The discovery of nucleic acids spanned decades, beginning in 1847 when Justus Liebig observed an acidic substance, later identified as inosinic acid, though its significance remained unclear. In 1869, Friedrich Miescher identified a phosphorus-rich material in cell nuclei, naming it nuclein, marking the first connection between this substance and cellular function. By 1889, Richard Altmann isolated the acidic component of nuclein and termed it nucleic acid. His work set the stage for Albrecht Kossel, who identified the chemical building blocks of nucleic acids—phosphoric acid, purine and pyrimidine bases, and a pentose sugar. Kossel’s contributions were fundamental to nucleic acid research and earned him the Nobel Prize in 1910 (https://www.nobelprize.org/prizes/medicine/1910/summary/).
By the early 1900s, researchers classified nucleic acids into two types: yeast nucleic acid, found in plants and containing uracil, and thymus nucleic acid, found in animals and containing thymine. However, early studies mistakenly believed that thymus nucleic acid contained a hexose (six-carbon) sugar instead of a pentose.
A major breakthrough in understanding nucleic acid composition came through Phoebus Levene’s work between 1908 and 1935. In 1909, he and Walter Jacobs investigated yeast nucleic acid, discovering nucleosides (sugar-base subunits) and correctly identifying d-ribose as the sugar in yeast nucleic acid, later known as RNA—which had previously been mistaken for l-xylose. However, they incorrectly assumed that ribose was present in all nucleic acids, failing to recognize that DNA contained deoxyribose, a sugar lacking one oxygen atom.
In 1929, Levene and London corrected this misconception by isolating 2-deoxy-d-ribose from thymus nucleic acid, definitively distinguishing DNA from RNA. This finding clarified that RNA contains ribose, while DNA contains deoxyribose, resolving a longstanding confusion in nucleic acid chemistry.
Levene also played a key role in establishing nucleic acids as polymeric macromolecules rather than simple, repeating tetranucleotide units. In 1908, he and Mandel proposed that nucleotides were linked in a series, leading to the tetranucleotide hypothesis. While Levene initially supported this model, he later recognized that nucleic acids were larger and more complex. Molecular weight measurements and enzymatic digestion experiments by Levene and Gerhard Schmidt confirmed that both DNA and RNA were polymers. Additionally, they pioneered ultracentrifugation to analyze nucleic acid chain lengths, reinforcing the understanding of long, linear macromolecules.
Levene’s work provided experimental proof that RNA and DNA are composed of linked nucleotides, laying the groundwork for recognizing DNA as a long, information-carrying molecule. His insights were instrumental in the eventual discovery of DNA’s double-helix structure by Watson and Crick in 1953.
Ref: Frixione E, Ruiz-Zamarripa L. The “scientific catastrophe” in nucleic acids research that boosted molecular biology. J Biol Chem. 2019;294(7):2249-2255. doi:10.1074/jbc.CL119.007397