The Importance of DNA Molecules

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DNA is one of the few combinations of letters at the core of a scientific discipline that seems to spark a significant level of understanding even in people with little lifetime exposure to biology or the sciences in general. Most adults who hear the phrase "It's in her DNA" immediately recognize that a particular trait is inseparable from the person being described; that the characteristic is somehow inborn, is never going away and is capable of being transferred to that person's children and beyond. This appears to hold true even in the minds of those who have no idea what "DNA" even stands for, which is "deoxyribonucleic acid."

Humans are understandably fascinated with the concept of inheriting traits from their parents and passing along their own traits to their offspring. It is only natural for people to ponder their own biochemical legacy, even if few can imagine it in such formal terms. Recognition that tiny unseen factors inside each of us govern how people's children look and even behave has surely been present for many hundreds of years. But not until the middle of the 20th century did modern science reveal in glorious detail not only what the molecules responsible for inheritance were, but also what they looked like.

Deoxyribonucleic acid is indeed the genetic blueprint all living things maintain in their cells, a unique microscopic fingerprint that not only makes each human a literal one-of-a-kind individual (identical twins excepted for present purposes) but reveals a great deal of vital information about every person, from the likelihood of being related to another specific person to the chances of developing a given disease later in life or transmitting such a disease to future generations. DNA has become not only the natural central point of molecular biology and of life science as a whole, but an integral component of forensic science and biological engineering as well.

The Discovery of DNA

James Watson and Francis Crick (and less commonly, Rosalind Franklin and Maurice Wilkins) are widely credited with the discovery of DNA in 1953. This perception, however, is erroneous. Critically, these researchers did in fact establish that DNA exists in three-dimensional form in the shape of a double helix, which is essentially a ladder twisted in different directions at both ends to create a spiral shape. But these determined and oft-celebrated scientists were "only" building on the painstaking work of biologists who toiled in search of the same general information as far back as the 1860s, experiments that were just as groundbreaking in their own right as that of Watson, Crick and others in the post-World War II research era.

In 1869, 100 years before humans would travel to the moon, a Swiss chemist named Friedrich Miescher sought to extract the protein components from leukocytes (white blood cells) to determine their composition and function. What he instead extracted he called "nuclein," and although he lacked the instruments needed to learn what future biochemists would be able to learn, he discerned quickly that this "nuclein" was related to proteins but was not itself protein, that it contained an unusual amount of phosphorus, and that this substance was resistant to being degraded by the same chemical and physical factors that degraded proteins.

It would be over 50 years before the true importance of Miescher's work first became evident. In the second decade of the 1900s, a Russian biochemist, Phoebus Levene, was the first to propose that, what we call nucleotides today, consisted of a sugar portion, a phosphate portion and a base portion; that the sugar was ribose; and that the differences between nucleotides was owed to the differences between their bases. His "polynucleotide" model had some flaws, but by the standards of the day, it was remarkably on-target.

In 1944, Oswald Avery and his colleagues at Rockefeller University were the first known researchers to formally suggest that DNA consisted of hereditary units, or genes. Following up on their work as well as that of Levene, the Austrian scientist Erwin Chargaff made two key discoveries: one, that the sequence of nucleotides in DNA varies between species of organisms, contrary to what Levene had proposed; and two, that in any organism, the total amount of the nitrogenous bases adenine (A) and guanine (G) combined, regardless of species, was virtually always the same as the total amount of cytosine (C) and thymine (T). This did not quite lead Chargaff to conclude that A pairs with T and C pairs with G in all DNA, but it later helped buttress the conclusion reached by others.

Finally, in 1953, Watson and his colleagues, benefiting from rapidly improving ways of visualizing three-dimensional chemical structures, put all of these findings together and used cardboard models to establish that a double helix fit everything that was known about DNA in a way nothing else could.

DNA and Heritable Traits

DNA was identified as the hereditary material in livings things well before its structure was clarified, and as often the case in experimental science, this vital discovery was actually incidental to the researchers' main purpose.

Before antibiotic therapy emerged in the late 1930s, infectious diseases claimed far more human lives than they do today, and unraveling the mysteries of the organisms responsible was a critical aim in microbiology research. In 1913, the aforementioned Oswald Avery began work that ultimately revealed a high polysaccharide (sugar) content in capsules of pneumococcal bacterial species, which had been isolated from pneumonia patients. Avery theorized that these stimulated antibody production in infected people. Meanwhile, in England, William Griffiths was performing work that showed that dead components of one kind of disease-causing pneumococcus could be blended with the living components of a harmless pneumococcus and produce a disease-causing form of the formerly harmless kind; this proved that whatever moved from the dead to the living bacteria was heritable.

When Avery learned of Griffith's results, he set about conducting purification experiments in an effort to isolate the precise material in the pneumococci that was heritable, and homed in on nucleic acids, or more specifically, nucleotides. DNA was already strongly suspected of having what were then popularly called "transforming principles," so Avery and others tested this hypothesis by exposing the hereditary material to a variety of agents. Those known to be destructive to DNA integrity but harmless to proteins or DNA, called DNAases, were sufficient in high quantities to prevent transmission of traits from one bacterial generation to the next. Meanwhile, proteases, which unravel proteins, did no such damage.

The take-home message of Avery's and Griffith's work is that, again, while people such as Watson and Crick have been rightly lauded for their contributions to molecular genetics, establishing the structure of DNA was actually a fairly late contribution to the process of learning about this spectacular molecule.

The Structure of DNA

Chargaff, although he obviously did not describe the structure of DNA in full, did show that, in addition to (A + G) = (C + T), the two strands known to be included in DNA were always the same distance apart. This led to the postulate that purines (including A and G) always bonded to pyrimidines (including C and T) in DNA. This made three-dimensional sense, because purines are considerably larger than pyrimidines, while all purines are essentially the same size and all pyrimidines are essentially the same size. This implies that two purines bound together would take up considerably more space between DNA strands than two pyrimidines, and also that any given purine-pyrimidine pairing would consume the same amount of space. Putting all of this information required that A bind to, and only to, T and that the same relationship hold for C and G if this model was to prove successful. And it has.

The bases (more on these later) bind to each other on the interior of the DNA molecule, like rungs in a ladder. But what about the strands, or "sides," themselves? Rosalind Franklin, working with Watson and Crick, assumed that this "backbone" was made of sugar (specifically a pentose sugar, or one with a five-atom ring structure) and a phosphate group linking the sugars. Because of the newly clarified idea of base-pairing, Franklin and the others became aware that the two DNA strands in a single molecule were "complementary," or in effect mirror-images of each other at the level of their nucleotides. This allowed for them to predict the approximate radius of the twisted form of DNA within a solid degree of accuracy, and X-ray diffraction analysis confirmed the helical structure. The idea that the helix was a double helix was the last major detail about DNA's structure to fall into place, in 1953.

Nucleotides and Nitrogenous Bases

Nucleotides are the repeating subunits of DNA, which is the converse of saying the DNA is a polymer of nucleotides. Each nucleotide consists of a sugar called deoxyribose that contains a pentagonal ring structure with one oxygen and four carbon molecules. This sugar is bound to a phosphate group, and two spots along the ring from this position, it is also bound to a nitrogenous base. The phosphate groups link the sugars together to form the DNA backbone, the two strands of which twist around the bound nitrogen-heavy bases in the middle of the double helix. The helix makes one complete 360-degree twist about once every 10 base pairs.

A sugar bound only to a nitrogenous base is called a nucleoside.

RNA (ribonucleic acid) differs from DNA in three key ways: One, the pyrimidine uracil is substituted for thymine. Two, the pentose sugar is ribose rather than deoxyribose. And three, RNA is almost always single-stranded and comes in multiple forms, the discussion of which is beyond the scope of this article.

DNA Replication

DNA is "unzipped" into its two complementary strands when it comes time for copies to be made. As this is happening, daughter strands are formed along the single parent strands. One such daughter strand is formed continuously via the addition of single nucleotides, under the action of the enzyme DNA polymerase. This synthesis simply follows along the direction of the separation of the parent DNA strands. The other daughter strand forms from small polynucleotides called Okazaki fragments that actually form in the opposite direction of the unzipping of parent strands, and are then joined together by the enzyme DNA ligase.

Because the two daughter strands are also complementary to each other, their bases eventually bond together to make a double-stranded DNA molecule identical to the parent one.

In bacteria, which are single-celled and called prokaryotes, a single copy of the bacteria's DNA (also called its genome) sits in the cytoplasm; no nucleus is present. In multicellular eukaryotic organisms, the DNA is found in the nucleus in the form of chromosomes, which are highly coiled, spooled and spatially condensed DNA molecules mere millionths of a meter long, and proteins called histones. On microscopic examination, the chromosome parts that show alternating histone "spools" and simple strands of DNA (called chromatin at this level of organization) are often likened to beads on a string. Some eukaryotic DNA is also found in organelles of cells called mitochondria.

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