FRONTIERS
Protein Structures
The key to understanding how protein molecules (enzymes) perform their chemical tasks lies in their complex three-dimensional shapes. The bumps and valleys on an enzyme’s surface serve to attract and then connect other chemical components. Each enzyme is thus a precise arrangement of thousands of atoms—primarily carbon, oxygen, nitrogen, and hydrogen. Protein crystallographers devote their research lives to unraveling the locations of all those atoms, in the hope of understanding the chemical basis of life. Deducing a protein structure is no easy task. It can take years of research to unravel the structure of a single modest-sized protein molecule.
We now know the structures of such important molecules as hemoglobin, chlorophyll, and insulin, but there are thousands of other complex proteins in living things. Protein crystallography, coupled with advances in computer modeling of protein folding, will remain an important research discipline for many decades to come.
Neurobiology
The nervous system of an animal is not a simple electrical circuit. When a signal gets to one end of a nerve cell, the cell sprays various molecules out for the next cell to pick up. Thus the transmission of a nerve impulse is a complex chemical, as well as electrical, phenomenon. An enormous research effort is under way to understand nervous systems and how single nerves and their connections lead to larger-scale phenomena like behavior and learning. Ultimately, the goal is to discover the working of the human brain, but in the meantime scientists are content to work on single nerve cells (like the axon of the giant squid) and on small, relatively uncomplicated creatures like worms and cockroaches.
Immunology
Like all other vertebrates, you possess an immune system designed to defend you against foreign cells and molecules. The main components of your immune system are five different types of white blood cells, each of which has a specialized role to play. One type (the so-called B cells) produces antibodies, which are Y-shaped molecules in which two ends of the Y fit specific kinds of foreign molecules. Antibodies thus lock onto the unwanted object. The third leg of the Y-shaped antibody then stimulates other parts of the immune system to destroy the entire antibody-plus-foreign-molecule package. This part of the immune system protects against small invaders like toxins and some bacteria.
Other white blood cells (called T cells) contain receptors that recognize molecules on the surface of foreign cells. The T cells then bind to the foreign cells and destroy them. In this way, your body eliminates parasites and cells altered by cancer or viruses. Other kinds of T cells regulate the actions of the immune system. Some cause antibodies to be produced after the first exposure to a new invader; this is how we acquire immunity to diseases like measles. Still others suppress the action of the immune system.
The immune system is being studied intensely today, primarily because of its importance in medical research and treatment. The AIDS virus, for example, destroys T cells that regulate the immune system, which then loses its ability to respond to new diseases or eliminate cancer. In organ transplants, the immune system may attack the new organ as “foreign” unless physicians can find ways to suppress the response. And many scientists suspect that regulating and stimulating immune system molecules like interferon provides the best hope for developing cures for cancer.
CHAPTER SIXTEEN
The Code of Life
WHEN JIM’S CHILDREN Dominique, Flora, and Tomas return to a café in their summer home in Red Lodge, Montana, they have no trouble picking out members of the town’s long-established families, even if they’ve never met them before. “You must be Joki,” they’ll say to a blond, Finnish-looking boy. They’re not great detectives, but living in a small town can be an exercise in practical genetics. Members of families do tend to look like one another, and with a little experience anybody can pick out resemblances.
But the genetic code is more than skin deep and it bears upon much more than casual questions of physical appearance. When Margee Hindle and Bob Hazen got married they knew that their children would have a fifty-fifty chance of suffering from Lynch’s syndrome, a genetic disease that invariably leads to colorectal cancer. Is Margee carrying the gene that afflicted her father and grandmother? Was that gene passed on, like a ticking bomb, to Bob and Margee’s children?
We pretty much take for granted one of life’s miracles: like always begets like. Bacteria beget bacteria, birds beget birds, bananas beget bananas. Offspring display many traits—both good and bad—of their parents. Each new organism begins with a single cell, yet within that microcosm lies all the information needed to create the whole organism in all its complexity. In every form of life a few different atoms and molecules, in cells with the same kinds of architecture, adopt very different designs. How are such complex and varied blueprints passed from one generation to the next? How are they read? Scientists now realize that every living thing on Earth uses the same strategy:
All life is based on the same genetic code.
MENDEL’S PEAS
Genetics, the branch of science devoted to studying how traits are passed from parents to their offspring, didn’t begin in a high-tech lab with fancy machines and technicians in white coats. Gregor Mendel (1822–84), an Austrian monk whose work was largely ignored in his own lifetime, performed the first comprehensive and systematic genetic experiments in a secluded monastery garden where he cultivated peas.
Mendel noticed that certain strains of peas bred true: tall plants, if bred together, gave rise to tall offspring, while short parents always yielded short offspring. When he produced a hybrid by fertilizing short plants with pollen from tall ones, the offspring were all tall, but if he then bred those hybrid offspring with one another, three-quarters of their offspring came out tall and a quarter came out short. Crossbreeding tall and short plants always resulted in tall and short plants—never medium-sized ones, as one might at first expect.
To explain many years’ worth of data of this type, Mendel introduced the concept of a basic unit of heredity, something we call the gene. His idea was that each adult possessed two sets of genes, one contributed by each parent. The interplay between these genes then determined the offspring’s characteristics. In this game, however, no compromise was possible—one gene or the other won.
To express this kind of competition, Mendel characterized genes as either dominant or recessive. A dominant gene is one that wins the competition if paired with a different gene. For example, in Mendel’s pea plants the gene for tallness is dominant. In the first generation of hybrids, where each offspring has one tall and one short parent, each offspring gets one gene for tallness, one for shortness. The fact that all offspring are tall says that in this situation tallness wins, so this gene must be dominant.
The role of recessive genes becomes obvious only in the second generation. All of the tall first-generation plants carry one gene for shortness, even though this gene is not expressed (to use the biologist’s term). Nevertheless, the gene is there and can be passed on to the next generation. Each parent, in fact, has a fifty-fifty chance of passing on the recessive gene for shortness, and an equal chance of passing on the dominant gene for tallness.
On the average, then, a fourth of the second-generation offspring receive genes for tallness from both parents. These offspring will be tall. Half the offspring receive one gene for tallness, one for shortness. Because tallness is dominant, these offspring will also be tall. The final fourth of the offspring receive a gene for shortness from each parent. These offspring will be short.
The existence of recessive genes explains many well-known phenomena in human heredity—the redhead who crops up in a dark family, for example, or the prevalence of hemophilia in the inbred royal families of Europe in the nineteenth century. The gene for light hair is recessive in humans, and so can be carried along by several generations without being expressed. When two dark-haired parents each carry the recessive gene, however, a fourth of their offspring (on the average) will be light-haired.
Similarly, the gene for sickle cell disease, in which red blood cells are misformed, is recessive in humans, but if families where the gene exists intermarry, the chances of an unhappy double recessive increase.
Millions of families across America know similar uncertainties, for there are hundreds of genetic diseases. Children with Tourette’s syndrome may suddenly display violent antisocial behavior. Individuals with retinitis pigmentosa suffer increasing loss of vision as the light-sensing parts of their eyes deteriorate. Each of these afflictions is passed on from parent to child, in nature’s cruel game of Russian roulette.
When Mendel introduced the gene it was purely a concept—an idea. Genes had no physical reality, and no one knew what they might be. Today we know that genes are a coded sequence of smaller molecules arrayed along a segment of a much larger molecule called DNA.
In passing from the gene as an idea to the gene as a real thing, we pass from classic Mendelian genetics to modern molecular genetics. This is but one example of what is probably the most important development in the history of biology—the shift in emphasis from studying organisms (like plants and animals) to studying the chemical basis shared by all living things.
DNA AND RNA:
MESSENGERS OF THE CODE
It has become a matter of folklore that DNA is the molecule that governs heredity, and that it is shaped like a double helix. DNA is one example of a nucleic acid—the NA of DNA (so named because it is found in the nucleus of the cell). Like other important molecules of life, DNA is modular—built up from repeated stackings of simple building blocks. In the case of DNA and RNA, the two types of molecule that carry the genetic code, there is modularity within modularity: DNA consists of a string of basic building blocks called nucleotides, which are themselves built from smaller molecules. Think of the process of making DNA as analogous to putting together a book from smaller components like letters, words, and sentences. Assembling DNA involves fitting the sub-assemblies together rather than starting everything from scratch.
Letters of the Code
Nucleotides represent the letters of your genetic code. Your body contains untold trillions of these molecules, like a printer’s shop overflowing with type just waiting to be set into prose. Each nucleotide is formed from three smaller molecules. The simplest of these, the phosphate group, consists of a phosphorus atom surrounded by four oxygens. Next comes a sugar: deoxyribose in DNA (the D of DNA), and ribose in RNA, another important nucleic acid. The phosphate and sugar are linked to one of four different molecules referred to collectively as bases. The four base molecules—adenine, cytosine, guanine, and thymine—are similar in size but quite different in shape, like four different letters in the alphabet. In fact, they are usually represented by the letters A, C, G, and T.
Each nucleotide is an L-shaped combination of one sugar, one phosphate, and one base. Taken alone, this molecule is not very interesting, just as a page with only one letter makes pretty dull reading. But link nucleotides together in just the right way and you have created the book of life.
The double helix DNA molecule, which carries the coded blueprints for all living things, is like a twisted ladder with sugar molecules for the vertical sides and base molecules for the rungs.
The Double Helix
The best way to think of the DNA structure is to imagine building a ladder out of nucleotides. The sugar-phosphate part of the nucleotide forms the sides of the ladder; the base pairs hook together to form the rungs. Once you have built the ladder in this way, imagine taking the ladder’s top and bottom and twisting in opposite directions. What you have is the famous double helix of DNA.
The sequence of the ladder’s rungs is crucial. The shape of the base molecules is such that when adenine and thymine are brought together, hydrogen bonds form between them and they lock together into a solid rung. The same thing happens with guanine and cytosine, but not with any other possible pairing of the four bases. Thus, there are only four possible rungs to the ladder:
DNA replicates itself by first splitting down the middle like a zipper. Each half of the original double helix attracts complementary bases to form two new identical molecules.
AT TA GC CG
The sequence of the bases along the double helix of DNA contains the genetic code—all the information a cell needs to reproduce itself and run its chemical factories, all the characteristics and quirks that make you unique. All of the genetic words, sentences, and paragraphs are spelled with combinations of four letters: A, T, G, and C.
RNA (ribonucleic acid), as we shall see, plays a critical role in transferring and reading the genetic messages. RNA molecules are similar to DNA molecules, except that (1) the sugar in their nucleotides is ribose instead of deoxyribose, (2) they have only half the ladder—that is, one sugar-phosphate spine with bases sticking out, and (3) a base called uracil (U) is substituted for thymine.
The Genetic Xerox Machines
All living systems must reproduce to survive, so at the most fundamental level there must be a way to copy molecules of DNA. The procedure for doing so is simple. First, enzymes unzip part of the DNA, breaking the bonds that hold the base pairs together (think of the enzyme as sawing through the rungs of the ladder). The unzipping opens the unattached bases to the environment. Inside the nucleus of cells, free-floating nucleotides are attracted (and become attached) to the exposed bases.
For example, suppose a particular rung of DNA is composed of the bases C and G. When the rung splits, the newly freed C will attract a free nucleotide with a G, while the newly freed G will attract a C. So the original CG rung is replaced by two identical CG rungs. Step by step, rung by rung, this process repeats as each of the separated halves plucks a replacement for its missing partner from the surrounding cell fluid. When this has been done for all of the rungs in the ladder, two identical double helix molecules stand where only one stood before. This process guarantees that each generation of cells has DNA identical to the preceding one.
The Genetic Code
The sequence of bases—A, C, G, and T—along the DNA molecule forms a coded message that tells the cell how to manufacture protein molecules. Since proteins serve as enzymes for reactions between molecules in cells, they determine every function the cell carries out: the very biochemical identity of the cell depends on information coded into the DNA.
In order to go from a sequence of base pairs on the DNA to a protein performing its function in the cell, two things must happen. First, the information on the DNA must be read and carried to the place in the cell where the protein is to be built. Then the coded information must be translated into the specific sequence of amino acids that results in the desired protein. These two functions are carried out by two different kinds of RNA molecules.
The transcription of the information on the DNA molecule occurs by a process that resembles the copying of the DNA molecule we’ve just described. An enzyme unzips a stretch of DNA, and nucleotides that are normally floating free in the nucleus link onto the exposed bases to form a molecule of RNA. If there is a sequence TGC along the DNA, for example, the corresponding sequence along the RNA will be ACG In this way, the entire sequence of bases in the stretch of DNA is copied onto the smaller molecule of RNA, much as a photograph is copied onto a negative.
The type of RNA made by this transcription process is called messenger RNA, or mRNA for short. These molecules are much smaller than the DNA (after all, they copy only short segments of the total). They can therefore pass out of the nucleus through small openings in the nuclear membrane and move into the main body of the cell, carrying the coded information as they go.
When the mRNA reaches the place in the cell where its work is to be done, a second form of RNA called transfer RNA (tRNA for short) comes into play. This key-shaped molecule has three bases along its top and a site on the tail that attracts an amino acid. There are four different kinds of bases, so there could be as many as 64 (4 x 4 x 4) possible arrangements of three bases, and thus 64 different varieties of t
RNA, equivalent to 64 different three-letter words in the code of life. Each tRNA has one triplet of bases along the top and attaches to one and only one type of amino acid along the bottom. Since there are 64 possible triplets and only 20 amino acids, the genetic code contains redundancies—several different triplets can produce the same amino acid, like different words that mean the same thing.
Transfer RNA works as shown in the illustration. Bases along the top of the molecule are attracted to their counterparts along the mRNA, and line up accordingly. When the bases are aligned, so too are the amino acids at the other end of the tRNA. These amino acids, held in their proper sequence by the RNA molecules, then link together to form the protein.
The term “genetic code” refers to the link that leads from three base pairs on a DNA molecule to a particular amino acid holding a certain position along a protein chain. This is not an abstract concept. If you reflect on the fact that everything chemical in your body is manufactured, moved, modified, and used by proteins that are built from scratch from a sequence of amino acids precisely dictated by the DNA sequence, you will see why we say that DNA holds the secret of life.
Each key-shaped transfer RNA molecule has three bases along the top that link to the appropriate bases on a strand of messenger RNA. At the bottom of each transfer RNA is a specific amino acid. As transfer RNA molecules line up at one end along messenger RNA, the amino acids line up to form a protein at the other end.
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