The Canon (37 page)

And so again we can see why a cell sets its sights beneath ours. The cell excels through micromanagement, and high protein density and perpetual protein flux are best accomplished aboard a tight, compact ship. With its waterproof membrane and modest dimensions, a cell can keep its proteins hemmed in, salts sorted out, pH optimized, dynamism equilibrated. Every cell is a stable community afeast on intrinsic instability, a living island like Manhattan, unto itself, but with all ears tuned to the world beyond.

The DNA inside your liver cells is identical to that inside the cells of your brain, tongue, pancreas, or bladder, and the DNA of every cell holds the instructions to do the work of any cell. Much of that work is routine and nonspecific, performed by every cell regardless of where it sits. All cells of the body must tap into their DNA codebook to make proteins that will crank the wheels of the Krebs cycle, for example, the stepwise transformation of food into usable cell fuel. All cells must also consult their DNA for making proteins to repair it whenever it gets broken or mutated; and sturdy though the molecule is, it needs upkeep every day.

But then there are the specialist codes, the protein formulas possessed by all cells, yet consulted by few. The genome within a bladder cell has the code for making insulin, and yet your bladder doesn't secrete insulin no matter how badly you need to pee. Your pancreas cells in theory can hammer out taste receptors to tell the bitter from the sweet, but the pancreas is a large, hammer-shaped gland hanging toward the rear of your abdominal cavity, and it has better things to do. Different cells of the body, then, differ somewhat in how their DNA behaves, in which genes are active, and which kept mum. Proteins are the laborers that do the fancy switchwork. They arouse genes, they stifle genes. Proteins in a brain cell will latch onto the DNA molecule and scan the code for making dopamine or serotonin, neurotransmitters that convey signals across our crinkled cortex. Why do brain cells have these proteins in their borders, while skin cells do not? How do brain cells know to make the proteins that home in on DNA and access the code for other brainy chemicals like serotonin and dopamine? If the DNA of your head cells is the same as the DNA of your toe cells, why can't you think with your feet, even when you try to vote with them?

Much of the answer to how cells differentiate and assume their tissue-specific identity remains hidden in the abiding mystery that is
embryonic development. You started out as a single cell, a fertilized egg, and that potentate cell knew everything and saw to the farthest horizon and had the potential to give rise to all organs of the body. But as your embryo grew, its rapidly proliferating population of cells began budding off into discrete colonies, layers, sectors, primordial organs; and the greater the number of cells, the less freedom of motion and possibility each cell retained, the more committed to its location and vocation as a member of a limb or kidney or lung. In the course of differentiating, the genome within each cell underwent a series of subtle modifications. If the cell was destined to become part of the liver, genetic codes necessary for the production of bile and sex hormones would have been gently pressed into an active configuration, perhaps with the kinks of the DNA on which they sit being turned slightly outward, made accessible to the transcription proteins that give the codes voice. At the same time, genetic sequences of no use to a liver cell were muffled, tucked under and inward or slapped over with a few chemical "methyl groups," the cell's version of duct tape on the mouth. We understand little about embryonic development and the balletic genetics behind it, although extensive research on the subject is well under way, including on the much feted and politically freighted class of cells called stem cells—founder cells from which more specialized cell types then stem.

Yet even after our cells have assumed their basic identity, have been programmed in the art of acting like a smooth muscle cell or a hairy follicle cell, they continue to hone their skills and refresh their memories by listening to the voices around them. A liver cell knows it is a liver cell by dint of priming during embryogenesis, and because all the cells around it remind it of its liverishness every moment of every day. Cells are gossips, scolds, eavesdroppers, and sheep. They attend to their neighbors and hector their neighbors and keep one another in line. About half of the proteins in a cell are devoted to communications—to receiving signals from other cells and conveying advice and counsel back again. Cell membranes bristle with hundreds or thousands of receptor proteins, which protrude from the cell like outstretched arms or woven baskets or egg whisks. Each receptor type is shaped to embrace a particular molecule, a hormone, a growth factor, a song for the cell; and on meeting its designated match, the receptor protein shifts its shape in no uncertain terms to ensure that the entire viscous village beneath it hears. Cells send molecular missives across the tiny spaces of the extracellular matrix, and across the body buoyed in the blood or lymph. The cells of the pituitary gland at the base of the brain secrete sex hormones that persuade ovary cells to help ripen an egg, or testes cells to supply fresh sperm. The mast cells of the immune system, on encountering an invading allergen that they deem dangerous—mildew spore, cheap eye shadow dust, red alert!—will flood the surrounding tissue with the chemical histamine; and any cells in the vicinity blessed with histamine receptors will gamely react, yielding the swollen eyes, dripping sinuses, serial sneezing, and asthmatic wheezing that can make the body's inflammatory response so much nastier than the pathetic threat that spurred it.

Beyond chemical diplomacy, there is good old brute force. Cells are strong, as we've seen, stronger than ants, and they can tug and yank at the cells adjacent to them, or extrude from their surface their thin, long streamers, called philopodia, to deliver a few pointed pokes. That mechanical stimulation acts on the recipient cells much as a powerful hormone would, rearranging the cell's internal protein furniture and setting off a signaling cascade that tumbles right down to the nucleus. Through the medium of massage, a group of uncoordinated, introverted cells, each minding its own business at its preferred pace, in a flash can be rallied and synchronized and swayed to behave as one. When you cut yourself, it is the sensation of being yanked and stretched that spurs surrounding cells to begin dividing and heal the gap. Conversely, if a cell infected with a virus initiates its suicide program for the sake of the greater good, the urgent membrane ruffling that is a hallmark of programmed cell death can induce neighboring healthy cells to kill themselves, too, just in case.

Again and again scientists have seen cellular groupthink in action and eavesdropped on its propaganda machine. If you extract stem cells from an early mouse embryo and inject them into the bloodstream of an adult mouse, the fate of those ingénue cells will depend on where they land. Stem cells that lodge in the liver become liver cells, those trapped in a muscle get muscular, those caught in the kidney learn to go with the flow. Obviously the injected stem cells didn't have a chance to experience the hazing of normal embryonic development and whatever stepwise genetic changes it entails. Instead, each cell had to learn on the job, by osmosis, imitation, indoctrination. If the elder cells around it talked of nothing but a liver's lot—of secreting bile, regulating the blood supply, storing fats and sugars, detox duties—the stem cell absorbed the ambient information, imbibed hormones and other molecules designed to stimulate liver cells, and began responding as a liver cell would. Inside the nucleus of the stem cell, the DNA molecule would
adapt itself to the specific demands of liver tissue. The pursuit of mastery never ends, and cell specialization requires lifelong education.

Cells must pay particular attention to their community when it comes to the monumental matter of division. Many cells of the body, as it happens, are primed to divide. Growth is their default position, the thing they will do unless told to do otherwise, and a lot of the chemical signals that cells send to one another are exactly that—signals of growth repression. Only on the removal of these inhibitory signals, coupled with the reception of positive signals that encourage growth, will a cell enter the tightly choreographed
ballet d'action
of division, a task carried out by a vast protein corps. The DNA molecule is pried apart, just as it is when its genes must be read, but this time the entire long-winded masterpiece is scanned, and a complementary copy made of all 3 billion exposed bases; and the copy is spell-checked for accuracy, and most of the mishaps repaired, at which point a matching strand can be made, and the newborn pair then entwined; and the two heavyweight molecules, mother DNA and her dutiful, duplicate daughter, are pulled over to opposite corners of the nucleus, and the nucleus is pinched down the middle into two little bubbles, each with its own copy of DNA, and the entire cell soon follows suit. Yes, just as cells love making protein, they love splitting up, and they do it quite well, in their well-controlled fashion. Millions of your body cells divide each day, and so your upper epidermis sloughs off and is replaced by new skin underneath, and your head hair grows half a foot a year, and your immune system can meet almost any pathogen it faces through the explosive expansion of suitable warrior cells.

Yet we live in the world, which may be the best of all possible worlds, but still it's not perfect. Every time a cell divides and its DNA is replicated, mistakes are made: a thymine is inserted where a guanine belongs, or a C base is inserted instead of the proper A; and really, what else would you expect in the course of copying a chemical text 3 billion nucleic letters long, which, if they were printed letters, would fill maybe 5,000 books the size of this one? Most of the mistakes in DNA replication are spotted by proofreading proteins and corrected before cell division is through; and of those few that slip through, most don't matter, for they fall into a harmless region of the genome. Once in a while, though, a serious mutation is overlooked and ends up in the final DNA script of the daughter cell, a change in the code that will yield a rotten, dysfunctional protein product somewhere down the line. And by far the rottenest proteins are those that "liberate" a cell from the constraints of its community, for they are the proteins that turn a cell cancerous. A cancer cell is a cell that is deaf to the chemical tutelage around it and indifferent to the slings and ruffles of its neighbors. It no longer needs hormonal inspiration from the outside to stabilize its stash of replication proteins but will make a set of the proteins and stabilize them of its own accord, and then make more and more and keep those, too. The receptors protruding from the surface of a cancer cell may be empty-handed above, but still their lower stalks shake and bend in the cytoplasm below and send shock waves through to the nucleus, with the order to grow, grow, grow. The sticky daubs on the outer membrane that keep healthy cells tethered together soften up until the cancer cell comes unglued, allowing it to travel where it pleases; and when the rebel cell settles down in new ground, still it hears nothing of the tissue around it, but listens only to its inner malignant hiss, telling it, You are a cell, and you must survive, and to survive, you must divide. But it is a false message, for in unhampered division, in its state of solipsistic genetic determinism, the cell kills the body and, with the body, itself.

The normal cells that we live with, the cells that abide by the laws and harmonics of multicellular existence, exemplify the dynamic equilibrium ever at work between a cell and its setting, or, zeroing in still further, between DNA and the proteins around it. Many biologists grumble about how DNA has been seriously misunderstood, stripped from its cellular context and petitioned for answers to everything—cancer, heart disease, bad moods, choice of mate. People talk about the nature-versus-nurture debate, and they want to know how much of who and what they are can be attributed to "nature," which is generally viewed as synonymous with their DNA, the specifics of their genetic code; and how much to "nurture" or "the environment," which commonly signifies the amorphous "world outside" and is characterized by variables like the childrearing practices and prejudices of their parents, or whether they attended an expensive, highly selective preschool or spent their formative years at the knee of Nanny Nickelodeon. Scientists have struggled mightily to impress on the public that the nature-nurture "debate" is dead, that it was an unscientific nonissue from the start, something pumped up and sustained by a media ever in love with conflict and horseraces. "It's unfortunate that there's a linguistic similarity between the words 'nature' and 'nurture,'" Stephen Jay Gould once lamented to me, for the euphonia alone "has helped keep this ill-formulated and misguided debate alive." You can't uncouple nature from nurture, he and other scientists insist, any more than you can uncouple a rectangle's length from its width. "It is a true union of influence," said Gould. "It's logically, mathematically, and philosophically impossible to pull them apart."

The result of all this assertive promotion of an interactionist rather than a dialectical perspective when it comes to dissecting the roots of human nature is the undoubtedly accurate but not terribly profound impression that, gee, maybe one's DNA and one's upbringing together help shape one's personality. In truth, the indivisible link between the two, between the instructions encoded in your genomic particulars, in your DNA, and the execution and interpretation of those instructions in real time, is profound, is embedded in the deep chemistry of every cell in your body. DNA may be called the master molecule, but it can do nothing on its own and must live through the proteins that subserve it; and those proteins attend closely and continuously to one another, and to the world around them, for clues to what they should make of their master. And on attending to external signals and looping back to the DNA, the proteins may sometimes change the very character of the genome, by subtly shifting which genes they activate, and how strongly, at any given time. Nature needs nurture, nurture kneads nature, and the codependent conversation never ends. It is ongoing everywhere within you. People often have the impression that if something is "encoded in their DNA," it must be static and unreachable. The environment, by contrast, is thought to be easily changed. Yet this impression is misleading. Your genome is not walled off from its setting. Every cell is a mad Manhattan microhabitat, and every genome a player in it. Genomes are responsive, open to change and modification.