Authors: Natalie Angier
There are other cells in this world that can be sized up by the bald eyeball. Most bacterial strains are decidedly microbial, in the range of a millionth of a meter across, but
Thiomargarita namibiensis,
a sulfur-loving bacterium first discovered off the coast of Namibia, is a defiant millimeter wide, as big as the period you're about to reach. Among the so-called protozoa, a ragtag phylum of single-celled and usually invisible creatures which includes such laboratory staples as the amoeba and the paramecium, we can also find a handful of outlying colossi. Largest by far are the foraminifers, ocean-dwelling protozoa that may grow to a length of two inches; like bird eggs, these overachieving unicells are encased in hard outer shells, a mothering matrix of crystalline calcite that each foramin forms for itself.
Yet such macrobial cells are the exception, and the vast bulk of the world's biomass is built of motes. Our cells, an elephant's cells, the cells of the largest animal that has ever livedâa female blue whaleâare tiny, an average of
1
/
2,500
of an inch across. What's so great about being so small? I asked many of the biologists I interviewed. Why cells? Why build bodies, no matter how big they're destined to be, of parts too tiny to see? Why shouldn't we be made of what we seem to be made ofâlarge sheets of unified matter, of tissue layers slathered one on top of another?
To be small is to have control, Cynthia Wolberger of Johns Hopkins University told me. Small is manageable. Small is flexible. The cell is
shielded from its environment and so can control what happens inside in a way it cannot control the world outside. And the smaller the space in need of oversight, the tighter and sharper and more dynamic that control can be.
Companies have learned this lesson again and again, of the inherent verve and elasticity of the small, close-knit, semiautonomous team. So long as your individual fiefdoms remain compact and defined, your corporation can retain the cunning of David even as it assumes the multinational grasp of Goliath. We multicellular beings can obviously grow huge as well, all the while remaining biochemically nimble and shielded from the vagaries of our volatile world, because we are constructed of manageably modest parts.
The best way to understand the benefits of smallness to a cell, Wolberger said, is by taking a quick look inside. And here, it must be said, is where the picture gets a little bit ugly. I asked Wolberger what the cell would look like if it were blown up to the dimension of a desktop accessory.
Without a moment's hesitation, she replied gaily, "It would look like snot."
Snot?
"Yes, cells are very gooey and viscous," she said. "We do a lot of experiments in vitro, in a test tube, isolating elements of a cell in what is essentially a glass of water with salt and a chemical buffer. I like to remind my students that in vivo, in the real conditions of the cell, things are much thicker and more syrupy than that. They're more like snot."
On top of this unappetizing imagery, we have the offputting thickness of cellular nomenclature. You may be the proud possessor of 74 trillion cells, but the jargon of cell biology can make you feel like an alien without a green card or city map. Breach the border of the plasma membrane, and, whoops, you're smack up against the rough endoplasmic reticulum, a series of flattened sacs where proteins are made; or scraping along the Golgi apparatus, another stack of flattened sacs, where proteins are stored or chemically adjusted as needed; or whap, whap, whapping across the vesicles, the lysosomes, the ribosomes, the mitochondria. Even the umbrella term for the many little structures of the cell, "organelles," seems unnecessarily officious.
Never mind. Do not be deterred by either the in vivo viscosity or the verbal pomposity. The world of the cell is really not so different from our own. Cells may be small, roughly halfway between the size of an adult human and the size of an atom, but they behave more along the lines of classical, Newtonian, pushmi-pullyu everyday physics than by
the foggy, probabilistic rules of quantum mechanics, where electrons vanish from one orbital lane and pop back up in another. Even the tiniest cells are shapely and fully 3-D, and though the basic cell morph may tend toward, shall we say, lava lamp droppings, specialized cells may assume specialized, elegant forms. Seen through a microscope, skin cells look like dinner plates fit for stacking, red blood cells like New York bialys, liver cells like shoeboxes lined up on their sides. Cells of the body normally stay put and obey the rules conveyed by the ambient chemical signals of the organ they're part of, but all cells at bottom are as fierce and twitchy as cats. Cut a few cells away from, say, a kidney, heart, or tongue, place them in a petri dish with a slick of broth and the right nutrients, and the cells will begin crawling like sovereign zootica, creatures of the Precambrian seabed. Watch the cells through a microscope and see how they thrust their edges out wide, like the wings of a bat or the fins of a manta ray, and how they drag themselves forward in search of more food, and cringe and rear back at the touch of another wandering cell. Cells are so strong that you wonder their owners can ever feel weak. Ants are famously heavy lifters, able to carry loads ten, twenty times their size; but cells, declares Scott Fraser, a bioengineer at Caltech, are at least one step up from the ants. In studies that use laser tweezers and plastic beads to explore how cells signal each other, a cell in a culture dish will grab at the beads by wrapping a bit of its plasma membrane around them, and then yank them free of the tweezers, an act not unlike a human uprooting a tree.
Cells are the unit of life, and they preen about it, throb with it, in every pore and ruffle. And the units of uppermost note in the unit of life, the molecules that do all the work of the cell, the moving, the shaking, the yanking, the eating and excreting, and the making of new movers and shakers of every make, are the proteins. Understanding the cell means understanding proteins, and this brings us to a minor point that many biologists admitted they find persistently frustrating: the public's narrow idea of what a protein is. Stephen Mayo is a professor at Caltech who runs a laboratory at the Broad Center for Biological Sciences, one of the newer buildings on campus and one of the few with an elaborate security system to prevent the theft of one or another $100,000 piece of equipment. He is young, tall, trim, dressed in crisp chinos and a striped tailored shirt rolled up at the sleeves. Mayo's office is spacious and sunny and understatedly luxurious, a reflection of the vast economic potential that his biomedical research is thought to hold. Mayo is trying to design new proteins that might in turn be incorporated into new drugs. Sometimes he attends or hosts social events with his wife, who is
a volunteer with the Junior League, and he meets people in all sorts of professions. "When they ask me, 'What do you do for a living?' I take a deep breath," he said. "I tell them that I run a lab at a university and that we work on proteins. 'Oh,' they say. 'So you're a nutritionist?' People hear the word 'protein,' and the first thing they think of is hamburger." He'll explain to them that, no, he's trying to develop computer technology to design new proteins, new biological molecules for use in medical and pharmaceutical products. "But all the time I can see that in the back of their mind, they're still thinking about hamburgers," Mayo said. "They're wondering, What's wrong with the hamburger I'm about to be served?"
There is, of course, a connection between the protein in hamburgers, and the proteins to which the Mayo team is devoted. When you eat meat, you are eating cells, and cells are full of proteins. When you eat broccoli, you're also eating cells that are full of proteins. Our bodies need a steady supply of dietary protein to build new cells, repair damaged ones, replenish the immune system, and otherwise keep all the parts powered. The reason why hamburger is so much more readily linked to the categorical term "protein" than is steamed broccoli is that animal meat, which is made of muscle cells, is a denser source of protein and because those proteins more closely resemble our own. Hence, it's quicker and easier to obtain the protein components essential to our fleshly upkeep by devouring the flesh of another animal than by reaching for a peach, although as any vegetarian can attest, the plant kingdom is vast and varied and, with reasonable attention to dietary details, you can accrue all the protein you need from somewhere beneath its verdant canopy.
Whatever their source, dietary proteins are dull and lifeless things, and a sad, blinkered way to view the proteins of which Mayo and other biologists speak. What does the stomach do, after all, but tear any proteins encountered into the smallest possible bits, deactivating, desecrating, and
denaturing
them, as a protein chemist might put it. That is the stomach's job, to flatten a meal so it can be scavenged for spare parts. Let's chuck the steak as synecdoche for the molecule. Proteins are so much more than dead meat.
What then is a protein, in its natural state, on its rightful cellular stage? Technically, a protein is a string of amino acids, distinctive clusters made primarily of the elements most strongly associated with lifeâcarbon, oxygen, hydrogen, and nitrogenâarrayed in a style that lends each amino acid a little knob of positive charge and a little knob of negative charge. That characteristic of molecular bipolarism, of carrying a duality of charges, makes amino acids ideal for linking together into a great diversity of structures, just as the holes and pegs of Lego pieces allow them to be snapped into model drawbridges, Ferris wheels, dinosaurs, and other marvels displayed on the cover of the Lego box, if not on your living room floor. Cells either synthesize amino acids from scratch or extract them from food, and then link the chemical subunits together to fashion a fresh protein supply. Those proteins differ considerably in size, from trinkets called peptides that are a couple of dozen amino acids long, to tumbling, operatic chains of several thousand amino acids. Keep in mind that "small" and "large" are relative terms here, and even the bulkiest proteins are still maybe a hundred-thousandth the size of a sesame seed.
Far more important than a protein's size is its shape, how its chain of amino acids folds, curls, puckers, and zags in three-dimensional space. Proteins are often described as being little "machines" in the cell, but that industrial, boxy term belies their Jean Arp curviness and Breck girl bounce. If you could watch proteins tumbling across your desk, they might look like an exceptionally stylish collection of Nerf balls, or origami animals made of butter and clay. And though proteins come in many textures, if you could touch a typical one, press down on it with an index finger, it would feel, in keeping with its cellular locale, viscous and mucousy on top, but with a decided firmness underneath. There is nothing silly about this protein putty, nothing slapdash about a protein's form, for from a protein's form its function follows. The specifics of a protein's shape, and the way its positive and negative electric charges are distributed along its contours, are what allow each protein to carry out its allotted tasks. A single cell might have 50,000 different proteins in its borders, some with deep notches, others with fingerlings thrust out in victorious V's, still others bearing confettilike streamers designed to wrap around a target molecule in a helical hug, or a combination of these and other recurring protein motifs. Most proteins have their stiff parts and their flexible parts, regions that remain relatively fixed throughout the life of the protein, and portions that respond to prodding from neighboring molecules and will shape-shift and switch tasks accordingly. Turn, turn, turn. Proteins live to work, and they live in a place much like Manhattan, a teeming city that never sleeps, where all that counts is how you look, and what you do.
What is it that proteins so busily, prodigiously do? Most of them are enzymes, proteins that help activate or accelerate chemical reactions in the cell by bringing together ingredients that might otherwise remain separate, or that change the shape of other proteins and hence prompt
them to venture forth and ignite a chemical reaction. The distinctive structure of an enzyme is designed to fit smartly with only one or a handful of target molecules in the cell, the way your cell phone will snap only into its official recharging device but not the one of your parents, spouse, or anybody else in your immediate zip code. Once the enzyme has coupled with its target, its substrate, it can fulfill its specialized transformative mission. For example, there are enzymes in liver cells that are shaped to recognize rings of cholesterol, and once they have latched onto the greasy circlets, they help suture them into necessary sex hormones like testosterone and estrogen. Other liver enzymes conjoin salts, acids, cholesterol, fats, and pigments into the bitter yellow-brown digestive brew called bile. Then there is the face-saving liver enzyme, alcohol dehydrogenase, which helps break down the alcohol molecules in your blender drink into smaller, nonintoxicating pieces before you have a chance to pass out, throw up, or begin impersonating Peggy Lee.
And that's not all there is, my friend, that keeps us dancing. Enzymes in white blood cells can dissolve away viral shells, enzymes in our pancreatic cells help police how much sugar thickens our blood, enzymes in nerve cells make the chemical signals that stream through our brain and allow us to think, feel, do things, regret doing those things instead of other things, and fill prescriptions for Effexor.
Apart from the straightforward enzymes, there are the structural proteins that form the cell's filamentous supportive matrix called the cytoskeleton, "cyto" being the Latin word for "cell." Like bones, structural proteins give the cell its shape and integrity, and like bone tissue they are not at all inert, are in fact so feisty and eager to flaunt their powers that one might think they belonged to the metaphoric skeletons that one tries to keep in one's closet. Most renowned among the structural proteins is actin, found in all eukaryotic cells, a versatile molecule that not only serves as material for the cell's beams and girders, but also operates in a transportation capacity, shuttling other cell proteins from place to place, or helping to haul the trash out of the cell and dump it into the bloodstream, or putting everything into position during that most delicate and complex of cellular maneuvers, the splitting of one cell into two. In muscle cells, actin cooperates with another structural protein, myosin, to pull muscle cells in during a contractile motion, like the flexing of biceps or the squeezing of a bolus of food down the throat, and to relax the muscle fiber when the curl or swallow is through.