Deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) are complex macromolecules, known as nucleic acids, that hold the genetic instructions for life. They transmit hereditary information and direct the machinery of life within every cell. Understanding their function began with identifying their basic structural units, or monomers, which link together to form the vast complexity of the genetic code. The discovery of these foundational building blocks was a necessary first step that paved the way for modern molecular biology.
Defining the Nucleotide Building Blocks
The individual units that assemble to create the long chains of DNA and RNA are called nucleotides. This chemical monomer is constructed from three distinct molecular parts. The first component is a phosphate group, which provides the acidic, negatively charged nature of the molecule. The second part is a five-carbon sugar, which is either ribose in RNA or deoxyribose in DNA.
The third component is a nitrogenous base, an aromatic, nitrogen-containing compound. These bases include adenine (A), guanine (G), cytosine (C), and either thymine (T) in DNA or uracil (U) in RNA. In a complete nucleotide, the phosphate group and the nitrogenous base are both chemically bonded to the sugar molecule. This three-part structure is the fundamental unit that links repeatedly to form the genetic polymer.
The Initial Isolation of Nucleic Acid Material
The initial step in uncovering the nature of the genetic material occurred in 1869. Swiss physician and chemist Friedrich Miescher isolated a new substance from the nuclei of white blood cells, which he collected from pus-soaked surgical bandages. He was the first to separate this material from the proteins and lipids of the cytoplasm.
Miescher named his discovery “nuclein,” noting that it was an acidic substance with a high content of phosphorus. He recognized that this material, which he also later isolated from salmon sperm, represented a new class of biological molecule distinct from proteins. While Miescher successfully isolated the raw material, he did not chemically break it down to identify the specific monomeric units. His work provided the crude substance that subsequent scientists would analyze to determine its exact chemical makeup.
Identifying the Three Chemical Components
The definitive identification of the individual monomer components came primarily through the work of Russian-American biochemist Phoebus Levene in the early 20th century. Levene used his skills in carbohydrate chemistry to chemically dissect Miescher’s “nuclein” and systematically identify the three parts of the nucleic acid building block. He confirmed the presence of the phosphate group and the nitrogenous bases.
Levene’s most significant achievement was the identification of the specific five-carbon sugars within the nucleic acids. In 1909, he successfully isolated d-ribose from yeast nucleic acid (RNA). He then identified 2-deoxyribose in 1929 from thymus nucleic acid, confirming the difference in the sugar component between RNA and DNA.
He established that these three components—phosphate, sugar, and nitrogenous base—were linked in a specific order, which he termed the nucleotide. Levene’s detailed chemical analysis showed that the phosphate group connected the sugar of one unit to the sugar of the next. This linkage created a continuous sugar-phosphate backbone and established the foundational chemical structure of the nucleic acid chain.
How Monomer Structure Guided Genetic Discovery
Levene’s work in establishing the nucleotide structure was a major milestone, but his interpretation of how these monomers arranged themselves was flawed. Based on his analysis, he proposed the tetranucleotide hypothesis, suggesting that DNA was a simple, repeating polymer where the four bases (A, T, C, G) were present in equal amounts. This structure implied DNA was too monotonous to carry complex genetic information, leading many scientists to incorrectly believe that proteins were the molecules of heredity.
Despite this incorrect conclusion, Levene’s correct identification of the phosphate-sugar-base monomer and its linear linkage was essential for all future progress. His structural model provided the chemical framework for later work by Erwin Chargaff, who demonstrated that the bases were not present in equal proportions, contradicting the tetranucleotide hypothesis. Chargaff’s subsequent discovery that the amount of adenine always equaled thymine (A=T) and the amount of guanine always equaled cytosine (G=C) was built upon the established knowledge of the nucleotide unit. This evidence allowed James Watson and Francis Crick to deduce the double helix structure in 1953.