Long for This World

by Jonathan Weiner

  By the late 1990s, Cuervo and other specialists had identified five different pathways by which the cell keeps house. Sometimes a lysosome digests a big chunk of the cell around it. This is known as macroautophagy—literally, consuming yourself in big bites. Sometimes the lysosome chews a smaller bite—microautophagy. And sometimes the lysosome takes in a single molecule, which is the smallest nibble possible and requires remarkable precision, like picking up a single grain of rice with chopsticks. The lysosome uses a sort of claw hand to seize and grasp individual molecules for engulfment and dismantlement. The claw hand grabs the molecule of junk and holds it while other lysosomal machinery unfolds and unspools it into a long loose ribbon. Then the ribbon is drawn into the lysosome like a sheet through a porthole, yanked or pushed and wadded through by still other molecular machines of a class known as “chaperones.” There are chaperones on both sides of the porthole. Some chaperones wad the sheet through the hole from the outside, and some of them yank it in from the inside.

  From the beginning, Cuervo was most interested in the ways that lysosomes might be involved in aging. By the year 2000, Cuervo and others had shown that most of the pathways by which the living cell carts bits of itself to the lysosomes for demolition and recycling do decline with age. The cells of young laboratory rats work twice as hard as old rats’ at carting bits of their cells to their lysosomes. The lysosomes in old cells grow swollen and frail. They fill with aging pigments, along with other indigestible junk, including the stuff that free radicals make as they carom into molecules inside the cell, leaving them tangled and cross-linked in ways the lysosomes can’t cleave and dismantle. One of the simplest kinds of detritus that accumulates in our bodies is the kind that makes our skin wrinkle. In the United States alone the market for what are now called “cosmeceuticals” is more than $8 billion a year for ointments that try to do what the first ointment claimed to do on the banks of the Nile in 1500 B.C. And the cause of our wrinkles is such a very simple thing. What makes our skin supple and smooth is a protein called collagen, as anyone knows who has read the ads and the labels of the antiwrinkle ointments. Each collagen protein is a molecule shaped something like a long rope. The ropes are very strong and they are arranged in the skin in great woven nets, something like the nets of rope baskets. Unlike rope baskets, however, they are alive. As part of our living bodies, part of the bright burning life of the Phoenix, they are continually made and destroyed. Unfortunately, as time goes on, they are made less well, less accurately. They tangle with each other at the edges. They collect what are known as cross-links, which are tiny ties that join one rope to its neighboring rope and stiffen the whole net. This is what makes our skin stiffen and wrinkle—and inside our bodies, too, daily, nightly, in each of our internal organs, in our arteries and veins, in the kidneys, the liver, the eyes, the brain, the same unfortunate cross-linking goes on, with results that can be much more serious than wrinkles. These cross-links are known in the jargon as advanced glycation endproducts (AGEs).

  When we’re young we have a spring in our step, as we say. Actually, we have a million springs that put that bounce in our steps. Picture what would happen to a spring or a Slinky over time if you stapled more and more of its coils together, at random. Eventually the body is not very springy, or slinky, anymore.

  It may also be that the cell, as it gets older, grows less nimble and deft at the crucial folding operations that produce the elegant origami of its molecules in the first place, so that there is more and more crumpled, badly folded trash for the lysosome to handle and dispose of. Chaperones inside the cell are actually able to decide if a given bit of origami is close enough to right in its folds to be worth fiddling with, or if the whole thing is such a botch that it would be better off chucked. And if the cell can’t make enough well-folded origami, and if the lysosome can’t split the stuff up and spit it back out to be recycled, then the cell has less raw material with which to try again with fresh origami. So the cell begins to weaken at both self-creation and self-destruction. The one can’t suffer without hurting the other. You can’t be creative without tools, fuel, and quality control. To make good things, you have to throw bad things out. As Isaac Bashevis Singer once said, a writer’s best friend is the waste-basket.

  Aubrey thought about housekeeping genes, and he thought about all the commonplace trash that escapes the broom and gathers in the corners, like molecules of lipofuscin, which litter billions of aging cells like little balls of dust. Although lipofuscin is a confusing substance to biologists, it is clearly related to metabolism, since it accumulates inside our lysosomes as we get older. “That says it’s not doing any good,” Aubrey says. “Even lysosomes can’t break it down. In spite of having about sixty different enzymes to break things down.” Lipofuscin is like the dust in the corner that the blunt broom can’t get at. It is like a spoon or fork in the garbage disposal, or the wad of glop in the S curve of a drain.

  Eventually Aubrey hit on a way to deal with this particular garbage problem. The idea came to him in an epiphany. It was the end of a long day’s journey with a duffel bag. He was attending the 1999 Annual Meeting of the Society for Free Radical Research, in Dresden. Aubrey had already been brooding about the kinds of specialized shears and scissors that might help to cut the cross-links in AGEs, the kind of junk that gives us wrinkles. Suddenly in Dresden it struck him, he says, that all of this junk is cross-linked. All of it is the by-product of metabolism. All of it is crazed and crumpled molecular origami. The body’s problem throughout—in the skin, the heart, the nerves—is that it has never evolved the proper tools for uncrumpling the most tightly wadded sheets, snipping the most tangled tangles, the toughest chains in the cross-links. And the reason the body has not evolved the tools is that it has not needed to do so. All this junk accumulates gradually, on the whole. It is not a problem for the body until midlife or beyond.

  And it dawned on Aubrey that he knew the man to fix the problem. He knew a good man in the genetics department in Cambridge, John Archer. Archer searches for soil microbes that can devour toxins that we are unable to seek out and destroy ourselves. He is a specialist in the field known as bioremediation, or environmental biotechnology. It is becoming possible in some cases to decontaminate soil that has been poisoned by dioxins: bioremediation experts have genetically engineered microbes that eat dioxin. Likewise, they have ways to clean water of PCPs, using still other poison-loving microbes. All of these pollutants, bizarrely, can be broken down by microbes.

  Rubber! Go to the side of the highway. Very tiny bits of rubber are continually flayed from spinning tires of cars and accumulating on the side of the highway. Specialized microbes have evolved there in the speeding shadows of our cars and trucks and they feast on the rubber dust. You can find bacteria there that will eat it. If you are looking for enzymes to dispose of rubber, that’s a good place, among the microbes of the roadsides. The microbes have already found the answer—so you can collect them from the grunge at the side of the road, and raise them in petri dishes, and study all of the tricks for the disposal of rubber that evolution has discovered.

  If roadsides are the places to look for the secrets of the disposal of rubber, then where are the places to look when you are concerned with the disposable soma—when your problem is the decades of accumulated trash in each and every human, mortal, disposable body? Where have we mortals disposed of this tragic debris for generation upon generation upon generation?

  Graveyards.

  Aubrey’s hometown is rich in old graveyards, including Coldham’s Common, where the people of Cambridge buried many generations of their dead, including corpses from their leper colony in the twelfth century, along with victims of the Black Death; and in the seventeenth century, the Great Plague. Midsummer Common is another hoary Cambridge graveyard. Aubrey thought of the planet’s most notorious mass graves, from Rwanda to Cambodia to Dresden itself.

  In the meeting that day in Dresden, one of the presenters was Ulf T. Brunk, chair of pathology at
Sweden’s University of Linköping. At the meeting in Dresden, Brunk showed slide after slide of elderly cells clogged with lipofuscin. The stuff glowed a dull red on his slides. Lipofuscin is Brunk’s specialty.

  Aubrey was sipping coffee after Brunk’s talk when the thought came to him, and he hurried across the conference room.

  “Listen, Ulf, I’ve just had the most fabulous idea…”

  Ulf’s reaction disappointed Aubrey. Ulf seemed rather cool about the idea of prospecting for a cure for aging in graveyards. Aubrey put it down to Nordic caution.

  After he got home to Cambridge, Aubrey shared the idea with Archer, who saw Aubrey’s point immediately. Archer summed it up in a single line: “Why don’t graveyards glow in the dark?” So many centuries of lipofuscin-laden remains have been buried there. They are the repositories of all of the tangled, mangled, ruined molecules that we the living (while we were still aboveground) had never quite managed to dispose of ourselves. And yet the soil of our graveyards does not fluoresce. After eighty, our retinas are fluorescent too, because of their loads of lipofuscin. Graveyards should be full of the stuff, and yet they do not glow. Obviously, microbes in the soil must have found ways and means to work through the coffin-lids and the winding sheets and cerements and devour the very last of the debris. After all, our bones are picked clean by the scavengers in the soils of graveyards. They whittle us down to skeletons as we rot. So Aubrey proposed that we dig in the old graveyards and look for the secret in the bacteria that have evolved there. Steal the tools from the Lord of the Underworld, from the Devil’s workshop.

  Aubrey was not the first gerontologist to follow his thoughts a little farther into the grave than most of us like to go. Medawar had gone there before him. In his essay “Old Age and Natural Death,” Medawar talks about the difficulty of defining the moment of death. He points out that because we are made up of trillions of tiny living cells, some of them are bound to survive us for a long time after the doctors pronounce us dead, “and those whose most pressing fear it is that they will be lowered living into their graves can have their doubts resolved: they will be.”

  This was the way Aubrey did science. He worked away in the Department of Genetics, like a newfangled scribe, on a great compendium called FlyBase, entering lines of computer code that define the genes and mutations of the fruit fly. Now and then he went dashing up and down the old spiral stairs, elvishly, to visit Archer, or to drop in on his wife, Adelaide, at her tiny lab under a stairway leading to the roof, and try out a new idea.

  “Well, I mean, it’s deucedly simple, really,” John Archer said, when Aubrey and I dropped in on him at his lab in the summer of 2004. Computers hummed on the desktop. Archer was running genomes. That took a lot of computer power. So the little room was warm, in spite of the labors of an expensive air conditioner of the same make and model as the ones that cool the sealed capsules of the London Eye, also known as the Millennium Wheel. Archer wore an Izod shirt, khakis, an ID around his neck. Everything about him said solid, a man with his feet planted on terra firma. Whereas Aubrey had, as always, that millennial hippie look. He wore a red “Drosophila” T-shirt over a flowered Hawaiian shirt, with a red elastic for his ponytail.

  Archer is an expert on the metabolism of explosives. He explained to me that soil around military camps may be contaminated with nuggets of TNT as big as an inch in diameter. When rainwater pools on ground that is loaded with TNT, it turns a telltale pink. To cure the soil of these explosives and poisons, some specialists work on sowing these fields with plants, including the wild tomato and the downy thorn apple, known in the Wild West as jimsonweed. Jimsonweed will take the pink out of a jar of pink water overnight. Some army bases now try to keep their poisons from seeping downward into the groundwater by planting trees that suck them upward.

  Archer prefers to work with a kind of bacteria called Rhodococcus, which is a master at the digestion of TNT. Archer feeds it pink water and watches what happens. (“Get a little drop of that on you and you’re going to have an interesting time at Heathrow,” Archer said.) Strains of Rhodococcus are robust and diverse and can eat up a wonderfully wide variety of explosives, poisons, and potions, including quinolone, some particularly stubborn thiocarbamate herbicides, and a chemical called 2-mercaptobenzothiazole, which is used in the manufacture of vulcanized rubber. Strains of Rhodococcus are the only bacteria known to eat benzothiophene and dibenzothiophene. They thrive in ethanol. Archer is proud of Rhodococcus, of its hardihood and its appetites. He keeps collections of polluted waters (“It’s wicked, wicked stuff!”) and he keeps potent antidote strains of Rhodococcus. He likes to talk like a plumber—he says that’s what he would probably have been a few centuries ago, an engineer tending the drains of some lord’s manor house. “When these first started growing, they et the petri dish,” Archer said, in mock-peasant style, pointing at one of his favorite strains. “Et it right up. They melted the petri dish and drank the solvent.” He boasted about the Rhodococcal metabolism. Our bodies can’t do a tenth of what his Rhodococcus can do when it comes to digesting explosives. “Humans are pathetic,” Archer said. We may be more complicated than bacteria, he said, “but metabolically we’re crap.”

  Bacteria are so gifted metabolically because they are far more diverse than we are, Archer explained. Four-point-eight billion years ago this planet was nothing but rock. Four and a half billion years ago, the planet came to life. Most life-forms are still devoted to being unicellular. Bacteria are phenomenally diverse. They made the world, and they will inherit it—they’ll still be here when we’re gone. “I mean, my God, you know we’re really Johnny-come-lately,” Archer said. “We just got here.” Bacteria have been fine-tuning their DNA for four and a half billion years.

  “Soil is more active than you’d ever realize,” said Archer in a hushed voice. “Tremendous energy.”

  Archer was very impressed by Aubrey’s energy, too, but he hadn’t done much with his graveyard idea. He had gone as far as to send a student to Midsummer Common with a trowel. There the bodies of plague victims of Cambridge have lain moldering for centuries. And he had done a preliminary experiment. Beyond that the soil samples from the graveyard were still sitting around in his refrigerator. Aubrey’s idea was only one of many projects that Archer could take up, and he did not seem in a hurry to do much with this one, when he had so many other experiments of his own to try.

  This is one of the hazards of being a theoretical biologist like Aubrey. You have to interest people with laboratories to take up your ideas, and they tend to have ideas and projects of their own. Hands-on biologists often remind Aubrey how hard it is to make things work in the laboratory. They’re inching up the mountain while Aubrey dreams of landing up there in one stride with his seven-league boots.

  They tell Aubrey, “It’s a grim life doing experiments.”

  “C’est la vie,” says Aubrey.

  From Adelaide, Aubrey might have learned some humility about the difficulty of doing experiments. Years had passed since her brilliant start as a geneticist, her discovery of a particle within life’s machinery; which had looked to her at first in her slides like a speck of dirt. That particle of molecular machinery helps to shuffle the genes in flies, mice, oaks, and people. She named it the recombination nodule. She was still famous in some quarters. But now, after that early success, she spent months or sometimes as much as a year as a technician in the genetics building, trying to unravel what had gone wrong with someone else’s experiments—because experiments don’t always work out. She labored under the eaves on the top floor of the Department of Genetics. She had a little nook beneath the stairs, with books stacked under the stairs, along with piles on piles of boxes, equipment, papers, books, tissues, yellow pads, pens, pencils, light-bulbs, a crumpled scarf, and an old brass magnifying glass with a wooden handle. Her desk was a few steps away from her fruit fly emporium, with a microscope, and an etherizer, everything she needs for breeding and sorting flies, and fixing the experiments of students w
hose work refused to go—projects that were failing to progress in anyone else’s hands.

  Computer programs can also provide lessons in humility. Aubrey’s friend Aaron Turner was still struggling toward their dream of the Cure-All, the computer program that would cure all other computer programs. When their branch of Sinclair Research was sold, Aubrey and Aaron had created a two-man company they called Man-Made-Minions and begun racing to develop the Cure-All. In the beginning of their collaboration, they often met at the Eagle or the Live & Let Live for pool, with beer (for Aubrey) and Coke (for Aaron), and talked of all things AI. Now Aubrey was saving the world from death (whether or not the world wanted saving). Poor Aaron was living out of his car, and quoting sardonic sayings of the computer trade, such as Hofstadter’s Law: “It always takes longer than you expect, even when you take into account Hofstadter’s Law.” Aaron slogged away at the prototype of the Cure-All, with moral support and occasional cash from Aubrey, who still served as codirector of Man-Made-Minions. Aaron has since written a memoir of the Cure-All adventure. The final section of his memoir is titled, “Tomorrow and Tomorrow and Tomorrow Creeps in This Petty Pace from Day to Day.”