DNA is probably one of the most complex molecules in living organisms. It stores genetic information needed for development and functioning of the organism. It is like a book of blueprints to make all the components for a live organism.

Amid the uncertainty, two researchers used the available data together with their own intuition and guesswork and put forth a suggested structure for DNA. The two researchers, James D. Watson and Francis H. C. Crick, performed no laboratory experiments, but they managed to guess the sum by analyzing the parts. In so doing, they gained international fame and put biochemists on the track to unlocking the secrets of heredity. The work of Watson and Crick was the jumping-off point for the science of DNA technology.

Establishing the structure of DNA has been one of the major achievements of the twentieth century. Not only did it yield myriad practical benefits, but it also gave scientists the philosophical pride of understanding how heredity works. Biology has many bedrock principles - the cellular basis of living things, the germ theory of disease, and the process of evolution are three - and the chemical basis of heredity is another of those principles. Unlocking the secret of DNA was the key to understanding this principle.

Although the structure of DNA was unknown in the early 1950s, its chemical components had been known for thirty years. In the 1920s, the basic chemistry of nucleic acids was determined by Phoebus A. T. Levene. Working with his colleagues at Rockefeller Institute in New York City, Levene isolated from yeast cells and thymus tissue two types of nucleic acid: ribonucleic acid (RNA) and deoxyribonucleic acid (DNA).

Levene's analyses revealed that both nucleic acids contain three basic components: (1) a five-carbon sugar, which could be either ribose (in RNA) or deoxyribose (in DNA); (2) a series of phosphate groups, that is, chemical groups derived from phosphoric acid molecules; and (3) four different compounds containing nitrogen and having the chemical properties of bases. Because of their nitrogen content and basic qualities, the four compounds are known as nitrogenous bases. In DNA the four bases include adenine, thymine, guanine, and cytosine in DNA; and in RNA, they are adenine, uracil, guanine, and cytosine. Adenine and guanine are double-ring molecules known as purines; cytosine, thymine, and uracil are single-ring molecules called pyrimidines.

Research performed by Levene's group indicated that DNA contains roughly equal proportions of phosphate groups, deoxyribose molecules, and nitrogenous bases. Levene therefore concluded (correctly, in retrospect) that DNA is composed of three essential components and that they are used to form units. He surmised that the units are strung together to form a long chain. In contemporary biochemistry, the units are called nucleotides. A nucleotide of DNA consists of a deoxyribose molecule attached to a phosphate group and to a nitrogenous base. The identity of the base is the only thing distinguishing one nucleotide from another.

To identify the various chemical components of DNA it is customary to number the carbon atoms of the nitrogenous base and deoxyribose molecule, then refer to the numberof the carbon atom when specifying where a chemical group is attached. The carbon atoms in deoxyribose are numbered 1' to 5' (pronounced one-prime to five-prime). The numbering begins to the right of the oxygen atom and proceeds clockwise. The phosphate group is attached to the 5' carbon atom of deoxyribose. Furthermore, a nitrogenous base is connected to the 1' carbon atom. In addition, a free -OH group (referred to in chemistry as a hydroxyl group) exists at the 3' carbon atom of the deoxyribose molecule.

When a cell constructs a molecule of nucleic acid from nucleotides, it forges linkages between the 5'-carbon atom of one deoxyribose and a phosphate group. It then links the phosphate group and the 3'-carbon atom of a second deoxyribose.The phosphate group thereby bridges two deoxyribose molecules. The binding is accompanied by the loss of a hydroxyl (-OH) group from the 3'-carbon atom of the second deoxyribose molecule.

To continue building the DNA molecule, linkages to other nucleotides are forged in the same way; that is, the phosphate group links to the 5'-carbon atom of one deoxyribose and the hydroxyl group at the 3'-carbon of another. In this way, tens or thousands (or millions,or any number) of nucleotides bond to one another in a long chain to form a DNA molecule. By agreement among scientists, the sequence of DNA's bases is usually expressed in the 5' to 3' direction as one proceeds along the molecule.

Levene's studies in the 1920s indicated that nucleotides with all four nitrogenous bases were present in DNA. His studies also showed that the bases were present in virtually the same amounts. This conclusion was later proven untrue, but at the time it encouraged the belief that DNA was simply a polymer of repeating nucleotide units (e.g., TGACTGACTGAC, for thymine-guanine-adenine-cytosine-thymine-guanine-adenine-etc.). Without sequence variation in a repeating chain, it was difficult to see how DNA could provide any biochemical or hereditary information. This was one reason why Avery's identification of DNA as the transforming substance in bacteria did not receive immediate acclaim. (Ironically, Avery and Levene both had laboratories at Rockefeller Institute, but on different floors). It appeared that DNA was nothing more than a structural element of chromosomes.

After World War II, Levene's chemical analyses were repeated with more sophisticated equipment and with quite a different set of results. Tests indicated that the DNA's four nitrogenous bases were present in unequal amounts. In addition, biochemists led by Erwin Chargaff reported that chromosomal DNA from different organisms has different amounts of the four nitrogenous bases. These observations suggested that DNA is not simply a repeating polymer. Moreover, if the base amounts vary in an organism's chromosomes, perhaps DNA might have an information-coding property. And if different organisms have different amounts of bases in their DNA, maybe the bases have something to do with difference in the organisms.

Chargaff's experiments, reported in 1949, resulted in other data that would in later years weigh heavily on determining the structure of DNA. His research indicated that in DNA the amount of adenine is always equal to the amount of thymine regardless of the source of the DNA. Moreover, the amount of cytosine is consistently equal to theamount of guanine. It appeared that for every adenine molecule there was a thymine molecule (and vice versa), and for every cytosine molecule there was a guanine molecule (and vice versa). Four years would pass before the significance of this observation was understood.

Students of the twenty-first century are taught the structure of DNA as if it has always been known. They learn about DNA's components and they study its double-stranded spiral form known as the double helix. But in the early 1950s, biochemists were unaware of either the strandedness or helical arrangement of DNA, nor did they have a clear understanding of its functions. Although the components of DNA and their relative amounts were known, the spatial arrangements of the components was still a mystery.

Against this backdrop, a young American graduate student named James D. Watson arrived at Cambridge University in London to study with Francis H. C. Crick, a prominent biochemist. Watson and Crick would do no laboratory bench work - their great contribution to science was interpreting the available data and putting them together to postulate a structure for DNA.

In the early 1950s, a new technique called X-ray diffraction was being used by chemists and other scientists in their molecular analyses. In X-ray diffraction, crystals of a chemical substance are bombarded with X rays as the crystals rotate within the X-ray field. Electrons in the chemical substance scatter (or "diffract") the X rays, and a diffraction pattern develops on a photographic plate. The pattern gives a strong clue to the three-dimensional structure of the chemical substance. The effect is somewhat similar to creating ripples in alake by tossing a rock into the water. (The ripples give an idea of the size and shape of the rock.)

Among the leading experts on the diffraction patterns of DNA were British biochemists Maurice H. E Wilkins and Rosalind Franklin. Wilkins had found a way to prepare more uniformly oriented fibers of DNA than available previously, and Franklin was using these fibers to obtain relatively good diffraction patterns of the molecule. The patterns were suggesting that the DNA molecule was a helix. (A helix is a spiral or coil similar to a wound telephone cord.) The patterns also indicated that the helix had a diameter of about 2.0 nanometers (nm) (a nanometer is a billionth of a meter). Moreover, the helix appeared to make a complete turn at every 3.4-nm distance, and a repeating pattern at intervals of 0.34 nm seemed to occur.

Franklin's data were scheduled to be published in 1953, but Watson and Crick obtained the data before publication and used them to construct a model of DNA. In constructing their jigsaw puzzle, Watson and Crick theorized that phosphate groups (P) bind with adjacent deoxyribose molecules (D) in alternating fashion (P-D-P-D-P-D-P-etc.). Then they suggested that a nitrogenous base is connected to each deoxyribose molecule, flaring out as a side group from the main backbone chain. Now, using the mathematical data, they concluded that the 0.34 nm distance was the space between successive nucleotides on the chain. Franklin's measurements showed 3.4 nm per turn of the spiral, so Watson and Crick (noting that 3.4 is exactly ten times 0.34) postulated that ten nucleotides exist per turn of the spiral.

When Watson and Crick attempted to apply the 2.0 nm diameter to the spiral, they encountered a problem: their calculations showed that a single helix with a diameter of 2 nm would have a density only half as great as the known density of DNA. After trying various combinations of molecules and densities, they hit on the idea that DNA was not a single-stranded molecule (a single helix) but rather a double-stranded molecule, a double helix. And if the bases were arranged to point inward (not outward, as some biochemists were suggesting), the density of DNA would come close to fitting the 2.0 nm diameter observed in the X-ray studies. The data were saying that a DNA molecule is composed of two nucleotide chains wound like a spiral staircase around a hypothetical cylinder. The deoxyribose-phosphate combinations form the backbones of both chains, and the nitrogenous bases point inward. The model was evolving.

Now the observations made years before by Erwin Chargaff came into the picture. Chargaff had reported that in any DNA molecule, the amounts of adenine and thymine are identical. Watson and Crick envisioned that for every adenine molecule on one DNA strand there must be a thymine molecule on the other DNA strand (and vice versa). Similarly, because DNA has equal amounts of guanine and cytosine, there must be a guanine molecule for every cytosine molecule. Moreover, the available space in the 2.0 nm diameter of DNA would accommodate an adenine-thymine pair or a cytosine-guanine pair perfectly. And the weak chemical bonds between the opposing base molecules would make chemical sense and hold the bases together. The model was complete.

So it was that Watson and Crick formulated the accepted structure of a DNA molecule. Scientists now agree that DNA is arranged as a double helix of two intertwined chains, with complementary bases (A-T and G-C) opposing each other. Moreover, the strands run opposite to one another, that is, the strands display the reverse polarity. They are said to be "antiparallel." This means that one strand of DNA will have a free phosphate attached to a 5'-carbon atom at the top of the strand and the other strand will have a free 3'-carbon atom at its top. Given the base sequence of one chain of DNA, the base sequence of its partner chain is automatically determined by simply noting which bases are complementary(adenine-thymine or cytosine-guanine). Furthermore, the structure provides a mechanism by which one chain can serve as a template (a model or pattern) for the synthesis of the other chain.

The announcement of the structure of DNA was greeted enthusiastically by the scientific community for its philosophical sake, as well as for another practical reason: knowing the structure of DNA made it easy to see how DNA could provide hereditary information. Biochemists saw that the nitrogenous bases, occurring in highly variable sequences, could provide a code of heredity. The sequence was not repeating (TGAC...TGAC...TGAC) as Levene's work had suggested. Rather it was variable (TGGACTTGCCTAAGCGATA...), and such a variable sequence could encode a variable sequence of amino acids in a protein chain. Knowing the coding ability was the real beauty of knowing the structure of DNA. Scientists could now let their minds ponder how a base sequence in DNA could be translated to an amino acid sequence in protein.Was this the key to heredity?

It should be noted that neither Watson nor Crick were experts in any of the scientific areas they used to construct their DNA model. Franklin was a better crystallographer, Chargaff understood base relationships better, and numerous scientists helped out with the chemistry of the discovery process. Watson and Crick achieved their goal because they were able to see the big picture. They took what they needed from several disciplines and used it to compose something greater than itsparts. In effect, they saw the proverbial "forest for the trees."

On April 25, 1953, three short articles appeared in Nature, the prominent British publication of science. The first article, by Watson and Crick, opened with the lines: "We wish to suggest a structure for the salt of deoxyribose nucleic acid...". The article described the structure of DNA accepted in contemporary biochemistry. The second article, by Wilkins, A. R. Stokes, and H. R. Wilson, presented general evidence from X-ray data to support the helical structure of "deoxypentose nucleic acid", another nucleic acid. The third, by Rosalind Franklin and Raymond Gosling, included photographs of the X-ray diffraction patterns from an alternative type of DNA. These data also supported the proposed helical structure of DNA.

More than fifty years later, controversy continues to swirl about the relationships between Watson, Crick, Franklin, and Wilkins. Questions remain about who influenced whom, whether one individual had the idea about DNA's structure before another, and how the thought process developed. Although the questions will probably never be resolved, the controversy gives us a glimpse of how scientists go about uncovering the truths waiting to be discovered in nature.

The contributions to science made by Watson, Crick, Franklin, and Wilkins were original, important, and sufficient to merit a place in the annals of scientific fame. DNA became the charter molecule of molecular biology. In 1962, Watson, Crick, and Wilkins were awarded the Nobel Prize in Physiology or Medicine. Unfortunately, Franklin had died of cancer in 1958 and because the Nobel committee does not cite individuals posthumously, she did not share in the award. However, Franklin's contributions to unraveling the structure of DNA have been universally acknowledged.

By the spring of 1953, as the articles in Nature were being printed, the evidence favoring the double helix structure of DNA was accumulating rapidly. Few biologists doubted the molecular model, and the ideas expressed in the Nature articles encouraged many investigators to think about a genetic code in terms of DNA. But how, they asked, could a chromosomal double helix pass on its hereditary messages to the next generation of cells; and how could it direct the construction of needed cellular materials? It was apparent that working out the structure of DNA was not an end in itself. Rather it was only a beginning - the beginning of the science of molecular biology and in time, its fruits in DNA technology.