DNA Testing History

The highlights of DNA testing and how it developed.

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The History of DNA Testing

On April 25, 1953, James Watson and Francis Crick, from Cambridge University, UK, reported the discovery of the structure of DNA (deoxyribonucleic acid), the molecule that makes up genes.

Crick and Watson built the now famous double helix of DNA, but it was the X-ray crystallographic data of Rosalind Franklin and Maurice Wilkins, from King’s College in London, that was crucial to the discovery.

The story of DNA began in 1869, when Swiss biochemist Friedrich Miescher isolated a new substance from the nuclei of white blood cells. Researchers were just becoming aware that cells were the basic unit of life and Miescher was interested in their chemical components. Each morning, he received bandages from the local clinic, which were covered in pus, a good source of white blood cells with their large nuclei. Adding alkali made the cell nuclei burst open, releasing their contents, enabling Meischer to extract the DNA (which he called nuclein).

Analysis of this nuclein showed that it was an acid, containing phosphorus, so it did not fit into any of the known groups of biological molecules like carbohydrates and proteins. Nuclein was renamed nucleic acid, yet its significance would not be fully realized for many more decades.

In 1879, Walther Flemming, a German biologist, discovered tiny thread-like structures called chromatin (later known as chromosomes) within the nucleus. Chromatin were able to absorb color from the new stains used to reveal cellular components. Later studies on cell division uncovered the significant role chromosomes play in inheritance – how they double up before the cell splits and then divide into two sets, taking a fresh copy into each ‘daughter’ cell. Further research suggested that chromosomes contained DNA, which led another German scientist, Oskar Hertwig, to report that “nuclein is the substance which is responsible…for the transmission of hereditary characteristics”.

By 1900, it was common knowledge that the basic building blocks of DNA were phosphate, a sugar (later called deoxyribose) and four heterocyclic bases – two of which were purines adenine (A) and guanine (G) and the other two were pyrimidines cytosine (C) and thymine (T).

It was Phoebus Levene, of the Rockefeller Institute in New York, and a former student of the Russian chemist and composer Alexander Borodin, who showed that the components of DNA were linked in the order phosphate–sugar–base. He called each of these units a nucleotide, arguing that the DNA molecule consisted of a string of nucleotide units linked together through the phosphate groups, which are the ‘backbone’ of the molecule.

Levene was also convinced that the amounts of the four bases were the same in all DNA molecules, whatever their origin. So even when Swedish researchers Torbjörn Caspersson and Einar Hammersten showed, in the 1930s, that DNA was a polymer, most people continued to believe in Levene’s ‘tetranucleotide hypothesis’.

A huge breakthrough came from a team of medical microbiologists at the Rockefeller Institute in New York. Oswald Avery, Colin McLeod and Maclyn McCarty were trying to identify the nature of the ‘transforming principle’ – a substance discovered by English microbiologist, Fred Griffith, in 1928. Griffith had been experimenting with two species of pneumococcus, the bacteria that cause pneumonia.

Avery and his team showed that it was DNA, not a protein, which was the transforming principle.

Finally, it was X-ray crystallography that solved the puzzle of DNA. The use of X-rays to show the structures of large biological molecules began with Dorothy Hodgkin’s work on penicillin, lysozyme and vitamin B12; and Max Perutz’s work on hemoglobin in the 1930s. By 1938, William Astbury, a student of William Bragg (who, with his son Lawrence, invented the technique in 1913) had X-ray pictures of DNA, although they were hard to interpret.

The late 1940s saw three separate groups working diligently on the DNA structure. At King’s College in London, Maurice Wilkins was fascinated by the long fibers that DNA forms when it is pulled out of a watery solution with a glass rod and he wondered if there was some regularity to its structure. In 1951, Wilkins was joined by Rosalind Franklin, who was already known for her work on X-ray crystallography of coals. She built an X-ray laboratory at King’s College and was able to produce the best images of DNA ever seen. From her observations, she believed that maybe the DNA molecule had a coiled helical shape.

Francis Crick, James Watson, Maurice Wilkins and Rosalind Franklin

In the USA, Linus Pauling, chemist and author of The Nature of the Chemical Bond, had already been doing similar research and discovered helical motifs in protein structures. Francis Crick, with his background in math and physics, and James Watson, with his expertise in the molecular biology of phage (viruses that infect bacteria), joined together at Cavendish Laboratory in Cambridge with the intention of solving the DNA structure themselves.

A significant moment came when Wilkins showed Watson one of Franklin’s photos of the so-called B form of DNA. Previous research had used the A form, which contains less water and led to images that were harder to analyze. This new picture was simple and easily revealed a helical structure for the molecule. As Watson stated in his memoir, “The instant I saw the picture, my mouth fell open and my heart began to race”.

Crick and Watson were now ready to build a model, using metal plates for the nucleotides and rods for the bonds between them. But they did not know whether to build their helix with the phosphates on the inside or outside and they were unsure how to incorporate Chargaff’s ideas on base pairing.

When Jerry Donohue, an American chemist, visited the Cavendish laboratory, he solved their dilemma. He showed how hydrogen bonding allows A to bond to T and C to bond to G. This allows a double helical structure for DNA, where the two strands have the bases on the inside, paired up and the phosphates on the outside.

With this knowledge, Crick and Watson built a model in which the structure suggested function. They implied in their Nature paper, “It has not escaped our notice that the specific pairing we have postulated suggests a possible copying mechanism for the genetic material”.

The DNA molecule is self-replicating (as was proven by experiments a few years later) because it can unwind into two single strands. Each base then attracts its complementary base, by hydrogen bonding, so that two new double helices are assembled.

Franklin and Wilkins were also given credit for their work on the DNA structure; their own papers were published in the same issue of Nature as Crick and Watson. Crick, Watson and Wilkins went on to win the Nobel Prize for their work in 1962.

The significance of the DNA discovery was profound as it opened up a new era in biology. Decades later, scientists deciphered the genetic code and realized that DNA directs the synthesis of proteins. There were technical advances, as well, such as DNA sequences, genetic engineering and gene cloning. Most recently, the complete sequences of many organisms, including the human genome in June, 2000 had been found. The next 50 years of the DNA story will be about realizing the practical benefits of Crick and Watson’s discovery for humanity – in industry, medicine, food and agriculture.