The Stuff of Life

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The Blueprints
The human body is built in layers of complexity. Viewed in its entirety, the body's different parts can be observed to work together in an integrative way. The brain controls the function of the heart, which in turn controls the function of the muscles and other organs. Likewise, the pituitary gland controls several hormone glands, which in turn determine electrolyte balance, blood pressure, and sugar metabolism. On a less global scale, each of the organs in the body (the liver, kidneys, skin, heart, and so on) are themselves composed of smaller units. Within the kidney, for example, specialized cells regulate the balance of salt and water in our bodies. Other groups of specialized kidney cells secrete hormones, or filter blood to remove waste products.
On an atomic scale, however, even a single cell is an entire universe. Within cells are smaller structures that make proteins, package chromosomes, and generate energy. To understand how these tasks are accomplished, we must look to the molecular level. A large protein molecule, for example, is composed of many smaller molecules called amino acids. But even an amino acid is not the smallest functional unit in a protein. Within any amino acid (or sugar molecule, or oxygen molecule, or any other molecule) are a number of atoms.
Just what is an atom, anyway? Every element, like hydrogen, nitrogen, and oxygen, is composed of atoms. Atoms are the smallest functional unit of matter. That is, an atom can be broken into subatomic (smaller than an atom) particles if sufficient (enormous) amounts of energy are provided, but those smaller bits of matter do not by themselves participate in biologically meaningful reactions. An atom can be crudely envisioned as a sort of mini-solar system, although in reality an atom's structure is much more complex and less orderly than a solar system. At the center of the system is the nucleus, composed of subatomic particles called protons and neutrons. Protons carry a positive electric charge, while neutrons have no charge (they are electrically neutral). Surrounding this densely packed nucleus are anywhere from 1 to more than 100 electrons, arranged in increasingly wide and complex orbits around the nucleus. The electrons are only a tiny fraction of the size of the nucleus and carry a negative electric charge.
Each atom has the same number of electrons as protons, which allows the two opposite electrical charges within the atom to cancel each other. Let's imagine a relatively small atom such as carbon, which contains a nucleus with six protons. It will, therefore, have six electrons orbiting around it. Although that gives an atom a neutral electrical charge, it turns out that there is "room" for two additional electrons to spin around a carbon nucleus. That's because electrons are arranged around the nucleus in poorly defined, mutually exclusive orbits, each of which has a predetermined capacity to permit extra electrons to buzz around within that orbital sphere. Having as close as possible to a full complement of electrons in the outermost shells of an atom increases a molecule's stability. So if two atoms--say, carbon and oxygen--come together under the right circumstances, they may "share" some of each other's outermost electrons. In that way, both atoms will appear to have filled up their empty "electron slots." This is true because the speed at which electrons zip around their orbital shells is so fantastic that it makes little difference if the shell is enlarged a bit by the merging of two or more atoms. When this happens, we say that the two atoms have formed a chemical bond and have joined to make a molecule. One atom of carbon and one of oxygen, by the way, would yield the poisonous molecule carbon monoxide.
It is common in nature to find two or more different kinds of atoms sharing electrons and combining to createa new, larger substance, a molecule. Some molecules are quite simple. Water, for example, is composed of one oxygen atom combined with two hydrogen atoms. Others are extremely complex; a protein may be composed of hundreds of amino acids, and each amino acid may be composed of several atoms of nitrogen, carbon, oxygen, hydrogen, and sulfur. Thus, molecules can be broken down into atoms, but atoms cannot be broken down into any other functional unit.
In the world of the molecule, anything heavier than about 0.00000000000000000000001 (one ten-billionth of one-trillionth) grams is considered large. If that number seems meaningless, then consider that there are about as many molecules of water in a drop of blood as stars in the known universe!
It may be a cliché, but proteins are truly the building blocks of all life. They are the cinder blocks and the 2x4's of our cells. While we hear about DNA, it only exists to direct the making of proteins. But proteins don't just provide the body with physical structure, they also catalyze chemical reactions, taxi gases like oxygen through the blood, and produce energy. Enzymes are also proteins. Enzymes are molecules with very precise three-dimensional structures, which allow them to interact with other molecules. In some cases, this interaction produces the destruction of another molecule. In other cases, enzymes help fuse two simple molecules to produce one complex molecule.
Different species of the same phylogenetic class (for example, mammals) share much of the same DNA, or at least DNA that is recognizably similar. And even species that on the surface bear little or no resemblance to each other have much of their DNA in common. The lowly nematode worm shares roughly 40 percent of its DNA sequence with that of humans. As you move up the scale of animal complexity, the similarity increases, of course, so that by the time you reach the other primates, such as chimps, the similarity to human DNA approaches 98 percent. Unrelated people share 99 percent similarity, and related people 99.5 percent. We are not as different from one another as we may think.
Despite this similarity, a relatively small amount of different DNA can make vast differences in the appearance and behavior of an organism. A single molecule of DNA may contain hundreds or thousands of separate functional units, called genes. Each gene is a strip of DNA distinguished from the next strip by telltale regions that signal the beginning of a new gene. The enzyme responsible for converting genes into RNA recognizes these starting positions. Every cell in our bodies has the exact same DNA, and thus the exact same set of genes. But cells in our skin, for example, have an active gene for a fibrous protein called keratin, which is the basis of skin. This same gene is inactive in most other cells, and this prevents keratin, and therefore skin, from showing up in, say, the liver or bone marrow. The waysin which a particular cell is able to activate only a specific subset of genes and not others is obviously of enormous importance to scientists, who are only beginning to find the answers. This question holds the key to understanding how an organism develops from an immature, undifferentiated embryo of just a few cells into a fully functional adult animal with, in the case of humans, trillions of cells. On a more practical level, it holds the key to regenerating lost or damaged tissues and having them function and appear like the original.
The discovery that the DNA molecule exists in the form of a twisted helix and contains only four major chemical elements, repeated in various arrays, was the landmark event that ushered in the field of science known today as molecular biology. That discovery has allowed us to begin understanding how genes can be active at one time and silent at others; how simple changes (mutations) in any of the four chemical elements of DNA can lead to the formation of abnormal proteins, or even premature death or failure of an embryo to develop; and how genes might someday be modified or even changed to correct human disease. All of the molecules discussed in this book are either formed from genes or act on genes to control their activity. Thus, it is fitting that we begin with a look at the chemistry and physiology of DNA, RNA, and the substances they make--proteins.
DNA and RNA
Chromosomes, genes, DNA, RNA--we hear these terms often, and for most of us they present something of a mystery. But DNA and RNA are just molecules made up of atoms linked one to the other, just like all molecules. Unlike many molecules, though, DNA is extremely long because of all the information it contains. In fact, to package all of our DNA into the nucleus, or command center, of a cell, the DNA must be folded, twisted, and folded again into a compact shape. Were it not, a single DNA molecule would be several inches long. Considering that the nucleus of one of our cells is only about 1/5,000th of an inch wide, it is easy to see why DNA must be so compact.
DNA (deoxyribonucleic acid) is made up of a molecule of sugar (ribose), some phosphates (phosphorus and oxygen bound together), and a group of four molecules known as bases. The latter are relatively simple molecules that are able to attach to one end of the ribose molecule. The phosphate groups also attach to the ribose, but at the opposite end. Phosphate groups are highly reactive and will link one ribose to another in a sort of linear chain. Thus, a molecule of DNA "grows" as one ribose--with its attached phosphates and bases--links up with another ribose, and so on.
To complete the molecule, each base forms weak electrical attractions to another base that is complementary in structure on another ribose-backed DNAchain. The two chains come together to form a sort of ladder-shaped molecule, with the bases forming the rungs of the ladder. As you walk along these rungs, you pass from one gene to another.
The linking together of two strands of DNA like this causes a physical strain on the molecule, and the double chain of DNA twists itself into a helical shape. This gives the molecule a certain stability, and the DNA can now be further contorted into smaller and smaller volumes. Thus, it wraps itself around proteins (called histones) found in the cell nucleus and continues folding and refolding on itself until all 100 million or so rungs of the ladder fit into the tiny cell nucleus. We call a single DNA molecule wrapped up in this configuration a chromosome. Different animals have different numbers of chromosomes in each cell; humans have a total of 46, all of which must be condensed in this way.
Why should a DNA molecule need to be so extraordinarily long? The function of DNA is to "code" or hold the blueprint for all of the body's proteins. But though there are upward of 3 billion base pairs (the rungs) along the chromosomes, only about 30,000 or so proteins are made from all that DNA. Clearly, the math does not add up.
As we've already learned, the coding within the DNA is packaged in units called genes. Each gene is a smaller bit of a chromosome, and the number of genes along a chromosome matches the number of proteins formedfrom that chromosome. Within a gene it takes three bases to code for one amino acid, the individual building blocks that make up all proteins. There are only four bases: guanine (G), cytosine (C), adenine (A), and thymine (T). Thus, a sequence of CTG along a gene codes for an amino acid called leucine, while a sequence of CGG codes for one called arginine. Whenever those sequences are present, a leucine or arginine molecule will be added to a growing protein. The next set of three bases will determine what the next amino acid will be in the protein, and so on. So part of the mystery of the "extra" DNA lies in the fact that you need three bases for each amino acid.
Oddly, there remains a very large amount of DNA that is not a code for anything. Some of these regions of DNA are known as introns, and they are interspersed within most genes. Although much of the DNA in a chromosome may be introns, the function and evolutionary significance of introns are still unknown.
Why did DNA need to have a second strand in the first place? This evolutionary milestone ensured that whenever a cell divided into two new cells, each would receive a full complement of the parent cell's DNA, with all of its genes intact. That's because when a cell divides, the two DNA strands split along the rungs of the ladder, and each new cell gets its own strand. By the time cell division is complete, the duplicate strand of DNA has been resynthesized in each new cell. The two newstrands of DNA come together, the DNA folds up, and two new, fully functional cells are born. In other words, the second strand is what makes heredity possible.
One last thing of great importance is how the encoded bases in DNA get translated into amino acids. How does a cell "know" that CTG is the right DNA sequence for leucine? Two intermediates must assist in this translation from one type of molecule (DNA) into another (protein). When a certain protein, such as an enzyme, is needed, that protein's gene is activated. Typically, the cell cytoplasm senses the protein deficiency and shuttles a signaling molecule to the cell's nucleus. There the signal finds the correct gene and begins the process of "unwinding" the coiled DNA.
As the DNA unwinds, the gene becomes exposed. Enzymes in the nucleus split the two-stranded DNA along the rungs, and a mirror image of the gene is created using available bases, riboses, and phosphate groups. This mirror image differs a bit from DNA, because the ribose has an extra oxygen atom (which is why it's called ribonucleic acid, RNA, instead of deoxy-ribonucleic acid), and because it uses a base called uracil (U) instead of thymine. Other than that, it's essentially the same as, just shorter than, a molecule of DNA. A perfect mirror image can be formed because the structures of uracil and the other bases prohibit them from binding to any other base but their perfectly matched partner. Cytosine can only bind to guanine, and uracil can only bind to adenine.
The RNA chain that corresponds to the gene is now clipped off the DNA, where it migrates to the cell cytoplasm and encounters a ribosome. Ribosomes are tiny, protein-rich structures that form a perfect pocket in which RNA and amino acids can dock. This RNA is called "messenger RNA" because it conveys the DNA's message from the cell nucleus to the cell cytoplasm.
Also entering the ribosomes is yet another type of RNA molecule, called "transfer RNA." These RNAs have at one end of their structure a short sequence of three bases that is complementary to the sequence of a region of the messenger RNA that codes for one, and only one, amino acid. Let's imagine that a messenger RNA molecule leaves the nucleus, with instructions to build a particular protein that happens to have a leucine amino acid (CUG) in its structure. As the messenger RNA reaches the ribosomes, a transfer RNA with a sequence on one side of GAC (the RNA complement to CUG) binds to the messenger RNA. They form a miniature double-stranded RNA molecule along those three bases. At the other end of the transfer RNA, a molecule of leucine is bound. This brings the leucine molecule into the ribosome, where enzymes can link it up with whatever the previous amino acid in the growing protein had been. The transfer RNA leaves, and another takes its place. This one has a complementary code for the next triple-base sequence of messenger RNA, which may correspond to arginine or any other amino acid. In this way, a protein is built up one amino acid at a time,until the entire base sequence of the messenger RNA has been translated.
DNA is sensitive to high energies, like those of radiation. Gamma rays, X rays, cosmic rays, ultraviolet light from the sun, as well as certain drugs and chemicals, can interfere with the sequence of bases in DNA. Such changes are known as mutations and can be as simple as substituting a single base (say, a T) for another (say, G) within the entire 3 billion base sequences. This may change the amino acid code for that tiny strip of DNA and could lead to consequences that range from trivial to lethal. Since DNA replicates itself each time a cell divides, the mutation will persist and will be passed on to offspring. If a mutation results in a disease, such diseases can often be treated but rarely cured. Curing the disease might require correcting the faulty gene so that it no longer produces an abnormal protein. Such a technical feat is on the horizon in science and medicine, but is only in its infancy at this time.
Proteins
Proteins (from the Greek proteios, "first," as in first in importance) are produced when a gene is activated by signaling molecules that are generated within cells; thus they are known as gene products. Proteins are involved in countless activities, such as forming the architectural "skeleton" of our bodies, acting as enzymes to initiate chemical reactions, acting as hormones in the brain andbloodstream, and serving as carriers for compounds that don't dissolve well in blood (like fats and oxygen). All living tissue in large measure is made up of various proteins.
All proteins can be divided into two classes, those that do not dissolve in water (fibrous proteins, such as keratin in your fingernails, collagen in your bones), and those that do (globular proteins, such as albumin and antibodies).
Regardless of their solubility in water or their specific functions, all proteins are composed of the same twenty amino acids, albeit in different combinations. An amino acid is a small, carbon- and nitrogen-containing molecule, with a slightly acidic nature. It is the order in which amino acids are strung together (via chemical bonds), known as the primary structure of a protein, that determines whether it becomes a hormone, a component of the muscle system, or an antibody. The simplest proteins have only a few amino acids, while larger ones have hundreds.
Certain amino acids repel or attract each other, because, for example, they may contain atoms with positive or negative electric charges. Other amino acids tend to form close "associations" with other amino acids because they may both share similar hydrophobic regions within their structure. These water-fearing regions tend to stick together, much like oil tends to form droplets on the surface of water. When the varous electric and hydrophobic forces occur, the protein folds andtwists as some amino acids strain to cluster together, and others try to push one another away. This new, twisted shape is known as the secondary structure of the protein, and sometimes resembles the way DNA forms a helix. It is this secondary structure that allows groups of hydrophobic amino acids to clump together. Secondary structure enables proteins to migrate into cell membranes, which--because of the oily nature of cell membranes--prefer water-shunning regions of molecules. By anchoring itself in a cell membrane, a protein can interact with molecules outside the cell (that is, it can act as a receptor, or sensory molecule) and convey information about the outside world to the cell interior.
As a protein assumes a secondary structure, new possibilities arise for interactions among amino acids. For example, two amino acids that may have been separated by 100 intervening amino acids in the linear chain, thus making them too far away to interact, may be much closer together in space once the molecule has been folded into the secondary structure. Thus, when the entire protein molecule has finished folding in on itself, a stable, three-dimensional shape is created that bears no resemblence to the simple, linear array of amino acids that began the process. This level of structure--known as a tertiary structure--is extremely important, because it is the 3-D shape of the protein, not a chemical reaction, that allows it to interact only with certain other proteins, like a lock-and-key mechanism. That's why an enzyme that reacts with one molecule will notexert the same actions on all other molecules in the body.
Finally, a fourth, quaternary, level of structure exists in which two or more proteins with 3-D structure come together to form a new, larger molecule that is highly stable. An example of such a protein is hemoglobin, the oxygen-shuttling molecule in red blood cells (figure 1).
All these twistings, turnings, attractions, and repulsions depend entirely on the cellular machinery getting the original linear array, or sequence, of the amino acids correct. If a gene contains an error (mutation), or the cell translates the gene's message incorrectly, a protein will not assume its normal shape. The consequences of this can be devastating. A single amino acid error in the hemoglobin molecule, for example, results in the disease known as sickle cell anemia.
Antibodies
The importance of the relationship of a protein's shape to its function is illustrated by the immune system. Other than the brain, the immune system is possibly the single most complex physiological system in the human body. It is composed of cells such as T-cells (T because they are produced in the thymus gland), which attack foreign bodies such as bacteria, viruses, and organ transplants. In addition, other kinds of immune cells secrete antibodies into the blood. These antibodies work to sequester foreign proteins out of the circulation--for example, proteins originating from infectious microorganisms.

Antibodies fall into the class of proteins called globulins (because of their water solubility and globular shape) and are given the more specific name immunoglobulins because of their origin in the immune system. The general shape of all antibodies is essentially the same. They consist of four separate chains held together by amino acid "bridges." A special amino acid called cysteine contains within it a sulfur atom connected to a hydrogen atom at one end and a carbon atom at the other end. When two cysteines along the length of a protein are in close proximity due to the tertiary structure of a protein, the hydrogens from each sulfur atom are kicked off, and the two sulfur atoms recombine to form a sulfur-to-sulfur linkage. This bridges one cysteine in the protein chain to another in a different region of the protein, or even one entire protein to another. Both of these situations occur to produce a four-chain antibody.
Antibodies have two heavy chains (so called because they are big) and two light, or small chains, all linked together by cysteine bridges (this gives the antibody its quaternary level of structure). A portion of the amino acids that constitute any antibody are identical in all antibodies. These identical regions play a role in allowing other cells and proteins to find and eliminate the antibody together with its attached foreign protein, regardlessof what that foreign protein may be. A second region of all antibodies is unique from one antibody to another. This unique region of the antibody is where binding reactions take place; it is here that the antibody attaches to a specific "antigen" or foreign molecule (for example, a protein released by a bacterium). The variability in this binding region thus allows a wide array of antibodies to be formed, each of which can attack its own particular antigen, and not others.
Sometimes the immune system runs amok. Molecules in an individual's body are incorrectly assessed as "foreign" and attacked by the immune system. Antibodies that mistakenly attack a wide variety of normal tissue proteins have been identified in certain diseases. Such diseases are known as autoimmune disorders because the immune system is attacking one's own self. Type I diabetes, systemic lupus erythematosus, Addison's disease, Graves' disease, and myasthenia gravis are all examples of this insidious breakdown. Sadly, the cause of these breakdowns in immune activity is not currently known.

Copyright © 2002 by Eric P. Widmaier