The Canon (36 page)

Let's say you are a pancreatic cell, and you have the misfortune of being hitched to an irrational organism who is angling for her ninth root canal by dipping repeatedly into her grandmother's candy dish. She unwraps and swallows three caramels in less than a minute. Her blood spikes with glucose. She needs a fresh batch of insulin—a protein that acts as a signal between cells and so is called a hormone—to stimulate her liver and muscle cells to mop up some of that excess blood sugar. The pancreas is the body's designated source of insulin, you are a working member of the pancreatic community, and you can't suddenly phone in diabetic; chances are you'll be expected to produce insulin.
How in the world do you do it? Luckily, you are a cell, the beneficiary of more than 3 billion years of evolutionary experience, and you know inherently what we
Homo sapiens
do not yet sapiens explicitly: every step needed to transmit a signal faithfully from the outside world, the extracellular environment, to the deepest tabernacle within, and to turn the signal into new protein. In rough sketch, though, this is what happens.

A pancreatic cell senses a need for its services when sugar molecules in the blood begin agitating and dimpling the cell's membrane. The distress signal is relayed down through the cytoplasm by squadrons of quickstepping, shape-shifting proteins. It's like a heartwarming Hollywood movie, in which a child writes a pleading letter to the president of the United States of America, and we see the envelope passing from the local postal clerk through the central post office along to the minions in the White House secretarial pool up to the assistants to the assistants and over to the president's outer ring of advisers, picking up a sense of flurried excitement at each stage, until finally, Should we show this letter to the president? Oh, yes, absolutely, the president must see this at once! The advisers burst into the suitably cellularly shaped Oval Office to find the president, as ever, surrounded on all sides—by bodyguards, legislators, lobbyists, dignitaries, indignitaries, the presidential physician, the presidential astrologer/personal trainer/hairstylist, and Ed Tatum from Omaha, Nebraska, who wandered in while looking for the bathroom. No matter the crowds. The letter bearers don't need the chief's undivided attention; like everyone else, they just want one little piece—a piece that they will, before conquering, quite expertly untangle.

DNA, as it sits in the nucleus, is a dense, matted hairball of nucleic acid strands cloaked in proteins and coiled and coiled and supercoiled again. Only when one cell is on the verge of splitting into two—as cells do with some frequency in high-turnover tissues like skin and blood, but only rarely in fairly stable organs like the brain—does the DNA then separate into the discernible bodies we call chromosomes. Otherwise, all the chromosomal pieces of the genome are fused and bunched together. In addition to being supercoiled, the DNA in an ordinary, nondividing cell, like our pancreatic cell with its epistolary subplot, is, of course, a double helix. It is a corkscrew configuration with one strand of bases matched up to a strand of complementary bases, and very chemically stable as a result. The relative toughness of the molecule explains why on rare occasions we can fish out samples of DNA from ancient sources, such as insects trapped in amber, and why the
premise of
Jurassic Park
—that dinosaurs might be regrown from remnants of dinosaur genes found in fossils—is not terribly far-fetched.

Stability and utility, however, are two different matters. Just as a book must be opened to be read, so the relevant region of the double helix must be cleaved apart for its instructions to be understood. In that pancreatic cell, then, there are proteins that know where on the massive, twisted body of their resident DNA can be found the step-by-step recipe for piecing together more insulin. We can't yet say quite how the proteins know where to look amid the nuclear haystack of 3 billion base pairs, but we know they know, we know there are recognition proteins that are needle-nosed for the insulin code, because the pancreas, as a rule, makes insulin every day. On attaching to the proper position on the DNA, the proteins, the teams of proteins, gently unwind that region of the genome and separate the two strands of the helix, revealing two rows of bases bared like teeth in an open jaw. Now other proteins can glean from the exposed code the knowledge needed to create new insulin protein, and so give those archival teeth a voice. Of course, you don't want to start puttering around on the prized original document any more than you'd want to lend the original Declaration of Independence to a fifth-grade student for show-and-tell, or to a member of the House Ethics Committee for any reason whatsoever. Working too long and too vigorously with the exposed, dehelixed DNA risks introducing a mutation into the molecule, a structural defect that could lead to a few problems later on, like, say, cancer. As the first order of business, then, transcription proteins make a working chemical copy of the insulin gene, an RNA message of the gene—or messenger RNA, as scientists call it. They flutter along one fiber of the gaping DNA, and they read it tactilely, as a blind person reads Braille. They gather spare bases from elsewhere in the cell, and they piece together the RNA message, which looks a lot like the original gene, with one small exception: wherever the DNA code holds a thymine base, the transcription crew will install into their message a very close chemical cousin of thymine, the base uracil. Nice job! A fine first draft! Before the message is worthy of publication as protein, though, it must be revised by editing proteins, which deftly delete all the bits of filler code in the transcript and splice together the serious passages into a working formula for insulin.

That cleaned-up message is then delivered to one or more of the cell's many ribosomes, the spherical bundles of protein and RNA that synthesize all new protein merchandise. The ribosomes glide over the message and they, too, interpret it by touch. They scan the bases as triplets, every threesome the call letters for an amino acid, though here, in the
argot of the cell's protein-making guild, it is not a CAT that yowls for histidine, but a CAU, not TGG that means the amino acid tryptophan, but UGG. The ribosomes read, scrounging for the requisite amino acids. Your cells are flea markets and yard sales filled with the building blocks for proteins and RNA and more proteins and new DNA. In the case of cobbling together insulin, the ribosomes need 110 amino acids. And when the pieces have all been stacked in a row, the artisans stand back, and let the new protein go. Sproing! Self-propelled, governed by an internal sense of proportion and purpose, the linear chain of amino acids folds and squirms and chases its tail and does the rumba and the ay, caramba, and, with very little help from the proteinous crowd around it, attains its three-dimensional Nerf ball origami form. This theatric transformation, from flat stack of amino acids to robust in-the-round protein, may happen with near spontaneity, driven by a thousand tiny pushes and pulls inherent in its constituent parts, but that doesn't mean it is child's play. Scientists remain baffled by the nuances of protein folding. They have become quite skillful at isolating and sequencing genes, and they have sequenced the entire genomes of many species beyond our own—of the mouse, fly, roundworm, rat, dog, horse, chimpanzee, a grim gallery of deadly pathogens. And with the DNA sequence of a gene in hand, they can say immediately what the amino acid chits of its protein "product" will be. Still, researchers can't predict from a genetic sequence or an amino acid sequence what the final, fully folded protein will look like, or what powers its contours will claim. That ignorance brings to mind Lewis Thomas's amusing meditation on how "deeply depressed" he'd be if he were told to do the job of his liver, and how he'd sooner take over the piloting of a 747 jet 40,000 feet over Denver. "Nothing would save me and my liver, if I were in charge," he wrote, "for I am, to face facts squarely, considerably less intelligent than my liver." Fortunately, the liver delivers without the good doctor's advice, and a newborn insulin protein needs neither understanding nor applause to find and fold on its own dotted lines and ready itself for duty in a wine-dark sea.

Every body is smarter than we are. For all the daunting complexity of protein synthesis, cells do it effortlessly, quickly, munificently. Often a single RNA message will be read by many ribosomes simultaneously, each reeling out its own copy of the protein. In the average human cell, some 2,000 new proteins are created every second, for a daily per-cell total of almost 173 million neonate proteins. Multiply that figure by the roughly 74 trillion cells in the human body, and you get a corpuswide quota of, egads, 1.28 × 10
²¹
proteins manufactured each day. In light of
this astonishing cellular productivity, why aren't we all just getting bigger and bigger? OK, we are, but this is no place to discuss the international obesity epidemic; besides, even the cells of hunter-gatherers whip up millions of trillions of new proteins a day, and look at how thin they are. The reason why our cells don't all swell and burst apart is that proceeding right in step with prodigious protein construction is ruthless protein destruction. Cells build proteins up, cells tear them back down again. A sizable number of a cell's proteins are enzymes devoted to the degradation of other proteins, including other degradative enzymes. There are enzymes that destroy collagen fibers, enzymes that destroy bone proteins, enzymes that destroy the enzymes that destroy collagen fibers and bone proteins. The average cellular protein survives only a day or two, and some perfectly good specimens emerge from their ribosomal birthing chamber and are instantly demolished.

All this protein turnover may seem terribly inefficient and wasteful. Why spend so much time eating the flesh and fiber of others only to have our cells spend so much time eating the flesh and fiber of themselves? Is the cell absurdly sloppy, absurdly perfectionist, or a contractor for the Pentagon? In truth, the constant protein churning illustrates a deep tenet of biology and brings us back to the question posed earlier of why cells are so small. Mary Kennedy, a neurobiologist at Caltech, explained it to me as the principle of "dynamic equilibrium," the idea that in a highly complex biological system like a cell, the pieces must fit together both precisely and loosely. An enzyme must fit the knobs and grooves of its intended target, but not the somewhat similar knobs and grooves of another molecule nearby. If the enzyme is supposed to attach to the section of the DNA molecule where the insulin gene is inscribed, for example, you don't want it attaching to the genetic sequence that holds the code for making thyroid hormone.

At the same time, you don't want the enzyme to stick to the DNA molecule at the insulin address and stay there as though bolted in place. You want the binding to be finicky but flexible, said Kennedy. Moreover, you want varying degrees of flexibility. Sometimes a protein will attach very firmly to its target, sometimes moderately so, sometimes barely so. And the relative commitment of the attachment itself conveys important information: I'm really holding on tight here, I'm serious about my assignment. I need a maximal output of insulin hormone. Or, I'm really just poking around here, window-shopping—there's no call for insulin output at the moment, but who knows what may happen tonight, after dessert. Maintaining a state of dynamic equilibrium, of
looseness crossed with precision, said Kennedy, "allows you to have a huge amount of control and feedback at every level of the system." One way to sustain that specific squishiness is by crowding the cell's occupants but keeping them moving at the same time—having lots of proteins and RNA messages and the great cramped chromosomes all pressed shoulder to shoulder, but stirring and shifting position and in constant communication. It's rather like a subway car at rush hour. Passengers get in, passengers get off, some push their way to the middle of the car, others cluster around the doorways, people mutter, Excuse me, excuse me, as they elbow their way to the door and disembark before the ding-dong knells and the doors shut again. A couple of seats open up, and passengers standing nearby eye the opportunity and glance at each other to see who's in greatest need. Go ahead, you take it. No, no, please have a seat. I'm getting off in a couple of stops anyway, and besides, I'm younger and in much better shape. And though the system always seems on the verge of anarchy, I can tell you, as somebody who grew up riding the New York City subways, that in fact it's a miracle of frenzied efficiency, delivering millions of people to and from work each day over hundreds of miles of tracks, and rarely breaking down, and no matter how suffocatingly stuffed into a subway car I've been, I have always managed to wiggle my way doorward and have never missed my stop. The analogy is highly inexact, and I'm glad the subway isn't a cell, for a lot of the "passengers" getting off aren't headed to home or the office, but to the wrecking ball. This is the cell's way of maintaining lubricated, edgy motion: headily spooling out new RNA transcripts and proteins, steadily shredding the old.

Constant protein turnover also happens to be an excellent way of controlling protein behavior. Many proteins debut with a contingent expiration date stamped on their forehead: they are designed to fall apart rapidly unless a chemical signal from the outside intervenes and instructs them to do otherwise. This trick is particularly useful for keeping the cell's most powerful proteins in line, like those that prompt the cell to begin dividing. The idea here, said Susan Lindquist, a cell biologist and former director of the Whitehead Institute, is that you want growth-prone proteins on hand and ready to respond at a moment's notice, especially if you're an immune cell that might need to start replicating at the earliest viral provocation. At the same time, you don't want replication proteins loitering around the cell indefinitely, lest they start acting of their own accord and fomenting unwanted cell division. The solution: synthesize the proteins constantly, but make them unstable. Only when the appropriate growth hormones or other molecular envoys enter the cell and bind to the proteins are the proteins stabilized and put to work.