The Canon (35 page)

Because structural proteins can be as bustling and busybodied as any of the body's textbook pyrotechnic enzymes, some scientists argue that all proteins are enzymes, are engines of change, and life, and levity. The word "enzyme" means "to leaven," an etymological tip of the hat to the yeasty proteins that leaven bread, and wine, and thou. "L'chaim," too, is thought to share etymological roots with "zyme." It is the Hebrew toast to be spoken at a feast, over an alcoholic beverage of the toaster's choosing, and it means, quite simply, "To life."

The cell, then, bristles with proteins, with enzymes, with life. If you could peel the top off the cell for an insider's view, said Tom Maniatis, a biologist at Harvard University, it would be like looking into an ant pile or beehive, but at fast-forward speed. "There would be frantic activity, with things moving in every direction, and molecules being transported from place to place at a lightning pace." Picture as well a lot of darting through doorways and giant silent suckings, and vanishings into thick air. The membranes that girdle the cell and the nucleus are pocked with pores and channels that open and shut, and molecules enter and molecules escape; and everywhere in the cytoplasm there are bubblelike baggies called vesicles that bobble along the cell's railway tracks of actin and approach molecules and tackle them with the straitjacket of themselves, and take them to a new locale and then spit them back out; and there are other, ghastlier sacks, the lysosomes, the little stomachs of the cell, filled with blistering acids that destroy whatever cytotrash they suck inside. And in this panting antsy atelier, this hive in hyperdrive, many protein players travel as gangs, as bulbous protein complexes of three, six, a dozen diverse enzyme talents locked together through their structural complementarity, the happy meshing of knobs and clefts, positives and negatives. Until very recently, biologists tended to think of proteins in isolation, as rugged individualists, a set of singletons or monomers in the cell single-mindedly doing their jobs. One of the major insights of the last few years, whose magnitude continues to mount the more we study the in vivo vales of the cell, is that most proteins operate in teams, as polyproteins, and that the result of their pooled talents may be radically different from what one might have predicted by considering their enzymatic properties independently. What's more, the protein-protein allegiances are fluid and fungible. A protein may insinuate itself into one polypod one moment, and then break away and join forces with another protein set the next, and then another a few seconds or minutes or days later—fulfilling a different enzymatic mandate with each collegial union. And nowhere is
protein clubbiness more evident than in matters of the family business: the procreation of proteins and of the busy, indefatigable, sometimes divisible republic on which they stand.

Tom Maniatis said that if you could strip the top off a eukaryotic cell, you'd see a tumult of activity; it's time to walk through the nuclear door, to the most rambunctious rumpus hall of all.

By popular reputation, DNA is a colossus among molecules, and certainly the bearer of many aliases. Our DNA is our genes, the things we inherit half from Mother, half from Dad, and that we offhandedly blame for our bad teeth, or our inability to separate light laundry from dark. Our DNA is our chromosomes, or our baby's chromosomes, the twenty-three pairs of little sausage-shaped bodies, as crimped and bent and acrobatic as Keith Haring cartoons, that are isolated in a prenatal amniocentesis test, stained, and finally scanned for signs of troubling breaks, imperfections, or duplications. Human DNA is also known as the human genome, star of the eponymous Human Genome Project, the multinational, multibillion-dollar effort to "map and sequence" the entire human genetic code, to specify every one of the 3 billion chemical letters of which human DNA is composed. DNA has been exalted to an almost idolatrous degree, the Holy Grail turned golden calf, and it now has the opposite problem of protein. Whereas a protein is seen as just another ingredient in meat, DNA feels far too storied for everyday bodies, and too big or too dangerous to eat. How else to explain the common misconception that the only grocery products with any genes in them are "genetically modified" foods, and the effort of some restaurateurs to advertise their refusal to use genetically modified foods in their kitchens by displaying on their menus a little picture of a double helix with a red slash drawn across it?

Of course, while you likely never give it a thought, you eat DNA all the time, even if your food is certified organic, the product solely of traditional means of genetic modification—i.e., the selective plant breeding, cross-hybridization, and animal husbandry techniques that humans have employed over the last 10,000 years—and guaranteed free of the contemporary "Frankenfood" finaglings that might have installed specific genes to confer on the crop resistance to, say, frost or fungus. Even then, while eating organic food, you swallow billions of genes arrayed along millions of DNA molecules every day. Every time you eat steak, you're eating a slab of cow muscle, composed of millions of cow cells, and those cells are full of protein, myosin and actin aplenty and more; and the plasma membrane around each cell and the smaller nuclear membrane within each cell are bubbles of cholesterol, and in
the middle of each cow nucleus is cow DNA, the complete set of cow genes distributed on the thirty pairs of cow chromosomes that constitute the cow genome. From each cow genome enthroned in each cow cell, an entirely new cow, a Dolly-like clone of the donor cow, can be grown, giving fresh meaning to the claim that you are so hungry you could "eat a cow." You eat potato DNA, bean genomes, tomato chromosomes; if your diet is healthfully varied, you've devoured the source codes for thousands of species in your lifetime. Genomes are not just the stuff of high-concept, high-priced projects. They are stuffed into all our body cells, unabridged copies of the DNA molecule that each of our parents had bequeathed to us in demipart at the moment of our conception, and that the briskly proliferating cells during fetal development had replicated and bequeathed to every daughter cell, and that our adult cells still hold and still solemnly copy every time they divide. The only cells without DNA are our circulating red blood cells, the specialized cells that carry oxygen throughout the body. Red blood cells develop in our bone marrow from precursor cells that do have DNA in them, but in the last stage of their maturation, when they are ready to serve as our breath of life, as the emissaries from the lungs to every far-flung cell we own, the red blood cells spit out their nucleus and its DNA molecule to leave plenty of room for the activities of their resident hemoglobin proteins, the molecules that capture oxygen.

This is perhaps the premier point in the story of DNA: that in almost every cell of our body can be found a personal copy of the complete DNA molecule, with all our genetic information, all twenty-three pairs of our chromosomes, all our genes, and all the lengthy filler between genes, all 3 billion bits that constitute our very own human genome. It may not be
the
Human Genome, the one that scientists have largely finished mapping and sequencing; that official map is based on a compendium of genetic samples extracted from a handful of people, including patients in long-standing, important genetics studies and a couple of scientists with a long-standing sense of self-importance. Our own human genomes, though, the humble ones tucked into the nuclei of nearly all of our cells, are very similar to the great Human Genome spelled out in the databanks of the National Institutes of Health and other research centers. We human beings are, genetically, 99.9 percent identical one to another. Those few places where our genomes differ—from the archived archetype and from one another—help explain the individual differences that our eyes easily seize on, and too easily magnify. If only we could see the genomes we carry within us; then we might appreciate the homogeneous depths of our common humanity.
Still, nothing can be as familiar to us as the genome we carry, for it is photocopied
in toto
into every nucleated cell of the body. Our liver cells may make enzymes to detoxify alcohol, and our white blood cells specialize in decapitating microbes, but at their core is the same DNA molecule, same genome, same chromosomes, same set of genes. Where the DNA of a liver cell differs from that found in kidney or bone is in how the molecule is mollycoddled by the protein company that it keeps.

To understand the dynamics between DNA clonality and protein heterodoxy, we must look closer at the pampered colossus on its nuclear divan. DNA is a molecule that, if stretched out, would be as tall as a kindergarten child; but even in its supercompressed state inside the microscopic nucleus, still DNA is hundreds of times the size of an average protein. Yet for all its bulk, DNA is ultimately a simple molecule, far simpler, in fact, than many of the proteins that surround it. Whereas proteins are constructed from twenty different types of subunits, twenty different amino acids from which to pick, mix, and patch, DNA, amazingly enough, makes do with just four different chemical modules, called bases, underlying its frame. Formally, the four are cytosine, guanine, adenine, and thymine, but, as with presidents and fashion designers, their initials—C, G, A, and T—usually suffice. Each of the four bases is a distinctive but also relatively simple construct of nitrogen and carbon rings, which are tacked onto a spiraling backbone of sugar and phosphate molecules. The nitrogen and carbon ringlings project outward from their backbone and search for companionship. DNA is a double helix, after all, which means it consists of two strands of bases attached to two sugar-phosphate spinal columns. The Cs, Gs, As, and Ts on one strand face their counterpart bases on the other strand, and are held face to face by the gentle tugging of a hydrogen bond. But the pairing of bases across the strands is not arbitrary: A is always partnered with T, and G with C. This is the complementary match that feels right, that allows the DNA molecule to settle down and maintain structural integrity and uniformity up and down its span. Adenines and guanines are both relatively large bases, while thymine and cytosine are relatively small. You match husky partners with petite partners, and you get a nice clean vertical lineup. Isn't that sweet? Big like a male, little like a female. You might as well usher these complementary couples, these base pairs, right up the plank of Noah's ark.

DNA, then, is a two-faced molecule, two corkscrewing chemical chains loosely but lovingly locked in comfortable complementarity. On one side, a strand of 3 billion bases, millions upon millions of Cs, Gs, As, and Ts, arrayed in varying patterns, with a plethora of CATs and
TAGs and ACTs and TATAs! and long, long stuttering stretches of Ts or As or GCs repeating themselves until you're ready to GAG. And on the facing strand, the complementary lineup of 3 billion bases, so that where there's a CAT on one strand you'll find GTA on the other. The aim of the Human Genome Project was to determine the precise chemical sequence of all 3 billion base pairs of human DNA, and let me tell you it was a grueling and often tedious task, for much of the genome proved to be dauntingly repetitive, a drab, seemingly pointless wasteland within us. Specifically, large regions of the human genome turn out to consist of what is often referred to as "junk DNA," filler bases that seem to play little role in the molecule's primary assignment, of encoding the rules for making new proteins and new strands of DNA. We still don't know whether the apparent junk is truly junk, and persists in the bosom of our DNA because it does no harm and therefore the cell is under no pressure to eject it, or whether the junk plays still hidden but nonetheless essential roles, for example, by helping DNA to bend in all the right places, or as fodder for future evolutionary gambits. What we do know is that only a tiny fraction of the 3 billion base pairs, something like 5 to 10 percent, is devoted to the pressing biobusiness of protein production. Only 10 percent of our DNA, in other words, is the stuff that we designate as genes.

Here, then, is what it comes down to, the genomic mystique, the "genes" that we say it's all in the: maybe 300 million bases, scattered among a cast of 3 billion. These key chemical sequences encode our body's proteins; they are the recipes, the formulas, the runes for those proteins. At its simplest, this is what a gene is: a recipe for a protein, written in the script of DNA, in a lineup of As, Cs, Ts, and Gs. The code works in triplets: three bases signify one amino acid. If the stretch of DNA says CAT, you are looking at the code for the amino acid histidine, which is felicitously abbreviated as the feline "his." If you see GTT, then you know, aha, the amino acid valine wanted here.
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And there are punctuation marks, too, triplets that mean "protein recipe starts here" and triplets that, like a square bullet or a ###, tell you you've reached the recipe's end. Other codes are like the dynamics notations in a musical
score, saying, juice it up here, make lots of that protein, or soft-pedal there, just a couple will do.

But these protein playbooks are not at all straightforward or linearly organized. Different parts of a gene, different steps in the recipe, may be inscribed in very different parts of the DNA macromolecule, and only get "read" as a coherent narrative at the moment the protein is fashioned. Junk and nonsense abound, not just between genes, but within the genes, too.
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Scientists may have largely completed the spelling out of the human genome, but the sequence is a bare-bones beginning, the opening ACT, and there's so much left to be divined from this gnostic epic poem. We're not even sure how many genes there are in human DNA; every time we scan the code more closely, the total drops. As recently as the late 1990s, the accepted figure for the approximate number of human genes was 100,000. By the turn of the millennium, it had fallen to 80,000. A couple of years later that number was slashed in half. The latest tally has us in the low- to mid-20,000s.

Yet the body has considerably more than 25,000 different proteins to its credit; by some estimates, there may be 200,000 at work in our cells. Obviously the dandy old rule of thumb that one gene equals one protein no longer stands: instead, genes are like the sentences "Eats shoots turkeys and ducks" or "Is there in truth no beauty?" or "Hereallyearnedforher." Change the spacing or punctuation of the sentence, and you upend its sense. Similarly, the body's genes obviously can be read many ways by the cell's sharp-eyed foremen—the proteins that sense the cell's need for new proteins and have the structural flair to latch onto the DNA molecule and jump-start the protein-making machine.