|CURRICULUM IN CARDIOLOGY - HISTORY OF MEDICINE
|Year : 2018 | Volume
| Issue : 2 | Page : 132-138
Story of the gene
Soumi Das1, Amitabh Biswas2
1 Department of Cardiology, AIIMS, New Delhi, India
2 College of Natural Sciences, Arba Minch University, Ethiopia
|Date of Web Publication||10-Sep-2018|
Department of Cardiology, AIIMS, New Delhi
Source of Support: None, Conflict of Interest: None
A lot of people believe that Watson and Crick discovered DNA, but it is not the case. Rather, it was first identified by Friedrich Miescher who coined the term nuclein for this unknown substance. Later, a series of researchers carried out further work which revealed the details of DNA. Franklin's Photo-51 is one of the major clues for Watson and Crick for discovering DNA double helix. Without the work done by earlier scientists, Watson and Crick could not get into the conclusion of 1953 that DNA exists as a three-dimensional double helix. This discovery was a turning point which had significant impact on science for years to come. In this review, we aim to discuss how gene discovery has moved from the early theories to gene and finally to DNA.
Keywords: Alkaptonuria, codon, inheritance
|How to cite this article:|
Das S, Biswas A. Story of the gene. J Pract Cardiovasc Sci 2018;4:132-8
| Introduction|| |
In the era when there was no concept and proof of evolution and inheritance, two great scholars Hippocrates and Aristotle hypothesized inheritance. According to Hippocrates, all the parts of a human came together in a man's seed and forms into a human being inside a womb. Later, his theory was criticized by Aristotle and a new theory was given, i.e. the theory of transmission of information which made a better sense. In the Charak Samhita, ancient medical practitioners wrote that the characteristics of any child are determined by mother's reproductive material, father's sperm, diet of any pregnant woman, and people around the pregnant woman.
In the early 18th century, people started having better knowledge of plants and animals. Agriculturists started developing hybrid plant and animal species, but till then, they did not have a theoretical knowledge of inheritance. They knew that the cause of variation is hidden in the process of sexual reproduction. George Mendel was the first to show the inheritance patterns in pea plants where he observed dominant and recessive traits which were following simple statistical rules. He was lucky in selecting those traits, the gene for which was present on different chromosomes. His conclusion was ahead of his time, but was not accepted for 34 years by the scientific community.
Charles Darwin in 1868 gave the theory of pangenesis, according to which minute particles called gemmules or pangene from each somatic cell get collected in the gametes and then get passed to the zygote. Gradually, this theory lost popularity when biologists replaced the theory of pangenesis with germ-plasm theory and then with chromosomal theories of inheritance and finally the concept of gemmules by genes.
Here, we aim to discuss how gene discovery has moved from the early theories to gene and finally to DNA.
| Early Studies by Charles Darwin|| |
Charles Darwin [Figure 1] was born on February 12, 1809, at Shrewsbury. At the age of 22, he went for a voyage on HMS Beagle with Captain Robert Fitzroy. Captain Robert Fitzroy wanted a young companion who could share his responsibilities. Being a budding naturalist, Darwin was flooded with opportunities as the ship was equipped for scientific purposes, so he accompanied the captain. Darwin during the voyage read his Grandfather's Zoonomia and derived the hypothesis that species change with time. Charles Darwin after returning from his 5-year voyage started outlining the Origin of Species in 1842. The Origin of Species was published on November 1859. Darwin himself says that the origin of species is the “mystery of mysteries.”
In the Origin of Species, the key component is the concept of evolution by natural selection. According to Darwin, advantageous variations within living systems are more likely to survive and reproduce at a higher rate. Natural selection is a process that obtains in the adaptation of a being to its environment by means of selectively reproducing changes occurring in its genotype. In natural selection, Darwin said that man chooses only for his desired thing and which is useful for them, but nature selects only those individuals which is useful for variation and are best adapted for environment, and others which are less fit for environment they are rejected by nature.
| Galapagos Islands|| |
Charles Darwin spent 5 weeks in the Galapagos Islands. Galapagos Islands were named after the large tortoises that were endemic to the area. This is an archipelago of volcanic islands which are situated around the equator in the Pacific Ocean. The Galapagos Islands are a group of islands of different sizes lying on the equator almost 1000 km west of Ecuador. These islands seemed to be a little world within itself.
Darwin noticed that the finches on the different islands are similar to each other, but they showed differences in their size, beaks, and claws from island to island. Darwin hypothesized that these species had a common ancestor which later evolved into 13 different species. These finches adapted themselves according to their environment and habitats, thus becoming progressively more different from the original population.
He wrote, “The distribution of tenants of this archipelago would not be nearly so wonderful, if for instance, one island has a mocking-thrush and a second island some other quite distinct species. But it is the circumstance that several of the islands possess their own species of tortoise, mocking-thrush, finches, and numerous plants, these species having the same general habits, occupying analogous situations, and obviously filling the same place in the natural economy of this archipelago, that strikes me with wonder.”
These finches were the best example of evolution on the islands. The finches of the Galapagos Islands gave an example of adaptive radiation, which is the formation of new species from ancestral species. Finches which got adapted to the environment survived and the rest died off.
Thus, it can be concluded that individuals who adapt to their environment can only survive and reproduce. These variations when inherited by the offspring cause selection to occur in the population, thus maintaining the advantageous variations.
Darwin wrote “If during the long course of ages and under varying conditions of life, organic beings vary at all in the several parts of their organization, and I think this cannot be disputed; if there be, owing to the high geometrical powers of increase of each species, at some age, season, or year, a severe struggle for life, and this certainly cannot be disputed; then, considering the infinite complexity of the relations of all organic beings to each other and to their conditions of existence, causing an infinite diversity in structure, constitution, and habits, to be advantageous to them, I think it would be a most extraordinary fact if no variation ever had occurred useful to each being's own welfare, in the same way as so many variations have occurred useful to man. But if variations useful to any organic being do occur, assuredly individuals thus characterized will have the best chance of being preserved in the struggle for life; and from the strong principle of inheritance they will tend to produce offspring similarly characterized. This principle of preservation, I have called, for the sake of brevity, Natural Selection.”
Gregor Mendel [Figure 2] was born on July 20, 1822, at Austria. He was known as the Father of Genetics. On the basis of his experiment on work with pea (Pisum sativum) plants, Gregor Mendel postulated the principles of inheritance. Mendel chooses the pea plant because of frequent availability and their offspring are easily and quickly reproduced. Gregor Mendel's deliberate idea and calculations made his experiment with pea (P. sativum) plant successful. Experiment on plant hybridization was presented by Mendel in a journal “The proceeding of the Brunn society of natural history” in 1865, but his work was ignored by scientists at that time, because at that time, scientists were busy in the controversy arisen by Darwin's theory of Origin of Species. Finally, his work got published in 1866. Later, in 1900, Hugo de Vries, Carl Correns, and Erich von Tschermak rediscovered Mendelism and slowly the significance of Mendelism and genetics was understood around the world.
| Mendel's Experiments|| |
Gregor Mendel studied seven types of traits in garden pea. He selected garden pea (P. sativum) for two reasons: (1) Peas were available in distinct shapes and color and (2) Peas can self-pollinate or cross pollinate. Mendel chooses each character and grew them for about 2 years to know that they were pure or not. Mendel was fortunate enough to get only two phenotypes for a particular character. The word phenotype was neither coined nor been used by Mendel during his experiments.
These seven characters are summarized in [Table 1].
Initially, he started his experiments with flower colors: purple and white flower colors. Purple-flowered line: when crossed with purple-flowered line, the offspring were all purple; similarly, white-flowered line produced only white line. When he did the reciprocal cross, i.e., reversing the sex of the plant, he obtained the same results.
Now, when he crossed purple-flowered plant with white-flowered plant, the first filial generation had all purple flowers. Mendel then self-pollinated F1 plants and interestingly the white phenotype reappeared in some of the plants and the ratio was 3 (purple):1 (white). Then, he did the same experiment with other six characters and found the same 3:1 ratio in F2 generation.
Such cross where only one character is involved is known as monohybrid cross.
With this finding, the blending inheritance theory was getting discarded and Mendel introduced the term dominant and recessive character. He proposed that the purple phenotype was dominant over white phenotype and the F1 generation receives both the dominant and recessive characters from their parents which later on get expressed in F2 generation.
Later, he crossed pea plants differing in two characters and such crosses are called dihybrid crosses. He crossed round and yellow characters with wrinkled and green characters and the F1 generation was round and yellow. When he selfed F1 generation, the F2 progeny showed four different phenotypes in 9 (round yellow seeds):3 (round green seeds):3 (wrinkled yellow seeds):1 (wrinkled green seeds) ratio. Reciprocal cross gave the same results.
Thus came the Law of Segregation and the Law of Independent assortment.
With these experiments, Mendel for the first time laid the foundation of new science called Genetics. For 35 years, his work was being ignored until it was rediscovered by 1900 Hugh de Vries, Carl Correns, and Erich von Tschermak.
Friedrich Miesche [Figure 3] was born on August 13, 1844, in Switzerland in an intellectual family. His father was a physician and uncle was a well-known embryologist.
Miescher wanted to work in the field of research, but due to his father's wish, at the age of 17, he started his medical studies and got specialized as an otologist. Due to his poor hearing (ear infection during childhood), he had to face problems in examining his patients; therefore, he decided to pursue his career in research. Miescher then went to the University of Tubingen, Germany, to study histochemistry where he worked in the laboratory of Adolph Strecker and Hoppe Seyler.
Hoppe Seyler's laboratory was one of the first in Germany to focus on “physiological chemistry.”
They had started the work on isolating the molecules that are made up of cells and introduced the term proteid which later became protein. Miescher started working on lymphoid cells, but working on lymph nodes was very difficult. So, he started collecting fresh surgical bandages from the nearby surgical clinics and washed off the pus. Initially, he was working on proteins, as cells are composed of proteins and lipids. During these experiments, Miecher observed that an unknown substance was getting precipitated when acid was added and was getting dissolved in the presence of alkali. Further, it resisted protease digestion, thus indicating the unknown substance was not protein. He wrote “In my experiments with weakly alkaline solutions, when neutralising the solution, I could obtain precipitates that could not be dissolved either in water, acetic acid, very dilute hydrochloric acid, or in solutions of sodium chloride, and which thus could not belong to any of the hitherto known proteins.” Further analysis showed that this substance contained large amount of phosphorous and no sulfur. Serendipitously, Miescher discovered DNA. Since he had isolated it from nucleus, it was known as nuclein. After discovering nuclin in leukocytes, he examined it in different cell types: testes, kidney, nucleated erythrocytes, and yeast cell. There also he could find nuclin.
However, getting this published was not easy for Miescher as Hoppe Seyler himself wanted the experiments to be replicated for further confirmation. In 1870, there was a war between Germany and France leading to further delay in the publication. Finally, the article got published in 1871 entitled “Ueber die chemischeZusammensetzung der Eiterzellen” (On the Chemical Composition of Pus Cells) along with P. Plo's article.
Sir Archibald Edward Garrod [Figure 4] was born on November 25, 1857, to Sir Alfred Baring Garrod. He got educated as a physician but was more of a scientist. Garrod himself said “Clinical medicine is not really my main interest, I am a wanderer down the by-paths of medicine.” He pursued his doctorate degree on rheumatoid arthritis from Oxford University. Garrod was the first to conclude that rheumatoid arthritis and gout are two different disorders and patients diagnosed with gout have increased uric acid in blood. He has been recognized as “the father of biochemistry” by the Royal Society of Medicine for his work on “inborn errors of metabolism.”
In 1897, for the first time, he observed a patient of alkaptonuria, a condition when the urine turns to dark color when exposed to air and contained homogentisic acid (HGA). In 1899, he postulated that alkaptonuria was due to errors in metabolism pathways but not due to any infections. Later on, Bateson and Garrod together found that alkaptonuria was common among congenital parents. In 1902, he has stated in his publication that “there seems to be little room for doubt that the peculiarities of the incidence of alkaptonuria and of conditions which appear in a similar way are best explained by supposing that, leaving aside exceptional cases in which the character usually recessive assumes dominance, a peculiarity of the gametes of both parents is necessary for its production.”
Alkaptonuria is caused due to deficiency of HGA oxidase deficiency leading to excretion of HGA in urine. In earlier age of life, there are no symptoms, but in later ages, there are symptoms of severe ochronotic spondyloarthropathy, ocular and cutaneous pigmentation, and genitourinary obstruction by ochronotic calculi.
Garrod has stated “… the administration of tyrosine by mouth to … an alcaptonuric subject … caused a very conspicuous increase of the output of homogentisic acid…. A corresponding increase follows an augmented intake of protein food, and especially of such proteins that are unusually rich in the aromatic fractions … the tyrosine and phenylalanine of proteins are the only parent substances of the alcapton acid (homogentisic acid)…. It will be obvious … that the error of metabolism, which is the basis of alkaptonuria, is a failure to deal with the aromatic fractions of proteins ….”
In 1901, Garrod for the first time expressed “inborn errors of metabolism” in his Croonian Lectures at the Royal College of Physicians in London and explained that the disease was inherited in recessive form due to defect in metabolic pathway. During this time, he did not had much knowledge of Mendelian genetics, but for the first time, the relation between biochemical and genetics was coming into light. Finally, in 1902, his observations got published in The Lancet.
Oswald Theodore Avery [Figure 5] was born on October 21, 1877, in Halifax, Canada. His father was a Baptist minister. At the age of 22, he was graduated with a degree in humanities. Later in 1900, he decided to enter medical school and in 1904 he was graduated as a physician from Columbia University's College of Physicians and Surgeons in New York. After doing few years of medical practice, he found medical research more interesting and joined the Hoagland Laboratory in Brooklyn as an assistant director and started working on bacteriology. Most of his patients had pneumonia or tuberculosis for which there was no proper treatment. Indeed, his mother also died because of pneumonia.
Avery published his work on tuberculosis which made Rufus Cole, the then Director of Rockefeller Institute, interested in it and in 1913 invited Avery to join Rockefeller Institute where he started working on Pneumococcus.
In 1928, Frederick Griffith from London reported an amazing finding where virulent strain of Streptococcus pneumonia even if dead can transform the nonvirulent strain into virulent strain and the change was heritable. Neither the heat-killed virulent nor nonvirulent strain alone could infect. Avery got interested in Griffith's experiment but had some doubts that it may have happened due to contamination. So, one of his laboratory members Lionel Alloway repeated the experiment and found the same results. Soon, they concluded, for transformation rat was not needed, the nonvirulent can get converted into virulent even in the test tube. Now, the big question was what is leading to the transformation.
Later, Avery was joined by Colin MacLeod followed by Maclyn McCarty. They started creating cultures of virulent bacteria and then heat killed. This filtrate was then treated with enzymes to remove proteins, carbohydrates, and lipids. The remaining filtrate when analyzed was a white fibrous substance which had the same chemical property as that of DNA. Further, it was treated with enzymes for removal of protein and RNA and then infected the nonvirulent bacteria which got transformed into virulent bacteria. Later, when DNA-digesting enzyme was added to it, it lost its property of transformation. Thus, it became clear that DNA was the substance which was leading to the transformation among bacteria and thus a material of genetic inheritance.
Later, in 1944, Avery with Colin MacLeod and Maclyn McCarty published “Studies on the Chemical Nature of the Substance Inducing Transformation of the Pneumococcal Type,” in the Journal of Experimental Medicine. During that time, many of the scientists did not support Avery's work. Many of the scientists still continued believing genes were proteins. Later, in 1945, Avery received Copley Medel from the Royal Society of Landon and in 1947 he received Lasker Award but was never awarded Nobel Prize for his work.
Erwin Chargaff [Figure 6] was born on August 11, 1905, in Czernowitz, capital of the easternmost province of the Austro-Hungarian Empire, Bukovina, to Hermann Chargaff and Rosa Silberstein Chargaff. In 1928, Chargaff obtained PhD in analytical chemistry from the University of Vienna followed by a 2-year postdoctoral research with R Anderson, an editor of the Journal of Biological Chemistry at Yale University where he learned bacterial chemistry. His dissertation was on organic silver complexes and with the action of iodide on azide. In the 1930s, he started working on the lipids of Bacillus Calmette–Guerin and fat and phosphatide fraction of diphtheria bacteria. With the rise of Nazis in 1933, Chargaff felt the need of leaving Germany and joined Pasture Institute in Paris. After working for 2 years in Paris, he went to Columbia University, United States. For the work of Oswald Avery, he stated that “Avery gave us the first text of a new language, or rather he showed us where to look for it. I resolved to search for this text. Consequently, I decided to relinquish all that we had been working on or to bring it to a quick conclusion.”
After the work of Avery, the challenge for Erwin Chargaff was to develop a method to analyze the nitrogenous components and sugar of DNA in different species. For this, he took 2 years to develop and identify the minute quantity of organic substance.
In 1950, when Chargaff published his findings on chemistry of nucleic acid, the tetra nucleotide hypothesis by Phoebus Levene got disproved. According to the tetra nucleotide hypothesis, DNA is made up of equal amounts of adenine, guanine, cytosine, and thymine. According to Chargaff rule, any double-stranded DNA, the number of pyrimidine are equal to the number of purines but DNA composition among species varies.
Chargaff's finding along with Rosalind Franklin's X-ray diffraction showed that in DNA base pairing occurs between adenine and thymine and between guanine and cytosine.
Later, in 1952, he discussed his work with Watson and Crick and also about his theory which gave them a hint of DNA's structure. In 1953, Watson and Crick published their famous work on double helix structure of DNA in Nature where they have cited Chargaff's paper.
Like Avery, he was also not awarded Nobel Prize, but had been awarded with Pasture Medal, Carl Neuberg Medal, Charles Leopold Mayer Prize, Heineken Prize, George Mendel Medal, and the National Medal of Science.
Rosalind Elsie Franklin [Figure 7] was born on July 25, 1920, in London to a Jewish family. She attended St. Paul's School for girls and later at the age of 18 she enrolled herself to Newnham Women's College at Cambridge University where she studied physics and chemistry. In 1941, she was awarded the graduation degree. Following in 1942, when the World War II was on, Franklin joined British Coal Utilization Research Association (BCURA) where she worked independently on microstructures of coals and was able to identify and measure these microstructures for the first time. In 1945, she received her PhD degree from Cambridge for her work done in BCURA. For the next 2 years, she worked at State Chemical Laboratory in Paris where she learned X-ray diffraction technology.
In 1951, she moved to Biophysics Laboratory at King's College, London, where she worked as a research fellow. Here, she started applying her knowledge of X-ray diffraction to study DNA. In May 1952, one of her students, Raymond Gosling at King's College, took a photograph of DNA often known as “Photo 51” [Figure 8], which revealed the double helix structure of DNA. She stated in a report submitted to Medical Research Council in February 1952 that “The results suggest a helical structure…containing probably 2, 3 or 4 coaxial nucleic acid chains per helical unit and having the phosphate groups near the outside.”
Later, in early 1953, one of her colleagues Maurice Wilkins showed Photo 51 to Watson without her knowledge when Franklin was planning to leave King's college and join Birkbeck College in London. Seeing the picture, Watson later stated “The instant I saw the picture my mouth fell open and my pulse began to race. the black cross of reflections which dominated the picture could arise only from a helical structure. mere inspection of the X-ray picture gave several of the vital helical parameters.” This was the only evidence which Watson and Crick did not have and this picture helped them conclude the double-helix structure of DNA. Finally with this evidence, Watson and Crick published the double-helix nature of DNA in Nature in 1953.
In Birkbeck College, she again started working on coal and closed the work on DNA as the head of King's college allowed her to leave on the condition that she would not work on DNA at Birkberg College. Later, she started working on viruses where she revealed the hollow center of tobacco mosaic virus with the help of X-ray crystallography.
Franklin died at the age of 37 due to ovarian cancer possibly due to extensive exposer to radiations. In 1962, Watson, Crick, and Wilkins jointly shared the Nobel Prize, but Franklin's work was hardly appreciated. Lewin Sime had later said “Hers is perhaps one of the most well-known and shameful instances of a researcher being robbed of credit.”
Francis Harry Compton Crick, mostly known as Francis Crick [Figure 9], was born on June 8, 1916, at Northampton, England. In 1937, he was graduated in physics from University College, London, and started working under Prof. EN da C. Andrade, but due to the World War II, he could not carry on his thesis. During the World War II, he worked as a physicist for British Admiralty and developed magnetic and acoustic mines for naval warfare. In 1947, he left Admiralty and started having interest in life sciences. In the very same year, he started working in Strangeways Research Laboratory, University of Cambridge, as a biologist. In 1950, he again started as a PhD fellow and obtained his degree in 1954. In 1951, Crick met James Watson at Cambridge. Both of them together worked on the model of DNA and in April 25, 1953, got it published in Nature and the title of the article was “A Structure for Deoxyribose Nucleic Acid.” The order of the author's name was decided by a coin flip.
|Figure 9: Francis Crick and James Watson, walking along the Backs, Cambridge, England, 1953.|
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James Dewey Watson [Figure 9] was born on April 6, 1928, in Chicago. In 1947, he was graduated in zoology from Indiana University in Bloomington and later in 1950, he was awarded PhD degree. His thesis was on the effect of hard X-rays on bacteriophage multiplication. In 1951, he started working on the structure of DNA along with Crick. Finally, in 1962, Watson, Crick, and Wilkins were awarded Nobel Prize for the double helical structure of DNA. With this Nobel Prize, many people started believing them as discoverers of DNA. The reality was that the work on DNA started long back when Miescher discovered nuclin followed by Chargaff and then Rosalind Franklin photographed crystallized DNA fibers. Thus discovering the structure of DNA was a part of a huge research work, but unfortunately, Watson and Crick got a major credit for the work.
Watson and Crick found that the DNA was a double helical structure which contains long chain of monomer nucleotides. In their first paper, they have not mentioned about the copying mechanism of DNA, but in the next article published in Nature, they have mentioned about the replicating mechanisms of DNA. By this finding, it could be understood that DNA replicates itself by separating itself into two strands and then working as templates for each other. Watson has stated in his book that after the finding, Crick has announced that “we had found the secret of life.”
Immediately after publication, the article was not cited frequently, but came into recognition only when it was understood by Meselson, Kornberg, and many other scientists that protein synthesis and DNA had some relation.
Later, in the 1990s, Watson helped in establishing human genome project.
| Conclusion|| |
Most of the credits for the discoveries of DNA have been given to Watson and Crick, but their work was directly dependent on the work of lots of scientists before them. All these researches together helped us to know a great deal about genetic structure and finally understanding the human genome, which has helped us to decode the reason of a number of diseases.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9]