Possibilities of medical genetics

Sergey Kutsev: "Don't confuse genetics with palmistry"

Igor Naumov, "Profile"

There have historically been many myths around medical genetics, often distorted ideas. Some believe in its unlimited possibilities, others believe that hereditary diseases are a verdict. What kind of science is it really, how can it help and what is it still powerless against? Sergey Kutsev, the chief freelance specialist in medical genetics of the Ministry of Health of Russia, told the Profile about this.

– Sergey Ivanovich, today there is a lot of talk about a genetic passport. Should it be issued to each person?

– Here it is necessary to understand what, in fact, it is about. In the way that now appears in official documents, a genetic passport is some genetic characteristics of an individual that allow him to be identified. And identification of a person with the help of any technology, and in particular genetic, is already forensic medicine.

Another thing is that the term "genetic passport" also means information about the genetic apparatus of a particular person, the structure of his genome. Such information will allow you to determine what he is predisposed to. But it's not all that simple. In my opinion, genetics is, in fact, trying to equate with palmistry. They guessed-they guessed, and it seems to be possible to say: someone will have a myocardial infarction or stroke, bronchial asthma, well, and other health problems in 20 years. That's all not true.

Or even better it happens. I know that gifts have become fashionable – genetic tests that supposedly allow you to determine what a child is predisposed to. Will he become a great athlete or musician, a famous writer… This is all frivolous, as they say, from the evil one. Medical genetics is the science of hereditary diseases. Their diagnosis, prevention and treatment.

When we talk about frequent diseases, such as arterial hypertension, heart attack, diabetes mellitus, bronchial asthma, especially about the predisposition of a child to certain talents, we must understand that the genetic apparatus reveals variants of the norm. It has long been confirmed on very large samples of sick and healthy, talented and ordinary people that there is no significant difference in the variants of the norm. Conclusion: all tests now and in the future are just a fantasy that has nothing to do with reality.

– Allow me, there are people who, as I understand it, are genetically predisposed to certain professions. Let's say a pianist needs long fingers…

– Yes, there is such a hereditary disease when a person has very long fingers – Marfan syndrome. Some pianists have them just like that. But, I assure you, if you take a group of people with Marfan syndrome, it turns out that there are very few pianists among them. That is, the future career of a musician does not depend on long fingers. Talent is a condition that is determined by very many genes. But the main thing is the external environment.

When children musicians are born in a family of musicians, it is not a genetic predisposition. I would say that everything here depends on the environment, on the family in which the child was born, lives and develops. As for "calculating" with the help of genetics the future talent in a particular type of professional activity, it is impossible.

– Well, the talents seem to have been sorted out. And what about hereditary diseases? How serious is the problem?

– There are different groups of hereditary diseases. There are chromosomal diseases when the structure or number of chromosomes changes, which can be seen in a microscope. A classic example is Down syndrome, an extra twenty–first chromosome is the most common pathology. In total, there are about 900 different chromosomal syndromes associated with changes in the number, and more often the structure of chromosomes. And these are always very serious diseases. With rare exceptions, they manifest themselves during the newborn period. Chromosomal syndromes are not such a rare event in the human population. According to statistics, this is almost 1% of newborns. And very often they lead to death in the first months of life.
The second group of hereditary diseases is monogenic, that is, associated with a change in the structure of the gene. If a chromosome contains several thousand genes, then the causes of monogenic diseases are a change in the structure of one gene that encodes a certain protein. Due to the fact that the structure of the gene changes, the structure of the protein changes, which cannot perform a certain function. The most studied group of hereditary diseases is fermentopathy. In such diseases, as a result of changing the structure of the gene, the structure of the protein – enzyme changes. And it is not capable of processing any substances.

One of the most common is phenylketonuria. With a mutation of the enzyme gene – phenylalanine hydroxylase, and more than a thousand mutations in this gene are already known, there is such a change in the structure of the protein that phenylalanine is not processed, more precisely, it is not metabolized. It accumulates and poisons the nervous system. This leads to the fact that the child develops a deep mental retardation.

There are a lot of hereditary diseases – more than 7 thousand. And almost all of them are very rare diseases – orphan. They are also called diseases-"orphans". Since they are rare, little attention has been paid to them. Now the trend direction is orphan diseases. Most of them are monogenic. Each one happens very rarely. One case per 7-8 thousand or 20 thousand newborns. Sometimes there is one case in 10 million, or only one or two cases are generally known in the entire history of observations. But together they, as well as chromosomal diseases, suffer from about 1% of the population. So it turns out a lot.

– Is it really possible to prevent the birth of people with severe hereditary diseases?

– If a child is born in a family with a suspected hereditary disease, then contact with a geneticist who prescribes certain types of instrumental and laboratory examinations is necessary. And, in the end, he can make the right diagnosis. For example, karyotype analysis, chromosome analysis is assigned. Or the study of some genes, when there is a picture showing a hereditary disease. Of course, the diagnosis should be made first of all among the diseases for which there is treatment.

As for the verdict, 30 years ago they really said that. Everyone remembers this, and many still think so.: this is genetics, what can you do ... but in fact, in recent years, there has been a treatment for more than 300 orphan diseases. Maybe, against the background of 7 thousand diseases, it will seem that this is not so much. In fact, a big step forward has been made so that we will someday stop considering hereditary diseases as a verdict.

– It is generally believed that the treatment of genetic diseases costs some crazy money.

– This is not always the case. Early diagnosis is important so that you can quickly diagnose and prescribe treatment, which is called pathogenetic. That is, we have studied this disease, understand the mechanisms of how it develops, developed medications, prescribe them and get a very good result. By the way, sometimes you can do without medications, and limit yourself to a diet.

Take the same phenylketonuria. This disease develops when both genes are mutated. That is, both parents are healthy, they have one gene with a mutation, and the other is normal. And for a child there is a high probability – 25% – to get both genes with a mutation. The so-called autosomal recessive type of inheritance. However, if it is possible to make a diagnosis during the first month of a child's life, then a restrictive diet is prescribed to him. Mother's milk is replaced with special mixtures that do not contain phenylalanine. This technique has been used since the late 80s of the last century. There are more than 10 thousand people in Russia who were born with phenylketonuria. Many of them have already become adults. Despite the hereditary disease, they grew up healthy, created families and, moreover, gave birth to healthy children. That's such a success.

– But there are diseases before which you are powerless.

– Unfortunately, it is. There is no cure for chromosomal diseases. And it won't appear any time soon. Simply because there are very serious changes in the genetic apparatus. So many genes are involved in the pathological process that there are not even theoretical approaches for treatment. Treatment is only symptomatic. For gene diseases, there is a treatment, as I have already said, for more than 300 nosologies. For the rest, it is also only symptomatic so far.

– There is no cure, but can gene and chromosomal diseases be prevented?

– There are options here. When we find out that both parents are carriers of mutant genes and there is a risk of 25% or 50% of the birth of a sick child, depending on the type of inheritance, then in vitro fertilization (IVF) is considered. And in specialized centers it is possible to conduct preimplantation diagnostics. Several cells are taken from the embryo, and their genetic apparatus is studied in order to find out whether the embryo inherited mutations from its parents or not. Depending on the result, embryo selection is carried out.

The second option is prenatal diagnosis. If pregnancy has already occurred, then in the early stages, in the first trimester, a chorion biopsy is possible – taking the material of the cells of the outer shell of the fetus. This also gives an answer to the question whether the fetus has a gene or chromosomal mutation or is healthy. Well, then the parents themselves decide whether to save or terminate the pregnancy. They always have the last word, because according to the current legislation, such a decision is made by the family.

In practice, there are different cases. Let's say I was talking about screening all newborns for hereditary diseases. But there is also prenatal screening, when all pregnant women are examined for Down syndrome and for congenital defects of the central nervous system – neural tube defects. It happens that screening shows Down syndrome with a very high probability.

Then they carry out prenatal diagnostics, again take a chorion biopsy, do research. Some women still retain pregnancy. Why not? Maybe this is the only pregnancy in a woman's entire life that happened at the end of the reproductive period, and the family wants to keep the child even with Down syndrome. She has the right to do so. There's nothing like that here. This is what they do all over the world.

– Tell me, will it be possible to guarantee the birth of absolutely healthy children in the future?

– Never! There is such a thing as spontaneous mutation. There are many genetic diseases that are not inherited, but arise anew. The fact is that the genome is characterized by two things. The first is the stability of the genetic apparatus. The second is its variability. And the genetic apparatus is constantly under some kind of pressure, pressure. Some of the germ cells formed in the gonads always have random genetic abnormalities. Therefore, there is no 100% confidence in the birth of a healthy child.

If we consider not germ cells, but somatic cells, which make up the human body, then the genetic apparatus necessarily changes in some part of the cells. If serious damage has occurred, for example, damage to double-stranded DNA, then the mechanisms of death of this cell are activated. However, this does not happen in other situations. Then the genetic apparatus changes, and the cell acquires certain features that are recognized by the immune system. She destroys these cells that have become alien. Oncological diseases occur when the mechanisms of DNA repair or programmed cell death are disrupted or the immune system fails.

– Do age factors matter?

– You want to ask what influences the appearance of mutations?

- Yes. What and how can age-related parents be protected from?

– Here it is necessary to talk first of all about reproductive behavior at the stage when the family is planning pregnancy and the birth of a child. Geneticists give some advice when consulting. Probably the most famous list of such tips is the Castillo decalogue. These are the ten commandments that must be observed when planning a pregnancy. However, following them is not a 100% guarantee that the child will be born healthy. Nevertheless, these are clear recommendations in terms of reproductive behavior. In fact, Castillo's 10 commandments are dedicated to a healthy lifestyle: proper nutrition, rest, absence of adverse factors related to the professional activities of future parents, and so on.

But if we talk about well-known scientific facts that lead to hereditary diseases, then this is a large number of mutagens. Various chemical, physical substances, radiation, leading to mutations, DNA breaks. The most studied, of course, is Down syndrome. It is absolutely clear and has long been proven that the frequency of the appearance of an extra chromosome increases with the age of a woman. After reaching the age of 35, the risks increase significantly. That is why, if a woman becomes pregnant after the age of 35, it is recommended to undergo prenatal diagnostics in any case.

– What about men?

– If we analyze the entire population of patients with Down syndrome, then in 80% of cases the reason for its appearance is that there was a non–divergence of the twenty-first chromosome in the female germ cell, in 20% - in spermatozoa.

– Don't modern technologies allow you to edit an embryo?

– Chromosomal abnormalities cannot be corrected. Correction of the genetic apparatus, that is, editing of genomes, with gene mutations is possible. But the associated risks are high. With preimplantation genetic diagnostics, we do not change anything, we only select, embryos are selected. And when editing, we interfere with the structure of the genome.

Modern systems, in addition to correcting a genetic defect, cause additional changes in the genetic apparatus. And this can lead to the development of hereditary diseases in the embryo or, in the future, to oncology. The second point. It cannot be excluded that editing will happen in some cells, but not in others. The risk of intervention is high, but the disease will still remain.

– Is it profitable for the state to invest in medical genetics? Is there an economic effect?

– Absolutely. The cost of the budget for screenings pays off. It is much cheaper to detect the disease at an early stage and start treatment than to support a disabled person for many years afterwards. It's not that benefits are provided for him, but that there are usually one or two people around who can't work either. They are turned off from the economy. Therefore, prevention and early treatment of hereditary diseases are economically beneficial.

– We are talking about hereditary diseases in relation to newborns. And how are adults treated?

– A very good question. Our knowledge is expanding. And a lot of diseases that were once considered as multifactorial are now moving into the category of hereditary. For example, strokes – it was believed that they were associated with atherosclerosis, age, and so on. Now we know that there are a number of diseases that are hereditary, and they lead to strokes. For example, some mitochondrial diseases. There are several dozen of them.

Many forms of diseases that were previously thought to manifest (first show clinical symptoms) only in childhood can also occur in an adult. Therefore, in addition to infant juvenile forms, today we identify adults.

– Is oncology also hereditary?

– Until recently, we said that the cause of all oncological diseases is somatic cells. In one or another human organ, changes in the genetic apparatus of cells occur, mutations appear. The cell is the source of the tumor. Everything was closed at the level of a specific tissue, organ. Then there were data on the hereditary nature of some types of oncology. At first it was thought that 5%, then – 10%, now – 15%, and according to some estimates, 20% of oncological diseases are hereditary. More often – breast cancer, ovarian cancer, less often – colon cancer, some forms of thyroid cancer. For example, a mutation in the BRCA‑1 and BRCA‑2 genes suggests a high probability of breast or ovarian cancer. The risk increases by 20 times compared to those who do not have mutations in these genes.

– How do women escape from breast cancer? Do I need a surgical operation, following the example of Angelina Jolie?

– American Association of Oncologists, Russian oncologists develop clinical recommendations. Of course, first of all, medical examination and constant monitoring are necessary. If we talk about breast cancer, when a mutation is detected in the BRCA‑1 and BRCA‑2 genes, then after 25 years a woman should do an MRI with contrast once a year, and after 30 years, if my memory serves me correctly, alternate: once every six months – mammography and six months later – MRI. To identify the oncological process at an early stage. If the diagnosis is confirmed, then, of course, breast resection is needed.

As for the example of Angelina Jolie, it seems to me that in her case it was unnecessary. Because if there is a monitoring system, then it should have been used. Moreover, preventive breast removal does not always guarantee a solution to the problem. The same applies to some other forms of oncology with hereditary causes.

– And what do you say about other common diseases, for example, rheumatoid diseases? This is the problem of millions.

– Rheumatoid diseases are a multifactorial pathology. Genetic predisposition to them also exists. Let's say there is Bekhterev's disease, when the intervertebral discs and ligaments of the spine lose elasticity and the spine loses mobility. The disease occurs with a frequency of 1 case per 10 thousand population. In almost all patients with this disease, the HLA-B27 gene is detected. It seems that we have found a marker of Bekhterev's disease. But if healthy people are examined, then the allele variant of HLA-B27 can be found in some populations in 10% of the population, that is, in 1 out of 10. Thus, out of 1000 carriers of the HLA-B27 gene, one may become ill with a high probability. Conclusion – as a predictive factor of predisposition to Bekhterev's disease, this approach is not suitable.

Geneticists will not be palmists, predictors. What is the point of stigmatizing society if you can say that a disease due to a mutation of some gene may or may not happen? The odds are one to one. The same can be said without genetic tests. Genetics is a science in which one must be very careful. On the other hand, to tell a person the whole truth, what a risk it is and what it can lead to. A balance is needed here. If the doctor is sure, he should tell me.

– How is the archive of family data collected, in which information about hereditary human diseases should be accumulated?

– It is necessary to come to the geneticist. Reception – about an hour. The doctor must collect all the information about the person during the survey. This is how the pedigree is compiled, which is one of the important points of the examination of a particular family. If a hereditary disease is suspected, an appropriate laboratory examination is prescribed. First, the proband – the person who came to the reception. If something is detected in him, then family members are examined. It is established which of them is the carrier and who has a hereditary disease. So here every time some kind of detective turns out.

– I have not met any geneticists in the district polyclinics…

– In general, geneticists are a piece product. You need to study a lot, get a modest salary. How many diseases can an ordinary doctor know – 100, well 200, but not seven thousand. However, a medical and genetic service has been established in the country. Almost every region has a specialized consultation or center. The Medical and genetic Research Center, which I head, is federal. In Bashkortostan, in Ufa, there is a medical and genetic center, which employs about 200 people. There are centers in Tomsk, Krasnoyarsk, Yekaterinburg, and St. Petersburg. In other regions, these are departments at regional hospitals or perinatal centers. The level of development is different everywhere. It all depends on the size of the subject of the Federation, the number of residents and the attention of the authorities to this issue. There are also problematic regions. There is no such service in the Jewish Autonomous Region and in Chukotka.

– Does Russian genetics – its level – meet international standards?

– Despite the fact that domestic healthcare is criticized a lot, our medical genetics is no different, and in some cases even surpasses Western ones. For example, we do not have to wait 6 months, as in the USA, for an appointment with a geneticist. In the regions, you can get an appointment within a few days. To our center, since it is federal, for a longer time – about two months. The qualification level of doctors is high. They come from all over the country. We accept 12 thousand families a year. By the way, consultations and examinations are free for patients.

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