Modern perinatologists have such a large variety of fetal examination tools at their disposal that parents now rarely have to think about two lists of names, male and female, at once. And if the interpretation of ultrasound is very rare, but can still turn out to be erroneous, then karyotyping of the fetus - determining the set of chromosomes - when performed carefully, never fails.
It is for this reason that Swiss doctors were very surprised when a completely healthy girl was born during childbirth seven years ago.
Fetal karyotyping is not mandatory procedure, but since the expectant mother was already old, doctors recommended this procedure to exclude congenital chromosomal abnormalities. They are responsible for up to 50% of spontaneous abortions and about 7% of all stillbirths. And the frequency of Down syndrome, caused by the tripling of the 21st chromosome, makes parents seriously think about early diagnosis.
Conducted at stage embryonic development and repeated karyotypic analysis, carried out after birth for obvious reasons, did not reveal any abnormalities in the structure of any of the 46 chromosomes, the list of which ended with the XY pair. But in front of the doctors there was clearly a girl.
IN clinical practice This is by no means the first case, and such situations should fall under the definition of Shereshevsky-Turner syndrome. It can develop with a 45X0 karyotype, when of the two sex chromosomes there is only one - female, or, in the case of chimerism, 46Xq - when the body has cells with a different set of chromosomes.
In this case, doctors conduct a thorough examination even at birth to remove underdeveloped sex glands that are prone to tumor formation. During the operation, the surprise only became greater - the surgeons did not find any traces of underdeveloped, or rather, undecided in the direction of their development, gonads, shriveled testicles or other congenital anomalies. Instead, the authors publications in American Journal of Human Genetics
They saw that the “chromosomal boy” had a full-fledged vagina, cervix and normal, healthy ovaries.
They took a small pinch of the latter for genetic and cytological analysis. The first assumption - that a defect in the SRY region, located on the “male” Y chromosome and playing a key role in sex determination, was to blame, could not be proven.
Anna Biason-Lauber of the University Children's Hospital, who led the work, believes that CBX2 helps the SRY gene carry out its function. That is why, even if there is a full-fledged SRY on a full-fledged Y chromosome, the female gender of the child is beyond doubt.
In the vast majority of cases, SRY triggers the work of two proteins even at the stage of embryonic development. One of them promotes the conversion of testosterone into estradiol, which stimulates the development of male gonads. The second factor encoded by SRY prevents the development of Müllerian ducts, the future fallopian tubes characteristic of the female body.
Now scientists face another question: can a girl have children?
Laboratory mice with a similar defect on chromosome 17 are sterile. However, in the case of a 7-year-old child who came under the care of a research team, everything is not so obvious. After all, the ovaries, which are responsible for the storage and formation of germ cells, and all the necessary genital organs are present and completely healthy.
Chromosomal diseases are a group of severe hereditary diseases caused by changes in the number of chromosomes in the karyotype or structural changes in individual chromosomes. This group of diseases is characterized by multiple congenital malformations, intrauterine and postnatal growth retardation, psychomotor development, craniofacial dysmorphia, dysfunction of the nervous, endocrine and immune systems (Vorsanova S.G.
Et al., 1999; Puzyrev V.P. et al., 1997).
The frequency of chromosomal abnormalities is 5-7 per 1000 births. In the general group of premature babies, chromosomal pathology accounts for about 3%. Moreover, among premature children with congenital malformations, the level of chromosomal abnormalities reaches 18%, and in the presence of multiple congenital malformations - more than 45% (Vorsanova S.G. et al., 1999).
The etiological factors of chromosomal pathology are all types of chromosomal mutations (deletion, duplication, inversion, translocation) and some genomic mutations (aneuploidy, triploidy, tetraploidy).
Factors contributing to the occurrence of chromosomal abnormalities include ionizing radiation, exposure to certain chemicals, severe infections, and intoxication. One of external factors is the age of the parents: older mothers and fathers are more likely to give birth to children with karyotype abnormalities. Important role A balanced combination of chromosomal abnormalities plays a role in the occurrence of chromosomal abnormalities. Full forms chromosomal syndromes arise as a result of the influence of harmful factors on germ cells in meiosis, while in mosaic forms negative events occur during the intrauterine life of the fetus in mitosis (Vorsanova S.G. et al., 1999).
Down syndrome - trisomy on chromosome 21 (Vorsanova S.G. et al., 1999; Lazyuk G.I., 1991; Sokh A.W., 1999). The frequency among newborns is 1:700-1:800. Cytogenetic variants of Down syndrome are represented by simple complete grisomy 21 (94-95%), translocation form (4%), mosaic forms (about 2%). The ratio of boys to girls among newborns with Down syndrome is 1:1.
Children with Down syndrome are born at term, but with moderately severe prenatal malnutrition (8-10% below average). Patients with Down syndrome are characterized by brachycephaly, Mongoloid eye shape, round, flattened face, flat occiput, flat nasal bridge, epicanthus, large, usually protruding tongue, deformed auricles, muscle hypotonia, clinodactyly V, brachymesophalangyly V, severe hypoplasia of the middle phalanx and single flexion fold on the little finger, changes in dermatoglyphics (4-digit fold), short stature. Eye pathology includes Brushfield spots, and cataracts are often found in older children. Down syndrome is characterized by congenital malformations of the heart (40%) and gastrointestinal tract (15%). The most common type of congenital heart defects is septal defects, the most severe of which is atrioventricular communication (about 36%). Congenital malformations of the digestive tract are represented by atresias and stenoses duodenum. Children with Down syndrome are characterized by profound mental retardation: 90% of children have mental retardation in the imbecility stage.
Defeats immune system presented secondary immunodeficiencies caused by damage to the cellular and humoral components. Patients with the syndrome often have leukemia.
To confirm the diagnosis, a cytogenetic study is performed. Differential diagnosis carried out with other chromosomal abnormalities, congenital hypothyroidism.
Treatment is symptomatic, surgical correction VPR.
Patau syndrome - trisomy of the 13th chromosome (Vorsanova S.G. et al., 1999; Lazyuk G.I., 1991; Sokh A.W., 1999). The frequency of this syndrome is 1:5000 newborns. Cytogenetic variants: simple complete trisomy of chromosome 13 and various translocation forms. The sex ratio is close to 1:1.
Children with Patau syndrome are born with true prenatal hypotrophy (25-30% below average). Polyhydramnios is a common complication of pregnancy (about 50%). Patau syndrome is characterized by multiple BIIPs of the skull and face: clefts of the upper lip and palate (usually bilateral), reduced skull circumference (trigonocephaly is rarely observed), sloping, low forehead, narrow palpebral fissures, sunken bridge of the nose, wide base of the nose, low-lying and deformed ears shells, scalp defects. Polydactyly and flexor position of the hands are noted (the second and fourth fingers are brought to the palm and are completely or partially covered by the first and fifth fingers).
Patients with Patau syndrome are characterized by the following defects of internal organs: heart septal defects, incomplete intestinal rotation, kidney cysts, and genital defects. Most children with Patau syndrome die in the first days or months of life (about 95% before 1 year).
To confirm the diagnosis, a cytogenetic study is performed. Differential diagnosis is carried out with other forms of chromosomal abnormalities, Meckel syndrome, orofacial-digital syndrome type II, Opitz trigonocephaly.
Edwards syndrome - trisomy 18 (Vorsanova S.G. et al., 1999; Lazyuk G.I., 1991; Sokh A.W., 1999). The frequency of this syndrome is 1:5000-7000 newborns. Cytogenetic variants are almost entirely due to simple complete trisomy 18 and, less commonly, mosaic forms of the disease. The sex ratio is M:F = 1:3.
Children with Edwards syndrome are born with severe prenatal malnutrition (birth weight - 2200). The skull is dolichocephalic in shape, microstomia, narrow and short palpebral fissures, protruding glabella, deformed and low-lying ears are noted. The flexor position of the hands is characteristic, however, unlike Patau syndrome, the adduction of the second and third fingers is more pronounced, the fingers are bent only at the first interphalangeal joint.
Edwards syndrome is characterized by defects of the heart and large vessels (about 90% of cases). Ventricular septal defects predominate. The frequency of valve defects is high: in 30% of cases there is aplasia of one leaflet of the semilunar valve of the aorta and/or pulmonary artery. These defects have diagnostic significance, since they are rare in other chromosomal diseases. Defects of the gastrointestinal tract (about 50% of cases), eyes, lungs, and urinary system are described. Children with Edwards syndrome die in early age from complications caused by BIIP.
To confirm the diagnosis, a karyotype study is performed. Differential diagnosis is carried out with Smith-Lemli-Opitz syndrome, cerebro-oculo-facioskeletal, VATER-ac association.
Shereshevsky Turner syndrome ( Bochkov N-P., 1997; Vorsanova S.G. et al., 1999; Lazyuk G.I., 1991). The frequency of the syndrome is 1:2000-1:5000 newborns. Cytogenetic forms are diverse. In 50-70% of cases, true monosomy is observed in all cells (45, XO). There are other forms of chromosomal abnormalities: deletion of the short or long arm of the X chromosome, isochromosomes, ring chromosomes, various forms of mosaicism (30-40%).
In newborns and infants, there is a short neck with excess skin and pterygoid folds, lymphatic edema of the feet, legs, hands and forearms, which is a reflection of developmental anomalies of various parts lymphatic system. In a third of patients, the diagnosis is made during the neonatal period. Subsequently, the main clinical manifestations are short stature, underdevelopment of secondary sexual characteristics, hypogonadism, and infertility. Defects of the heart, kidneys, wide chest, epicanthus, micrognathia, and high palate are described.
To confirm the diagnosis, a cytogenetic study is performed.
Treatment", surgical correction of congenital heart disease (CHD), plastic correction of the neck, hormone replacement therapy.
Wolf-Hirschhorn syndrome is a partial monosomy of the short arm of chromosome 4 (Kozlova S.I. et al., 1996; Lazyuk G.I., 1991). Frequency - 1:100,000 newborns. The syndrome is caused by a deletion of a segment of the short arm of the fourth chromosome. Among children with Wolf-Hirschhorn syndrome, girls predominate.
A pronounced delay in physical and psychomotor development is one of the main clinical signs of the syndrome. In this disease, prenatal hypotrophy is more pronounced than in other chromosomal diseases: the average birth weight of full-term children is 2000. The following craniofacial dysmorphia is characteristic: moderate microcephaly, beaked nose, hypertelorism, epicanthus, large, protruding auricles, clefts lips and palate, abnormalities eyeballs, anti-Mongoloid eye shape, small mouth. Hypospadias, cryptorchidism, sacral fossa, foot deformity, and convulsive syndrome are also noted. More than 50% of children have congenital malformations of the heart, kidneys, and gastrointestinal tract.
“Cry of the cat” syndrome is a partial monosomy of the short arm of chromosome 5, (5p) syndrome (Kozlova S.I. et al., 1996; Lazyuk G.I., 1991). The frequency of this syndrome is 1:45,000 newborns. In most cases, a deletion of the short arm of the fifth chromosome is detected, mosaicism due to deletion, the formation of a ring chromosome, and translocations occur (about 15%). Girls with this syndrome are more common than boys.
The most characteristic clinical signs syndrome 5p- are specific crying, reminiscent of a cat's meow, and mental and physical underdevelopment. The following craniofacial anomalies have been described: microcephaly, low-lying, deformed ears, moon face, hypertelorism, epicanthus, strabismus, muscle hypotonia, diastasis recti. “Cat cry” is usually caused by changes in the larynx (narrowing, soft cartilage, swelling and unusual folding of the mucous membrane, reduction of the epiglottis).
Congenital malformations of internal organs are rare. There are congenital defects of the heart, central nervous system, kidneys, and gastrointestinal tract. Most patients die in the first years of life, about 10% reach the age of ten.
To confirm the diagnosis, a cytogenetic study is performed. Differential diagnosis is made with other chromosomal abnormalities.
Microcytogenetic syndromes. This group of diseases includes syndromes caused by minor divisions or duplications of strictly defined sections of chromosomes. Their true etiological nature was established using molecular cytogenetic methods (Bochkov N.P., 1997).
Cornelia de Lange syndrome (Kozlova S.I. et al., 1996; Puzyrev V.G. et al., 1997). The frequency of this syndrome is 1:12,000 newborns. The syndrome is caused by microduplication of the long arm of chromosome 3 - dup (3) (q25-q29). Sex ratio M:F = 1:1.
As a rule, children are retarded in growth and psychomotor development. This syndrome is characterized by the following craniofacial dysmorphia: microcephaly, synophrysis, thin eyebrows, long, curled eyelashes, a small nose with nostrils open forward, deformed ears, long filter, thin upper lip, high sky and cleft palate. Characteristic features are acromicria, oligodactyly, clinodactyly V, and radial hypoplasia. Myopia, astigmatism, optic nerve atrophy, strabismus, late teething, large interdental spaces, hypertrichosis, high voice, and muscle hypertonicity have been described. This syndrome is characterized by the following congenital malformations: polycystic kidney disease, hydronephrosis, pyloric stenosis, cryptorchidism, hypospadias, intestinal defects, congenital heart disease.
Two clinical variants of the syndrome have been described. The classic version is accompanied by severe prenatal malnutrition, significant retardation of physical and mental development, and gross malformations. Benign - facial and skeletal anomalies, slight delay in psychomotor development, congenital malformations, as a rule, are not typical.
The diagnosis is made clinically based on the characteristics of the phenotype. Differential diagnosis is made with Coffin-Siris syndrome.
Lissencephaly syndrome (Miller-Dieker syndrome)
(Kozlova S.I. et al., 1996; Puzyrev V.II. et al., 1997). The syndrome is caused by a microdeletion of the short arm of chromosome 17 - del (17) (p 13.3). Sex ratio M:F = 1:1.
The disease is characterized by a pronounced lag in psychomotor development and convulsive syndrome. Craniofacial dysmorphia includes: microcephaly, high forehead, narrowed at temporal areas, protruding occiput, rotated ears with a smoothed pattern, anti-Mongoloid eye shape, eye hypertelorism, “carp” mouth, micrognathia, facial hypertrichosis. Characterized by polydactyly, campodactyly, transverse palmar fold, muscle hypotonia, difficulty swallowing, apnea, increased tendon reflexes, decerebrate rigidity.
The following CNRs have been described: BIIC, renal agenesis, duodenal atresia, cryptorchidism. Patients die in early childhood. An autopsy reveals the absence of grooves and convolutions in the cerebral hemispheres.
The diagnosis is based on the characteristics of the phenotype and clinical picture, as well as molecular genetic research data. Differential diagnosis carried out with chromosomal pathology, Zellweger syndrome.
Smith-Magenis syndrome (Smith A.S.M. et al., 2001). The frequency of this syndrome is 1:25,000 newborns. The syndrome is caused by an interstitial deletion of the short arm of chromosome 17 - del (17) (pi 1.2). In 50% of cases a decrease is described motor activity fetus in the prenatal period. The weight and height of children at birth are normal, but subsequently their height and weight indicators lag behind the age norm.
Smith-Magenis syndrome is characterized by a specific phenotype, retardation of mental and physical development, and behavioral characteristics. Facial dysmorphias include: hypoplasia of the midface, wide, square face, brachycephaly, protruding forehead, sinophrisis, Mongoloid eye shape, deep-set eyes, wide bridge of the nose, short upturned nose, micrognathia, thick, upturned upper lip. One of the characteristic clinical symptoms is muscle hypotonia, hyporeflexia, poor sucking, swallowing, and gastroesophageal reflux are noted. Sleep disturbances (drowsiness, frequent falling asleep, lethargy) occur in infancy.
The diagnosis is based on a combination of phenotypic and behavioral characteristics and data from molecular genetic research. Differential diagnosis is carried out with Prader-Willi, Williams, Martin-Bell syndromes, velocardiofacial syndrome.
Beckwith-Wiedemann syndrome (Kozlova S.I. et al., 1996). The syndrome belongs to the group of syndromes with advanced physical development and is caused by duplication of the short arm of chromosome 11: dup(ll)(pl5).
At birth, as a rule, there is macrosomia with an increase in muscle mass and subcutaneous fat layer (weight more than 4 kg). In some cases, advanced physical development develops postnatally. In the neonatal period, hypoglycemia may develop. The most common are macroglossia, omphalocele, and sometimes divergence of the rectus abdominis muscles. A characteristic sign of the syndrome is vertical grooves on the earlobes, less often - rounded depressions on the back surface of the helix. A typical symptom is visceromegaly: enlargement of the liver, kidneys, pancreas, heart, uterus, bladder, and thymus are described. Microcephaly, hydrocephalus, protruding occiput, malocclusion, exophthalmos, hemigynertrophy, immunodeficiency states are characteristic, and moderate mental retardation is possible. Bone age is ahead of passport age. In 5% of cases they develop malignant tumors. Hypercholesterolemia, hyperligshdemia, and hyocalcemia are detected.
The diagnosis is based on a combination of clinical data and the results of molecular genetic research. Differential diagnosis should be made with congenital hypothyroidism and omphalocele.
The system of chromosomes in the cell nucleus is the result of a long evolution; it contains a complex control apparatus of the cell that controls the specifics of metabolism. When generations change, the stability of this system is ensured by meiosis and fertilization. During individual development, chromosomes, thanks to autoreproduction and the mechanism of mitosis, are steadily transmitted to billions of somatic cells. It is quite clear that in the case of quantitative or qualitative disturbances in the human chromosomal apparatus, various deviations from normal development arise.
Qualitative and quantitative violations of human genotypic properties are associated with the appearance of gene mutations. These changes in the molecular structure of DNA affect such a small part of the chromosomes that they are not visible under a microscope. Any new mutant gene by chromosome autoreproduction
passed on to all subsequent generations. These gene mutations can dramatically disrupt development and cause congenital diseases. In the X chromosome alone, more than 70 loci are currently known to exhibit gene mutations, each of which causes a specific hereditary disease.
Quantitative disturbances in the composition of the nucleus are very important for hereditary diseases in humans. Additional chromosomes appear in the set of chromosomes or individual chromosomes are lost, as a result of which the historically created integral system of genetic information is disrupted and quantitative and qualitative violations development of the individual.
Classic studies on Drosophila, Datura and other objects have long shown that the most common type of such changes is aneuploidy, i.e. the addition or loss of individual chromosomes from a set, or polyploidy, i.e. a multiple increase in the set of chromosomes. It has been shown that all these changes in the number of chromosomes lead to changes in the development of the individual.
Aneuploidy in humans can affect any of its 23 pairs of chromosomes. There may be 23 types of zygotes with 47 and the same number of types of zygotes with 45 chromosomes. Each of them, due to a specific change in the gene balance, must have a specifically impaired development. It is possible that in many cases this disturbance is so severe that the embryos die. Last years witnessed exceptional advances in human cytogenetics, demonstrating the existence of a number of types of chromosomal mutations that cause serious congenital diseases, the reason for the appearance of which until now was completely incomprehensible.
The first example of the role of trisomy for a certain pair of chromosomes in causing a severe congenital disease was the description of the chromosome set in people with Down syndrome. People with Down syndrome suffer from physical abnormalities in the structure of the face, eyelids, tongue and other parts of the body and severe congenital idiocy. Down syndrome is not rare. It occurs in many places and accounts for 0.15% of all births.
Lejeune, Turpin and Gautner in France made an unexpected discovery. Culturing fibroblasts and cells bone marrow patients with Down's disease, they found that these cells, unlike normal ones, had 47 chromosomes (Fig. 145). It turned out that the 21st chromosome was extra. It was this small acrocentric chromosome that turned out to be represented in triple numbers in the set of patients with Down syndrome.
A number of chromosomal disorders have been identified for human sex chromosomes.
It has been established (Fig. 146) that individuals even have four X chromosomes (XXXX). When super-Klinefelter syndrome appears, aberrant male structures are found XXXY and even XXXXY. Yes, among aberrants XXXXYAdditionally, skeletal anomalies, severe underdevelopment of the testes, and idiocy occur. At the same time, in these cases the special role of the X chromosome in determining the male type of development is clearly demonstrated. Men have also been described as having excess Y-chromosomes - XYY (Fig. 147).
The study of disorders in the number of sex chromosomes was greatly facilitated by M. Barr and his colleagues
Discovery of the so-called sex chromatin. It was shown that 65-75% of interphase nuclei in female mammals and humans directly under the egg shell contain compact chromatin bodies, called sex chromatin (Fig. 148). Analysis of the nature of sex chromatin showed that it appears under the nuclear membrane in a single or more, and the number of chromatin bodies is equal to the number of X chromosomes minus one. Therefore, in men who have one X chromosome, as a rule, there are no chromatin bodies in the interphase nuclei. In women, in the presence of two X chromosomes, one chromatin body appears, in XXX individuals, two chromatin bodies, etc. The study of sex chromatin itself is extremely simple and effective; it is produced on smears in interphase cell nuclei taken from scrapings of the oral mucosa. This makes it possible to very quickly detect violations in the composition of sex chromosomes in patients, because each type of violation of the normal number of sex chromosomes (XY) chromosomes is accompanied by the appearance of a corresponding number of chromatin bodies.
Attempts have now been made to conduct a mass survey of the population using the sex chromatin method with the aim of broadly analyzing the extent to which sex chromosome abnormalities are common in people.
When germ cells mature during meiosis, nondisjunction can affect any pair of chromosomes, including any of the 22 pairs of autosomes. As a result of these disorders, the human sperm or egg contains, instead of the normal haploid set of chromosomes, one extra chromosome or, conversely, one of the chromosomes of any pair is missing. After fertilization of such a gamete by another, normal gamete, individuals develop in whose body cells there will be either an extra autosome or a lack of autosome.
In 1959, the first chromosomal disease was discovered - Down syndrome, which we described above. Currently, a number of chromosomal diseases caused by a violation of the number of autosomes have been identified. In a number of cases, defects in the development of an individual caused by trisomy reach very sharp expression. For example:
a) trisomy on one of the chromosomes in group 13-15 causes severe mental retardation, seizures, deafness, cleft palate, visual defects, foot deformities, hematomas;
b) trisomy on chromosome 17 causes a “triangular” mouth in newborns, absence of a neck, ear defects, heart defects;
c) trisomy on the 18th chromosome causes underdevelopment of skeletal muscles, jaws, ear degeneration, incorrect position of the index finger, and foot defects;
d) trisomy on the 21st chromosome - clinical idiocy (Down syndrome);
e) trisomy on the 22nd chromosome - cases of schizophrenia. For Down syndrome, it has been shown that the likelihood of its occurrence increases with maternal age. Thus, at the age of the mother up to 30 years, the probability of nondisjunction of chromosome 21 and, as a result, the birth of a child with Down syndrome is about 0.05%; at the age of 30-35 years - about 0.33%; at the age of 40-44 years - more than 1% and then increases more sharply (up to 12.5%) at the age of 45-47 years. The same tendency for an increase in chromosome nondisjunction with maternal aging was found for other pairs of autosomes.
Trisomy for a number of autosomes leads to very severe consequences. Apparently, the frequency of appearance of trisomics in all pairs of autosomes is quite high. However, in most cases, these trisomics lead to such developmental disorders that the fetus dies. This is the cause of many early spontaneous abortions and stillbirths.
A special class of chromosomal mutations are structural rearrangements of chromosomes. In one case, the appearance of Down's disease was associated with a translocation of the entire body of chromosome 21 to one of the autosomes. The patient had 46 chromosomes, not 47, as is usually the case with Down syndrome. However, in fact there were 47 of them, since the entire body of the 21st chromosome was transferred to another chromosome.
For the first time, the dependence of a certain disease on translocation was described in France. A patient with polydyspondylia (physical and mental retardation, complex spinal defects) had 45 chromosomes instead of the normal 46. However, the absence in this case of one of the small acrocentric chromosomes (the 22nd chromosome) was not a simple case of loss. It turned out that almost the entire body of this acrocentric chromosome was translocated to the arm of one of the large acrocentric autosomes (chromosome 13). The patient had a translocation between the 13th and 22nd chromosomes.
This is one of the cases of the frequent occurrence of translocation in the group of acrocentrics (13, 14, 15, 21, 22 pairs of chromosomes), which is due to their connection with the nucleolus, where they associate with each other.
Among structural mutations in humans, deletions have been found, i.e., the loss of individual sections of chromosomes. The first case of deletion was identified in England in a woman who had a number of defects in the development of sex and mental development. It turned out that 2/3 of its substance was lost in one of the X chromosomes.
The discovery of a deletion in the 21st chromosome made by cytogeneticists in Philadelphia played a major role in the development of the doctrine of the chromosomal basis of hereditary diseases. Chronic myeloid leukemia in humans has been found to be associated with a very specific defect in the chromosomal makeup of white blood cells. This change is that in one chromosome 21, up to 1/3 of its substance was lost. This damaged 21st chromosome became known as the Philadelphia chromosome (symbol Ph). In this case, the malignant growth of the blood turned out to be associated with a certain structural change in a certain chromosome.
In some cases, complex changes in the structure of the human nucleus lead to the appearance of complex hereditary defects. In this regard, the case of analysis at the chromosomal level of the appearance of Down syndrome and leukemia in a sick boy is of great interest (Fig. 149). It has been established that among patients with Down syndrome, leukemia occurs 15 times more often than in people without this syndrome. A number of researchers have shown that Down syndrome individually is associated with the presence of an extra (21st) chromosome. In the studied example of the coexistence of Down syndrome and leukemia, the chromosomal situation turned out to be new and very interesting.
Analysis of the pedigree of a large family, the structure of a number of members of which was studied cell nuclei(Fig. 150), shows that the boy, who had leukemia and also had Down syndrome, had a complex chromosomal rearrangement (Fig. 150, III, 20). The nuclei of this boy's cells contained 46 chromosomes, that is, they had a seemingly normal structure. However, a detailed cytological analysis showed that in the patient’s nuclei one chromosome from group 13-15 (Fig. 151) turned out to be associated by translocation with one of the acrocentric chromosomes (from the group of pairs 21-22 or withY-chromosome). In addition, one of these acrocentric chromosomes has an elongated short arm. Therefore, the patient’s karyotype has a translocation
between two chromosomes and duplication of part of one of the chromosomes. We see (Fig. 150,III, 17, 18, 21), that among the patient’s three brothers, two have a translocation in their karyotype, and one of them (Fig. 150, III, 17) has only a translocation, and the other has a translocation and a small centric fragment (Fig. 150, III, 21). Both of them were normal healthy people. The sister who had a normal karyotype (Fig. 150, III, 19), was quite healthy. The father of these children had a normal chromosome structure (Fig. 150, II, 4). The mother of this family (Fig. 150, II, 5) had a translocation and a small centric fragment. She exhibited several small but distinct abnormalities (did not walk until she was five years old, was very short in stature, etc.). In two cases, chromosomal changes were found among cells with a normal karyotype in members of this family. So, the uncle of a sick boy (Fig. 150, II, 2), having a normal set of chromosomes, in one of the cells a clear picture of translocation between chromosomes was found within group 7- 12. Here is a remarkable example of high chromosomal variability within an individual family. In some cases, the presence of a chromosomal rearrangement does not affect the health of its carrier (Fig. 150, III, 17, 21), in other cases it turns out to be known bad influence disturbed karyotype (Fig. 150, II, 5). Finally, with a specific change in the structure of chromosomes in the form of a combination of translocation with duplication on part of one of the chromosomes, a specific double disease occurs in the form of Down syndrome and leukemia. It is now known that Down syndrome occurs when various changes chromosomes, in which, however, in In all cases, it appears to be involved
the same chromosome, namely the chromosome of a pair 21. It was shown above that trisomy on this chromosome leads to the development of the syndrome. There is evidence showing that the same syndrome develops in people who have the same chromosome 21 entered into a translocation with some other chromosome. In the case described above, the presence of one translocation did not lead to Down syndrome. The combination of translocation with duplication of part of one of the chromosomes caused both Down syndrome and leukemia.
The described materials show the significance of disturbances in chromosomal structures in the nuclei of human cells for the appearance of certain serious illnesses. These discoveries led to the rapid development of a new field of medical genetics, namely the cytogenetics of hereditary human diseases and the cytogenetics of cancer.
- Source-
Dubinin, N.P. Horizons of genetics / N.P. Dubinin. – M.: Education, 1970.- 560 p.
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Chromosome 17
The process of accumulating knowledge means not only the emergence of new connections between neurons, but also the removal of old connections. In the embryonic brain, nerve cells form a much more complex network of connections, many of which break down and disappear as they mature. For example, in newborns, half of the cells in the visual cortex of the brain receive impulses from both eyes at once. Soon after birth, as a result of radical pruning of excess axons, the visual cortex of the cerebral hemispheres is divided into areas that process information only from the left or right eye. Removal of non-essential connections leads to functional specialization of brain regions. In the same way, a sculptor chips away excess parts in a block of marble to release the hidden work of art. In mammalian infants who are blind from birth, specialization of the visual cortex does not occur.
Eliminating unnecessary connections between nerve cells means not only breaking synapses. The cells themselves die. We have heard so many times the sad story that nerve cells die and are never restored. You can lose up to 1 million nerve cells per day. But a mouse with a defective gene ced-9 nerve cells do not die, which does not make her smarter. On the contrary, such a mouse will meet a sad end with a huge but completely undeveloped brain. In embryos in the later months of development and in infants, nerve cells die in the brain at an incredible rate. But this is not the result of the disease, but a way of brain development. If cells didn't die, we wouldn't be able to think.
Pushed by certain genes to which the gene belongs ced-9, healthy cells of the body commit mass suicide. (Different genes of the family ced cause the death of cells in other organs.) Cell death is carried out in strict accordance with the predetermined plan. Thus, in the microscopic nematode worm, the embryo before birth from the egg consists of 1090 cells, but then 131 of them die, leaving the adult organism with exactly 959 cells. These cells seem to sacrifice themselves for the sake of the prosperity of the body, like soldiers who, shouting “For the Motherland,” go into a deadly attack, or like worker bees who die, leaving their sting in the body of an uninvited guest. The analogy, by the way, is not so far-fetched. The relationships between the cells of the body really resemble the relationships between bees in a hive. The ancestors of all cells in the body were once free-living single-celled organisms. Their “decision” to organize a cooperative, made once 600 million years ago, was a consequence of the same reasons that forced the ancestors of social insects to unite into families (only this happened much later, about 50 million years ago). Genetically related creatures, in one case at the cellular level, and in the other at the level of organisms, turned out to be much more resistant to the vicissitudes of fate when they distributed functions among themselves, leaving the reproductive function in one case to the sex cells, and in the second to the queen of the family.
The analogy turned out to be so good that it allowed scientists to better understand the nature of many non-infectious somatic diseases. Mutinies often arise among soldiers against the command, and among bees, discipline is maintained not only by instinct, but also by collective vigilance and the expulsion of lazy people from the hive. At the genetic level, the loyalty of worker bees to their queen is maintained by the fact that the queen bee mates with several males at once. The genetic heterogeneity of the offspring does not give the opportunity to manifest genes aimed at breaking up the family and returning to a solitary lifestyle. The problem of rebellion is also acute for the cells of multicellular organisms. Some cells constantly forget about their patriotic duty, which is to provide the reproductive cells with everything they need. Instead, they begin to divide and behave like independent organisms. After all, every cell is a descendant of free-living ancestors. The cessation of division goes against the basic tendency of the development of all living organisms, or rather, their genes, to reproduce themselves. In all tissues of the body, rebellious, randomly dividing cells appear every day. If the body cannot stop them, a cancerous tumor occurs.
But usually the body has the means to suppress the rebellion of cancer cells. Each cell contains a system of genes that guard the body and turn on a self-destruction program at the first signs of uncontrolled cell division. The most famous cellular suicide gene, about which many articles have been written since the day it was discovered in 1979, is the gene TP53, lying on the short arm of chromosome 17. In this chapter we will talk about the problem of cancer from the point of view of genes, whose task is to ensure the self-destruction of cancer cells.
At the time Richard Nixon declared war on cancer in 1971, scientists knew virtually nothing about their enemy, other than the obvious fact that cells were dividing rapidly in the affected tissues. It was also obvious that in most cases, oncology is neither an infectious nor a hereditary disease. It was generally accepted that cancer is not a separate disease, but a manifestation of a wide variety of dysfunctions of the body, often associated with exposure to external factors that lead to uncontrolled cell division. Thus, chimney sweeps “earn” scrotal cancer as a result of constant contact with tar; X-ray or radiation exposure leads to leukemia; smokers and builders working with asbestos develop lung cancer, etc., etc. It was also clear that the influence of carcinogenic factors may not be direct, but associated with a general weakening of the body’s immune system.
The problem of cancer was looked at from a different angle thanks to the discoveries of several competing groups of scientists. Thus, in 1960, Bruce Ames from California showed that what carcinogens such as X-rays and tar have in common is their ability to destroy DNA. Ames suggested that the cause of cancer lies in genes.
Another discovery occurred much earlier, back in 1909: Peyton Rous proved the infectious nature of chicken sarcoma. His work went unnoticed for a long time, since infection was quite difficult to reproduce in the experiment. But in the 1960s, many new animal oncoviruses were described, including chicken sarcoma virus. At the age of 86, Rous received the Nobel Prize for his early discovery. Soon, human oncoviruses were discovered and it became clear that a whole group of oncological diseases, such as cervical cancer, should be considered to some extent infectious.
As soon as it became possible to sequence (read) the genomes of organisms, scientists learned that the well-known Rous sarcoma virus carries a special gene called src, which is responsible for the oncological transformation of cells. Their own “oncogenes” have been discovered in the genomes of other oncoviruses. Just like Ames, virologists saw the genetic nature of oncology. But in 1975, the emerging theory about the role of genes in the development of cancer was turned upside down. It turned out that the terrible gene src It is not of viral origin at all. This is a normal gene of any organism - chicken, mouse and ours - which the harmful Rous sarcoma virus simply stole from one of its hosts.
More conservative doctors have long refused to acknowledge the genetic basis of cancer - after all, with the exception of some rare cases, oncology is not a hereditary disease. They forgot that the genome has its own history not only from generation to generation, but also in each individual cell of the body. Genetic diseases in individual organs or individual cells, although not inherited, still remain classic genetic diseases. In 1979, to confirm the role of genes in cancer, tumors were experimentally induced in mice by injecting DNA from cancer cells into cells.
Scientists immediately had hypotheses regarding what class of genes oncogenes might belong to. Of course, these must be genes responsible for cell growth and division. Our cells need such genes for prenatal growth of the embryo and for the development of children, as well as for the healing and healing of wounds. But it is extremely important that these genes remain turned off most of the time. Uncontrolled inclusion of such genes leads to disaster. In a “heap” of 100 trillion constantly dividing cells, oncogenes have plenty of opportunities to bypass restrictions and remain turned on even without the help of mutagens such as cigarette smoke or solar ultraviolet light. Fortunately, cells also have genes whose role is to kill rapidly dividing cells. The first such genes were discovered in the mid-1980s by Henry Harris of Oxford, and they were named tumor suppressors. Their action is opposite to the activity of oncogenes. They perform their function in different ways. Typically, the cell development cycle is blocked at a certain stage until the internal control mechanisms check the cell's condition. If the alarm was false, the cell will be unlocked. It became clear that for a cancer cell to arise, two events must occur in it: the inclusion of an oncogene and the destruction of a suppressor gene. The likelihood of both conditions being met is quite low, but that's not the end of the story. Having deceived the suppressor genes, the cancer cell must now undergo yet another more stringent genetic control. Special genes are activated as a result of unnatural cell division and instruct other genes to synthesize substances that kill the cell from the inside. This role is taken on by the gene TP53.
Gene TP53 was first discovered by David Lane in Dundee, UK. At first it was mistaken for an oncogene. Only later did it become known that its role is to suppress cancer cells. Lane and his colleague Peter Hall were once arguing in a pub about the purpose of a gene. TP53, and Hall proposed using himself, like a guinea pig, to prove the anti-cancer role of the gene. To obtain permission to conduct experiments on animals, one had to wait months, and a volunteer was nearby. Hall irradiated a small area of skin on his arm several times, and Lane took tissue samples for biopsy over the course of two weeks. A significant increase in the content of the p53 protein in the cells was found - the product of the gene TP53 following irradiation. The experiment showed that the gene is turned on in response to the action of a carcinogenic factor. Lane continued his research into the p53 protein as an anticancer drug. By the time this book was published, clinical trials of the drug on a group of volunteers under the supervision of doctors were to begin in Dundee. A small Scottish town at the mouth of the Tay, which until now was famous only for burlap and marmalade, is gradually turning into a global center for cancer research. The p53 protein has become the third promising anti-cancer drug developed by Dundee scientists.
Mutation in the gene TP53- one of the necessary conditions for lethal cancer. In 55% of human cancers, a defect in this gene is found in cancer cells, and in lung cancer the mutation is found in more than 90% of cases. In people with a congenital gene defect TP53 on at least one chromosome, the probability of developing cancer at a young age reaches 95%. Take, for example, colorectal cancer. This disease usually begins with a mutation in a suppressor gene APC. If the following mutation in the oncogene occurs in the developed polyp RAS, then an adenoma tumor appears at the site of the polyp. The disease enters a more dangerous phase after the third mutation in one as yet unidentified suppressor gene. But the tumor becomes a lethal carcinoma only after the fourth mutation in the gene occurs TP53. Similar developmental patterns apply to other forms of cancer. And it is always the last mutation to occur in the gene TP53.
Now you can see why early diagnosis of cancer is so important for successful treatment. The larger the tumor becomes, the greater the likelihood of another mutation becomes, both due to the general theory of probability and as a result of the ever-accelerating frequency of cell division, which leads to errors in the genome. People predisposed to cancer often have mutations in so-called mutator genes, which leads to an increase in the number of random mutations in the genome. These genes most likely include breast cancer genes, BRCA1 And BRCA2, which we talked about when considering chromosome 13. Cancer cells are under pressure from the same evolutionary process that weighs on the rabbit population. Just as the offspring of a rapidly reproducing pair of rabbits soon displace their more passive neighbors, in a cancerous tumor lines of rapidly growing cells displace moderately growing cells. Just as in a population of rabbits, only those who skillfully hide from owls and foxes survive and leave offspring, in a cancer tumor, from the many mutations, only those are selected that help cancer cells successfully resist the body’s defenses. The development of a cancerous tumor occurs in strict accordance with Darwin's evolutionary theory. Despite the huge variety of mutations, the course of cancer is similar in most cases. Mutations are random, but the direction of the selective process and its mechanisms are the same for all people.
It also becomes clear why the likelihood of cancer doubles with every decade of our age, being predominantly a disease of older people. As a result of random mutations, some people in the population sooner or later experience mutations in suppressor genes, such as TP53, or in oncogenes, which leads to irreversible and often fatal consequences. The share of oncology among the causes of death of people ranges from 10 to 50% in inverse proportion to the level of development of medicine. The better doctors cope with other diseases, the longer the average life expectancy becomes and, accordingly, the more mutations a person manages to accumulate, and the more likely the occurrence of cancer becomes. The likelihood that, as a result of random mutations, important suppressor genes will be damaged and dangerous oncogenes will be activated is extremely low. But if we multiply this probability by the number of cells in the body and the number of divisions, then by a certain time this probability will turn into a pattern. “One fatal mutation per 100 trillion cell divisions is becoming not so rare,” Robert Weinberg said on this occasion.
Let's take a closer look at the gene TP53. The gene consists of 1179 “letters” and encodes a fairly simple p53 protein, which is quickly destroyed in the cell by other proteins and “lives” on average for no more than 20 minutes. Moreover, all this time the p53 protein is in an inactive state. But as soon as certain signals arise in the cell, protein synthesis rapidly increases, and its degradation by cell enzymes stops. What these signals are is still not clear. Certainly, DNA fragments resulting from the destruction or incorrect copying of chromosomes are one such signal. Broken DNA fragments also affect the activity of the p53 protein itself. Like special forces soldiers, protein molecules rush into the fray. One can imagine the dashing protein p53 walking onto the stage and declaring, “From now on, I am in charge of the operation.” The main function of the p53 protein is to enable other genes and proteins to function. Further events develop according to one of the following scenarios: either the cell stops proliferation and DNA replication until the situation is clarified by special repair proteins, or a self-destruction program is activated.
Another signal that activates the p53 protein is a lack of oxygen in the cell, which is typical for a cancer tumor. Inside a rapidly growing tumor, the blood supply is disrupted and the cells begin to suffocate. Malignant neoplasms cope with this problem by producing special hormones that force the body to grow new arteries to feed the tumor. It is these arteries, reminiscent of the claws of cancer, that the tumor owes its name, used in Ancient Greece. An entire direction in the development of cancer drugs is devoted to the search for substances that block the process angiogenesis- formation of new blood vessels in a cancerous tumor. But usually the p53 protein understands the situation even before the tumor begins angiogenesis and destroys it in the early stages of development. In tissues with poor blood supply, such as skin, the lack of oxygen signal is not clear enough, allowing tumors to develop and neutralize the p53 protein. This is probably why skin melanoma is so dangerous.
It is not surprising that the p53 protein was given the name “Defender of the Genome,” or even “Guardian Angel of the Genome.” Gene TP53 is something like a capsule with poison in the soldier’s mouth, which dissolves only at the first sign of treason. This cell suicide is called apoptosis, from the Greek word for autumn leaf fall. It is the most effective natural remedy against cancer and the body's last line of defense. There is now increasing evidence that almost all modern successful cancer treatments in one way or another affect the p53 protein and its colleagues. It was previously believed that the effect of radiotherapy and chemotherapy was reduced to the destruction of DNA in rapidly dividing cells. But if this is so, why is treatment effective in some cases, while in others it has no effect? There comes a time in the development of any cancerous tumor when its cells stop responding to radiotherapy and chemotherapy. What is the reason for this? If the therapy simply kills growing cells, the effectiveness of the treatment should only increase as the tumor grows faster.
Scott Lowe from the Cold Spring Harbor Laboratory found the answer to this question. "Anticancer therapies do damage some DNA in growing cells," he said, "but not enough to kill them." But fragments of destroyed DNA are the best stimulators of the activity of the p53 protein, which triggers the process of self-destruction of cancer cells. Thus, radio and chemotherapy are more reminiscent of vaccination - the process of activating the body's internal defenses. Experimental data soon appeared confirming Lowe's theory. Radiation, as well as the chemicals 5-fluorouracil, etoposide and doxorubicin, often used in chemotherapy, induced apoptosis in a laboratory tissue culture infected with an oncovirus. And in cases where, in the later stages of the disease, cancer cells stop responding to therapy, this is always accompanied by a mutation in the gene TP53. In untreatable tumors of the skin, lungs, breast, rectum, blood and prostate, a mutation in the gene TP53 occurs in the early stages of the disease.
This discovery was important for the search for new means to combat cancer. Instead of looking for substances that kill growing cells, doctors should look for substances that trigger the process of cell suicide. This does not mean that chemotherapy is useless, but its effectiveness was the result of a coincidence. Now that the mechanisms of therapeutic effects on cancer cells are becoming more clear, we can expect a qualitative breakthrough in the creation of new drugs. In the near future, it will be possible to at least spare patients from unnecessary suffering. If a doctor uses genetic testing to determine that a gene TP53 already destroyed, there is no need to subject the patient to painful but useless therapy in the last months of his life.
Oncogenes, in their normal unmutated state, are necessary for cells to grow and divide throughout the life of the body: skin must regenerate, new blood cells must form, bones must grow together, wounds heal, etc. Mechanisms for suppressing the growth of cancer cells must be regulated so that do not interfere with the normal growth and development of the body. The body has means that allow cells not only to quickly divide, but also to quickly stop growing at the right time. Only now is it becoming clear how these mechanisms are implemented in a living cell. If these control mechanisms were developed by man, we would marvel at his inhuman genius.
Once again, apoptosis is the key element of the system. Oncogenes cause cells to grow and divide, but at the same time, surprisingly, some of them act as triggers of cell suicide. For example, gene Myc is responsible for both cell growth and death, but its killing function is temporarily blocked by external factors called life signals. If life signals stop coming, and the gene protein Myc is still in active form, cell death occurs. The Creator, knowing the unrestrained nature of the gene Myc, provided it with two opposing functions. If in any of the cells the gene Myc gets out of control, the same gene leads the cell to commit suicide immediately after growth signals stop coming. The creator also took additional precautions by linking three different oncogenes together, Myc, Bcl-2 And Ras, so that they control each other. Normal cell growth is possible only if all three genes coordinate their work with each other. According to the scientists who discovered this phenomenon, “as soon as the proportions are violated, the shutter of the trap is triggered, and the cell is dead or in such a state that it no longer poses an oncological threat.”
My story about the p53 protein, like my entire book, should serve as an argument in a dispute with those who consider genetic research dangerous for humanity and propose to limit scientists in every possible way in penetrating the secrets of nature. All attempts to understand the workings of complex biological systems without touching them are flawed and fruitless. The dedicated work of doctors and scientists who have studied cancer for centuries, while worthy of recognition, has yielded little compared to the achievements of the last decade, when doctors got their hands on genetic research methods. One of the first to voice the idea of the Human Genome Project was Italian Nobel Prize laureate Renato Dulbecco in 1986, who simply stated that this was the only way to defeat cancer. For the first time, people have a real opportunity to get a cure for cancer - the most common and terrifying cause of death for modern people. And this opportunity was provided by geneticists. Those who scare people with mythical monsters of genetic experiments should remember this.
Once nature finds a successful solution to one problem, the same mechanism is used to solve other problems. In addition to serving the function of eliminating cancer cells, apoptosis plays an important role in resisting infections. If a cell discovers that it is infected with a virus, it will be better for the body if it self-destructs (sick ants and bees also leave the colony so as not to infect their fellows). There is experimental evidence of the suicide of infected cells, and the mechanisms by which some viruses attempt to block cell apoptosis are known. Such functionality of the membrane protein of the Epstein-Barr virus, which causes mononucleosis, was noted. Two proteins in the human papillomavirus, which causes cervical cancer, block the gene TP53 and other suppressor genes.
As I noted in Chapter 4, Huntington's syndrome causes unscheduled apoptosis of nerve cells in the brain that cannot be replaced. In an adult, neurons do not recover, so damage to the brain and spinal cord often leads to irreversible consequences. Neurons lost their ability to reproduce during evolution, since during the development of the organism, each neuron acquires its own unique functional uniqueness and special significance in the network of neurons. Replacing a neuron with a young, naive and inexperienced cell will do more harm than good. Therefore, apoptosis of virus-infected neurons, unlike apoptosis in other tissues, only leads to escalation of the disease. Some viruses, for as yet unknown reasons, actively stimulate apoptosis of nerve cells, in particular the encephalitic alphavirus.
Apoptosis plays an important role in the elimination of active transposons. Particularly strict control over selfish genes is established for germ cells. It was clear that control functions were assumed by follicular cells in the ovaries and Sertoli cells in the testes. They induce apoptosis in maturing germ cells if they show any signs of transposon activity. Thus, in the ovaries of a five-month female embryo there are up to 7 million eggs. By the time of birth, only 2 million of these remain, and only about 400 eggs will be produced by the ovaries during a woman's lifetime. All other cells, which strict controllers consider not perfect enough, receive a command to commit suicide. The organism is a totalitarian despotic state.
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