Discovering the Genetic Material: From Griffith to the Double Helix

A mystery that took more than 80 years

By the early 1900s biologists knew that traits are inherited and that chromosomes carry them. But chromosomes are made of two kinds of molecule: protein and DNA. Which one is the genetic material?

Most scientists bet on protein. Proteins are built from 20 different amino acids, so they seemed rich enough to hold a huge amount of information. DNA has only 4 kinds of building block, and many people thought it was a boring, repetitive molecule, perhaps just scaffolding.

They were wrong. This lesson follows the experiments that proved it, step by step. As you read, act like a scientist reviewing each study: What was tested? What was the control? What does the evidence actually show? This is the curriculum's expectation D3.7: describing the historical contributions that built our understanding of molecular genetics.

1869: Miescher finds "nuclein"

The Swiss physician Friedrich Miescher isolated a new substance from the nuclei of white blood cells in 1869. It was rich in phosphorus and was not a protein. He called it nuclein. Today we call it nucleic acid. Nobody yet knew what it did.

In the early 1900s, Phoebus Levene worked out that nucleic acids are chains of nucleotides, each with a sugar, a phosphate and a base. But he also proposed that DNA repeated the four bases in a simple, fixed pattern. That (wrong) idea made DNA look too simple to carry information, and it held back the field for years.

1928: Griffith and the "transforming principle"

Frederick Griffith, a British medical officer, was trying to make a vaccine against pneumonia. He worked with two strains of the bacterium Streptococcus pneumoniae:

• The S strain (smooth) has a sugar capsule that hides it from the immune system. It causes pneumonia and kills mice.
• The R strain (rough) has no capsule. The mouse's immune system destroys it.

Griffith concluded that some substance from the dead S cells had transformed the living R cells into S cells, and the change was inherited: the new S cells had S offspring. He did not know what the substance was. He called it the transforming principle.

1944: Avery, MacLeod and McCarty identify it

Oswald Avery, Colin MacLeod (also born in Nova Scotia) and Maclyn McCarty, working at the Rockefeller Institute in New York, purified the transforming principle from S cells. Then they used enzymes to destroy one kind of molecule at a time:

• Treated with a protease (destroys protein): transformation still happened.
• Treated with RNase (destroys RNA): transformation still happened.
• Treated with DNase (destroys DNA): transformation stopped.

Only destroying DNA blocked it, so DNA is the transforming principle. Many scientists were still unconvinced: perhaps a tiny trace of protein contaminated the sample. More evidence was needed.

1950: Chargaff's rules

Erwin Chargaff measured the bases in DNA from many species. He found two patterns:

1. The amount of A equals T, and the amount of G equals C, in every species.
2. The overall composition varies between species (for example, human DNA is about 30% A, while some bacteria have much less).

The second pattern killed Levene's idea of a simple repeat: if DNA differs between species, it can carry species-specific information. The first pattern was a clue to base pairing that nobody understood yet.

1952: Hershey and Chase settle it

Alfred Hershey and Martha Chase used the bacteriophage T2, a virus made of just a protein coat and DNA. When T2 infects a bacterium, something goes inside and directs the cell to make new viruses. Which part?

They used a clever fact: protein contains sulfur (in some amino acids) but almost no phosphorus, while DNA contains phosphorus (in every nucleotide) but no sulfur.

• Batch 1: phages grown with radioactive sulfur-35, which labels the protein.
• Batch 2: phages grown with radioactive phosphorus-32, which labels the DNA.

1951 to 1953: finding the shape

At King's College London, Rosalind Franklin and her student Raymond Gosling made very sharp X-ray diffraction images of DNA fibres. Their image known as Photo 51 (1952) showed an X-shaped pattern that indicates a helix. Franklin's measurements showed the phosphate backbones are on the outside, the molecule is about 2 nm wide, and the pattern repeats every 3.4 nm.

At Cambridge, James Watson and Francis Crick were building models. Through Franklin's colleague Maurice Wilkins, and a research report, they saw her unpublished data without her knowledge at the time. Combining her measurements with Chargaff's rules, they realized that A pairs with T and G pairs with C across the middle, with the two strands running in opposite directions. Their one-page model was published in the journal Nature in April 1953, in the same issue as papers by Franklin and Gosling and by Wilkins and his colleagues.

In 1962, Watson, Crick and Wilkins shared the Nobel Prize in Physiology or Medicine. Franklin had died in 1958, and Nobel Prizes are not awarded after death. Today historians agree her data were essential, and her role is a well-known example of how credit in science is not always shared fairly.

What came next

The double helix immediately suggested how DNA could be copied: each strand is a template for the other. Matthew Meselson and Franklin Stahl confirmed this in 1958 (you will analyse their experiment in the DNA replication lesson). In the following decades scientists cracked the genetic code (1960s), learned to cut and join DNA (1970s), sequence it (1977) and copy it by PCR (1983), and read the whole human genome (2003). Each of those has its own lesson in this unit.