The sequence of life
DNA, or deoxyribonucleic acid, is the material that contains hereditary information in all living organisms and some types of viruses, others are based on RNA or ribonucleic acid. The majority of DNA is found in the cell nucleus, also known as nuclear DNA, which is why its original term was “Nuclein”. A small amount of DNA can also be found in mitochondria or plant chloroplasts, which are organelles responsible for cellular respiration and photosynthesis and were once thought to be free-living organisms engulfed by the cell, thus having their own DNA. Adenine (A), guanine (G), cytosine (C), and thymine (T) are the four chemical bases that make up the informational code that is stored in DNA. Similar to how the letters of the alphabet occur in a specific order to form words and sentences, the order or sequence of these bases influences the information accessible to construct and maintain an organism.
Adenine (A) and thymine (T) and cytosine (C) and guanine (G) bond with each other to produce DNA base pairs. A sugar and phosphate molecule are also joined to each base. Nucleotides are a grouping of bases, sugars, and phosphates, and the double helix is a spiral formed by two long strands of nucleotides.
The sequencing of small oligonucleotides has given way to the sequencing of millions of bases, and the struggle to deduce the coding sequence of a single gene has given way to quick and accessible whole genome sequencing. The National Human Genome Research Institute (NHGRI) completed the current human reference genome in April 2022, 22 years after the first release of the reference human genome and 69 years after Watson and Crick discovered the structure of deoxyribonucleic acid (DNA). DNA has evolved over the past seven decades from a mysterious molecule thought to have structural roles inside the nucleus to the symbol of contemporary biology. DNA can now be edited by contemporary technology to fix mistakes and treat hereditary diseases.
People typically associate DNA with the 1953 discovery of its structure by James Watson and Francis Crick, and most people believe that DNA’s history began in 1944, when Avery, MacLeod, and McCarty proved that DNA is a hereditary material structure. The DNA story, however, began in 1869, with the young Swiss physician Friedrich Miescher. Friedrich Miescher completed his work on one of the great scientific discoveries of our time, the isolation and identification of DNA, “Nuclein”, as a central cellular component, 153 years ago, in October 1869.
The 19th century’s context in science
The second half of the 19th century saw the development of many important biological ideas. The biologists Matthias Schleiden and Theodor Schwann demonstrated that all tissues have a cellular beginning, and both plants and animals are made up of the same basic building blocks of an organization, the cells. It was long believed that new cells could spontaneously form from lifeless matter (spontaneous generation theory), but Louis Pasteur and Rudolph Virchow disproved this theory in 1855 by demonstrating that new cells can only develop from existing ones.
The fundamental ideas of heredity and evolution were being developed concurrently with these advances in cytology (or study of cells). In 1858, Charles Darwin and Alfred Wallace published their theories of evolution by natural selection, and one year later, Darwin published his renowned book “On the Origin of Species”. Gregor Mendel’s pea breeding experiments in 1865 led to the discovery of the principles of heredity, which Carl Correns, and Hugo de Vries, rediscovered in 1900.
In 1866 Haeckel’s theory proposed that the cellular nucleus is the structure for the transmission of hereditary. Flemming, who coined the words “chromatin” and “mitosis,” described the architecture and behavior of the chromosomes during mitosis (the process by which a cell replicates its chromosomes) in the 1870s.
Most of these discoveries were met with great enthusiasm by the scientific community at the time, but the discovery of DNA, which had a significant impact on the field of genetics half a century later, received less attention than it deserved. Friedrich Miescher, who died of tuberculosis in 1895, was mostly forgotten and hardly given credit for his discoveries.
The discovery of DNA
Some of the top scientists of his time had a significant impact on Johann Friedrich Miescher. Miescher’s family life frequently featured visits from a number of scientists, which exposed him to a range of scientific ideas and notions at a young age. Both his father and his uncle (Willhelm His) were eminent anatomists and physiologists who held distinguished positions at the University of Basel in Switzerland.
Miescher followed in their footsteps and enrolled in Basel’s medical school at the age of 17, graduating in 1867 at the age of 23. He was, in fact, a shy and introverted individual. It has been hypothesized that the cause of his introversion may have been the poor hearing he had since boyhood due to a serious illness, which made it challenging for him to interact with those around him. Despite his concerns that he had the skills and education required to work as a scientist, Miescher was persuaded to pursue scientific study as a career by his fascination with the field and encouragement from his uncle.
Miescher began his investigation into the mysteries of cellular life with lymphocytes, a kind of immune cell found in blood and lymphatic tissue. He attempted to collect the lymphocytes from lymph glands but discovered that it was difficult to purify and isolate enough of them for chemical examination. Hoppe-Seyler, his mentor who focused on the components of blood, is presumably the one who proposed that Miescher starts with closely similar leukocytes, another type of immune cell found in the blood that is much more abundant.
Miescher turned to a readily available source for the required starting material: pus from fresh surgical bandages available from the local surgical clinic. Miescher’s decision to move to this kind of cell gave him access to the appropriate amounts of material for additional biochemical investigation and laid the groundwork for his ground-breaking finding.
When investigating the many kinds of proteins present in leukocytes, Miescher discovered the presence of a material that precipitated from the solution when acid was added but vanished after the solution was neutralized. It was clear from this activity, which deviated significantly from what was expected of proteins, that this was a material of a completely other class. The first crude nucleic acid precipitation had recently been completed by Miescher.
Miescher was a perfectionist. He was extremely critical of his findings, discarded samples that appeared even slightly abnormal, meticulously examined his isolated nuclei under the microscope to make sure they had not undergone abnormalities during the extraction, and only published after thoroughly verifying his findings. But it’s obvious that Miescher wasn’t a particularly good communicator. Since he did not actively advertise his work, a large audience was not reached by his conclusions. “On the chemical composition of pus cells”, his first paper described the isolation and discovery of DNA, although the scientific world at the time hardly paid it any attention.
Years later, Miescher repeated his basic research using highly pure Nuclein from salmon sperm and found that the phosphoric acid content was 22.5 percent of the total mass, which is quite similar to the actual percentage in DNA (22.9%). With the use of these discoveries, Miescher was able to establish that Nuclein was a molecule with a large molecular weight and at least four basic acids. However, Miescher was unsure about nuclein’s role in the cell. He wondered if it might work as a phosphorus reservoir or a storage area for other compounds that might be synthesized from nuclein if necessary.
With the feeling of a promising career unfulfilled, Friedrich Miescher died suddenly in 1895 at the young age of 51. Wilhelm His collected and published his nephew’s papers after his death. As he stated in the preface, “The admiration of Miescher and his works will not wane; on the contrary, it will expand, and his discoveries and thoughts will be seeds for a bright future.” However, the true function of Nuclein, or nucleic acid as it had come to be known, was not fully understood for another 50 years. In 1944, Oswald Avery, Colin MacLeod, and Maclyn McCarty published a seminal paper in which they hypothesized that DNA, not proteins, carried genetic information.
The legacy of Miescher
The unanswered questions that Miescher’s work had raised had already been pursued by others during his lifetime. Albrecht Kossel is a well-known example, who determined the basic components of Nuclein the purine (A, G) and pyrimidine (T, C) bases, one sugar, and phosphoric acid and established that it is only found in the nucleus. Kossel further deduced from his tests that nucleic acids are integrally linked to the creation of new protoplasm during growth and replacement rather than acting as energy or storage materials. His discoveries in the chemistry of proteins and nucleic acids earned him the Nobel Prize in Physiology or Medicine in 1910.
In a seminal work published in 1944, Oswald Avery, Colin MacLeod, and Maclyn McCarty proposed that DNA, not proteins, carried genetic information. Then, in 1952, Al Hershey and Martha Chase validated these discoveries by noting that viral DNA, but not protein, enters bacteria after infection by a virus known as a bacteriophage, which only infects bacteria, and that this DNA is also present in new viruses created by infected bacteria.
Key questions, such as how this information was kept in DNA and how it could be accurately copied prior to each cell division, came to the forefront of discussion after it was discovered that DNA held the hereditary information. In 1953, Watson and Crick solved the three-dimensional structure of DNA using crystallographic data produced by Rosalind Franklin and Maurice Wilkins, contributing to a conceptual framework for both DNA replication and protein-encoding in nucleic acids. But it was not until the middle of the 1960s that Robert W. Holley and associates ultimately decoded the genetic code, that is, how DNA’s four bases A, C, G, and T are linked together so that the ribosome, a component of the cell’s machinery, can read them and translate them into proteins. The age of molecular genetics was officially launched when biologists were finally able to start sequencing and modifying DNA thanks to their understanding of its structure and mechanism of operation.
In the end, Miescher’s narrative centers on a brilliant but reclusive scientist who was obsessed and whose circumstances prevented one of the greatest scientific discoveries from being completely realized at the time. The goal of Friedrich Miescher’s examination of leukocytes was not to identify the molecular underpinnings of hereditary information. His objective was no less grandiose, though. What is the chemical basis of life? was one of the most important problems in biology at the time that he wanted to address.
Despite the fact that Miescher is mainly forgotten and did not accomplish enough to fully comprehend the implications of his work, he did take the first step toward understanding the common ground of all life on Earth. The DNA discovery!
Credit: Warren Umoh on Unsplash
Figure 1. A nucleic acid is a long molecule made up of smaller molecules called nucleotides. Nucleic acids were discovered in 1868 when Friedrich Miescher conducted experiments on the chemical composition of leukocytes at the University of Tübingen, which led to the discovery of DNA.
References
- Greenstein, J. P. Friedrich Miescher, 1844-1895. Sci. Mon. 57, 523–532 (1943).
- Dahm, R. Friedrich Miescher and the discovery of DNA. Dev. Biol. 278, 274–288 (2005).
- Dahm, R. Discovering DNA: Friedrich Miescher and the early years of nucleic acid research. Hum. Genet. 122, 565–581 (2008).
- Hall, K. & Sankaran, N. DNA translated: Friedrich Miescher’s discovery of nuclein in its original context. Br. J. Hist. Sci. 54, 99–107 (2021).
- Nurk, S. et al. The complete sequence of a human genome. Science 376, 44–53 (2022).
