No act of creation or vital spark was required to transform dead matter into living matter. Both are made of the same atoms, and the difference lies only in their architecture.
Jacob Bronowski. The Identity of Man
Bronowski begins his famous book The Ascent of Humanity with these words: “Man is a unique creation of nature. He actively changes the world around him, observing the habits of animals and skillfully using the knowledge gained. Modern people“occupied a special position among living beings because they managed to settle on all continents and adapt to any conditions.” But why do people not only inhabit our world, but also actively change it? From a cheetah or from seahorse We are distinguished by genetic inheritance - the totality of DNA in which our existence is encoded. We call this collection the genome or, in this case, human genome.
Our genome is what defines us at a deep level. It is present in each of the approximately 100,000 billion cells that make up the human body and is specific to each individual. But it doesn't end there. The myriad of minute differences inherent in our genome represent our very essence in a genetic and hereditary sense. We pass them on to our descendants, contributing through them to the total evolutionary heritage of our species. To understand the genome is to truly know what it is to be human. There are no two people in the world with exactly the same genome. Even identical twins who share the same genome at conception are born with slight genetic differences. These differences may occur in parts of the genome that are not responsible for coding elements, called genes.
It seems strange that our genome is more than just a collection of genes. But let's not go into details for now and focus on a more general topic. How a person is created from a relatively simple chemical code - complex Living being? How did the human genome develop during evolution? How does he work? Once we ask these questions, we are faced with many mysteries.
To get answers, we need to examine the basic structure of the genome, its OS, mechanisms of expression and control. Some readers may be skeptical about this proposal. Doesn't this mean immersion in incredible mysterious world, too complex for an unprepared person? In fact, this book is intended for precisely such a reader. As you will see basic concepts are easy to understand, you just need to divide our journey into several simple logical stages. The path will pass through a series of brilliant discoveries in the history of mankind and will take us into the distant past, to our ancestors and their knowledge of the Earth in ancient times.
As we travel, new questions will arise, including quite important ones. How does this amazing substance, which we call the human genome, ensure that people reproduce their own kind, that is, the fertilization of the mother's egg with the father's sperm? How does the genome control the incredible process of embryonic development in the womb? Returning for a second to general issues, we note that important element genome and its essence is memory- for example, the memory of the integrity of the genetic heritage of each person. But how exactly is it preserved? We already know that a magical substance called DNA acts as a code. How can code reproduce the complex instructions for creating cells, tissues and organs, and then combine them into a single whole that we call the human body? But even after answering these questions, we will barely touch the mysteries human genome. How does this wonderful structure receive a program that gives the child the ability to develop speech, learn and write? How does a newborn baby turn into an adult who, when he becomes a father or mother, starts this cycle again?
The magic of the genome is that all these processes can be recorded in a tiny cluster chemical substances, including the main molecule - deoxyribonucleic acid, or DNA. This chemical code contains the genetic instructions for creating a human being. Built into it is the freedom of thought and ingenuity that makes the world's artists, mathematicians, and scientists exist. It forms the basis of our inner individuality, what we call our “I”. The same code responsible for this “I” gave humanity the geniuses of Mozart, Picasso, Newton and Einstein. It is not surprising that we look with reverence at the container of such a miracle and dream of revealing the secret that hides the very basis of existence.
We have only recently been able to understand the human genome completely and deeply enough to understand it. amazing story, - for example, that it represents something more than just DNA. This is the story I tried to convey in this book.
Several years ago I gave a lecture on a similar topic at King's College London. The chairman of the meeting asked me if I was ever going to write a book about it. When I answered in the affirmative, he asked me to use language in the book that any untrained person could understand.
How accessible should this book be? - I asked.
Well, imagine that I am your reader and don’t know anything at all.
This is exactly what I promise you. This book will not contain complex scientific language, mathematics or chemical formulas, abstruse terms or dozens of illustrations. I'll start with the basic principles, assuming that my readers know next to nothing about biology or genetics. Even those who are not involved in biology can remember how many surprises the first deciphering of the human genome, the results of which were published in 2001, presented to the world. Discoveries made since then have confirmed that a significant part of the human genome (its evolution, structure and mechanisms of operation) differs from our earlier ideas. These unexpected facts do not detract from the importance of previously accumulated knowledge, but, like any scientific discoveries, only enrich them. Thanks to this new knowledge, humanity has entered the golden age of genetic and genomic enlightenment, covering many areas of our activity - from medicine to early history humanity. I believe that our society must understand the importance of this discovery for the future.
Oswald T. Avery
I probably became a scientist because I was very curious as a child. I remember being 10, 11, 12 years old and constantly asking myself, “Why is this happening? Why do I observe this or that phenomenon? I want to understand him."
Linus Pauling
The Misterious World of the Human Genome
© FPR-Books, Ltd., 2015
© Translation into Russian, edition in Russian, LLC Publishing House "Peter", 2017
© New Science Series, 2017
Introduction
No act of creation or vital spark was required to transform dead matter into living matter. Both are made of the same atoms, and the difference lies only in their architecture.
Jacob Bronowski. The Identity of Man
Bronowski begins his famous book The Ascent of Humanity with these words: “Man is a unique creation of nature. He actively changes the world around him, observing the habits of animals and skillfully using the knowledge gained. Modern people have occupied a special position among living beings because they managed to settle on all continents and adapt to any conditions.” But why do people not only inhabit our world, but also actively change it? What distinguishes us from a cheetah or a seahorse is genetic inheritance - the totality of DNA in which our existence is encoded. We call this collection the genome or, in this case, human genome.
Our genome is what defines us at a deep level. It is present in each of the approximately 100,000 billion cells that make up the human body and is specific to each individual. But it doesn't end there. The myriad of minute differences inherent in our genome represent our very essence in a genetic and hereditary sense. We pass them on to our descendants, contributing through them to the total evolutionary heritage of our species. To understand the genome is to truly understand what it is to be human. There are no two people in the world with exactly the same genome. Even identical twins who share the same genome at conception are born with slight genetic differences. These differences may occur in parts of the genome that are not responsible for coding elements, called genes.
It seems strange that our genome is more than just a collection of genes. But let's not go into details for now and focus on a more general topic. How is a complex living being created from a relatively simple chemical code? How did the human genome develop during evolution? How does he work? Once we ask these questions, we are faced with many mysteries.
To get answers, we need to examine the basic structure of the genome, its operating systems, expression and control mechanisms. Some readers may be skeptical about this proposal. Doesn't this mean immersion in an incredibly mysterious world, too complex for an unprepared person? In fact, this book is intended for precisely such a reader. As you will see, the basic concepts are easy to understand, we just need to divide our journey into several simple logical steps. The path will pass through a series of brilliant discoveries in the history of mankind and will take us into the distant past, to our ancestors and their knowledge of the Earth in ancient times.
As we travel, new questions will arise, including quite important ones. How does this amazing substance, which we call the human genome, ensure that people reproduce their own kind, that is, the fertilization of the mother's egg with the father's sperm? How does the genome control the incredible process of embryonic development in the womb? Returning for a second to general issues, we note that an important element of the genome and its essence is memory– for example, the memory of the integrity of the genetic heritage of each person. But how exactly is it preserved? We already know that a magical substance called DNA acts as a code. How can code reproduce the complex instructions for creating cells, tissues and organs, and then combine them into a single whole that we call the human body? But even having answered these questions, we will barely touch the mysteries of the human genome. How does this wonderful structure receive a program that gives the child the ability to develop speech, learn and write? How does a newborn baby turn into an adult who, when he becomes a father or mother, starts this cycle again?
The magic of the genome is that all these processes can be recorded in a tiny cluster of chemicals, including the main molecule - deoxyribonucleic acid, or DNA. This chemical code contains the genetic instructions for creating a human being. Built into it is the freedom of thought and ingenuity that makes the world's artists, mathematicians, and scientists exist. It forms the basis of our inner individuality, what we call our “I”. The same code responsible for this “I” gave humanity the geniuses of Mozart, Picasso, Newton and Einstein. It is not surprising that we look with reverence at the container of such a miracle and dream of revealing the secret that hides the very basis of existence.
We have only recently been able to understand the human genome completely and deeply enough to understand its amazing history - for example, that there is more to it than just DNA. This is the story I tried to convey in this book.
Several years ago I gave a lecture on a similar topic at King's College London. The chairman of the meeting asked me if I was ever going to write a book about it. When I answered in the affirmative, he asked me to use language in the book that any untrained person could understand.
– How accessible should this book be? – I asked.
- Well, imagine that I am your reader and don’t know anything at all.
This is exactly what I promise you. This book will not contain complex scientific language, mathematical or chemical formulas, abstruse terms or dozens of illustrations. I'll start with the basic principles, assuming that my readers know next to nothing about biology or genetics. Even those who are not involved in biology can remember how many surprises the first deciphering of the human genome, the results of which were published in 2001, presented to the world. Discoveries made since then have confirmed that a significant part of the human genome (its evolution, structure and mechanisms of operation) differs from our earlier ideas. These unexpected facts do not detract from the importance of previously accumulated knowledge, but, like any scientific discoveries, they only enrich it. Thanks to this new knowledge, humanity has entered a golden age of genetic and genomic enlightenment, covering many areas of our activity - from medicine to early human history. I believe that our society must understand the importance of this discovery for the future.
1. Who would have thought?
The big, important and often discussed question is this: how should physics and chemistry analyze space-time phenomena occurring within a living organism?
Erwin Schrödinger
In April 1927, a young Frenchman named Rene Jules Dubos arrived at the Rockefeller Institute for Medical Research in New York to undertake a seemingly hopeless task. This a tall man bespectacled, recent graduate of Rutgers University and recipient of doctorate in soil microbiology, had an unusual philosophical approach to science. After reading the works of the prominent Russian microbiologist Sergei Vinogradsky, he came to the conclusion that there was no point in studying bacteria in test tubes and laboratory cultures. Dubos believed that in order to understand bacteria, you need to observe them where they live and interact with each other and with life in general - in nature.
After graduating from university, Dubos was unable to find a job. He applied for a grant to the Research Council, but it was rejected because the scientist was not American. However, in the margin of the refusal letter, someone wrote a handwritten note (Dubos later recalled that the handwriting was female - probably the entry was made by the kind secretary of some official): “Why don’t you seek help and advice from your famous compatriot, Dr. Alexis Carrel of the Rockefeller Institute? Dubos followed this recommendation, and in April 1927, he arrived at the address on York Avenue on the banks of the East River.
Dubos had never heard of Carrel or the Rockefeller Institute for Medical Research before and was intrigued to learn that Carrel was a vascular surgeon. Dubos had no academic knowledge of medicine, and Carrel had no idea about microbes living in the soil. The result of their conversation was predictable: Carrel could do nothing to help the young scientist. The conversation ended in the middle of the day, and Dubos decided to have lunch in the institute's canteen, which attracted the hungry Frenchman with the smell of freshly baked bread.
At some point, a short, frail-built gentleman with a round bald head sat down next to Dubos. A stranger speaking with a Canadian accent politely addressed our hero. This man's name was Oswald Theodore Avery. Dubos later admitted that he knew as little about him as he did about Carrel, but Professor Avery (or Fess, as his relatives called him) was at that time a luminary of medical microbiology. This meeting was of historical significance for both biology and medicine.
Avery made Dubos his research assistant, and while working in this post, Dubos discovered the first antibiotics based on the culture of soil bacteria. At the same time, Avery and his small team, working on what he called “little kitchen chemistry,” were engaged in another problem, by solving which they hoped to obtain the key to the secret of heredity. Why does society know almost nothing about this brilliant scientist? To explain this anomaly, we need to go back in time and talk about Avery himself and the problems he faced three quarters of a century ago.
* * *
In 1927, when Dubos met Avery, scientists still had little understanding of the principles of inheritance. The term "gene" was coined two decades earlier by the Danish geneticist Vilhelm Johansen. Interestingly, Johansen himself adhered to a vague concept of inheritance called “pangen”, which was proposed by Charles Darwin. Johansen modified it taking into account the discoveries made in the 19th century by Gregor Mendel.
Readers may be familiar with the story of Mendel, the abbot of the Augustinian monastery in Brno in Moravia (today part of the Czech Republic). Mendel looked like the monk Tuck, loved cigars and spent brilliant Scientific research crossing peas in the monastery garden. These experiments allowed him to formulate the foundations of modern laws of inheritance. It turned out that some characteristics of the parent generation of peas were passed on to their offspring in a predictable way. These characteristics included plant height, the presence or absence of yellow and green hues in flowers or leaf axils, and the wrinkled or smooth surface of the peas. Mendel discovered that the primordial germ cells of plants are responsible for heredity (later this conclusion will be extrapolated to all living organisms), which are discrete packets of information encoding certain physical characteristics, or traits. Johansen derived the term “gene” from Mendel’s image of a package of hereditary information. Around the same time, the British scientist William Bateson derived from the word “gene” the name of the discipline concerned with the nature and processes of inheritance - genetics.
If you open a modern explanatory dictionary on the Internet, you can find the following definition of a gene: “Basic physical unit inheritance; a linear sequence of nucleotides that represents a segment of DNA and contains encoded instructions for the synthesis of RNA, which, when converted into protein, results in the expression of hereditary properties.” But Mendel didn’t imagine genes that way at all, and he didn’t even know about DNA. His research was published in unpopular publications, forgotten for 40 years, and then rediscovered and reinterpreted. However, in his time, Mendel's idea of genes as discrete elements of heredity helped reveal an important medical mystery: how some diseases manifest themselves through hereditary distortions.
Today we know that genes are the basic constituent elements heredity. They are akin to atoms, particles of matter that make up the entire physical world. In the early decades of the 20th century, no one had any idea what genes were made of or how they worked, but some scientists tried to study them through physical expression, such as in the formation of embryos or during hereditary diseases. Geneticist Thomas Hunt Morgan, working in a laboratory in Chicago, used fruit flies as an experimental model for his pioneering research. His collaborators discovered that genes are located on chromosomes, structures found in the nuclei of insect sex cells. Botanist geneticist Barbara McClintock has confirmed that this is also true for plants. She developed technologies that allowed biologists to see chromosomes in corn cells. This led to an incredible discovery: it turns out that during the formation of male and female germ cells, the matching, or homologous, chromosomes of both parents are located opposite each other, and then exchange identical parts. So the descendant inherits mixed signs father and mother. This interesting genetic phenomenon (called homologous sexual recombination) explains why children of the same parents are different from each other.
By the early 1930s, biologists and medical researchers already understood that genes are physical objects - chemical information blocks strung on chromosomes, like beads on a fishing line. To use another comparison, the genome can be called a library of chemical information, in which chromosomes play the role of books. In this case, discrete units called genes are individual words on the pages of a book. Libraries are stored in the nuclei of germ cells, that is, in eggs and sperm. The human library has 46 books in each cell. The egg and sperm each contain 23 chromosomes, and when a child is conceived, the two sets of chromosomes fuse together in the fertilized egg. But the answer to one inheritance mystery has only opened a Pandora's box of new genetic mysteries that are found in abundance among the living organisms of our fertile planet.
For example, do all life forms - from worms to eagles, from protists swarming in the mud of reservoirs to humanity - have the same genes in their chromosomes?
Microscopic single-celled creatures (bacteria, archaea and others) do not store hereditary information in the nucleus. Such living organisms are called prokaryotes, that is pre-nuclear. All other forms of life, called eukaryotes, hereditary information is contained in cell nuclei. Studies of fruit flies and plants, as well as medical experiments, show that all eukaryotes share common underlying features. But is it possible to apply the same genetic concepts(starting with the gene) to prokaryotes that reproduce vegetatively by budding and do not form germ cells? At the dawn of bacteriology, there was debate about whether bacteria could even be considered forms of life. And viruses, which are often much smaller than bacteria, have been very poorly studied.
Over time, many scientists came to the conclusion that bacteria are living organisms and began to classify them according to the binomial Linnaean system. Thus, the causative agent of tuberculosis was named Mycobacterium tuberculosis, and the coccus-like microbe that causes suppuration is Staphylococcus aureus. An extreme conservative, Oswald Avery was in no hurry to join either camp, refrained from using the binomial system, and still used the expression “tuberculosis bacterium.” Interestingly, Dubos, who knew Avery better than other colleagues, observed the same conservatism in his approach to laboratory research. Science must, with puritanical rigor, adhere only to facts that can be logically deduced and unequivocally confirmed in the laboratory.
In 1882, the German doctor Robert Koch discovered that the causative agent of a deadly disease at that time - tuberculosis - was Mycobacterium tuberculosis. Koch compiled logical rule to identify the pathogenicity of a particular microorganism. This rule is called Koch's postulates. Once identified, the causative agent was examined under a microscope and properly classified. If the cells of a microorganism were round, it was called a coccus, if it was oblong, it was called a rod, and if it was spiral-shaped, it was called a spirochete. Bacteriologists methodically examined the culture medium in which a particular organism grows best: pure agar or agar with the addition of bovine blood or something else. They also studied the appearance of bacterial colonies on culture plates: their color, size, chaotic or orderly boundaries, convexity or flattening, granularity, and the various geometric shapes that a particular colony took. The scientific basis of bacteriology textbooks expanded due to precise research and observations. As knowledge grew, more and more discoveries were used in the fight against infections.
Among useful information, which bacteriologists received about disease-causing (pathogenic) bacteria, there was also the following fact: the course of the disease and, accordingly, the behavior of the pathogen in relation to the carrier of the disease can be changed using certain measures (for example, using a certain sequence of cultures in the laboratory or infecting experimental animals with bacteria of different generations ). Such manipulations made it possible to strengthen or weaken the disease, making the microbe more or less virulent. Bacteriologists were looking for ways to use this knowledge in medicine. Thus, in France, Louis Pasteur applied the principle of weakening pathogens and developed the first effective vaccine against rabies, which was considered a fatal disease.
As a result of these studies, scientists also noticed that as a microbe's virulence increased or decreased, changes in its behavior were passed on to future generations. But can this happen due to some changes in heredity?
Bacteriologists explained this phenomenon adaptation. This term just began to come into fashion among evolutionary biologists and denoted evolutionary changes in living organisms that arise over time in connection with adaptation to the environment. At that time, scientists did not yet assume that the heredity of bacteria could be determined by genes, so they tried to associate it with physical structure the microorganisms themselves and their colonies, with internal chemical processes or even with their behavior towards the carriers. These were measurable characteristics, the bacterial equivalent of what evolutionary biologists call phenotype(collection physical properties organism as opposed to genotype, that is, a complex of genetic characteristics).
Bacteriologists have also found that the same bacteria can exist in several subtypes, the difference between which is often determined by antibodies. Such subtypes are called serotypes. In 1921, the British bacteriologist J. A. Arkwright noticed that colonies of the virulent type of dysentery pathogen Shigella, grown on mucus-coated culture plates had a smooth surface and a convex hemispherical shape, while colonies of weakened and nonvirulent bacteria of the same species had broken boundaries and a rough surface and were much flatter. To describe the characteristics of such colonies, he introduced the terms “smooth” and “rough” (or S and R - from English words smooth and rough). Arkwright noted that R forms arise in cultures grown in an artificial environment, and not in colonies of bacteria taken from the tissues of an infected person. He came to the conclusion that he was witnessing with his own eyes the Darwinian process of evolution.
Here's how Arkwright wrote about it: “The infected human body may be considered the environment that gives pathogenic bacteria the form in which we usually find them.”
Soon, researchers from other countries confirmed that the loss of virulence in some pathogenic bacteria was accompanied by similar changes in appearance colonies. In 1923, Frederick Griffith, an epidemiologist working for the Ministry of Health in London, reported that pneumococci (the causative agents of epidemic pneumonia and meningitis, which were of particular interest to Oswald Avery at the Rockefeller Laboratory) formed similar S and R forms in culture plates. Griffith was known as a conscientious scientist, and Avery was intrigued.
Griffith's experiments had other results that amazed and even shocked Avery.
Griffith once injected laboratory mice with nonvirulent R-type pneumococci, a strain known as type I. To the injection, he had to add a so-called adjuvant, a substance that stimulates an immune response to R-type pneumococci. The most common adjuvant in this case was mucus from the stomach of the experimental animal. But for some unknown reason, Griffith replaced the adjuvant with a suspension of S-pneumococci derived from a type II strain that had been specifically killed by heat. Laboratory mice died from an acute infection, and Griffith expected to find in their blood a large number of breeding R-bacteria type I, which he introduced at the beginning of the experiment. Imagine his surprise when he found S-bacteria type II instead! How could adding dead bacteria to an injection change the serotype of live bacteria from R-type I to the extremely virulent S-type II?
Researchers, including Avery, had already shown that the difference between types S and R was determined by differences in the composition of the polysaccharide capsules in which the bacterial cells were enclosed. Griffith's experiment showed that the test bacteria, originally R-type pneumococci, changed their polysaccharide membranes inside the infected organisms and brought them into line with the virulent strain. But they couldn't just shed one shell and put on another. The composition of the shell is determined by the heredity of the bacterium - it is an inherited characteristic. Cultures of type S bacteria obtained from dead bodies mice continued to reproduce. There could only be one explanation for this: the addition of dead S-bacteria to living R-bacteria caused a mutation in the latter and literally transformed them into type II S-bacteria.
According to Dubos, “[at the time] Griffith considered it natural that any change should remain within the species. He had no idea that the type of pneumococcus could be changed - it was akin to changing from one type to another. Nothing like this has ever been seen before.”
* * *
Not surprisingly, Avery was shocked by Griffith's discoveries. Like Robert Koch before him, Avery believed that the heredity of bacterial strains remains unchanged. The very concept of mutation, that is, a change in heredity under the influence of the actions of an experimenter, was at that time a very controversial issue both in biology and in medicine. To understand why, we must first explain what it is mutation.
IN late XIX century, a crisis began in Darwinian theory. Darwin himself understood that the process of natural selection relied on some additional mechanism or mechanisms capable of altering heredity so that several heritable variations could be selected from. Many decades later, Julian Huxley pointed this issue out directly in the early chapters of his book Evolution: A Modern Synthesis: “Natural selection as an evolutionary principle underwent an important critical rethink, and attention then became focused on the nature of heritable variation.” In 1900, the Dutch biologist Hugo de Vries proposed an innovative mechanism that could allow such variation to occur: the concept of random changes in a unit of inheritance. The opportunity for change arises when genes are copied during the process of reproduction. An error in copying hereditary information can lead to an accidental change in gene coding. De Vries called this source of hereditary change mutation. After this, Julian Huxley developed the theory of synthesis, combining Mendelian genetics (including the potential for changing inherited genes through mutation) and Darwinian natural selection, acting on hereditary variations within a species. Only after this did Darwin's theory regain its authority in scientific circles.
After some time, it will be proven that the results of Griffith's experiment are precisely mutation - the process that Avery was so interested in. Geneticists will show that the transformation of R-type pneumococci into S-type pneumococci was achieved by the transfer of genes from dead bacteria of strain II to living bacteria of strain I. The transferred genes were incorporated into subsequent reproduction cycles, during which R-type I bacteria were transformed into S-type II . At the bacterial level, this was tantamount to a change in species. Griffith was right in believing that Darwinian natural selection was at work even during short periods of illness in laboratory mice.
The results of Griffith's experiments shook the bacteriological and immunological communities. His discovery was confirmed by several research centers, including the Robert Koch Institute in Berlin, where pneumococci were first classified into several types. This news was also widely discussed in Avery’s team, but Dubos recalls: “At first we didn’t even try to repeat these experiments. We were amazed and, one might even say, intellectually paralyzed by these incredible results.”
From the very beginning, Avery simply did not believe in the possibility of transformation different types bacteria. This is understandable, because he was one of the authorities in his field and many years ago became convinced of the stability of bacterial reproduction. But in 1926, Avery invited the young Canadian doctor M. G. Dawson, who worked in the laboratory of the Rockefeller Institute, to study this issue. According to Dubos, Dawson, unlike Avery, was confident in the correctness of Griffith's conclusions, since he believed that “if the work was done by the British Ministry of Health, there could be no errors in it.”
Dawson began by confirming Griffith's discovery in experiments with laboratory mice. His work showed that most of non-virulent bacteria (R-type) can, under certain circumstances, transform into pathogenic S-type. By 1930, Dawson's Chinese colleague Richard P. Hsia began working on the same question. Together, they advanced their experimental observations even further, proving that hereditary transformations can occur not only in mice, but also in the cultural environment. At this stage Dawson left Avery's department and his work was continued by another young doctor, J. L. Alloway. He found that all that was required to initiate transformation was a soluble fraction, obtained by exposing living S-pneumococcal cells to sodium deoxycholate and then filtering the solution to remove cell fragments. When Alloway added alcohol to the filtered solution, the active material precipitated out in the form of a sticky syrup. This syrup was called the transforming principle in the laboratory. The work continued, the years passed, experiment followed experiment.
When Alloway left the department in 1932, Avery devoted some of his own time to researching the transformations of pneumococci, in particular to refining the process for preparing the transforming substance. However, one disappointment after another awaited him along this path. After some time, Avery decided to focus on chemical composition transformative beginning. Lively discussions began in the laboratory: someone believed that it was “plamagen”, which supposedly causes cancer in chickens (today we know that this term meant a retrovirus), someone believed that genetic changes in bacteria have a viral nature. According to Dubos, Alloway suggested that the transforming agent could be a protein-polysaccharide complex. But by 1935, Avery began to think in a different direction. In the department's annual report, he indicated that it was possible to obtain a transforming material that did not contain capsular polysaccharides. In 1936, biochemist Rollin Hotchkiss, who became a member of Avery's department, made a historical note in personal diary: “Avery convinced me that the transforming agent was unlikely to be a carbohydrate and that it also had little resemblance to protein, and then dreamily suggested that it might be a nucleic acid!” At that time, Dubos, who many years later would write a book about Avery and his work, regarded this as just another speculation. And there were good reasons for this.
That year, several researchers from different countries the world suggested that nucleic acids could be the key to the secret of inheritance. These compounds were discovered at the end of the 19th century by the Swiss biochemist Johann Friedrich Miescher. He was interested in the chemistry of cell nuclei, and from white blood cells contained in pus, as well as from salmon sperm, he was able to isolate a new chemical compound highly acidic, rich in phosphorus, and made up of incredibly large molecules. After years of research, Miescher's student Richard Altmann coined the term "nucleic acid" to describe this discovery. By the 1920s, geneticists knew that there were two types of nucleic acids: ribonucleic acid, or RNA, which is made up of four structural substances (guanine, adenine, cytosine and uracil, or GACU), and deoxyribonucleic acid, or DNA, which is the main component chromosomes. Its elements are almost identical to the components of RNA, only instead of uracil, DNA contains thymine (GACT). Scientists knew that these basic components could be divided into two pairs of similar organic matter: Adenine and guanine are pyrines, and cytosine and thymine are pyrimidines. It was also clear that, when bonding, these substances form very long molecules. Initially, geneticists believed that RNA was characteristic of plants and DNA was characteristic of animals, but by the early 1930s it was discovered that both nucleic acids were equally common in both plant and animal kingdoms. However, the role of nucleic acids in the cell nucleus was still unclear.
Frank Ryan
The mysterious human genome
Oswald T. Avery
I probably became a scientist because I was very curious as a child. I remember being 10, 11, 12 years old and constantly asking myself, “Why is this happening? Why do I observe this or that phenomenon? I want to understand him."
Linus Pauling
The Misterious World of the Human Genome
© FPR-Books, Ltd., 2015
© Translation into Russian, edition in Russian, LLC Publishing House "Peter", 2017
© New Science Series, 2017
Introduction
No act of creation or vital spark was required to transform dead matter into living matter. Both are made of the same atoms, and the difference lies only in their architecture.
Jacob Bronowski. The Identity of Man
Bronowski begins his famous book The Ascent of Humanity with these words: “Man is a unique creation of nature. He actively changes the world around him, observing the habits of animals and skillfully using the knowledge gained. Modern people have occupied a special position among living beings because they managed to settle on all continents and adapt to any conditions.” But why do people not only inhabit our world, but also actively change it? What distinguishes us from a cheetah or a seahorse is genetic inheritance - the totality of DNA in which our existence is encoded. We call this collection the genome or, in this case, human genome.
Our genome is what defines us at a deep level. It is present in each of the approximately 100,000 billion cells that make up the human body and is specific to each individual. But it doesn't end there. The myriad of minute differences inherent in our genome represent our very essence in a genetic and hereditary sense. We pass them on to our descendants, contributing through them to the total evolutionary heritage of our species. To understand the genome is to truly know what it is to be human. There are no two people in the world with exactly the same genome. Even identical twins who share the same genome at conception are born with slight genetic differences. These differences may occur in parts of the genome that are not responsible for coding elements, called genes.
It seems strange that our genome is more than just a collection of genes. But let's not go into details for now and focus on a more general topic. How is a complex living being created from a relatively simple chemical code? How did the human genome develop during evolution? How does he work? Once we ask these questions, we are faced with many mysteries.
To get answers, we need to examine the basic structure of the genome, its operating systems, expression and control mechanisms. Some readers may be skeptical about this proposal. Doesn't this mean immersion in an incredibly mysterious world, too complex for an unprepared person? In fact, this book is intended for precisely such a reader. As you will see, the basic concepts are easy to understand, we just need to divide our journey into several simple logical steps. The path will pass through a series of brilliant discoveries in the history of mankind and will take us into the distant past, to our ancestors and their knowledge of the Earth in ancient times.
As we travel, new questions will arise, including quite important ones. How does this amazing substance, which we call the human genome, ensure that people reproduce their own kind, that is, the fertilization of the mother's egg with the father's sperm? How does the genome control the incredible process of embryonic development in the womb? Returning for a second to general issues, we note that an important element of the genome and its essence is memory- for example, the memory of the integrity of the genetic heritage of each person. But how exactly is it preserved? We already know that a magical substance called DNA acts as a code. How can code reproduce the complex instructions for creating cells, tissues and organs, and then combine them into a single whole that we call the human body? But even having answered these questions, we will barely touch the mysteries of the human genome. How does this wonderful structure receive a program that gives the child the ability to develop speech, learn and write? How does a newborn baby turn into an adult who, when he becomes a father or mother, starts this cycle again?
Then we get our boots and go outside.
We play square on a marked area of the field. Eight people pass the ball to each other, and two in the middle try to intercept it. This exercise helps us get used to the ball. We then do short spurts between the cones to fire up our lungs and legs.
Now comes my favorite part of training – the game.
I never know what we will practice in a particular game. Sometimes we work on possession, sometimes on tactics. Today we are looking at how we will break into the opponent’s defense for the next match – Charlton. At this time, the Manager stands on the edge of the field and watches us play. He demands to increase the pace when necessary. He demands that we get the ball into the penalty area faster. He changes our places.
In a practice game, everyone wants to win, even in the format as it is now - eight on eight. The tackles fly one after another.
Wes Brown makes a late tackle, his foot over the ball. He hits me on the ankle. I'm in the penalty area, but the referee, our physical training coach, doesn't whistle. My team is complaining, I'm furious. A few moments later, in the same place, Wes catches me again. His spikes fly into the air and it's a flagrant foul, but again there's no sign of us getting a penalty. Wes runs to the other end of the field and scores.
The manager watches from the edge. Suddenly he stops the game.
- Guys, calm down! Be careful with tackles. I don't want anyone to get hurt.
The next time I'm in the penalty area, I feel a slight touch and decide to dive (we're all guilty of this in training).
I'm furious!
I start screaming at the referee because I want to win this game as much as I want to win a Premier League match against Chelsea, City or Aston Villa. Quarrels happen regularly, but this is par for the course. The fighting spirit comes from the Manager - he wants us to train as if we were playing for real.
The referee whistles.
Game over.
I'm pissed that we lost, but I'm staying to work on my shots. I hit the goal for ten minutes. It's all part of the routine: I prepare for any opportunity that might come my way over the weekend.
I've been hitting since the summer.
I shoot from outside the penalty area.
I hit after a pass, which I receive on my chest.
Penalties, free throws.
One of the coaches puts me with my back to the ball. He passes the ball into the penalty area in a random direction and then calls out to me. I turn around, react and hit as quickly as possible. This kind of drill prepares me for loose balls - I have to be alert at all times.
I'm not alone. When I look at the training ground, I see different players working on different drills. Rio practices heading, our goalkeeper Tim Howard practices crosses, and Giggsy practices free kicks.
We can all improve, even at United.
People constantly talk about the art of goalscoring and whether it is due to hard training or natural talent. To be honest, I believe that goals come from a combination of both factors. You can train some things, but you cannot train instinct. Either he is, or he is not.
I probably have it. Always was. Even as a child, I felt all the restless balls in the penalty area. When I'm up front at United, I'm always ready for action. Sensitive to any scoring opportunity. All the time I try to guess where the ball will be in the next second so that I have time to prepare. I search, look out, guess loose balls and defensive errors, but this is a natural ability. Anticipating which way to move (and then scoring if you're one-on-one with the goalie) is a skill that some players have and some don't. It is this instinct that can make the difference between scoring five or twenty-five goals in a season, at any level.
Every time I play for United I have to react differently to everything that happens around me. If I see one of our wingers - Ronaldo or Giggsy, for example - crossing from the flank, my instinct tells me to run to the far post. I know that the ball can go to the side and I will have the opportunity to finish it. If I see Scholesy or Alan Smith shoot, I always look for the rebound. It may fly in my direction, or it may not fly away. But even if I only get it once in 20 tries, it could be enough for an extra two or three goals in the season.
It's not just about predicting the flight of the ball after a shot or pass - it's also about reading body position. Before a decisive action on the wing or in the center, I carefully monitor what position my teammate will choose before passing. From his movement, I can roughly estimate where he is going to pass the ball, and I run to that point.
If I'm lucky and have judged everything correctly, I end up in front of the goal with the ball. That's when I have to be ready for the next action: control, movement, strike. This is where the training comes in.
By constantly working on technique, I develop muscle memory. I instinctively know what to do when a pass comes my way. If the ball hits me on the chest near the penalty mark, without thinking twice I know how to put it down and hit it because I'm training my brain. Not only me. All the best scorers in the world do the same thing.
I train everything: long shots, volleys, rebounds, set pieces. My movement in the box has improved a lot over the years thanks to experience, plus I do benefit from great crosses from teammates like Giggsy and Ronaldo - but only when he gets off the ball quickly. Don't get me wrong, Ronnie is developing into a great footballer, but if we play together, I never know what he's going to do next.
He goes to the flank. I am running.
It moves to the center. I stop and make a dash in the other direction.
He steps back. I stop again and then break the offside position.
He curls the ball into the penalty area, and I stand there disappointed. Sometimes it's really annoying.
We finish just after noon. At the end of each session we relax. Some people jump into ice baths, others go to the pool. After that the gym. It looks a bit like an old-school leisure centre: mats, weights, bikes, one of those green drapes that separates the two halves of the gym. Ryan sometimes does yoga after working out. I tried it once or twice, but it's not my thing - too boring. For 45 minutes, the instructor forces me to stretch and hold a certain position. When I ask Giggsy why he does it, especially when it's so boring, he tells me it strengthens his muscles.
“I think it extends a player's career by increasing their flexibility,” he hopes.
Maybe in a few years I will be able to get into yoga better. Right now I don't feel like I need it.
Sometimes I study in gym, but only if I am injured and cannot participate in training or run normally. If we have a free week - this is when there is a game on Saturday, and then the next Saturday without matches in between - the whole team works out with weights. Some players work according to a program, others do everything their own way. I go there from time to time, but really, if there's no ball, I'm not interested.
I just want to play football.
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