13.1 Discovery of DNA Structure and Function

The discovery of DNA's structure and function revolutionized our understanding of genetics. A series of experiments across three decades established that DNA, not protein, carries hereditary information. That conclusion set the stage for Watson and Crick's double helix model in 1953, which finally explained how genetic information is stored, copied, and passed between generations.

This topic traces the key experiments, the people behind them, and the structural features of DNA that make it such an effective molecule for heredity.

DNA as Genetic Material

Experiments Demonstrating DNA as Genetic Material

Before the 1940s, most scientists assumed proteins carried genetic information because proteins are far more chemically complex than DNA. Proteins are built from 20 different amino acids, while DNA has only four types of nucleotides. That complexity made proteins seem like the obvious candidate. Three landmark experiments overturned that assumption.

• Griffith's Transformation Experiment (1928): Frederick Griffith worked with two strains of Streptococcus pneumoniae: a virulent (deadly) "smooth" strain (which had a polysaccharide capsule) and a harmless "rough" strain (which lacked one). When he mixed heat-killed smooth bacteria with live rough bacteria and injected them into mice, the mice died. Something from the dead smooth bacteria had "transformed" the live rough bacteria into a virulent form. Griffith called this unknown substance the transforming principle, but he couldn't identify what it was.
• Avery, MacLeod, and McCarty (1944): These researchers set out to identify Griffith's transforming principle. They systematically destroyed different molecules (proteins, lipids, RNA, DNA) in extracts from smooth bacteria and tested which removal stopped transformation. Only when they destroyed DNA did transformation fail. This was the first direct evidence that DNA carries genetic information, though many scientists remained skeptical because the result was so unexpected.
• Hershey-Chase Experiment (1952): Alfred Hershey and Martha Chase used bacteriophages (viruses that infect bacteria) to settle the debate. Their logic relied on a simple chemical difference: DNA contains phosphorus but no sulfur, while proteins contain sulfur but no phosphorus. They labeled viral DNA with radioactive phosphorus ($^{32}P$) and viral protein with radioactive sulfur ($^{35}S$). After the phages infected bacteria, they used a blender to separate the empty viral coats from the bacterial cells, then centrifuged the mixture. Only the $^{32}P$ label (DNA) was found inside the bacterial cells, while the $^{35}S$ (protein) stayed outside. This confirmed that DNA, not protein, is the genetic material.

Chargaff's Rules and DNA Composition

While those experiments established what the genetic material was, Erwin Chargaff's biochemical analysis in the late 1940s provided clues about how DNA is organized.

Chargaff measured the amounts of each nitrogenous base in DNA from multiple species and found a consistent pattern:

• The amount of adenine (A) always equals the amount of thymine (T)
• The amount of guanine (G) always equals the amount of cytosine (C)

These ratios (now called Chargaff's rules) suggested a complementary relationship between specific bases. Importantly, while the A=T and G=C ratios held across all species, the ratio of A+T to G+C varied from one species to another. This variation meant DNA wasn't just a boring repeating polymer; it could carry species-specific information. At the time, no one knew exactly why these ratios held, but they turned out to be a critical clue for building the correct structural model.

DNA's Double Helix Structure

Composition and Arrangement of DNA

Each nucleotide in DNA has three components: a deoxyribose sugar, a phosphate group, and one of four nitrogenous bases (A, T, G, or C). These nucleotides link together into long strands, and two such strands combine to form the double helix.

• DNA consists of two antiparallel polynucleotide strands (one runs 5'→3', the other 3'→5') wound around each other in a right-handed double helix.
• The sugar-phosphate backbones face outward, forming the structural "rails" of the helix.
• The nitrogenous bases point inward, where they form complementary base pairs held together by hydrogen bonds:
  • Adenine (A) pairs with thymine (T) via two hydrogen bonds
  • Guanine (G) pairs with cytosine (C) via three hydrogen bonds
• This base-pairing rule is exactly what Chargaff's ratios predicted.

The helix completes one full turn every 10 base pairs, spanning about 3.4 nm per turn (with 0.34 nm between each pair). These measurements, derived from X-ray crystallography, were essential for confirming the model's accuracy.

Significance of the Double Helix Structure

The structure itself explains several key biological functions:

• Replication: Because the two strands are complementary, each strand can serve as a template for building a new partner strand. This is how DNA copies itself before cell division. Watson and Crick famously noted in their 1953 paper: "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism."
• Faithful heredity: Complementary base pairing ensures that genetic information is copied with high accuracy, so daughter cells receive virtually identical DNA.
• Protection of genetic information: The nitrogenous bases, which encode the actual instructions, are tucked inside the helix. The sugar-phosphate backbone on the outside shields them from chemical and physical damage.

DNA's Role in Genetics

DNA as a Blueprint for Life

DNA stores the instructions for building proteins, which carry out most of a cell's functions. The genetic information is encoded in the sequence of nucleotides along each strand. Each set of three nucleotides is called a codon, and each codon specifies a particular amino acid (or a start/stop signal).

Central Dogma of Molecular Biology

Francis Crick articulated the "central dogma" in 1958 to describe the flow of genetic information in cells: DNA → RNA → Protein.

1. Transcription: The DNA sequence of a gene is copied into a complementary messenger RNA (mRNA) molecule. This happens in the nucleus.
2. Translation: The mRNA travels to ribosomes in the cytoplasm, where the codon sequence is read. Each codon directs the addition of a specific amino acid, assembling a protein.
3. DNA Replication: Before a cell divides, the entire DNA molecule is copied so each daughter cell inherits a complete set of genetic instructions. This is what makes heredity possible.

Note that replication isn't really part of the DNA→RNA→Protein flow; it's listed here because it's the other major thing DNA does. The central dogma specifically describes the direction information travels: from nucleic acid to protein, not the reverse. (Exceptions exist, such as reverse transcriptase in retroviruses, but the general principle holds for normal cellular life.)

Discoverers of DNA's Structure

Watson and Crick's Double Helix Model

James Watson and Francis Crick proposed the double helix model in their famous 1953 paper in Nature. They didn't do the key experiments themselves. Instead, they built physical models and tested whether different arrangements were consistent with the available evidence:

• Chargaff's base-pairing ratios
• X-ray crystallography data showing a helical shape with specific dimensions
• Known chemical properties of nucleotides

Their approach was essentially model-building by trial and error, constrained by experimental data. They initially tried a triple helix with the bases facing outward before arriving at the correct two-stranded, bases-inward structure. Their model explained both how DNA could replicate and how it could encode genetic information. Watson, Crick, and Maurice Wilkins received the Nobel Prize in Physiology or Medicine in 1962.

Contributions of Franklin and Wilkins

• Rosalind Franklin produced high-quality X-ray diffraction images of DNA, most famously "Photo 51." This image revealed that DNA was helical, showed the spacing between bases (0.34 nm apart), indicated that the phosphate groups were on the outside, and suggested two strands rather than three. Without this data, Watson and Crick could not have built their correct model. Franklin also distinguished between two forms of DNA (the "A" and "B" forms), with the B form providing the clearest evidence of helical structure.
• Maurice Wilkins, Franklin's colleague at King's College London, shared her crystallography data with Watson and Crick without her knowledge or consent. This remains one of the most debated ethical episodes in the history of science. The working relationship between Franklin and Wilkins was strained, partly due to institutional miscommunication about their respective roles.
• Franklin died of ovarian cancer in 1958 at age 37, possibly linked to her extensive exposure to X-ray radiation. Because the Nobel Prize is not awarded posthumously, she was not included in the 1962 prize. Her essential contributions went largely unrecognized for decades, though historians of science have since worked to correct that record.