Identifying the genetic material

Every living thing carries a set of instructions for building and running its body. Today we know those instructions are written in DNA, but for decades most scientists were betting on protein. Settling the question took a clear list of what hereditary instructions must do, plus a few clever experiments with bacteria.

Four jobs of the genetic material

The substance that carries hereditary instructions from one generation to the next is the genetic material. Whatever molecule plays that role has to meet four requirements:

1. Information. It holds the instructions needed to build a whole organism, from a fertilized egg to an adult.
2. Replication. It can be copied accurately. Copying DNA is called DNA replication.
3. Transmission. Once copied, it can be passed from parent to offspring, and from cell to cell when a cell divides.
4. Variation. Differences in it explain why individuals of a species differ, and why species differ from each other.

Why protein looked like the better bet

By the early 1900s, researchers had traced inheritance to chromosomes, the threadlike structures in cells that are passed on when cells divide. Chromosomes contain two main kinds of large molecules: proteins and DNA.

Protein seemed the obvious choice. Proteins are built from 20 different amino acids and do an enormous range of jobs, so they looked complex enough to encode an organism. DNA is built from only four kinds of repeating units (nucleotides, covered in the next segment), so it looked too simple. Experiments with bacteria overturned that expectation.

Griffith: something can transform bacteria

In the late 1920s, Frederick Griffith worked with two strains (genetically distinct lines) of the bacterium Streptococcus pneumoniae:

• Type S (smooth) bacteria make a slimy outer coat called a capsule. The capsule hides them from the immune system, so type S bacteria cause a fatal infection in mice.
• Type R (rough) bacteria can’t make a capsule. The mouse’s immune system destroys them, so they’re harmless.

Griffith injected mice with different combinations and checked whether they died and whether living bacteria turned up in their blood.

The last row was the surprise. Neither ingredient could kill a mouse alone, yet together they did, and the mouse’s blood held living type S bacteria. Something from the dead S cells had converted the living R cells into S cells. Griffith called this conversion transformation and named the unknown substance the transformation principle.

The result fits all four requirements. The transformed bacteria gained the information to build a capsule. That ability was replicated and transmitted to their offspring as they multiplied in the mouse. And the two strains already showed variation in this trait.

Avery, MacLeod, and McCarty: the answer is DNA

In the 1940s, Oswald Avery, Colin MacLeod, and Maclyn McCarty set out to identify the transformation principle. They separated type S cells into their main classes of large molecules (proteins, DNA, and RNA) and tested each class on type R bacteria. Only the purified DNA turned type R into type S.

A skeptic could object that the DNA sample might carry traces of protein or RNA, and that a contaminant did the transforming. So the team treated portions of the DNA extract with enzymes that each destroy one kind of molecule:

As a control, type R cells given no extract at all never became type S.

Check yourselfIn the Avery, MacLeod, and McCarty experiment, why wasn’t it enough to show that a DNA extract could transform type R bacteria?

The extract might not have been perfectly pure, so a small amount of contaminating protein or RNA could have been the real transforming substance. Treating the extract with protease or RNase didn’t stop transformation, but DNase did, which ruled out the contaminants and pointed to DNA.

Check yourselfSome bacteria survive the antibiotic tetracycline and others don’t. How could you show that resistance is carried in the resistant strain’s DNA?

Purify DNA from the resistant strain and mix it with sensitive bacteria, with separate batches treated with protease, RNase, or DNase. Then grow the cells on plates containing tetracycline. If DNA carries the trait, resistant colonies appear in every batch except the DNase one.