The Discovery of DNA

will1278; Various Authors - See Each Chapter Attribution

7 The Discovery of DNA

By the end of this section, you will be able to:

Explain how DNA was determined to be the molecule of inheritance.
Identify the contributions of Chargaff, Franklin, Watson, and Crick to the discovery of the structure of DNA

In the previous chapters, we learned about the structure and function of DNA, but where did all of this knowledge come from? In this chapter, we learn about some of the key events in the discovery of DNA.

By the early 1900s, biochemists had isolated hundreds of chemicals from living cells. Which of these was the “genetic” material? Proteins seemed like promising candidates since they were abundant, diverse, and complex molecules. However, a few key experiments demonstrated that DNA, rather than protein, is the genetic material.

Lecture Video: The Discovery of DNA, The Central Dogma, Genomics, and Proteomics.

Griffith’s Experiment and the basis of inheritance (1929)

Frederick Griffith was a microbiologist interested in what made some bacteria pathogenic and others not. At the time, microbiologists had identified two strains of the bacterium Streptococcus pneumoniae. The R-strain produced rough colonies on a bacterial plate, while the other S-strain was smooth. More importantly, the S-strain caused fatal infections when injected into mice, while the R-strain did not (Figure 1). Neither did “heat-treated” S-strain cells. Griffith in 1929 noticed that upon mixing “heat-treated” S-strain cells together with some R-type bacteria (neither should kill the mice), the mice died and there were S-strain, pathogenic cells recoverable. Thus, some non-living component from the S-type strains contained genetic information that could be transferred to and transform the living R-type strain cells into S-type cells (Figure 1).

Diagram illustrating Griffith's experiment on the transformation principle in bacteria. The image shows four experiments on mice. The first mouse is injected with live non-virulent bacteria (smooth strain) and remains alive. The second mouse is injected with live virulent bacteria (rough strain) and dies. The third mouse is injected with heat-killed virulent bacteria and remains alive. The fourth mouse is injected with a mixture of live non-virulent and heat-killed virulent bacteria, leading to the death of the mouse. The diagram visually represents the discovery that the non-virulent bacteria were transformed into virulent bacteria by acquiring genetic material from the heat-killed virulent strain. — **Figure 1.** Griffith’s experiment illustrates the “transforming principle” in heat-killed virulent smooth pneumococcus (S-strain) that enables the transformation of rough, non-virulent rough pneumococcus (R-strain). (Original-Deyholos-CC:AN)

Avery, MacLeod and McCarty’s Experiment demonstrate the DNA is the molecule of inheritance (1944)

What kind of molecule from within the S-type cells was responsible for the transformation? To answer this, researchers named Avery, MacLeod and McCarty separated the S-type cells into various components, such as proteins, polysaccharides, lipids, and nucleic acids. Only the nucleic acids from S-type cells were able to make the R-strains smooth and fatal. Furthermore, when cellular extracts of S-type cells were treated with DNase (an enzyme that digests DNA), the transformation ability was lost. The researchers therefore concluded that DNA was the genetic material, which in this case controlled the appearance (smooth or rough) and pathogenicity of the bacteria (Figure 2).

Diagram showing the effects of DNase and protease on the transformation of bacteria in mice. The first part of the image shows that when DNase is added to a mixture of heat-treated virulent bacteria (S strain) and non-virulent bacteria (R strain), the injected mouse remains alive, indicating that DNA is necessary for transformation. The second part shows that the mouse dies when protease is added to the same mixture, indicating that proteins are not responsible for the transformation. This experiment demonstrates that DNA is the transforming principle. — **Figure 2.** Illustration of the experiment that showed DNA, not protein, is the substance responsible for transforming non-virulent bacteria into a virulent form, as shown by the survival of the mouse when DNase was used to destroy DNA. (Original-Deyholos-CC:AN)

Chargaff’s Rule and base-pairing (1950)

Scientists now were confident that DNA was the molecule of inheritance, but they were not certain what it looked like or how exactly it worked. A critical breakthrough came from Erwin Chargaff, who uncovered the base pairing rules that became essential to understanding DNA’s structure. Chargaff’s experiments showed that in any DNA molecule, the amount of adenine (A) consistently equals the amount of thymine (T), and the amount of cytosine (C) equals the amount of guanine (G) (Table 1).

Chargaff’s findings demonstrated that DNA was not just a random sequence of nucleotides, but rather a built around specific base pairing rules.

The percentages represent the proportion of each base relative to the total DNA content.
Chargaff’s rules are reflected in the nearly equal proportions of adenine to thymine and cytosine to guanine in each organism.
While the exact percentages vary between species, the 1:1 ratio between adenine and thymine, and between cytosine and guanine, remains consistent across different organisms.
This table highlights the universality of Chargaff’s findings across a range of species, which was critical to understanding the structure and function of DNA.

Table 1. Data from Chargaff’s experiments. Chargaff’s rules are reflected in the nearly equal proportions of adenine to thymine and cytosine to guanine in each organism. While the exact percentages vary between species, the 1:1 ratio between adenine and thymine, and between cytosine and guanine, remains consistent across different organisms.
Organism	Adenine (A)	Thymine (T)	Cytosine (C)	Guanine (G)
Human	30.30%	30.30%	19.90%	19.50%
Escherichia coli	24.70%	23.60%	26.00%	25.70%
Yeast	31.30%	32.90%	17.10%	18.70%
Calf Thymus	29.00%	29.10%	22.00%	20.90%
Wheat	27.30%	27.10%	22.70%	22.80%
Rat	28.60%	28.40%	21.40%	21.50%

A model of DNA

In the 1950s, multiple teams were trying to model the structure of DNA. Linus Pauling discovered the secondary structure of proteins using X-ray crystallography. X-ray crystallography is a method for investigating molecular structure by observing the patterns formed by X-rays shot through a crystal of the substance. The patterns give important information about the structure of the molecule of interest. Maurice Wilkins inspired by Pauling’s work, set about studying the structure of DNA with X-ray crystallography. Rosalind Franklin, who recently joined Wilkins Lab, led the effort to use X-ray crystallography to understand the structure of DNA. Her work produced the famous “Photo 51,” which provided crucial evidence that DNA has a helical structure (Figure 3).

Figure 3
$Photograph of X-ray diffraction pattern known as 'Photo 51,' taken by Rosalind Franklin. The image shows a circular pattern with an X-shaped diffraction at the center, which provided crucial evidence for the helical structure of DNA.$ Figure 3a. Franklin and Gosling’s X-ray diffraction image of B DNA, known as Photograph 51. (King’s College London Archives/Science Photo Library)	Figure 3b. Rosalind Franklin (CSHL, CC BY-SA 4.0 via Wikimedia Commons)

James Watson and Francis Crick used data collected by Franklin, Chargaff, and others to piece together the puzzle of the DNA molecule. In 1953, Watson and Crick proposed a double-helix model for the structure of DNA, which is the model we still use today (Figure 4).

Part A shows an illustration of a DNA double helix, which has a sugar phosphate backbone on the outside and nitrogenous base pairs on the inside. Part B shows base-pairing between thymine and adenine, which form two hydrogen bonds, and between guanine and cytosine, which form three hydrogen bonds. — **Figure 4:** DNA (a) forms a double stranded helix, and (b) adenine pairs with thymine and cytosine pairs with guanine. (credit a: modification of work by Jerome Walker, Dennis Myts)

In 1962, James Watson, Francis Crick, and Maurice Wilkins were awarded the Nobel Prize in Medicine for their work in determining the structure of DNA.

Rosalind Franklin passed away from cancer in 1958 and was not recognized by the Nobel Committee, despite her research providing principal evidence toward our understanding of DNA (you can learn more about the fascinating life of Rosalind Franklin here and here).

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