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Sedona, Arizona

January 13, 2021

Not my typical post. I did not learn about DNA in school. I read an article about it yesterday and got all confused by words I did not understand. So I sought out "DNA for dummies" and found the following article. I found another article about the history of discovering DNA. As I read the history, I thought it would make a great book. There probably is one -- I did not bother looking. Pretty sure there is not one by one of the giants of history book authors.

DNA For Dummies

DNA is a long chain of molecules that contains all the information necessary for the life functions of a cell. The individual molecules that make up DNA are called nucleotides. There are four nucleotides; they are Adenine (A), Thymidine (T), Guanine (G), and Cytosine (C). A strand of DNA is much like a really long sentence that uses only four letters. DNA has two strands, much like a zipper and the nucleotides are like the teeth of that zipper. This two-strand system is the key to how DNA is able to make copies of itself. This can happen because one strand is 'complementary' to another strand. A always matches up with T and G always matches up with C. Because they pair up, they are called "base pairs".

Let's take a short segment of DNA as an example:

If one strand of the DNA sequence is A T T C G A C then the other 'complementary' strand must be T A A G C T G

So the two strands together look like this

Now let's split them apart in order to make copies:

The cell's machinery will find new pairs for all the nucleotides

We now have two exact copies of the DNA sequence we started with.

Since they're 'complementary', scientists will often just report the sequence of one strand. Our exact combination of three billion of these letters is the human genome sequence. [A genome is an organism's complete set of genetic instructions. Each genome contains all of the information needed to build that organism and allow it to grow and develop.]

As you can imagine, making copies of 3 billion nucleotides every time a cell multiplies is no easy task. The cell uses enzymes to make copies of its DNA. Even though these enzymes are very precise, mistakes do happen, and the wrong letter gets placed in the sequence. Such a mistake can be either harmless or fatal to the cell depending on where the mistake was made. To keep mistakes to a minimum, the cell uses another set of enzymes whose job is to check the new copy and repair any mistakes.

Chromosomes The chains of nucleotides in human DNA are wound up and compacted into 46 chromosomes (two sets of 23) that are found in the nucleus of a cell. The DNA is held together by proteins called histones which help to keep the shape of the chromosomes. [The dictionary definition of chromosome is: A structure found inside the nucleus of a cell. A chromosome is made up of proteins and DNA organized into genes. Each cell normally contains 23 pairs of chromosomes.]

Genes Genes are the functional regions of the genome, they are a blueprint for all the useful bits and pieces in our cells. Genes contain the information that tells the cell how to make a particular protein. Proteins themselves are just chains of amino acids. A gene gives the instructions for making the amino acid chain. Proteins (including all enzymes) run our cells - deciding what happens when and where.

Said another way, genes are segments of DNA that contain the code for a specific protein that functions in one or more types of cells in the body. Chromosomes are structures within cells that contain a person's genes. Genes are contained in chromosomes, which are in the cell nucleus.

Proteins are polymers of amino acids. Each amino acid contains a central carbon, a hydrogen, a carboxyl group, an amino group, and a variable R group. The R group specifies which class of amino acids it belongs to: electrically charged hydrophilic side chains, polar but uncharged side chains, nonpolar hydrophobic side chains, and special cases.

Proteins have different “layers” of structure: primary, secondary, tertiary, quaternary.

Proteins have a variety of function in cells. Major functions include acting as enzymes, receptors, transport molecules, regulatory proteins for gene expression, and so on.

Enzymes are biological catalysts that speed up a chemical reaction without being permanently altered. They have “active sites” where the substrate/reactant binds, and they can be either activated or inhibited (competitive and/or noncompetitive inhibitors). Amino acids are small molecules that are the building blocks of proteins. Proteins serve as structural support inside the cell and they perform many vital chemical reactions. Each protein is a molecule made up of different combinations of 20 types of smaller, simpler amino acids. The Discovery Of DNA Many people believe that American biologist James Watson and English physicist Francis Crick discovered DNA in the 1950s. In reality, this is not the case. Rather, DNA was first identified in the late 1860s by Swiss chemist Friedrich Miescher. Then, in the decades following Miescher's discovery, other scientists--notably, Phoebus Levene and Erwin Chargaff--carried out a series of research efforts that revealed additional details about the DNA molecule, including its primary chemical components and the ways in which they joined with one another. Without the scientific foundation provided by these pioneers, Watson and Crick may never have reached their groundbreaking conclusion of 1953: that the DNA molecule exists in the form of a three-dimensional double helix. The First Piece of the Puzzle: Miescher Discovers DNA Although few people realize it, 1869 was a landmark year in genetic research, because it was the year in which Swiss physiological chemist Friedrich Miescher first identified what he called "nuclein" inside the nuclei of human white blood cells. (The term "nuclein" was later changed to "nucleic acid" and eventually to "deoxyribonucleic acid," or "DNA.") Miescher's plan was to isolate and characterize not the nuclein (which nobody at that time realized existed) but instead the protein components of leukocytes (white blood cells).

Miescher thus made arrangements for a local surgical clinic to send him used, pus-coated patient bandages; once he received the bandages, he planned to wash them, filter out the leukocytes, and extract and identify the various proteins within the white blood cells. But when he came across a substance from the cell nuclei that had chemical properties unlike any protein, including a much higher phosphorous content and resistance to proteolysis (protein digestion), Miescher realized that he had discovered a new substance .Sensing the importance of his findings, Miescher wrote, "It seems probable to me that a whole family of such slightly varying phosphorous-containing substances will appear, as a group of nucleins, equivalent to proteins."

More than 50 years passed before the significance of Miescher's discovery of nucleic acids was widely appreciated by the scientific community. For instance, in a 1971 essay on the history of nucleic acid research, Erwin Chargaff noted that in a 1961 historical account of nineteenth-century science, Charles Darwin was mentioned 31 times, Thomas Huxley 14 times, but Miescher not even once. This omission is all the more remarkable given that, as Chargaff also noted, Miescher's discovery of nucleic acids was unique among the discoveries of the four major cellular components (i.e., proteins, lipids, polysaccharides, and nucleic acids) in that it could be "dated precisely... [to] one man, one place, one date."

Laying the Groundwork: Levene Investigates the Structure of DNA Meanwhile, even as Miescher's name fell into obscurity by the twentieth century, other scientists continued to investigate the chemical nature of the molecule formerly known as nuclein. One of these other scientists was Russian biochemist Phoebus Levene. A physician turned chemist, Levene was a prolific researcher, publishing more than 700 papers on the chemistry of biological molecules over the course of his career. Levene is credited with many firsts. For instance, he was the first to discover the order of the three major components of a single nucleotide (phosphate-sugar-base); the first to discover the carbohydrate component of RNA (ribose); the first to discover the carbohydrate component of DNA (deoxyribose); and the first to correctly identify the way RNA and DNA molecules are put together.

During the early years of Levene's career, neither Levene nor any other scientist of the time knew how the individual nucleotide components of DNA were arranged in space; discovery of the sugar-phosphate backbone of the DNA molecule was still years away. The large number of molecular groups made available for binding by each nucleotide component meant that there were numerous alternate ways that the components could combine.

Several scientists put forth suggestions for how this might occur, but it was Levene's "polynucleotide" model that proved to be the correct one. Based upon years of work using hydrolysis to break down and analyze yeast nucleic acids, Levene proposed that nucleic acids were composed of a series of nucleotides, and that each nucleotide was in turn composed of just one of four nitrogen-containing bases, a sugar molecule, and a phosphate group. Levene made his initial proposal in 1919, discrediting other suggestions that had been put forth about the structure of nucleic acids. In Levene's own words, "New facts and new evidence may cause its alteration, but there is no doubt as to the polynucleotide structure of the yeast nucleic acid."

Indeed, many new facts and much new evidence soon emerged and caused alterations to Levene's proposal. One key discovery during this period involved the way in which nucleotides are ordered. Levene proposed what he called a tetranucleotide structure, in which the nucleotides were always linked in the same order (i.e., G-C-T-A-G-C-T-A and so on). However, scientists eventually realized that Levene's proposed tetranucleotide structure was overly simplistic and that the order of nucleotides along a stretch of DNA (or RNA) is, in fact, highly variable. Despite this realization, Levene's proposed polynucleotide structure was accurate in many regards. For example, we now know that DNA is in fact composed of a series of nucleotides and that each nucleotide has three components: a phosphate group; either a ribose (in the case of RNA) or a deoxyribose (in the case of DNA) sugar; and a single nitrogen-containing base. We also know that there are two basic categories of nitrogenous bases: the purines (adenine [A] and guanine [G]), each with two fused rings, and the pyrimidines (cytosine [C], thymine [T], and uracil [U]), each with a single ring. Furthermore, it is now widely accepted that RNA contains only A, G, C, and U (no T), whereas DNA contains only A, G, C, and T (no U) (Figure 1).

Strengthening the Foundation: Chargaff Formulates His "Rules" Erwin Chargaff was one of a handful of scientists who expanded on Levene's work by uncovering additional details of the structure of DNA, thus further paving the way for Watson and Crick. Chargaff, an Austrian biochemist, had read the famous 1944 paper by Oswald Avery and his colleagues at Rockefeller University, which demonstrated that hereditary units, or genes, are composed of DNA. This paper had a profound impact on Chargaff, inspiring him to launch a research program that revolved around the chemistry of nucleic acids. Of Avery's work, Chargaff (1971) wrote the following:

"This discovery, almost abruptly, appeared to foreshadow a chemistry of heredity and, moreover, made probable the nucleic acid character of the gene... Avery gave us the first text of a new language, or rather he showed us where to look for it. I resolved to search for this text."

As his first step in this search, Chargaff set out to see whether there were any differences in DNA among different species. After developing a new paper chromatography method for separating and identifying small amounts of organic material, Chargaff reached two major conclusions. First, he noted that the nucleotide composition of DNA varies among species. In other words, the same nucleotides do not repeat in the same order, as proposed by Levene. Second, Chargaff concluded that almost all DNA--no matter what organism or tissue type it comes from--maintains certain properties, even as its composition varies.

In particular, the amount of adenine (A) is usually similar to the amount of thymine (T), and the amount of guanine (G) usually approximates the amount of cytosine (C). In other words, the total amount of purines (A + G) and the total amount of pyrimidines (C + T) are usually nearly equal. (This second major conclusion is now known as "Chargaff's rule.") Chargaff's research was vital to the later work of Watson and Crick, but Chargaff himself could not imagine the explanation of these relationships--specifically, that A bound to T and C bound to G within the molecular structure of DNA (Figure 2).

Putting the Evidence Together: Watson and Crick Propose the Double Helix Chargaff's realization that A = T and C = G, combined with some crucially important X-ray crystallography work by English researchers Rosalind Franklin and Maurice Wilkins, contributed to Watson and Crick's derivation of the three-dimensional, double-helical model for the structure of DNA. Watson and Crick's discovery was also made possible by recent advances in model building, or the assembly of possible three-dimensional structures based upon known molecular distances and bond angles, a technique advanced by American biochemist Linus Pauling. In fact, Watson and Crick were worried that they would be "scooped" by Pauling, who proposed a different model for the three-dimensional structure of DNA just months before they did. In the end, however, Pauling's prediction was incorrect.

Using cardboard cutouts [🤪] representing the individual chemical components of the four bases and other nucleotide subunits, Watson and Crick shifted molecules around on their desktops, as though putting together a puzzle. They were misled for a while by an erroneous understanding of how the different elements in thymine and guanine (specifically, the carbon, nitrogen, hydrogen, and oxygen rings) were configured. Only upon the suggestion of American scientist Jerry Donohue did Watson decide to make new cardboard cutouts of the two bases, to see if perhaps a different atomic configuration would make a difference. It did. Not only did the complementary bases now fit together perfectly (i.e., A with T and C with G), with each pair held together by hydrogen bonds, but the structure also reflected Chargaff's rule (Figure 3).

Although scientists have made some minor changes to the Watson and Crick model, or have elaborated upon it, since its inception in 1953, the model's four major features remain the same yet today. These features are as follows:

  • DNA is a double-stranded helix, with the two strands connected by hydrogen bonds. A bases are always paired with Ts, and Cs are always paired with Gs, which is consistent with and accounts for Chargaff's rule.

  • Most DNA double helices are right-handed; that is, if you were to hold your right hand out, with your thumb pointed up and your fingers curled around your thumb, your thumb would represent the axis of the helix and your fingers would represent the sugar-phosphate backbone. Only one type of DNA, called Z-DNA, is left-handed.

  • The DNA double helix is anti-parallel, which means that the 5' end of one strand is paired with the 3' end of its complementary strand (and vice versa). As shown in Figure 4, nucleotides are linked to each other by their phosphate groups, which bind the 3' end of one sugar to the 5' end of the next sugar.

  • Not only are the DNA base pairs connected via hydrogen bonding, but the outer edges of the nitrogen-containing bases are exposed and available for potential hydrogen bonding as well. These hydrogen bonds provide easy access to the DNA for other molecules, including the proteins that play vital roles in the replication and expression of DNA (Figure 4).

One of the ways that scientists have elaborated on Watson and Crick's model is through the identification of three different conformations of the DNA double helix. In other words, the precise geometries and dimensions of the double helix can vary. The most common conformation in most living cells (which is the one depicted in most diagrams of the double helix, and the one proposed by Watson and Crick) is known as B-DNA. There are also two other conformations: A-DNA, a shorter and wider form that has been found in dehydrated samples of DNA and rarely under normal physiological circumstances; and Z-DNA, a left-handed conformation. Z-DNA is a transient form of DNA, only occasionally existing in response to certain types of biological activity (Figure 5). Z-DNA was first discovered in 1979, but its existence was largely ignored until recently. Scientists have since discovered that certain proteins bind very strongly to Z-DNA, suggesting that Z-DNA plays an important biological role in protection against viral disease.

Summary Watson and Crick were not the discoverers of DNA, but rather the first scientists to formulate an accurate description of this molecule's complex, double-helical structure. Moreover, Watson and Crick's work was directly dependent on the research of numerous scientists before them, including Friedrich Miescher, Phoebus Levene, and Erwin Chargaff. Thanks to researchers such as these, we now know a great deal about genetic structure, and we continue to make great strides in understanding the human genome and the importance of DNA to life and health.

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