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The Search for the Genetic Material

Central Dogma

The Search Narrows

Now it had to be determined which component of the chromosome, DNA or protein , was the genetic material. Many scientists were sure that it was protein. After all, there were so many subunits (20 amino acids) that it seemed obvious that there existed within protein the possibility for much more diversity in expressing the genetic code than in DNA, which only has 4 subunits. DNA was considered a boring molecule.

The Discovery of DNA

DNA was first identified in 1868 by Friedrich Miescher, a Swiss biologist, in the nuclei of pus cells obtained from discarded surgical bandages. He called the substance nuclein, noted the presence of phosphorous, and separated the substance into a basic part (which we now know is DNA) and an acidic part (a class of acidic proteins that bind to basic DNA).

The Transforming Principle - DNA Might be the Genetic Material

In 1943, Oswald Avery, Colin Macleod, and Maclyn McCarty, at the Rockefeller Institute, discovered that different strains of the bacterium Strepotococcus pneumonae could have different effects on a mouse. One virulent strain could kill an injected mouse, and another avirulent strain had no effect. When the virulent strain was heat-killed and injected into mice, there was no effect. But when a heat-killed virulent strain was coinjected with the avirulent strain, the mice died. What transforming principle was the dead virulent strain giving to the avirulent strain to make it lethal?

Avery and his colleagues separated the dead virulent cells into fractions and coinjected them with the avirulent strain, to see which fraction contained the transforming principle. They discovered that the fraction was DNA. Most scientists at the time, in favour of the theory of protein as genetic material, discounted this result and said that there must have been some protein in the fraction that conferred virulence.

The Hershey-Chase Experiment - DNA is the Genetic Material

Finally, in 1952, Alfred Hershey and Martha Chase performed the definitive experiment that showed that DNA was, in fact, the genetic material. Recall the mechanism of bacteriophage infection. By radiolabelling sulphur in one culture, they could tag the path of proteins and not DNA, because there is no sulphur in DNA and there is sulphur in the amino acids methionine and cysteine. By radiolabelling phosphorous, the opposite effect could be achieved. DNA could be traced and not protein, because there is phosphorous in the phosphate backbone of DNA and none in any of the amino acids. Cultures could be grown in each of these two ways and the phage purified away from the host bacteria, resulting in one culture in which only the phage protein was labelled, and one culture in which only the phage DNA was labelled.

Hershey-Chase Blender Experiment

Side by side experiments were performed with separate phage cultures in which either the protein capsule was labeled with radioactive sulfur or the DNA core was labeled with radioactive phosphorus.

Experiment Summary

  1. The radioactively labeled phages were allowed to infect bacteria.
  2. Agitation in a blender dislodged phage particles from bacterial cells.
  3. Centrifugation pelleted cells, separating them from the phage particles left in the supernatant.

Results Summary:

  1. Radioactive sulfur was found predominantly in the supernatant.
  2. Radioactive phosphorus was found predominantly in the cell fraction, from which a new generation of infective phage was generated.
Thus, it was shown that the genetic material that encoded the growth of a new generation of phage was in the phosphorous-containing DNA.

Chargaff - Nucleotide Content in DNA

Now that it had been established that DNA was the genetic material, scientists began fervently looking for its mechanism and structure. In 1950, Erwin Chargaff at Columbia University discovered that no matter what tissue from an animal he looked at, the percentage content of each of the four nucleotides was the same, though the percentages could vary from species to species. This insinuated that the structure of the DNA was specific and conserved in each organism. He also found, more importantly, that in all animals:

%G = %C
%A = %T

The significance of these results was overlooked for three years, but they were crucial to elucidating the structure of DNA.

Watson and Crick - The Double Helix

In late 1953, James Watson and Francis Crick presented a model of the structure of DNA. It was already known from chemical studies that DNA was a polymer of nucleotide (sugar, base and phosphate) units. X-ray crytallographic data obtained by Rosalind Franklin, combined with the previous results from Chargaff and the chemists, were fitted together by Watson and Crick into the following model:

DNA Molecule: Two Views

In the double helix the two strands of DNA run in opposite directions and are complementary, being matched by the hydrogen bonds of the A - T and G - C base pairs. This complementary pairing of the bases suggests that, when DNA replicates, an exact duplicate of the parental genetic information is made. The polymerization of a new complementary strand takes place using each of the old strands as a template.

For their outstanding work in discovering the double helical structure of DNA, Watson and Crick shared the 1962 Nobel Prize for Physiology and Medicine with Maurice Wilkins. Sadly, Rosalind Franklin, whose work greatly contributed to this key discovery, died before this date, and the rules do not allow a Nobel Prize to be awarded posthumously.

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