Explain what the story of determining the structure of dna tells us about the nature of science

At King’s College London, Rosalind Franklin obtained images of DNA using X-ray crystallography, an idea first broached by Maurice Wilkins. Franklin’s images allowed James Watson and Francis Crick to create their famous two-strand, or double-helix, model.

In 1962 Watson (b. 1928), Crick (1916–2004), and Wilkins (1916–2004) jointly received the Nobel Prize in Physiology or Medicine for their 1953 determination of the structure of deoxyribonucleic acid (DNA). Wilkins’s colleague Franklin (1920–1958), who died from cancer at the age of 37, was not so honored. The reasons for her exclusion have been debated and are still unclear. There is a Nobel Prize stipulation that states “in no case may a prize amount be divided between more than three persons.” The fact she died before the prize was awarded may also have been a factor, although the stipulation against posthumous awards was not instated until 1974.
 

Discovering the Structure of DNA

The molecule that is the basis for heredity, DNA, contains the patterns for constructing proteins in the body, including the various enzymes. A new understanding of heredity and hereditary disease was possible once it was determined that DNA consists of two chains twisted around each other, or double helixes, of alternating phosphate and sugar groups, and that the two chains are held together by hydrogen bonds between pairs of organic bases—adenine (A) with thymine (T), and guanine (G) with cytosine (C). Modern biotechnology also has its basis in the structural knowledge of DNA—in this case the scientist’s ability to modify the DNA of host cells that will then produce a desired product, for example, insulin.

The background for the work of the four scientists was formed by several scientific breakthroughs: the progress made by X-ray crystallographers in studying organic macromolecules; the growing evidence supplied by geneticists that it was DNA, not protein, in chromosomes that was responsible for heredity; Erwin Chargaff’s experimental finding that there are equal numbers of A and T bases and of G and C bases in DNA; and Linus Pauling’s discovery that the molecules of some proteins have helical shapes—arrived at through the use of atomic models and a keen knowledge of the possible disposition of various atoms.
 

Rosalind Franklin

Of the four DNA researchers, only Rosalind Franklin had any degrees in chemistry. She was born into a prominent London banking family, where all the children—girls and boys—were encouraged to develop their individual aptitudes. She attended Newnham College, one of the women’s colleges at Cambridge University. She completed her degree in 1941 in the middle of World War II and undertook graduate work at Cambridge with Ronald Norrish, a future Nobel laureate. She resigned her research scholarship in just one year to contribute to the war effort at the British Coal Utilization Research Association. There she performed fundamental investigations on the properties of coal and graphite. She returned briefly to Cambridge, where she presented a dissertation based on this work and was granted a PhD in physical chemistry.

After the war, through a French friend, she gained an appointment at the Laboratoire Centrale des Services Chimiques de l’Etat in Paris, where she was introduced to the technique of X-ray crystallography (see video on this page) and rapidly became a respected authority in this field. In 1951 she returned to England to King’s College London, where her charge was to upgrade the X-ray crystallographic laboratory there for work with DNA.
 

Maurice Wilkins

Already at work at King’s College was Maurice Wilkins, a New Zealand–born but Cambridge-educated physicist. As a new PhD he worked during World War II on the improvement of cathode-ray tube screens for use in radar and then was shipped out to the United States to work on the Manhattan Project. Like many other nuclear physicists, he became disillusioned with his subject when it was applied to the creation of the atomic bomb; he turned instead to biophysics, working with his Cambridge mentor, John T. Randall—who had undergone a similar conversion—first at the University of St. Andrews in Scotland and then at King’s College London.

It was Wilkins’s idea to study DNA by X-ray crystallographic techniques, which he had already begun to implement when Franklin was appointed by Randall. The relationship between Wilkins and Franklin was unfortunately a poor one and probably slowed their progress.
 

James Watson and Francis Crick

Meanwhile, in 1951, 23-year-old James Watson, a Chicago-born American, arrived at the Cavendish Laboratory in Cambridge. Watson had two degrees in zoology: a bachelor’s degree from the University of Chicago and a doctorate from Indiana University, where he became interested in genetics. He had worked under Salvador E. Luria at Indiana on bacteriophages, the viruses that invade bacteria in order to reproduce—a topic for which Luria received a Nobel Prize in Physiology or Medicine in 1969. Watson went to Denmark for postdoctoral work, to continue studying viruses and to remedy his relative ignorance of chemistry. At a conference in the spring of 1951 at the Zoological Station at Naples, Watson heard Wilkins talk on the molecular structure of DNA and saw his recent X-ray crystallographic photographs of DNA. He was hooked.

Watson soon moved to the Cavendish Laboratory, where several important X-ray crystallographic projects were in progress. Under the leadership of William Lawrence Bragg, Max Perutz was investigating hemoglobin and John Kendrew was studying myoglobin, a protein in muscle tissue that stores oxygen. (Perutz and Kendrew received the Nobel Prize in Chemistry for their work in the same year that the prize was awarded to the DNA researchers—1962.)

Working under Perutz was Francis Crick, who had earned a bachelor’s degree in physics from University College London and had helped develop radar and magnetic mines during World War II. Crick, another physicist in biology, was supposed to be writing a dissertation on the X-ray crystallography of hemoglobin when Watson arrived, eager to recruit a colleague for work on DNA.

Inspired by Pauling’s success in working with molecular models, Watson and Crick rapidly put together several models of DNA and attempted to incorporate all the evidence they could gather. Franklin’s excellent X-ray photographs, to which they had gained access without her permission, were critical to the correct solution. The four scientists announced the structure of DNA in articles that appeared together in the same issue of Nature.
 

Separate Career Paths

Then they moved off in different directions. Franklin went to Birkbeck College, London, to work in J. D. Bernal’s laboratory, a much more congenial setting for her than King’s College. Before her untimely death from cancer she made important contributions to the X-ray crystallographic analysis of the structure of the tobacco mosaic virus, a landmark in the field. By the end of her life she had become friends with Francis Crick and his wife and had moved her laboratory to Cambridge, where she undertook dangerous work on the poliovirus. Wilkins applied X-ray techniques to the structural determination of nerve cell membranes and of ribonucleic acid (RNA)—a molecule that is associated with chemical synthesis in the living cell—while rising in rank and responsibility at King’s College.

Watson’s subsequent career eventually took him to the Cold Spring Harbor Laboratory (CSHL) of Quantitative Biology on Long Island, New York, where as director from 1968 onward he led it to new heights as a center of research in molecular biology. From 1988 to 1992 he headed the National Center for Human Genome Research at the National Institutes of Health. Afterward he returned to CSHL as chancellor. Watson’s racist remarks about the intelligence of Africans in 2007 led the CSHL to force him into retirement, though the Lab named him an emeritus professor and honorary trustee. When Watson doubled down on his racist views in a 2018 documentary, the lab revoked these honors and severed ties with Watson. Watson’s fame as a discoverer of the structure of DNA also made his continued public expression of sexist views on women in science and his previous eugenicist comments on homosexuality particularly harmful during the first decades of the 21st century.

The information contained in this biography was last updated on July 28, 2022.

The sentence "This structure has novel features which are of considerable biological interest" may be one of science's most famous understatements. It appeared in April 1953 in the scientific paper where James Watson and Francis Crick presented the structure of the DNA-helix, the molecule that carries genetic information from one generation to the other.

Nine years later, in 1962, they shared the Nobel Prize in Physiology or Medicine with Maurice Wilkins, for solving one of the most important of all biological riddles. Half a century later, important new implications of this contribution to science are still coming to light.

What is DNA?

The work of many scientists paved the way for the exploration of DNA. Way back in 1868, almost a century before the Nobel Prize was awarded to Watson, Crick and Wilkins, a young Swiss physician named Friedrich Miescher, isolated something no one had ever seen before from the nuclei of cells. He called the compound "nuclein." This is today called nucleic acid, the "NA" in DNA (deoxyribo-nucleic-acid) and RNA (ribo-nucleic-acid).

Francis Crick and James Watson, 1953. Photo: Cold Spring Harbor Laboratory Archives	Maurice Wilkins.

Two years earlier, the Czech monk Gregor Mendel, had finished a series of experiments with peas. His observations turned out to be closely connected to the finding of nuclein. Mendel was able to show that certain traits in the peas, such as their shape or color, were inherited in different packages. These packages are what we now call genes.

For a long time the connection between nucleic acid and genes was not known. But in 1944 the American scientist Oswald Avery managed to transfer the ability to cause disease from one strain of bacteria to another. But not only that: the previously harmless bacteria could also pass the trait along to the next generation. What Avery had moved was nucleic acid. This proved that genes were made up of nucleic acid.

Solving the puzzle

In the late 1940's, the members of the scientific community were aware that DNA was most likely the molecule of life, even though many were skeptical since it was so "simple." They also knew that DNA included different amounts of the four bases adenine, thymine, guanine and cytosine (usually abbreviated A, T, G and C), but nobody had the slightest idea of what the molecule might look like.

In order to solve the elusive structure of DNA, a couple of distinct pieces of information needed to be put together. One was that the phosphate backbone was on the outside with bases on the inside; another that the molecule was a double helix. It was also important to figure out that the two strands run in opposite directions and that the molecule had a specific base pairing.

As in the solving of other complex problems, the work of many people was needed to establish the full picture.

The original DNA model by Watson and Crick. Photo: Cold Spring Harbor Laboratory Archives

Using X-rays to see through DNA

Watson and Crick used stick-and-ball models to test their ideas on the possible structure of DNA. Other scientists used experimental methods instead. Among them were Rosalind Franklin and Maurice Wilkins, who were using X-ray diffraction to understand the physical structure of the DNA molecule.

When you shine X-rays on any kind of crystal – and some biological molecules, such as DNA, can form crystals if treated in certain ways – the invisible rays bounce off the sample. The rays then create complex patterns on photographic film. By looking at the patterns, it is possible to figure out important clues about the structures that make up the crystal.

"Photograph 51". X-ray diffraction photo of a DNA molecule, structure B. Photo: Cold Spring Harbor Laboratory Archives

A three-helical structure?

The scientist Linus Pauling was eager to solve the mystery of the shape of DNA. In 1954 he became a Nobel Laureate in Chemistry for his ground-breaking work on chemical bonds and the structure of molecules and crystals. In early 1953 he had published a paper where he proposed a triple-helical structure for DNA. Watson and Crick had also previously worked out a three-helical model, in 1951. But their theory was wrong.

Their mistake was partly based on Watson having misremembered a talk by Rosalind Franklin where she reported that she had established the water content of DNA by using X-ray crystallographic methods. But Watson did not take notes, and remembered the numbers incorrectly.

Instead, it was Franklin's famous "photograph 51" that finally revealed the helical structure of DNA to Watson and Crick in 1953. This picture of DNA that had been crystallized under moist conditions shows a fuzzy X in the middle of the molecule, a pattern indicating a helical structure.

Model of the alpha helix, 1951. Photo: Oregon State University's Special Collections

Specific base-pairing

The base-pairing mystery had been partly solved by the biochemist Erwin Chargoff some years earlier. In 1949 he showed that even though different organisms have different amounts of DNA, the amount of adenine always equals the amount of thymine. The same goes for the pair guanine and cytosine. For example, human DNA contains about 30 percent each of adenine and thymine, and 20 percent each of guanine and cytosine.

With this information at hand Watson was able to figure out the pairing rules. On the 21st of February 1953 he had the key insight, when he saw that the adenine-thymine bond was exactly as long as the cytosine-guanine bond. If the bases were paired in this way, each rung of the twisted ladder in the helix would be of equal length, and the sugar-phosphate backbone would be smooth.

Structure shows action

"It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material" wrote Watson and Crick in the scientific paper that was published in Nature, April 25, 1953.

This was indeed a breakthrough in the study of how genetic material passes from generation to generation. Once the model was established, its mere structure hinted that DNA was indeed the carrier of the genetic code and thus the key molecule of heredity, developmental biology and evolution.

The specific base pairing underlies the perfect copying of the molecule, which is essential for heredity. During cell division, the DNA molecule is able to "unzip" into two pieces. One new molecule is formed from each half-ladder, and due to the specific pairing this gives rise to two identical daughter copies from each parent molecule.

We all share the same building blocks

Different species need different amounts of DNA. Therefore the copying of the DNA that precedes cell division differs between organisms. For example, the DNA in E. coli bacteria is made up of 4 million base pairs and the whole genome is thus one millimeter long. The single-cell bacterium can copy its genome and divide into two cells once every 20 minutes.

The DNA of humans, on the other hand, is composed of approximately 3 billion base pairs, making up a total of almost a meter-long stretch of DNA in every cell in our bodies.

In order to fit, the DNA must be packaged in a very compact form. In E. coli the single circular DNA molecule is curled up in a condensed fashion, whereas the human DNA is packaged in 23 distinct chromosome pairs. Here the genetic material is tightly rolled up on structures called histones.

A new biological era

This knowledge of how genetic material is stored and copied has given rise to a new way of looking at and manipulating biological processes, called molecular biology. With the help of so-called restriction enzymes, molecules that cut the DNA at particular stretches, pieces of DNA can be cut out or inserted at different places.

In basic science, where you want to understand the role of all the different genes in humans and animals, new techniques have been developed. For one thing, it is now possible to make mice that are genetically modified and lack particular genes. By studying these animals scientists try to figure out what that gene may be used for in normal mice. This is called the knockout technique, since stretches of DNA have been taken away, or knocked out.

Scientists have also been able to insert new bits of DNA into cells that lack particular pieces of genes or whole genes. With this new DNA, the cell becomes capable of producing gene products it could not make before. The hope is that, in the future, diseases that arise due to the lack of a particular protein could be treated by this kind of gene therapy.

Was Rosalind Franklin nominated?

Rosalind Franklin. Photo: Cold Spring Harbor Laboratory Archives

Many voices have argued that the Nobel Prize should also have been awarded to Rosalind Franklin, since her experimental data provided a very important piece of evidence leading to the solving of the DNA structure. In a recent interview in the magazine Scientific American, Watson himself suggested that it might have been a good idea to give Wilkins and Franklin the Nobel Prize in Chemistry, and him and Crick the Nobel Prize in Physiology or Medicine – in that way all four would have been honored.

Rosalind Franklin died in 1958. As a rule only living persons can be nominated for the Nobel Prize, so the 1962 Nobel Prize was out of the question. The Nobel archives, at the Nobel Prize-awarding institutions, that among other things contain the nominations connected to the prizes, are held closed. But 50 years after a particular prize had been awarded, the archives concerning the nominees are released. Therefore, in 2008 it was possible to see whether Rosalind Franklin ever was a nominee for the Nobel Prize concerning the DNA helix. The answer is that no one ever nominated her - neither for the Nobel Prize in Physiology or Medicine nor in Chemistry.

The DNA-helix

The sugar-phosphate backbone is on the outside and the four different bases are on the inside of the DNA molecule.

The two strands of the double helix are anti-parallel, which means that they run in opposite directions.

The sugar-phosphate backbone is on the outside of the helix, and the bases are on the inside. The backbone can be thought of as the sides of a ladder, whereas the bases in the middle form the rungs of the ladder.

Each rung is composed of two base pairs. Either an adenine-thymine pair that form a two-hydrogen bond together, or a cytosine-guanine pair that form a three-hydrogen bond. The base pairing is thus restricted.

This restriction is essential when the DNA is being copied: the DNA-helix is first "unzipped" in two long stretches of sugar-phosphate backbone with a line of free bases sticking up from it, like the teeth of a comb. Each half will then be the template for a new, complementary strand. Biological machines inside the cell put the corresponding free bases onto the split molecule and also "proof-read" the result to find and correct any mistakes. After the doubling, this gives rise to two exact copies of the original DNA molecule.

The coding regions in the DNA strand, the genes, make up only a fraction of the total amount of DNA. The stretches that flank the coding regions are called introns, and consist of non-coding DNA. Introns were looked upon as junk in the early days. Today, biologists and geneticists believe that this non-coding DNA may be essential in order to expose the coding regions and to regulate how the genes are expressed.

By Lotta Fredholm, Science Journalist

First published 30 September 2003