Part 4 (1/2)
”Yes, as a matter of fact.”
That's a completely different material deterioration, Sparrow said. The lenses of our eyes turn yellow with age. The yellowing is caused by the chemical changes in the lens, and diminishes our ability to see the color blue, because yellow filters out blue light. So as we get older, we see blue less brightly. Often, people who undergo cataract surgery to have a cloudy, yellowed lens removed and replaced by a clear new artificial lens can suddenly see all the blue light they experienced sixty or seventy years before. ”Patients say, 'Oh, blues are so bright. The sky is so blue! I haven't seen that blue since I was a child!'”
The yellowing of the lens has nothing to do with lipofuscin. Neither does still another kind of junk, called drusen, which eye doctors can see glittering in the back of an aging eyeball through an ophthalmoscope. Drusen looks through the scope like tiny, s.h.i.+ny crystalline dots, whitish and yellowish. The term comes from the German word for a geode: drusen resembles the cup of semiprecious crystals you find when you split open a geode. Eye specialists have known about drusen for more than a century without being able to figure out where the crystals come from or whether they're early-warning signs of macular degeneration. Drusen crystals also start showing up around the age of fifty.
That's the way it is throughout the body. You get rare, semiprecious, specialized kinds of junk like drusen crystals in the eyeball, or crystals of calcium oxalate in the kidneys, which are called kidney stones. Other kinds of junk are found throughout aging bodies and can turn up almost anywhere, like lost sheets of newspaper, cigarette b.u.t.ts in gutters, plastic bags in trees, crumpled tissues in wastebaskets. Lipofuscin piles up in cells in many parts of the aging body, but seems to acc.u.mulate most in cells that do not divide. Skin cells and the cells that line our guts are always dividing and being sloughed off. Not much trash builds up in them before they die and are replaced. But heart cells and nerve cells have to last us our whole lives. About 10 percent of the ma.s.s of the heart of a centenarian is lipofuscin.
After making his study of aging mitochondria, Aubrey de Grey was fascinated by this problem of the acc.u.mulation of junk, rust, and sc.r.a.p in the body. If that's all aging really is, the slow acc.u.mulation of damage, then it's reasonable to argue that there are three ways to fix it. You can try to repair our metabolism so that it does not generate so much trash; you can try to clean up the trash itself; or you can try to deal with the harm the trash does to the body. That's when the problem pa.s.ses into the domain of surgeons and geriatricians and home health aides. They help elderly patients with their weakening muscles, weakening eyes, cloudy lenses, stiffening joints, wrinkling skin, thinning hair, rusting memories, and on and on, the whole lugubrious list of symptoms that we all know from the inside out, and have always a.s.sumed that every generation that follows ours will have to endure as we do.
Aubrey decided that the easiest place to attack the problem is in the middle, in the cleaning up of the trash. The beginnings are too complicated. Metabolism consists of too many interconnected networks for anyone to safely intervene. It's almost beyond imagination how complicated and delicate the action is in the retina when light strikes. And when you eat a piece of food, and some of those nutrients reach a cell in your skin, all of the networks of genes in your cell that have to work together to turn that bit of nutrient into a bit of you are unimaginably complicated, too. In the immortal verse of Walter de la Mare, It's a very odd thing-As odd as odd can be-That whatever Miss T. eatsTurns into Miss T.
Metabolism is a terribly complicated thing as well as odd, and to try to intervene in all of those invisible molecular pathways would make trouble for Miss T.
The pathologies of old age are also complicated, and-as anyone knows who is in the middle of them, or has watched a loved one endure them-they are interconnected. If macular degeneration is allowed to progress untreated it causes incurable blindness. In the Western world, it is now the most common cause of incurable blindness. Before you reach fifty, it's rare, but by the time you pa.s.s eighty, the incidence is one in ten. Once Miss T.'s retinas are damaged, she is more likely to fall; once her bones have grown frail because of osteoporosis, she is more likely to break her pelvis when she falls. She is often dizzy anyway, and she has lost some of the redundant systems of nerves that used to help her keep her balance. Meanwhile, because of the osteoporosis, the vertebrae in her lower back are painfully compressed. When she breaks her pelvis, her surgeon finds it hard to operate on the vertebrae; and on and on. Meanwhile more damage keeps piling up.
But the dirt itself, the little piles of dust and lipofuscin and miscellaneous debris that acc.u.mulate in the corners and crannies of the cells, and cause the damage-that is comparatively simple to deal with, in Aubrey's view. Cleaning it up may be hard, of course. But it should be easier to clean up the dirt than to overhaul the entire industrial landscape of the body, which produces the pollution; or to repair the body as it falls apart at last and Miss T. breaks down and dies.
Aubrey began seeking out researchers who study the pollution and ways to clean it up. On trips to Boston, Aubrey visited Ana Maria Cuervo, who was then in training at Tufts University and now runs a gerontology laboratory at the Albert Einstein College of Medicine, in the Bronx.
Cuervo studies the action of lysosomes throughout the body. The lysosome is the organ of self-sacrifice, within the cell. With its lysosomes the body does unto itself what it does unto others. Chomp, chomp, chomp. Producing nutrients to digest and recycle, along with a kind of microscopic excrement, indigestible trash.
Cuervo has done as much as anyone to show that the body gets weaker and weaker at taking out garbage as we get older. She has been working on garbage and lysosomes ever since she started out working toward a Ph.D. in the early 1990s. The lysosomes have fascinated her all her working life. (”Such a little fellow, and so much to offer.”) Cuervo wants to understand the ways the body carries out its continuous acts of self-immolation, in which not only old mitochondria are carted off to be sc.r.a.pped but virtually every bit of the cell is perpetually dismantled and recycled for spare parts and rea.s.sembled.
Ana Maria Cuervo and Aubrey de Grey are friends-an odd pair of friends. He lives on beer and she lives on Diet c.o.ke. She keeps a shelf of Diet c.o.ke cans from all over the world above her desk and she's always pouring another plastic cup of Diet c.o.ke for herself and her guests. She is one of the few people I've ever met who talks faster than Aubrey. She agrees with him that the key to the problem of aging may well lie in a kind of sophisticated detoxification of our cells. She's an experimentalist who hopes we can make cells live a long, long time by giving them extra genes for taking out the garbage. She writes papers with t.i.tles like ”Keeping That Old Broom Working” and ”The Ultimate Cleansing Diet.” In their campaign to figure out how to detoxify the body, to take out the garbage, she and Aubrey are comrades in arms. But when he talks about immortality, she just laughs. Immortality has absolutely no appeal for her. English is not her first language (she comes from Barcelona) and for some reason she always calls him Audrey.
”Audrey,” she says, ”if I have to be here five thousand years, take me now!”
In her laboratory, Cuervo is trying to understand the molecular action in the cell's chop shop. The lysosome is constantly devouring the rest of the cell and cutting it up into recyclable pieces and exporting those pieces to be rea.s.sembled in its daily acts of renewal.
Until recently, few people were interested in aging lysosomes. Aubrey was ahead of the curve in focusing on them and befriending Cuervo. She and her handful of fellow researchers worked in obscurity. Science has fas.h.i.+ons, and elderly lysosomes were unfas.h.i.+onable. The genes that control the pathways by which the cell sweeps and carts bits of itself into the lysosome are known as ”housekeeping” genes, and almost n.o.body was excited about housekeeping genes. Two biologists at the NIH, s.h.i.+wei Song and Toren Finkel, began a paper on housekeeping genes with a complaint about their low status. ”In most schools, students tend to stratify into groups like the cool kids and the nerds,” Song and Finkel wrote. In the genome, too, some genes seem to get all the attention, and ”life is a lot less glamorous for everybody else.” At the bottom of the ”uncool” list were housekeeping genes.
If lysosomes were called the nest of the Phoenix, instead of the trash can, they might have more glamour. Of course, the whole field of gerontology suffers from the same image problem. It is seen as the science of aging, and most scientists in their prime find the thought of aging as unattractive as the thought of housekeeping.
But housekeeping is an inadequate description of the magical act of self-renewal on which life depends day by day; and aging is an inadequate description of the mysterious way in which this act of renewal slips and declines, very gradually, day by day. And this is not a corner of our existence; this is what we are. When we talk about eating, and taking out the trash, we are talking about fantastically complicated acts of creation and destruction. We are talking about the ways our bodies, some of the most complicated things in the known universe, destroy and rebuild themselves daily and hourly.
Humble housekeeping genes help cells divide and develop. They help cells fight off invading bacteria and viruses; they help the immune system. When something goes wrong with all this housekeeping we can develop cancer; or neurodegenerative diseases like Alzheimer's and Parkinson's. One of the secrets of success, we say, is just showing up; and one of the secrets of staying alive is just housekeeping.
Cuervo set out to learn if the decline in housekeeping is a major cause, or even the major cause, of aging. Clearly the decline makes the cell less efficient, which means that the cell produces more trash and cleans up less. If this failure of housekeeping leads to our mortality, then in effect we die from a pileup of junk.
The level of fine detail with which Cuervo and others can watch all this mortal housekeeping is amazing. Maria Rudzinska could only stare at a cell with a microscope as it grew old and filled with strange dark particles and died. She could no more see molecules than a tourist at the top of a skysc.r.a.per can see pebbles. Now Cuervo has the benefit of the half a century of tools that have been invented since Watson and Crick opened up the exploration of molecular reality. The tools with which Cuervo's generation watches the action include not only light microscopes and electron microscopes but also special stains that make the working parts of molecular machines light up and glow in living cells as if they were followed by Broadway spotlights; along with all kinds of tricks that she and others have developed, including centrifugation of cell corpses through dense cus.h.i.+ons, and the use of fluorescent dyes that stain certain streams of the autophagic traffic red and blue. Tricks of genetic dissection and X-ray crystallography allow them to open up molecular machines and count the teeth on each gear.
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 cla.s.s 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 acc.u.mulates 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 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 b.a.l.l.s of dust. Although lipofuscin is a confusing substance to biologists, it is clearly related to metabolism, since it acc.u.mulates 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 acc.u.mulates 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 acc.u.mulating 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 acc.u.mulated 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 h.o.a.ry Cambridge graveyard. Aubrey thought of the planet's most notorious ma.s.s 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 Linkoping. 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 p.r.o.nounce 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 das.h.i.+ng 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 s.h.i.+rt, 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-s.h.i.+rt over a flowered Hawaiian s.h.i.+rt, 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 appet.i.tes. 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 c.r.a.p.”
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 G.o.d, 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.