work with and have worked with before is only small sections of the genetic text, separate “pages.” We have learned to “read” them – to find mutations. We know that “in the first volume on the tenth page in the second paragraph” there is a word that interests us. We will read it, if necessary, we will correct the typo, and everything will be fine. But what about the other dozens or hundreds of pages? Everything between the genes, everything outside the coding part. So far, we have not yet learned to understand what we can read, although, of course, we, both Russian and world science, are moving in this direction. We have more and more information that is not meaningless, but it is premature to say that reading the genome will bring practical benefits all over the world and solve all problems with genetic health. We need to learn, but there is still a lot of movement to be done.

What opportunities can appear in medicine thanks to genetics? What does genetics not yet know how to do, but can learn in the near future?

Genetics is one of the basic fields of modern medicine. And one of the most accurate. And as my teacher, Academician Valery Puzyrev said, it was genetics that made medicine a science. Now we are moving towards individual, personalized medicine. And the genetics of each person, each family can make medicine personalized. To continue this thesis, modern genetics makes personalized medicine a science.

We have already learned how to do a lot. As I have already said, theoretically and practically any monogenic disease can be diagnosed. Theoretically, anything can be fixed. But not all diseases have methods of treatment.

Now we can learn some information at any stage of the body’s development, even long before its appearance. For example, when counseling married couples. To some extent, we can predict what the future child will be like when he or she is not even in the plans yet. We can do this during pregnancy, immediately after birth at any stage of the body’s development. And it always gives a new share of information and new grounds for some medical actions: diagnosis, therapy, and prevention of diseases.

We can read the whole genome. We have not learned to fully understand it, but we have not only read a significant part of the text, but also mastered it, and made our conclusions.

To some extent, genetics can predict the risk of developing a wide range of diseases. Another thing is that this risk is not necessarily realized in every person: it also depends on their lifestyle, environment, and the cumulative effect of genes, but this information is not meaningless. For example, if a person finds out that they have a risk of stroke 5 times higher than the average in the population, then this can attract the attention of this person to their health.

Gene therapy and genome editing are very tempting prospects and are already being implemented. It remains only to learn how to do them completely safe. Targeted therapy, pharmacogenetics, when we can predict which specific drug options are recommended for a particular person, or what doses they can take. Targeted therapy means that we can choose the appropriate medicine specifically for each mutation. And for some monogenic diseases, including cystic fibrosis, such targeted drugs have been developed that modify a specific breakdown in the gene, or replace it.

Will we ever have 22 thousand drugs for each of the 22 thousand genes? It is unlikely, but some areas of medicine have already switched to these “genetic rails,” and soon the rest will. These are practical things. But there are also very important basic ones.

We get to know nature, generate new knowledge. Not randomly, but to understand how the world works, nature, how human health, and diseases work. We are moving towards making the identification of the disease not by external manifestations, phenotypes, but based on what exactly is disturbed by this disease, in the genes themselves. Ultimately, genetics will bring and already brings a huge amount of benefits, practical benefits to humanity as a whole and, of course, to each person individually.

What advantage does personalized medicine have and how does it manifest itself?

The advantages are obvious. For example, as for a fashionista who goes to a department store and buys a hat like everyone else, or goes to an exclusive boutique or atelier, where they sew her a beautiful hat that no one else has, specifically for her requirements. “I am so unique, beautiful, and so different from everyone,” she will think. And we are so different from everyone else, too. The question is to find how exactly, and how to use it.

Personalized medicine solves the problem of optimal selection of medical means of influence: diagnosis, treatment, prevention for a particular person. It may look different. In certain areas, this is a fairly good trajectory. When I talked about genetic diagnosis and testing of monogenic diseases, this is a good example of a personalized approach, where each family is a separate story, each patient has a separate mutation. A personal system is being developed for them to identify the mutation, and then give birth to a healthy child. In the same way, it can work in other areas.

Another important point: personalized medicine will not work without a sufficient degree of understanding by the patient of the necessity of their needs. For recommendations to have an effect, a person should listen to them and understand why they need them. For example, with invasive diagnostics, women have questions: what risks are associated with it, what will happen in the end. The patient in this case should understand that they participate voluntarily. They should not be a subject who agrees with everything and is only interested in the result, the patient here is also a participant in the process of personalized treatment or diagnosis. Personalized therapy, perhaps, depends on the patient even more than on the doctor or technology.

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