The discovery of DNA
Johann Friedrich Miescher was born on August 13, 1844 into a family of scientists. His father and uncle were renowned physicians and professors of anatomy and physiology at the University of Basel. As a result of growing up in this environment, Miescher developed a keen interest in the sciences at a very early age. At 17, he began his medical studies in Basel, concluding them at the age of 23. However, the practice of medicine was difficult for him due to his poor hearing. Inspired by his uncle’s interest in biochemistry, he turned to research.
In the spring of 1868, Miescher relocated to Tübingen to work in the laboratory of the distinguished biochemist Felix Hoppe-Seyler, who was one of the pioneers in this new discipline, then referred to as „physiological chemistry“. His laboratory was housed high above the Neckar river valley in the former kitchen of Tübingen Castle. Here, a few years earlier, Hoppe-Seyler had made ground-breaking discoveries regarding the properties of the red blood pigment hemoglobin. This achievement represented a significant step for later investigations into the structure and function of this and other proteins.
As Hoppe-Seyler’s student, Miescher’s first task in Tübingen was to determine the chemical composition of cells. White blood cells served as the source material for his studies. With this „most simple and independent cell type,“ he hoped to unravel the mysteries of the life of cells. And thus, the discovery of DNA was off to a rather unappetizing start: Miescher obtained the cells for his experiments from pus-covered bandages, which he got from a local hospital.
The young scientist initially investigated the components of the cell body, focusing particularly on the various types of proteins that make up the pus cells. In Miescher’s time, proteins were considered the most promising part of a cell and scientists analyzed them hoping to understand how cells worked. Miescher described their properties in detail and attempted to classify them. However, his work was marked by setbacks: The combination of proteins in the cells was too complex for the simple analytical methods and equipment available at the time.
Miescher ultimately turned to the nucleus, a part of the cell about which hardly anything was known at the time. A decision with far-reaching effects: The young scientist noticed a precipitate in extracts from nuclei, which did not appear to be made of proteins. Enzymes that cleave proteins had no effect on it. Moreover, Miescher also realized that this precipitate was different from proteins in other ways: Proteins are almost exclusively composed of the elements carbon, hydrogen, oxygen and nitrogen. However, the new substance, Miescher noted, also contained large amounts of phosphorus, which only occurs in small quantities in proteins. As Miescher discovered the compound in the cells’ nuclei, he called it „nuclein“.
On February 26, 1869, Friedrich Miescher reported on the discovery of this mysterious substance for the first time. In a letter to his uncle, Wilhelm His, he wrote: „In my experiments with low alkaline liquids, precipitates formed in the solutions after neutralization that could not be dissolved in water, acetic acid, highly diluted hydrochloric acid or in a salt solution, and therefore do not belong to any known type of protein.“ Already then, Miescher recognized that he had discovered a new substance, equal in importance to proteins. Still, his mentor Hoppe-Seyler was skeptical of the unusual results and opted to re-examine them. Finally, after a year he was convinced. Miescher’s results were published 1871 in a journal edited by Hoppe-Seyler himself.
Following his time in Tübingen, Miescher spent one year at the University of Leipzig. In order to expand his horizons, he dedicated himself to new areas: Under the direction of Carl Ludwig, he investigated among other things the nerve tracts that transmit pain signals in the spinal cord. In 1871, he returned to his hometown of Basel and within a year he was offered the Chair of Physiology at that city’s university.
In Basel, Miescher continued his research on nuclein, although owing to poor working conditions, his progress was slow. In a letter to a friend he complained: „In the past two years, I have avidly yearned for the meat pots of the laboratory in Tübingen Castle again, for I had no laboratory here and was (…) merely tolerated in a small corner of the chemistry laboratory, where I could hardly move, as it is more than overcrowded with students and the professor of chemistry also works there.“ He continued, „You can imagine how it must feel to be hindered in the energetic pursuit of an endeavor on account of the most miserable conditions, knowing that I may never have such a fine opportunity again …“
Fortunately, Miescher was ultimately able to complete his work. In 1874, he published his results on the occurrence of nuclein in the sperm of various vertebrates, a publication that caused a considerable interest. Researchers at the time were already trying to understand how an embryo develops and how characteristics and traits are passed on from one generation to the next. Miescher came very close to finding the answer himself. In his article he wrote: „If one (…) wants to assume that a single substance (…) is the specific cause of fertilization, then one should undoubtedly first and foremost consider nuclein.“
Yet, Miescher was not convinced that only one substance could be responsible for transmitting hereditary traits. He discarded the idea because, among other reasons, it seemed implausible to him that the same substance could result in the diversity of different animal species whose sperm he had examined. He conceded that „differences in the chemical structure of these molecules will occur”, but then went on to say that “they will only do so in a limited diversity,“ Too few, Miescher believed for this phenomenon to even explain the slight differences between individuals of the same species. Instead he believed that mechanical stimuli, triggered through the movement of the sperm, and electrochemical processes, such as those that occur when nerves and muscles are stimulated, were responsible for the development of the fertilized egg cell.
His fellow scientists though were happy to continue with investigations into the nuclein. Albrecht Kossel, another scientist in Hoppe-Seyler’s laboratory and later winner of the Nobel Prize in Medicine, discovered that nuclein was comprised of four bases and sugar molecules. The botanist Eduard Zacharias showed that nuclein was an integral part of chromosomes and Theodor Boveri proved that genetic information was contained in the cell’s nucleus. Several biologists gradually became convinced that nuclein played a key role in the mechanisms of inheritance. Due to the fact that nuclein behaved like an acid, Richard Altmann renamed it „nucleic acid“ in 1889, which it is still called today.
However, Miescher more and more turned his attention to other matters and never again published on this subject. In the mid-1870s, he began researching the changes that occurred to the bodies of salmon as they migrated from the ocean to their spawning grounds in the Rhine River. During the winter months he would get up in the middle of the night and spend the early morning hours on the banks of the Rhine catching salmon. He transported thousands of them to his laboratory, measured and weighed them, and examined their muscles, internal organs and blood. However, he was primarily fascinated by the extent to which the reproductive organs of the salmon grow during this time – up to a quarter of their body weight.
He also spent a great deal of time preparing lectures for his students. Furthermore, the government asked him to assess the nutrition of inmates in Basel’s prison – a task Miescher found less than sapid. Nevertheless, the authorities were so impressed with his work that more Swiss prisons and other institutions ended up asking him for advice. Amused by this development, his uncle wrote: „Every prison wanted his special menu.“ But Miescher had finally had enough. „I have made myself too green, now the goats are eating me up,“ he noted with dismay. He added, „Investigation into the nutrition of the Swiss people, a cookbook for workers, nutrition charts for the national fair, controversies with the Chamer Milk Company – to put it in a nutshell, I am well on my way to becoming the Zionist guardian for the stomachs of my three million fellow countrymen.“
Instead, Friedrich Miescher once again took on a new challenge and founded the city’s first anatomical-physiological institute. After some initial stumbling blocks, it was decided in 1883 to construct the new building; two years later, in 1885, the institute was officially opened. Miescher took his job as head of the new institute very seriously. He provided for a lively scientific atmosphere and attracted several renowned precision mechanics, who devised innovative tools and instruments for physiological measurements, permitting a previously inconceivable degree of precision. However, Miescher’s various obligations began to wear on him. His obsession with his work and tendency towards perfectionism left him less and less time to rest. He slept little, hardly fulfilled any of his social obligations and even spent most of his vacations in the laboratory. Completely exhausted, he began to weaken. Finally, at the beginning of the 1890s, he contracted tuberculosis. As a result, he had to abandon his work and move to a sanatorium in Davos. One last time, he attempted to write a summary of his work (including his results on nuclein), but did not have the strength. Friedrich Miescher died on August 26, 1895, at the age of only 51 years. After his death, his uncle, Wilhelm His, wrote: „The appreciation of Miescher and his work will not diminish; on the contrary, it will grow and his discoveries and thoughts will be seeds for a fruitful future.“ However, not even His himself knew how accurate his words actually were.
Long after Miescher’s death, the vast majority of scientists remained convinced that the complex proteins were the carriers of genetic information. Proteins are comprised of 20 different amino acids, while DNA is made up of only four different nucleotides – too few, it was believed, to store the enormous amount of genetic information. Widespread interest in DNA was not rekindled until the 1940s, when Oswald T. Avery, Colin MacLeod and Maclyn McCarthy demonstrated that DNA is the carrier of genetic information. In 1953, Watson und Crick figured out the structure of DNA and provided the first insight into how it works. For their work, the scientists were awarded the Nobel Prize in 1962. Eight years later, Robert W. Holley, Har Gobind Khorana and Marshall W. Nirenberg finally cracked the genetic code, which also earned them the Nobel Prize in 1968. At this point it had become clear how the information for creating the various organisms could be encoded in a single molecule with only four bases. This information served as the point of departure for the development of a completely new biological discipline, namely, molecular genetics.
Today, DNA is considered far more than just a molecule. It has become the icon of the modern biosciences. It has been immortalized in numerous paintings and sculptures, postage stamps have been dedicated to it, a perfume has been named after it, stairways and even entire buildings are being designed based on its form. The most recent breakthrough in the history of DNA research has been the publication of the human genome sequence in 2001. However, despite impressive advances in the past decades, our understanding of how DNA works is still far from complete. Nearly 150 years after its discovery, no one has yet solved the remaining mysteries of DNA.
Publications on this topic:
Dahm, R: Discovering DNA: Friedrich Miescher and the early years of nucleic acid research. Human Genetics (in press).
Dahm, R: Festpäckchen mit DNA-Knüller. Leipziger Volkszeitung, Ausgabe vom 18./19. Dezember 2004, Seite M 2.
Dahm, R: The molecule from the castle kitchen. Max-Planck-Research (2004), Issue 2/2004, p. 50-55.
Dahm, R: Das Molekül aus der Schlossküche. Max-Planck-Forschung (2004), Ausgabe 1/2004, S. 50-55.
Dahm, R: Friedrich Miescher: Ein Basler auf der Spur des Lebens. Basler Zeitung, 14. Oktober 2003, Seite 3.
Dahm, R.: Menschen – Johann Friedrich Miescher. Biologie in unserer Zeit (BiuZ), Verlag Wiley-VCH), Ausgabe 3, Mai 2003, S. 202.
Dahm, R.: In der Tübinger Schlossküche wurde die DNA entdeckt. Schwäbisches Tagblatt, 26. April 2003, Seite 26.
Publications on other aspects of the history of science:
Dahm, R: Menschen: Vor hundert Jahren – Alois Alzheimer beschreibt eine rätselhafte Krankheit. Biologie in unserer Zeit (Verlag Wiley-VCH), Volume 37(1), 2007, p. 65-66.
Dahm, R (2006): Alzheimer’s Discovery. Current Biology, Vol. 16(21), p. R906-910.
Dahm, R: Alois Alzheimer and the beginnings of research into Alzheimer’s disease. pp. 31-43. In „Alzheimer: 100 Years and Beyond“, Jucker M, Beyreuther K, Haass C, Nitsch RM, Christen Y (eds.). Springer-Verlag Berlin Heidelberg 2006.