Long for This World

by Jonathan Weiner

  The morning presented an unusual situation for her. It was awkward. She realized that they did not know each other’s names.

  His name was Aubrey David Nicholas Jasper de Grey.

  It was after they were married, sitting across the table from each other at breakfast and dinner, that Aubrey began to quiz Adelaide about the biology of longevity. He gathered that almost no biologist was working on it. Whenever he brought it up with Adelaide, she told him that aging was almost impossible for biologists to study and absolutely impossible for doctors to treat or to cure. “I know now that most biologists around that time did take that view,” Aubrey told me. “They looked very much down on gerontologists.” He assumed that the problem was too hard to work on. When scientists could work on it, they would.

  Like anyone else, Aubrey says, he was interested in the problem of aging, and of course he loved a problem with the reputation for impossibility, but Adelaide did not seem to want to talk about it. She was happy to tell him about her experiments over the breakfast or dinner table, but she seemed sadly pessimistic about the subject of old age. She herself studied the brighter side of life. She worked on meiosis, which is part of a series of magic acts by which cells make sperm and eggs. All the action at the start of life, from meiosis to the meeting of those sperm and eggs to the growth and development of embryos, is magic on the finest scale. By the time Aubrey began learning from Adelaide, the science of development was one of the most successful fields of study on the planet. Using the tools that Watson and Crick had discovered in the double helix, more and more biologists had devoted themselves to the study of that spectacularly orderly sequence by which one cell becomes two, two become four, four eight, and thence to the embryo, and thence to the newborn baby. Adelaide had made a name in the field by discovering a tiny molecular mechanism she called a recombination nodule. It lies at the very beginning of all this spectacularly orderly growth. She studied the phenomenon in fruit flies, which are convenient animals to watch in embryo. They develop very quickly, not in nine months but in eleven days, they’re cheap to raise, and their embryos have much of the same machinery as we do. It was a small but extraordinarily successful field, the study of the developing fruit-fly embryo; three of its pioneers, Ed Lewis, Christiane Nüsslein-Volhard, and Eric Wieschaus, later shared a Nobel Prize.

  Aubrey couldn’t see why we shouldn’t understand the second half of life with the same success as the first half. But Adelaide had grown up and come of age in a time when the study of the first half of life was booming and the study of the second half was stagnant. And development is beautiful anywhere in life you look. The development of the roundworm Caenorhabditis elegans, for instance, is spelled out in such fantastically careful detail that when it crawls to maturity it will have precisely 959 cells in its body, not one cell more and not one less. That was marvelous—elegant—to a developmental biologist. The subject of aging was depressing, with so much living order in the beginning and so much fatal disorder at the end. It was easy to see that you could hope to find something like a recombination nodule. It was hard to see how you could hope to find a destruction nodule. If there were destruction nodules they worked very differently. They didn’t shuffle the deck the way sperm and egg shuffle genes. They tossed the deck into the air, or threw the cards out the window one by one, or set the deck on fire, or lost it under the hedge in the rain. And where would you look for the secret? With development you could look at almost any embryo and find the same machinery at work. With aging you were talking about the whole life span, and the life cycles of living things are bizarrely distinct and differentiated one from the next. There is so much variation in aging that it is hard to know where to hunt for first principles and first causes. Where is the speck of dirt that will turn out to matter?

  By and large, of course, in the big picture, the pattern on display is the same everywhere. But in the details, there is infinite variation. Back in the early 1600s, in his program proposal The History of Life and Death, Bacon had recommended that “the higher physicians” begin by collecting life histories more or less at random and then looking for patterns. Even in the late 1980s, biologists interested in aging were still doing that. They now had many theories, and they had many more volumes filled with observations, but most gerontologists were still lost in the forest—in what Bacon called the Sylva Sylvarum, the Forest of Forests. Where exactly should you look? Imagine grappling with the rock at the bottom of a cliff. You need a purchase on the cliff face. If the face is all smooth you can’t start up. Or if the base is all clinking rubble it’s hard to start up. The study of aging suffered from too many barriers, too many theories, too many observations.

  Aging is not neat, and of course it is the neat patterns that are the simplest for science to solve.

  It is amazing to watch the development of an embryo from the meeting of a sperm and an egg. First you have that one fertilized cell. From that one you get two, then four, then eight. By the arithmetical law of doubling you soon arrive at the astronomical number of cells in an early embryo. That much is astonishing but basically comprehensible because it is pure arithmetic. Then new kinds of order begin to emerge where there had been nothing but that little soccer ball. You get the head and the tail and the gut and so on. And of course the orderly progress of development doesn’t stop there. If the sperm and egg came from frogs, you get a tadpole, which metamorphoses into another adult frog. If the cells came from a painted lady butterfly, you get a caterpillar, then a chrysalis, then a painted lady. All of that is regular, repeatable, and predictable, again and again. If it weren’t, you wouldn’t have frogs and butterflies. And likewise with people. Frogs, butterflies, and human beings all begin in very much the same way. Then come spectacular divergences, all of which are predictable, all of which are in some sense as scripted and lovely as Shakespeare’s sonnets. The rise of each organism from that fertilized egg is one of the most beautiful things on Earth to watch. You can watch again and again and feel the same sense of wonder as the very first time you saw it. And part of the beauty is in the predictability: the sonnet unfolds the same way with each rereading.

  But then of course comes the decline. If you look closely at aging organisms you see endless, desperately depressing, unpredictable variations on the theme of decline. It is nothing like the detailed harmonious unfolding of the beginning. It is more like the random crumpling of what had been neatly folded origami, or the erosion of stone. The withering of the roses in the bowl is as drunken and disorderly as their blossoming was regular and precise. In growth you see the genius of life, and in its slow destruction you see chaos.

  Think of the creation of a work of art and its destruction. Leonardo made many notes in his secret notebooks about his search for durable pigments that would keep their colors. But of course they faded and there is no artistry visible, no genius apparently at work in the fading of the Last Supper. Michelangelo once made a snow sculpture in the garden of his patron Lorenzo de’ Medici. He took that commission with reluctance, to indulge his patron, who was the most powerful man in Italy. What happened to that snow sculpture within a few days was nothing like the act of genius that went into the shaping of it. The making and the melting were two different processes entirely.

  Of course, there are a few regularities in aging. Seen from a certain distance, in fact, our rise and fall are so predictable that we can usually guess a stranger’s age within a few years. Shakespeare wrote the best description of the problem of aging in the famous speech in As You Like It, “The Seven Ages of Man.” “All the world’s a stage…” And each of us plays seven parts. First the infant, mewling and puking in his nurse’s arms. Then the whining schoolboy who creeps unwillingly to school. Then the lover who sighs his way through a poem to his mistress’s eyebrow. And so on.

  …Last scene of all,

  That ends this strange eventful history,

  Is second childishness and mere oblivion;

  Sans teeth, sans eyes, sans taste, sans everything.


  That description of aging in As You Like It is one of the greatest passages in English. It is characteristic Shakespeare, intimately sympathetic and cosmically amused. Shakespeare seems to feel each age and stage as if he has already lived it himself; at the same time he views them all from outside, as if he is looking down at the whole theater of life from ten thousand feet up in the sky. And we can still recognize them now and they all move along pretty much on the same schedule. In that sense our decline does seem to be orderly. Even centuries later we all recognize Shakespeare’s seven ages of man. So many of the little painful moments of the decline seem to progress on schedule. You complain to an older friend at dinner that you can’t read the print on the menu anymore. How old are you, he asks, forty? Yep, right on schedule. A man still reaches the age of spectacles on nose; and then the age when his big manly voice begins to pipe and squeak once more, “turning again toward childish treble.”

  So aging is both predictable and unpredictable. It is both inevitable and erratic, even in extended families. One sister gets bad knees at thirty-five and can’t jog anymore. Another sister gets a bad back at sixty and can hardly walk. The third sister gets such a lucky body that she is still running marathons at seventy-five. If you had that kind of wide variation in the womb, none of those girls would ever have been born. The very broad pattern of aging is the same for each of us, always the same slow subtraction of powers. But where and when each power gets subtracted—that seems almost unbearably random from one body to the next, or even from one part of the body to the next. The Koreans have a saying, “Each finger can suffer.” Every people has a saying that translates, roughly: We all have to go sometime. But which part of you will go first, and which next, or how, when, and where you will suffer, no one can say.

  This chaos makes it hard for biologists to figure out what is going on in aging bodies, or where to try to intervene. When you are looking at order, you can investigate its causes and hope to understand them. You can hope to find processes as neat and clear as the progression itself, as for instance that arithmetic code, two, four, eight, sixteen…. But there doesn’t seem to be anything so arithmetically predictable about aging except that it happens again and again, happens every time. You watch, as Shakespeare watched,

  And every fair from fair sometime declines

  By chance, or nature’s changing course untrimmed.

  Every beautiful human body loses its beauty and then loses its life, by chance or by something built into the nature of the body itself. But no one can say what that something is or where it might be hiding. Where is it? What is it? For years the murkiness and muddiness of the biology of aging has scared away many of the best and the brightest.

  Even if you step back and look at the problem of mortality in the tree of life as a whole, you see confusing variation. It’s not enough to say that aging is the way of all flesh, because not all flesh does age. Life cycles are so diverse that you can find arguments for almost any theory of aging depending on which creature you study, which chapter and verse you choose to quote. Consider the hydra. Hydra is one animal that may be practically immortal. Biologists have argued for more than a hundred years: Does hydra age very, very slowly, or does it live forever?

  Hydra is a sort of stick figure of life, a tiny tube with a head at the top and a foot at the bottom. Around its head and mouth, it has tentacles that it waves around like the arms of a squid or an octopus. Some species of hydra have just a few tentacles; other species have as many as a dozen, which can stretch four or five times the length of the body. From these tentacles they can throw a sort of harpoon on a thread, armed with neurotoxins, to paralyze their prey. The hydra is related to sea anemones, jellyfish, and the Portuguese man-of-war. They’re found in most freshwater ponds and streams, and most of them are only a few millimeters long.

  Our own bodies are vastly more complicated. Men have sperm cells, women have egg cells. We all have muscle cells, nerve cells, skin cells, liver cells—about two hundred different kinds of cells. But the stick figure of the hydra is made up of only about twenty kinds of cells, including cells of the outer layer of the skin, the inner layer, and nerve cells to control the waving and firing of the tentacles, and both sperm and eggs (each hydra being a hermaphrodite). Cells in the body column, the stick of the stick figure, are constantly making more cells—more copies of the hydra’s twenty types. Some of these cells migrate up to the tips of the tentacles and then are sloughed off. Other cells migrate down to the tip of the foot and then are sloughed off. And some migrate into buds in the middle of the stick figure. There they break off and grow into new hydra.

  Biologists who study the near-immortality of the hydra describe its body as a kind of fountain. The cells in the stalk are at the base, and the fountain sprays upward and outward in all directions, slowly. A cell that forms in the center of the body, somewhere inside the long stick of the body column, takes about twenty days to reach the outer limits of the body, the head or the foot, and fall away.

  Daniel Martínez, a biologist at Pomona College, in California, is studying a collection of hydras that was begun in the late twentieth century and so far show no signs of aging. The fountain of each hydra in his collection remains as vigorous as ever. Each hydra buds as much as ever. One individual hydra during its first four years of observation produced 448 buds that matured into full-grown hydras. At the same time, each hydra in that first four years of the study replaced its whole body sixty times over. Even in the lab, of course, an individual hydra does die now and then, if it is mishandled by a student or a technician. But otherwise these stick figures seem prepared to live forever, or at least a very very long time.

  Some gerontologists wonder if the hydra really does come as close to immortality as Martínez claims. The case rests mostly on a single paper he published in 1998. Martínez hasn’t published much on it since, and no one else has followed a population of hydras for nearly as long. Gerontology is such a young science that it is still full of blanks like that along the frontiers. Single travelers come back with reports that some choose to believe and others disbelieve. It is almost as bad as the days of the old writer Sir John Mandeville, in the fourteenth century, who describes the precise location of Paradise in his book of travels, and how hard it is to reach by rowing upriver because the currents are so strong.

  Gerontologists do agree that the source of the fountain of the hydra is traceable to certain cells concealed in the central stick of the stick figure, the body column: stem cells. They are called stem cells because they are able to make all twenty varieties of cells of the simple body of the hydra; all of the diverse cells of the hydra’s body can be said to stem from them. We, too, with our far more complicated body plans, have stem cells concealed in the interstices of our bodies. But our bodies do not replace themselves successfully and perpetually as the hydra seems able to do. So the question is: Why can’t we do what the hydra does? Why can’t we do what we ourselves seem to be able to do at the age of twelve, when we are still green and growing?

  Of course hydras are simpler than humans. But simplicity alone can’t explain the difference between the stick figure and the human figure, because there are creatures that look and act like hydras but are far, far simpler. In fact, they are almost as simple as life gets: they live their whole life cycle as single cells. Even so, like human beings, they do grow old and die.

  I know this because it was one of the first things I wrote about as a science writer. I was just starting out in the early 1980s when I went to visit one of the then-rare researchers who was working on aging, an elderly biologist named Maria Rudzinska. She worked at Rockefeller, on York Avenue, in Manhattan, where Alexis Carrel had made all those black-draped, spooky efforts to cheat death with immortal cells at the turn of the twentieth century. I’d heard about Rudzinska’s latest experiment and had wooed her for months with polite letters before she’d agreed to talk with me.

  Rudzinska was late for our meeting, so I parked myself in a chair by
the door to the Rockefeller cafeteria and opened a book. I’d been doing a lot of reading about the science of life, mortality, and longevity, and had discovered Bacon’s History of Life and Death.

  I was sitting there by the cafeteria door, scribbling notes in the back of my book, when an elderly voice called my name. I looked up and saw Maria Rudzinska. Her hair was gray, pulled back in a tight bun, her glasses thick and mended with tape. Behind the goggle lenses, her eyes looked huge and watery. She stooped. Her cardigan hung loosely from her shoulders, as if she had been wearing it ever since the age when it had fit. Around her neck she wore a medallion so big that I had to force myself not to stare at it, a big bronze sun. She was so stooped and the chain was so long that the sun hung down almost to her belt.

  “Look, he is always writing!” she exclaimed, speaking not to me or to anyone standing nearby but to an invisible audience. I recognized that voice and that audience. They both belonged to the Old World, where people loved writers who were always writing, because they themselves were always reading.

  Rudzinska led me into the cafeteria. Over lunch she told me her story. During the war, she said, she and her husband, Aleksander Witold Rudzinski, had fought in the Resistance in Warsaw. Aleksander had been wounded. At the same time, working under great difficulties, without supplies, sometimes without much food, she had managed to carry on her research. I’ve long since lost my notes, but as I remember the story now, she told me that she’d scraped gunk from the side of an aquarium tank in a half-abandoned laboratory and studied what she found through the microscope. It was unusual for a woman to become a scientist in those days; much less while half-starving in the war. But she’d been entranced by the lives of single-celled animals ever since her first scientific paper in Cracow in 1928: “The Influence of Alcohol on the Division Rate in Paramecium caudatum.”