DNA (deoxyribonucleic acid)

DNA (deoxyribonucleic acid)

Genetics is the science of heredity that involves the study of the structure and function of genes and the methods by which genetic infomation contained in genes is passed from one generation to the next. The modern science of genetics can be traced to the research of Gregor Mendel (1823–1884), who was able to develop a series of laws that described mathematically the way hereditary characteristics pass from parents to offspring. These laws assume that hereditary characteristics are contained in discrete units of genetic material now known as genes.

The story of genetics during the twentieth century is, in one sense, an effort to discover the gene itself. An important breakthrough came in the early 1900s with the work of the American geneticist, Thomas Hunt Morgan (1866–1945). Working with fruit flies, Morgan was able to show that genes are somehow associated with the chromosomes that occur in the nuclei of cells. By 1912, Hunt's colleague, American geneticist A. H. Sturtevant (1891–1970) was able to construct the first chromosome map showing the relative positions of different genes on a chromosome. The gene then had a concrete, physical referent; it was a portion of a chromosome.

During the 1920s and 1930s, a small group of scientists looked for a more specific description of the gene by focusing their research on the gene's molecular composition. Most researchers of the day assumed that genes were some kind of protein molecule. Protein molecules are large and complex. They can occur in an almost infinite variety of structures. This quality is expected for a class of molecules that must be able to carry the enormous variety of genetic traits.

A smaller group of researchers looked to a second family of compounds as potential candidates for the molecules of heredity. These were the nucleic acids. The nucleic acids were first discovered in 1869 by the Swiss physician Johann Miescher (1844–1895). Miescher originally called these compounds "nuclein" because they were first obtained from the nuclei of cells. One of Miescher's students, Richard Altmann, later suggested a new name for the compounds, a name that better reflected their chemical nature: nucleic acids.

Nucleic acids seemed unlikely candidates as molecules of heredity in the 1930s. What was then known about their structure suggested that they were too simple to carry the vast array of complex information needed in a molecule of heredity. Each nucleic acid molecule consists of a long chain of alternating sugar and phosphate fragments to which are attached some sequence of four of five different nitrogen bases: adenine, cytosine, guanine, uracil and thymine (the exact bases found in a molecule depend slightly on the type of nucleic acid).

It was not clear how this relatively simple structure could assume enough different conformations to "code" for hundreds of thousands of genetic traits. In comparison, a single protein molecule contains various arrangements of twenty fundamental units (amino acids) making it a much better candidate as a carrier of genetic information.

Yet, experimental evidence began to point to a possible role for nucleic acids in the transmission of hereditary characteristics. That evidence implicated a specific sub-family of the nucleic acids known as the deoxyribonucleic acids, or DNA. DNA is characterized by the presence of the sugar deoxyribose in the sugar-phosphate backbone of the molecule and by the presence of adenine, cytosine, guanine, and thymine, but not uracil.

As far back as the 1890s, the German geneticist Albrecht Kossel (1853–1927) obtained results that pointed to the role of DNA in heredity. In fact, historian John Gribbin has suggested that the evidence was so clear that it "ought to have been enough alone to show that the hereditary information... must be carried by the DNA." Yet, somehow, Kossel himself did not see this point, nor did most of his colleagues for half a century.

As more and more experiments showed the connection between DNA and genetics, a small group of researchers in the 1940s and 1950s began to ask how a DNA molecule could code for genetic information. The two who finally resolved this question were a somewhat unusual pair, James Watson, a 24-year old American trained in genetics, and Francis Crick, a 36-year old Englishman, trained in physics and self-taught in chemistry. The two met at the Cavendish Laboratories of Cambridge University in 1951, and became instant friends. They were united by a common passionate belief that the structure of DNA held the key to understanding how genetic information is stored in a cell and how it is transmitted from one cell to its daughter cells.

In one sense, the challenge facing Watson and Crick was a relatively simple one. A great deal was already known about the DNA molecule. Few new discoveries were needed, but those few discoveries were crucial to solving the DNA-heredity puzzle. Primarily the question was one of molecular architecture. How were the various parts of a DNA molecule oriented in space such that the molecule could hold genetic information?

The key to answering that question lay in a technique known as x-ray crystallography. When x rays are directed at a crystal of some material, such as DNA, they are reflected and refracted by atoms that make up the crystal. The refraction pattern thus produced consists of a collection of spots and arcs. A skilled observer can determine from the refraction pattern the arrangement of atoms in the crystal.

The technique is actually more complex than described here. For one thing, obtaining satisfactory x-ray patterns from crystals is often difficult. Also, interpreting x-ray patterns—especially for complex molecules like DNA—can be extremely difficult.

Watson and Crick were fortunate in having access to some of the best x-ray diffraction patterns that then existed. These "photographs" were the result of work being done by Maurice Wilkins and Rosalind Elsie Franklin at King' s College in London. Although Wilkins and Franklin were also working on the structure of DNA, they did not recognize the information their photographs contained. Indeed, it was only when Watson accidentally saw one of Franklin's photographs that he suddenly saw the solution to the DNA puzzle.

Racing back to Cambridge after seeing this photograph, Watson convinced Crick to make an all-out attack on the DNA problem. They worked continuously for almost a week. Their approach was to construct tinker-toy-like models of the DNA molecule, shifting atoms around into various positions. They were looking for an arrangement that would give the kind of x-ray photograph that Watson had seen in Franklin's laboratory.

Finally, on March 7, 1953, the two scientists found the answer. They built a model consisting of two helices (corkscrew-like spirals), wrapped around each other. Each helix consisted of a backbone of alternating sugar and phosphate groups. To each sugar was attached one of the four nitrogen bases, adenine, cytosine, guanine, or thymine. The sugar-phosphate backbone formed the outside of the DNA molecule, with the nitrogen bases tucked inside. Each nitrogen base on one strand of the molecule faced another nitrogen base on the opposite strand of the molecule. The base pairs were not arranged at random, however, but in such a way that each adenine was paired with a thymine, and each cytosine with a guanine.

The Watson-Crick model was a remarkable achievement, for which the two scientists won the 1954 Nobel Prize in Chemistry. The molecule had exactly the shape and dimensions needed to produce an x-ray photograph like that of Franklin's. Furthermore, Watson and Crick immediately saw how the molecule could "carry" genetic information. The sequence of nitrogen bases along the molecule, they said, could act as a genetic code. A sequence, such as A-T-T-C-G-C-T . . . etc., might tell a cell to make one kind of protein (such as that for red hair), while another sequence, such as G-C-T-C-T-C-G . . . etc., might code for a different kind of protein (such as that for blonde hair). Watson and Crick themselves contributed to the deciphering of this genetic code, although that process was long and difficult and involved the efforts of dozens of researchers over the next decade.

Watson and Crick had also considered, even before their March 7th discovery, what the role of DNA might be in the manufacture of proteins in a cell. The sequence that they outlined was that DNA in the nucleus of a cell might act as a template for the formation of a second type of nucleic acid, RNA (ribonucleic acid). RNA would then leave the nucleus, emigrate to the cytoplasm and then itself act as a template for the production of protein. That theory, now known as the Central Dogma, has since been largely confirmed and has become a critical guiding principal of much research in molecular biology.

Scientists continue to advance their understanding of DNA. Even before the Watson-Crick discovery, they knew that DNA molecules could exist in two configurations, known as the "A" form and the "B" form. After the Watson-Crick discovery, two other forms, known as the "C" and "D" configurations, were also discovered. All four of these forms of DNA are right-handed double helices that differ from each other in relatively modest ways.

In 1979, however, a fifth form of DNA known as the "Z" form was discovered by Alexander Rich and his colleagues at the Massachusetts Institute of Technology. The "Z" form was given its name partly because of its zig-zag shape and partly because it is different from the more common A and B forms. Although Z-DNA was first recognized in synthetic DNA prepared in the laboratory, it has since been found in natural cells whose environment is unusual in some respect or another. The presence of certain types of proteins in the nucleus, for example, can cause DNA to shift from the B to the Z conformation. The significance and role of this most recently discovered form of DNA remains a subject of research among molecular biologists.

Judyth Sassoon, ARCS, PhD