Blazing the Gene Trail

ANY INTELLIGENT fool can make things bigger and more complex. . . It takes a touch of genius, and a lot of courage, to move in the opposite direction. — Albert Einstein From the time of Gregor Mendel’s experiments on pea plants to the completion of Human Genome Project, medical science has made many advances that have helped us understand the mechanisms of the human body. In fact, gene therapy and stem cells allow us today to foresee diseases and to take measures to prevent their occurrence. Mendel, an Augustanian monk of the nineteenth century, led to the foundation of genetics as a scientific discipline through his work on garden pea plants. While working in a distinguished monastery of St Thomas in a town currently located in the Czech Republic, he observed that the characteristics of plants, such as the shape of a seed and the length of a plant, were inherited from a parent plant and passed onto subsequent generations. The thing that made Mendel’s work stand out was his ability to identify the dichotomized traits of plants, such as round seeds versus wrinkled seeds and his selection of true breeding varieties of pea plants. He observed that a true breeding variety of a pea plant germinated from a round seed always produced round seeds if allowed to self-pollinate (pollen from the flower fertilizes the eggs of the same flower), or a tall parent pea plant always produced tall plants. On the basis of this simple observation, he concluded that traits were passed on from one generation to another and were controlled by factors or units which we now call genes. Mendel extended his observations in the form of scientific experiments in which he grew more than 33,500 pea plants from 1856 to 1863. In these experiments, in addition to self-pollination, he introduced cross-pollination in pea plants — that is, cross-pollination in pea plants — that is, cross-breeding tall plants with short ones or plants having round seeds with plants having wrinkled ones. He observed these plants for generations and eventually proved that the fate of a particular trait in a plant was controlled by two copies of the same factor or unit (gene), one copy being inherited by each parent plant. Mendel was the first person who scientifically proved that traits were inherited. Shortly before his death, he told one of the younger monks: “My scientific work has brought me a great deal of satisfaction, and I am convinced that it will be appreciated before long by the whole world. “Mendel’s work on pea plants led to the foundation of the field of genetics and only 16 years later, other scientists in Europe duplicated his work and published similar results, fulfilling Mendel’s prophecy. Although he proved inheritance scientifically, the description of disorders and traits which pass from one generation to the next appear in ancient myths too. In some ancient cultures, piety and one’s closeness to God was considered to be a heritable trait, as priests to kings and queens were selected from a particular family only. A couple of centuries before Mendel’s carefully conducted and controlled experiments on pea plants, Frederick William I, when crowned as a king of Prussia in 1713, began recruiting tall soldiers in his army. He wanted his army to be full of giants. He was so obsessed with this idea that he ordered that every tall soldier marry a tall woman so that their future generations would be tall. Surprisingly, his human breeding experiments were a complete failure as most of the children born as a result of his selective breeding were shorter than their parents. One can’t help but wonder what went wrong with the king’s experiments. The difference between the two breeding experiments was in the units controlling height in pea plants, on the one hand, and humans, on the other. Presently, we know that there is only one gene (Mendel called it a “factor”) for controlling length in pea plants. However, in humans it is a combination of different genes and environmental factors that determines height — a continuous variable. The inheritance of height in humans is thus rather “complex”. There are other traits and diseases controlled by the interplay of genetic and environmental factors. It is comparable to a jigsaw puzzle, where every piece is important to make a complete picture. In humans, these include height, intelligence, skin colour and severe diseases like myocardial infarction (heart attacks), stroke and hypertension. However, it must be emphasized that there are traits and diseases in humans which are inherited the same way as the length of the plant or the shape of the seed is inherited in peas — that is, inheritance is controlled by a single gene. Such diseases include cystic fibrosis, Huntington’s disease and sickle-cell anemia and are caused by defect in a single gene. Such traits and disorders are known as monogenic. The difference between monogenic and complex disorders was completely unknown in the beginning of the last century. In the early twentieth century, Francis Galton, a cousin of Charles Darwin, believed that certain families were superior to others. He was the founder of Eugenics, a movement mounted by a group that believed that people with traits, such as intelligence, leadership skills and musical ability should be allowed to have larger families whereas people with undesirable traits should not be allowed to reproduce. The biggest flaw of eugenics was the complete lack of knowledge about environmental factors which influence complex traits. Galton believed that noble traits ran in families. It was as part of this movement that socially unacceptable people from Great Britain were shipped to faraway islands, such as Australia, from where they could not escape to return to their homeland. The forced relocation of people from Great Britain to Australia was initially limited to criminals and began in the eighteenth century owing to overcrowded prisons there. Eugenics reached the United States in the third decade of the last century. The US government was so influenced by the concept that the Supreme Court in 1927 upheld the right of the state of Virginia and all other states in the country to use forced sterilization (a process by which a man or a woman was biologically disabled to reproduce). The ruling included the following statement: “It is better for all the world, if instead of waiting to execute degenerate offspring for crime, or to let them starve for their imbecility, society can prevent those who are manifestly unfit from continuing their kind. The principle that sustains compulsory vaccination is broad enough to cover cutting the fallopian tubes. “By the mid-1930s, about twenty thousand sterilizations had been carried out. This regulation is still applicable to many US states, although federal regulations restrict its use. The Nazis in Germany were quick to follow suit. They wanted to have a strong and disease-free society. They did not ship criminals to a faraway island or sterilized women. Instead, they appointed special doctors who killed all those people who were mentally retarded, physically disabled or deformed, or who were thought to be social misfits. They called the ruthless termination of lives as “mercy killings”, which further extended to newborns with hereditary disorders and to adults in psychiatric hospitals. Later, they expanded the rule to include all those who belonged to other ethnicities and religions, including Jews. During the killings, the doctors isolated the diseased organs and studied them for scientific reasons. Although this highly unethical research led to the understanding of disorders like the Hallervorden-spatz syndrome (a paediatric disorder in which there is an excessive accumulation of iron in the brain), it also made scientists look like monsters. Thus, genetic studies were avoided until the end of the Second World War. The discovery that revived genetics was the unveiling of the DNA structure by Watson and Crick in 1953. The double helix, an essential feature of every biology book today, was indeed one of the greatest d
iscoveries of the twentieth century. The helical structure of the DNA molecule — the “code of life” — has led to a series of discoveries in the past six decades, which have helped in decoding many human disorders. However, it should not be inferred from this discussion that before Watson and Crick, the chemical nature of DNA was not being investigated. On one hand, if people like Mendel were busy studying inheritance through experiments on plants, scientists like Fredrich Mieshcer in 1868, while studying the chemical nature of different cells including sperm cells, concluded that nuclein (nucleic acid) in some way was associated with inheritance. Although he did not have any direct evidence, Oswald T. Avery, Maclyn McCarty and Colin Macleod, in 1944, were the first ones who demonstrated DNA as a carrier of genetic information. The 160 years of genetic journey, starting from the work of Mendel, is still continuing and scientific knowledge continues to grow in a logarithmic manner. The completion of the Human Genome Project is one of the most important achievement of recent times. This project, involving thousands of scientists, has generated the DNA sequence of the entire human genome. For purposes of analogy, we can compare the DNA sequence to a building made up of four different types of bricks. Watson and Crick identified the DNA structure and proved that the human building was composed of bricks called nucleotides, namely consisting of Adenine (A), Cytosine (C), Guanine (G) and Thymine (T). Each one, from viruses to humans, is made up of a particular order of these nucleotides, known as sequence. This sequence of nucleotides makes humans look different from a mouse or a monkey. All human beings share the same genome sequence of nucleotides that are 99. 9 per cent similar. The remaining 0. 1 per cent is responsible for the genetic diversity between individuals, a difference that makes you look different from your neighbour. A small change in this sequence in specific areas can lead to deadly disorders. For instance, cystic fibrosis, a paediatric disorder characterized by a defect in the glands that produce mucous, digestive enzymes and sweat is caused by a change in the sequence of a particular gene known as CFTR. After this discovery, which aided in the correct diagnosis and appropriate treatment, the life expectancy of patients suffering from cystic fibrosis has increased dramatically. However, there are disorders about which not much is known. In order to fully understand all monogenic and complex disorders, it was essential to know the sequence of the human genome. The Human Genome Project has now decoded the alignment of the “bricks” that make us humans. Information about this has been made available on the internet free of cost. Disorders that are a result of sequence variations of a particular gene such as CFTR, in the case of cystic fibrosis, are known as monogenic disorders. On the other hand, complex disorders, such as myocardial infarction and stroke, occur owing to the interplay of various genetic and environmental factors. Controlling either the genes or the environment can prevent a complex disease or alter the progression of the disease. Indeed, there are many factors at play when it comes to hereditary disorders and their importance cannot be underestimated. The trick lies in understanding which one of them is playing a greater part in determining the course of the disease.