Long for This World: The Strange Science of Immortality - Jonathan Weiner (2010)
Part I. THE PHOENIX
Chapter 3. LIFE AND DEATH OF A CELL
Ever since he was a boy, Aubrey de Grey has felt that he was cut out for an extraordinary destiny. He was always interested in making a difference in the world by doing things that were hard, things that required a certain virtuosity, things that the world thought well-nigh impossible. It started with playing piano. His mother wanted him to play, but he wasn’t particularly apt. He came to the conclusion early on that it was a waste of his time. If he was out to contribute something unique to the world, to change the world, this was not his way: With lots of people good at it, much better than he would ever be, why did the world need another piano player? He still sees no point in doing things that other people are doing well already. “That’s certainly one of the reasons why I don’t have kids—one of the main reasons,” he says. “Anyone can have kids. A lot of people are very good at it. I want to make a difference.” Nor does he claim to understand people who work in highly crowded fields of science, fields in which, if they went up in a puff of smoke, the very same thing they’d done would be achieved by someone else five minutes later. “That’s completely incomprehensible to me.”
He has a sort of roguish strut. His arrogance is made just tolerable by his matey readiness to confess it, and his willingness to try and fail at great things. At Cambridge it is traditional to race around the Great Court of Trinity College. A student named David George Burghley once ran all the way around while the Trinity clock chimed one, two, three…to twenty-four, a sprint of 373 yards in 43 seconds. Burghley later became an Olympian and the hero of the movie Chariots of Fire. Once, after a party, when Aubrey was a student at Cambridge, he ran that race against the Trinity clock, trying in a way to go Burghley one better. Aubrey sprinted around the Great Court stark naked. He was happy to get more than two-thirds of the way around before the bells tolled twenty-four. But he slipped on some cobblestones along the way and fell on his face. The next day he hobbled around Cambridge with a magnificent pair of purple-and-black eggplant-colored circles around his eyes. That adventure earned him the nickname Aubrey Aubergine, after a sad-eyed character in a British series of children’s books, part of a gang of unwanted fruits, vegetables, and nuts. “Aubergine” is not only the color of eggplants, it is also computer jargon: “A secret term used to refer to computers in the presence of computerphobic third parties,” according to the Free On-line Dictionary of Computing.
Aubrey studied computer science at Trinity Hall, Cambridge. When he graduated, in June 1985, he was hired by Sinclair Research, a high-tech company in town. There he got involved almost immediately in a suitably difficult artificial-intelligence project. A computer program involves a long sequence of commands written in code. If even one line contains a glitch the whole program can crash. Aubrey and a friend at Sinclair, a software engineer named Aaron Turner, began working on the design of a program that could inspect any other program on Earth and debug it automatically. The creation of such a Cure-All is one of the legendary problems of computer science. Its solution is believed by most programmers to be virtually impossible.
While Aubrey was working on the Cure-All, Adelaide Carpenter arrived in Cambridge on a sabbatical. She was a professor at the University of California, in San Diego, at the time. It was her second sabbatical and she was burned out and thinking of quitting science. One day she heard about a party from a graduate student in her laboratory, a young man from whom she bummed cigarettes. Every day she bummed a cigarette, and every week she bought him a pack.
It was a birthday party for someone young, and she did not expect to enjoy herself. As she tells the story, she was standing nervously in the front room when a handsome young bloke came up to her and said, “Justify your existence!” Almost immediately he was called away to deal with something electrical. Apparently it was the bloke’s place. She watched him go. She thought he was charming and cocky. He was twenty years younger, the age of her students. He walked with the air of a man who owns every place he goes, a man who is always saying: Remember my name. She lost him for a time, but later on they bumped into each other again by the wine. Then they danced at each other for a while. There was a couch. Then his bedroom was free.
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…Â. 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.”
Somewhere in the gunk on the wall of the tank she found a rare, single-celled pond creature called Tokophrya, and she fell in love with it. The adult Tokophrya looks like a miniature hydra. It’s another stick figure of life. Its body is a stalk. At the base it has a sort of suction cup called a holdfast. At the top it has sixty or seventy tentacles. The tentacles stand out from it in long straight lines like rays around a child’s drawing of the sun, waving in the water. If a paramecium swims too close, it gets stuck and impaled. Then Tokophrya sucks its victim’s innards through the tentacles, as if it were drinking its prey (still alive and struggling) through a dozen straws.
In all that, it is like the hydra. But the way Tokophrya gives birth is more like us. A tiny bud, a baby, grows in the cell inside a miniature womb called a brood pouch. When the baby is ready to be born, it whirls and struggles in the pouch for ten or twenty minutes, and then bursts out. The parent looks pretty tired. But it recovers quickly and gives birth again in a couple of hours. A healthy Tokophrya can perform this miracle as many as twelve times in twenty-four hours. Its name means, in Greek, “the well of birth.”
Each newborn Tokophrya swims away. Within a few hours it metamorphoses into a young adult, growing a sturdy holdfast, with which it grips the floor of the test tube or the petri dish. It stays put in that one spot for the rest of its life, giving birth to more Tokophrya.
This vaguely mammalian style of labor and delivery fascinated Rudzinska. When a paramecium or an amoeba is ready to reproduce, it just splits in two. After each of the halves is full-grown, those split also. Biologists thought of cells like that as virtually immortal. There is never a moment when you can say that one has died. It just goes on and on.
By contrast, Tokophrya endures the labor of birth, like us. And day by day, while standing on its holdfast and trawling with its tentacles for food, Tokophrya grows old—just like us. So Tokophrya makes a good subject for a study of mortality, and because of its holdfast, it is a convenient one; unlike the amoeba or the paramecium, or the yeast cells that swirl around in a pint of beer, each Tokophrya stays put. Each mortal poses for the camera all its life. Through the microscope, Rudzinska could watch a single cell on its ride from birth to old age and death and try to figure out what goes wrong inside the cell. It was as if she had the whole problem of life and death on the head of a pin.
When Rudzinska came to New York as an émigré after the war, she worked on other things, including the longevity of the amoeba. She was one of the first biologists to use the new high-powered electron microscope to study the intricate machinery inside cells, those tiny bubbles that keep themselves alive and intact so much longer than a mere bubble of water drifting on a pond. Her microscope back in Poland could make things look one hundred, two hundred, five hundred times larger than life. The electron microscope made them more than fifty thousand times larger than life.
That was useful research, she told me, but as a scientist her heart still belonged to Tokophrya and the way it seemed to diagram the mystery of aging. She was convinced that Tokophrya would be ideal for the study of length of days. Only a few people in the world were working with Tokophrya. She’d lost her own stocks of the creature as an exile and émigré the stocks that a biologist in Brooklyn shared with her were not ideal for her purposes. She must have told me why, but I’ve forgotten. What I remember is the tale of her search. She looked everywhere, in ponds, lakes, ditches, and puddles in several states, but she could not find Tokophrya, and she could not quite find her way back into the thrill and romance of scientific research that she had felt in Poland during the war. Eventually she fell sick with a high fever, and spent weeks lying in a bed in Rockefeller’s research hospital. She thought, Can this be where my story ends?
Then, one day in the hospital, while looking out her window, she thought of the fountain pool near her laboratory in Theobald Smith Hall. The pool was not far from York Avenue, but like the rest of the Rockefeller campus it seemed a world apart. It was surrounded by slate walks and marble love seats and ivy-covered sycamores.
From her hospital bed, she asked one of her young laboratory assistants to go down to the pool and collect some water there. She told her assistant to take the water and put a drop under the microscope. And there at last, just as she had hoped, was Tokophrya.
That was how Maria Rudzinska recovered her life’s work.
After our lunch, she led me to her laboratory. When successful scientists are in the prime of their careers they can command whole floors of prime research space, as Alex Carrel did in his heyday in Founder’s Hall. But when they are old and retired, they have to make room for the next generation, Rudzinska explained, ruefully. She worked in the basement of Theobald Smith Hall. Rockefeller’s buildings are linked by a system of underground tunnels, and because it was a cold winter day, she led me from the cafeteria through a few of these twisting tunnels until we came to her small, windowless laboratory. She walked slowly and it took us a while to get there.
In her recent experiment, she’d been assisted by two younger scientists, although she usually preferred to work and publish alone. She’d invited both of them to be there when I arrived. They were older than I was, but they looked very young when they stood next to her. They each wore an extra-bright, extra-wide smile that was somewhere between the beaming of reverence for the old master and the beaming of indulgence for the ancient.
Rudzinska explained her latest experiment. With the help of her two young collaborators, she’d collected a few more jars of water from the fountain pool. In her laboratory, they had grown—or, in the jargon of cell biologists, they had isolated and cultured—more Tokophrya infusionum in screw-capped tubes. Through the microscope they could see a field of Tokophrya waving their tentacles in the water, each one standing on its holdfast. The researchers would search for a single healthy specimen. Using a very fine platinum wire with a tiny loop at the end, like a shepherd’s crook, they’d pick out that specimen. They transferred it to a glass slide that had a little shallow depression, called a well. The well was filled with sterilized water.
At the end of each day of the experiment, Rudzinska had inspected the Tokophrya in the well through a microscope. It gave birth again and again. She counted the new arrivals, removed the parent with the shepherd’s crook, and put it in a fresh drop of water. On Monday, Tuesday, and Wednesday the cell gave birth all day long. But it was growing older: only one birth on Thursday and one on Friday. None on Saturday.
The aging cell’s tentacles weakened, too. Rudzinska was feeding the cell with Tetrahymena, which is another protozoan that lives in pond scum. (Through the microscope, it looks something like a hairy mango.) She made sure her Tokophrya specimen got just enough Tetrahymena every day, not too many and not too few, by directing a stream of them with a fine pipette right at the Tokophrya. When it had caught enough food, she would remove the Tokophrya, with its prey still in its arms, and transfer it to a fresh well, filled with two drops of sterile pool water.
The healthy cell’s cytoplasm was bright and clear. The old cell was dark and shabby, full of dirt and age spots. One of the most famous researchers at Rockefeller, Christian de Duve, had won the Nobel Prize in 1974 for his discovery of a key way the cell cleans up its garbage. He spotted a sort of floating garbage disposal inside the cell, which he called the lysosome, from the Greek: literally “splitting body.” Lysosomes swallow cellular trash and digest it. That is one of the cell’s great secrets of rejuvenation. The process by which the cell consumes itself in the lysosome is known as autophagy, which means, literally, “self-eating.” It is as vital to the life of the cell as eating; but in Rudzinska’s aging Tokophrya cell, the garbage-disposal system seemed to be failing, too. Everything was failing. When Tetrahymena brushed against the elderly cell, they just pulled away and swam on. The cell got darker and weaker, and on Sunday it died.
Rudzinska was looking at a relatively simple life through the transparent walls of its body using one of the most powerful microscopes in the world, and she still could not figure out what was going wrong inside it. The cell died and she did not know why. There were so many possible explanations. At about that time a biologist tried to list them all and counted three hundred theories of aging: genetic theories, evolutionary theories, mathematical and physicomathematical models of aging. Which one was right? This is what Rudzinska was trying to understand, quietly and patiently. Where was the fatal damage? Was it in the clear jelly of the cytoplasm or inside the dark coiled ball of the nucleus? And why did it happen? Did it have to happen at all?
In retrospect, I was lucky to have met a gerontologist in 1984. I was just in time to catch a glimpse of the slightly depressive backwater that the field had been for generations. “Research on aging, like its subject matter, does not move very fast,” as the British immunologist Peter Medawar put it in 1981, when that science was still in the doldrums. “In almost any other important biological field than that of senescence,” wrote Alex Comfort, another British gerontologist, in 1979, “it is possible to present the main theories historically and to show a steady progression from a large number of speculative ideas to one or two highly probable, main hypotheses. In the case of senescence this cannot be profitably done.”
Comfort was a familiar name to me. Yes, Rudzinska said, Alex Comfort was not only a gerontologist; he was also the author of the worldwide bestseller The Joy of Sex.
“We were so angry with him for writing that,” she added.
Such a hard and unappetizing problem, aging. The aging of a living thing is not like the aging of a fine cheese or a fine wine. There the chemistry alters, the molecules change around, and the cheese and wine improve. Nor is aging like the deterioration of a car or a can-opener or any other manmade machine. When gadgets break down they can’t fix themselves, and neither can they make more of themselves—whereas a living body, even a microscopic bubble of life like Tokophrya, can accomplish both those miracles as long as it lives. Even when Tokophrya is ancient, too frail to reproduce, it is still repairing and remaking its own working parts, which is also a kind of reproduction, in a sense; the cell performs the hard work of passing its own body along from one moment to the next, creative work that never stops till death.
So what is aging? Why does the cell stop repairing itself? This is the question that Bacon was asking at the start of the scientific adventure. He knew nothing about single cells but he understood this question. Again, we are so very good at growing and staying in shape when we are young. The mortal body of that single coddled Tokophrya would have a chance to last and last if it could only keep up the repairs on Friday the way it did on Monday, when it was young.
Through the microscope, Rudzinska could see so many signs of trouble. Tokophrya wears a few coats, or membranes, one on top of the other. Its outermost membrane, called the pellicle, is made of two separate layers that are linked by fine mortise-and-tenon joints. Those joints were popping loose, and the layers were separating. The cell was literally coming apart at the seams.
Of the many studies of aging that she had on her mind in 1984, the most interesting was already fifty years old. In 1934, a biologist at Cornell University named Clive McCay had reported a remarkable breakthrough with laboratory rats. McCay found that if he fed the rats all the nutrients they needed but cut their daily allowance of calories in half, the rats would live about twice as long. Since that time, McCay’s discovery had survived test after test. Back when I visited Rudzinska, experimenters were still raising thousands of rats and mice on calorie-restriction diets. The rats and mice got thin and scrawny, but they did live a long time. Nobody knew why.
So Rudzinska investigated the clue of caloric restriction with her Tokophrya. Was there something about the reduction of calories that slowed down the metabolic rates of the cells of those mice? Did slowing down their metabolisms make them live longer? She found that when she kept the cells chilly and half-starved, they did live longer.
Rudzinska tried that experiment again and again. She put a single Tokophrya in a hanging drop of water on the glass lid of a chamber. Then she fed it, say, three Tetrahymena. The next day when she checked on it, it was still healthy and it had produced about that same number of babies. But if she gave a Tokophrya forty Tetrahymena, it would produce only one baby. If she gave it a hundred Tetrahymena, swamped it with fish food, the Tokophryajust ate and ate, gorged without stopping. It ballooned out into a giant—dark, opaque, with short, stunted tentacles. It stopped giving birth. It lost its tentacles. And after a few hours, the cell fell apart—cut short in its prime. On the other hand, if she kept a Tokophrya on a restricted diet, half-starved for Tetrahymena, fed them only one day every two weeks, her Tokophrya would live about twice as long.
So calorie restriction worked for species as far apart on the tree of life as mice and Tokophrya, which seemed to argue that it might also work for us.
Rereading her papers now, I can see that for all her pains she was a bit isolated, cut off from the news. Most of the names she cites in her papers were already half-forgotten then, biologists who had studied aging in the paramecium and in the amoeba when she was a young scientist in Poland. All around her, biologists at Rockefeller were helping to establish molecular reality; but she did not work with genes and molecules. What you can see inside a cell at 500 or even 100,000 times life size is still coarse compared to what you can see if you get down to the molecular level. The brave new world of molecules was passing her by. And of course she could not begin to explain why multicellular animals like us age, and why unicellular animals seem to escape from aging, or why some multicellular animals do not seem to age at all, like the hydra; while some unicellular animals do age, like Tokophrya, even though these two creatures have such a strong family resemblance in body plan and lifestyle that each is like a crude sketch of the other. This kind of confusion is discouraging to scientists, to people who like to figure things out.
Down in the basement of Theobald Smith Hall, Rudzinska and her two young assistants had set up a little demonstration for me. I looked through a microscope on the laboratory bench and saw a whole field of Tokophrya standing close together, swaying gently on their holdfasts like a field of alien corn. I turned the knob of the microscope slowly and surveyed the field. There were hundreds and hundreds of cells. It was something to see them, after hearing so much about them, and I looked up to thank the old biologist. Then I put my eye back to the lens. Just when I was about to take my eye away for the last time, I spotted a cell that was shaking back and forth on its holdfast. There was a baby trembling inside it. After a moment, the baby popped out and swam away.
I left the basement laboratory and swung out of Theobald Smith Hall into the pale winter day. Before I walked down the main path to the stone gate on York Avenue, I made a detour through the campus and found Rudzinska’s fountain. It had been drained for the winter. A few wet dark leaves from the ivy and the sycamores, the last of the wreckage of the year before, lay plastered to the concrete basin like tea leaves in the bottom of a cup. Somewhere in there, Tokophrya lay dormant and encysted, waiting out the winter.
At the time, I found it romantic that science could not answer these elemental and universal questions, questions that must have struck every thoughtful mortal again and again from more or less the beginning of their lives and from more or less the beginning of time. How did we come to be mortal? Do we have to be mortal? What can the science of life do about our mortality? What is aging? The image of that microscopic birth in the laboratory still floated before my eyes. I felt as if I had just been granted a glimpse into the fundamentals of birth and death—as if I’d seen as much as anybody could see, looked down to the bottom of the well. No one understood the problem of mortality.
It was clear that Maria Rudzinska loved her work. She loved the questions. She used to sign her letters Doctor Tokophrya. But it was also clear to me that she would not be the one to find the answers. And I found that beautiful. I loved the mystery—or else I’d persuaded myself to love it. Everyone knows that we have to grow old and die, just as surely as everyone hopes for long life. If you drink your cup to the bottom, you reach dregs. If you blunder, if you mess up, if you fumble as you reach for the cup, it spills and it shatters. That is our portion on this planet. The lines of an inscription in Osmington Church, Dorset, carved in 1609, take the shape of the cup:
Man is a Glas: Life is
a water that’s weakly
walled about: sinne bring
es death: death breakes
the Glass: so runnes
the water out
Finis! End of all mortal explanations—whether you think of the problem as spiritual or physical, sacred or secular. We are glass, and we break. We are water, and we spill. We are dust, and to dust we shall return.
That was the problem of mortality as I’d grown up with it. That was the problem of aging with which my generation came of age. Rockets might take us to Mars someday, or out beyond the asteroid belt, but wherever we baby boomers went we would go on bearing the same mortal weight. Rockets might take us to the stars, but only myths could take us to Mount Olympus. We were mortals—and yet the Eagle had landed on the Moon.
So we believed in limits, and we didn’t—just like the readers of Mandeville’s travels when he described a wonderful bird the size of an eagle in the Egyptian city of Heliopolis, the City of the Sun. The bird is called the Phoenix. “And he hath a crest of feathers upon his head more great than the peacock hath,” and his neck is iridescent like “a stone well shining.” And the Phoenix lives forever.