A short history of DNA

DNA, or deoxyribonucleic acid, is the blueprint for life itself. The discovery of DNA paved the way to an understanding our genetic heritage. But for a molecule with such a grand purpose, DNA had humble beginnings – after it was first identified it languished in obscurity for more than half a century.

Discovering DNA

In the 1860s, German medical researcher Friedrich Miescher joined Felix Hoppe-Seyler’s laboratory at the University of Tubingen, Germany. There, at a time when scientists were still debating the concept of a “cell”, Hoppe-Seyler’s lab was isolating the very molecules that make up cells.

Miescher was given the task of researching the composition of lymphoid cells -- white blood cells. These cells were difficult to extract from the lymph glands, but could be gathered in great quantities with the pus from infections. So Miescher collected bandages from a nearby clinic and washed off the pus. He experimented and isolated a new molecule – a white, slightly acidic substance he called nuclein. Isolated from the cell nucleus, nuclein – which was later purified to DNA -- was rich in nitrogen and phosphorus, as well as containing carbon, hydrogen, and oxygen.

Miescher’s paper on nuclein was not published until 1871, two years after his discovery. Hoppe-Seyler, sceptical because nuclein was such a unusual molecule, confirmed the results by repeating all the experiments himself.

The molecule of heredity

Image from "What's A Genome?". Original art by Mary S. Gibbs, Genome News Network, the Center for the Advancement of Genomics

Around the time of Miescher’s discovery, Austrian monk Gregor Mendel and British scientist Charles Darwin were both publishing works on the theories of genetics and evolution. But no one suspected that Miescher’s new compound was the key to all this. DNA was in the right place to control our heredity -- in the chromosomes inside the cell’s nucleus -- but it was such a simple molecule that some doubted it had any function at all.

The proteins in the chromosomes of cell nuclei were considered much better candidates for carrying the information necessary to build a living organism. Miescher himself, though he continued to work on “nuclein’ for the rest of his career, believed that proteins were the molecules of heredity.

Part of the problem was that proteins were already known to be important as the enzymes and structural components of living cells. They are made up of a combination of 20 amino acids, an “alphabet” that can be configured into many different ways to convey a lot of information. DNA, on the other hand, is much simpler. It consists of the sugar deoxyribose, plenty of phosphate, and only four bases: adenine, cytosine, guanine and thymine, or A, C, G and T. What’s more, early studies of DNA had erroneously suggested that the four bases were always repeated in the same order, such as ACGTACGTACGT.

But in the 1920s new experiments began to point the genetic finger at DNA. English bacteriologist Fred Griffith was working with two strains of the pneumonia bacterium: a virulent wild strain, which could kill, and a harmless mutant that did not. Griffith killed some of the virulent strain by boiling them (rendering them harmless). But when he tried mixing the dead bacteria with the live harmless mutant, he found that the mutant somehow gained the capability to kill. The dead bacteria apparently provided some chemical that transformed the harmless bacteria to infectious ones. This so-called “transforming principle” is now known to be a gene.

In the 1940s, a team of scientists led by Oswald Avery at the Rockefeller Institute followed up on these experiments. They found that a pure extract of the “transforming principle” was unaffected by protein-digesting enzymes but was destroyed by a DNA digesting enzyme. This showed clearly that the “transforming principle”, and thus genes, are made of DNA.

Many scientists were slow to accept this as proof that DNA, not protein, is the genetic molecule, but Avery’s results did push them in the right direction. Researchers soon found that different species each have different relative amounts of A, G, C and T. They also found that in DNA the ratio of As to Ts and Gs to Cs was always the same, suggesting that each pair of bases are somehow connected.

The double helix

Around this time, advances in X-ray diffraction techniques had allowed scientists like Maurice Wilkins and Rosalind Franklin to look directly at DNA. These showed that DNA probably had the corkscrew structure of a helix.

Mary S. Gibbs, GNN, the Center for the Advancement of Genomics

In 1953, James Watson and Francis Crick, after building successive scale models of possible DNA structures, deduced that it must take the twisted-ladder shape of a double helix. The sides of the ladder consist of a “backbone” of sugar and phosphate molecules. The nitrogen-rich bases, A, T, G and C, form the “rungs” of the ladder on the inside of the helix. The pair discovered that base A would only pair with T, while G would only pair with C. This is known as complementary base pairing, and neatly explains DNA’s equal amounts of A and T, or G and C.

Watson and Crick noted in their 1953 paper that complementary pairing pointed out an obvious way to copy DNA. The helix can be "unzipped", breaking the rungs of the ladder in half so that the molecule separates down the middle. New bases can then hook up with complementary bases along each strand and join together to form the other side of the ladder. The unzipping gradually proceeds, the new strands continue to grow, and one DNA molecule becomes two identical DNA molecules.

Mary S. Gibbs, GNN, the Center for the Advancement of Genomics

With a few exceptions, every cell in your body contains DNA, and every cell needs to copy its DNA each time it divides. In a complicated organism like humans, who have a total of about 3 billion base pairs of DNA, this copying process takes about eight hours. While this may seem like a long time, reading the same sequence aloud -- even at a speedy rate of 10 bases per second -- would take around 9.5 years.

Controlling our construction

The complementarity of DNA bases is also central to the molecule's other main function – coding for the proteins that carry out our bodies' activities. For this RNA, a nucleic acid that is abundant in the cytoplasm outside the nucleus of a cell, is needed.

An impression of protein construction at the ribosome; transfer RNAs attaching amino acids.
Sourced from Nicolas Guex, of the Glaxo Wellcome Experimental Research Centre in Switzerland.

RNA is usually single-stranded, but otherwise very similar to DNA. It has complementary base pairing and can even form a double helix in combination with DNA, with one side of the helix DNA and the other RNA. In fact, this is the first step in making proteins: a RNA copy of a stretch of DNA is made, and then this “messenger” RNA travels from the nucleus out to the ribosome, a large protein and RNA complex.

Because there are 20 amino acids that make up proteins, there must be at least 20 different DNA "words", each specifying a particular amino acid. This means that three bases form a "word" or codon, coding for one amino acid. Some codons do other things, such as specifying the beginning or end of the sequence coding for the protein.

In the cytoplasm there is another type of RNA, “transfer” RNA. The 20 different types of transfer RNA each read just one codon in the messenger RNA and attach to the amino acid specified by that codon. The amino acids are then plucked from their transfer RNAs by the ribosome and strung together into the protein coded for by the messenger RNA. The stretch of DNA that codes for an entire protein is what we know as a gene.

RNA seems a very versatile molecule, and in the 1960s experiments showed that mRNA has the ability to store genetic information. It now seems certain that RNA was the first molecule of heredity, and evolved all the essential techniques for storing and expressing genetic information. But RNA is unstable and easily damaged. DNA, with one less oxygen per sugar molecule, is a much more stable structure for the storage of genetic information.

Not all of our DNA makes genes. Most DNA consists of long, repetitive sequences. This ‘junk’ DNA, with no known purpose, even interrupts the protein coding regions within genes. It is estimated that only about 5% of human DNA actually encodes proteins.

Humans have about 35,000 genes, carried on 23 pairs of chromosomes. The object of the Human Genome Project was to catalogue all of these genes, determining the actual sequence of bases along each one. New Zealand scientists have been sequencing the genomes of several microorganisms, plants, and animals, such as pinus radiata or the cheese-making lactobacillus bacteria.

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