Long for This World

by Jonathan Weiner

  In his program Strategies for the Engineering of Negligible Senescence (SENS), he’d called for mending seven weak links in the chain of life. And in his first flush of enthusiasm for SENS, he’d come up with proposals for mending six of these seven. But even Aubrey had despaired of fixing the seventh link, the weakest link, which is the problem known as cancer. Cancer is caused by mutations in the DNA in the cell’s nucleus, and Aubrey didn’t see what could be done about that. Our bodies already have huge troops of DNA proofreaders and DNA repairers. The proofreaders evolved long ago to keep cells in multicellular bodies from running amok. They do an extremely good job. But since there are many trillions of cells in a human body, and every one of them is subject to daily mutations, errors do eventually slip through. All you need is one nasty typo in one errant cell among the trillions, and you start building a tumor, and the great chain of your mortal life is broken. A few prophets of regenerative medicine do talk about engineering even better proofreaders than evolution has produced thus far. Aubrey did not believe that this was the answer. He could not see how we could ever do much better at proofreading than nature already does. If we are going to live indefinitely, our proofreaders would have to be absolutely perfect. They would have to catch every single mutation indefinitely, and that seemed like too tall an order.

  And then, once a tumor grows it is very hard to kill. Many tumors evolve swiftly because they have escaped the body’s proofreaders. They mutate wildly. As Aubrey has written, “Each cell in a tumor is a furnace of inventive potential.” Because they evolve so swiftly, these cancers are apt to find ways to resist any attack we mount against them. Some tumors invent ways to eat and digest anticancer medicine. Others invent ways to coat themselves so that the medicine won’t get inside them. Then, one day—“one dark spring,” as Aubrey writes—the cancer blossoms again. The power of evolution is the secret of the secret of life, the spring of life’s creativity. It has brought forth the fruitful tree of life; and in each generation it cuts us down in the most horrible of deaths.

  Aubrey was satisfied with the first six proposals in his SENS program. He had demonstrated to his own satisfaction that with work we could fix six of the seven weak links in our mortal chain. For junk inside cells, we could stimulate the cell’s garbage-disposal system to do a better cleanup job. In principle, that would cure Parkinson’s disease, Alzheimer’s disease, and so on. So that was one link mended. For junk outside cells, we could stimulate the body’s immune system. That would cure heart disease and prevent strokes. That’s two links. For trouble in the mitochondria, we could inject a healthy set of mitochondrial genes into the cell’s nucleus and thus keep aging cells from losing energy and winding down. That’s three. For our cross-linked, snarled, tangled proteins, we could find medicines that snip the links. Human bodies would no longer wrinkle or crumple, inside or out. That’s four. Some of our cells slow down and become dormant as we grow older, but we can train our immune system to clear those away. That’s five. Some cells die, and their corpses pollute their neighborhoods with toxins; the immune system can clean that up, too. That’s six.

  Those Strategies for Engineering Negligible Senescence were fine and good; but Aubrey could not conquer aging without a cure for cancer. Without that, SENS would do very little to extend human life. Eliminate every other disease of old age and millions of people would live just a few years longer, only to die of cancers of the colon, brain, breast, lung, or skin. Aubrey’s first broadside about SENS had left out cancer, but he knew he could not avoid it forever. “If you read that paper closely,” Aubrey says, “you’ll see I knew damn well the whole business of curing cancer was a massive hole in the scheme.” He knew that he had to cure all seven of the deadly ills of aging. The better we do with any six, the worse we will suffer from the seventh. In fact, this trouble is already upon us, in the form of cancer, thanks to the successes of modern medicine. The longer we live, the more likely we are to get it; the younger we die, the more likely we are to escape it. “It’s very easy to cure cancer,” as Aubrey puts the problem, sarcastically. “All you do is fire all the heart surgeons and so on. It’s very cheap as well.”

  To stay young for centuries, we have to learn to cure every kind of cancer. And we have to eliminate for all eternity, or at least for a thousand years, the chance of developing cancer. Yet the longer we live, the more likely we will be to develop it. As one oncologist has put it, “Advancing age is the most potent of all carcinogens.”

  “So it all seems a bit sad, really. It all seems a bit of a lost cause,” said Aubrey. “How could we ever cure cancer?”

  This problem had begun to worry him as soon as the glow faded from his eureka moment in California, the night he’d resolved to fight his “seven deadly things.” As Aubrey confesses in his book Ending Aging, he feared “that mutations would act as ship-smashing cliffs to any ark that we might build to survive the deluge of metabolism and emerge into an ageless future.”

  He was so close. His glass was almost full. In principle, he had already cured six of the seven deadly troubles of age.

  On your left, the dream of the Phoenix, the bird of immortality. On your right, the nightmare of the Hydra, the metastasizing demon. These are the dreams that have surrounded us from the beginning—life, immortal life; and death, inevitable, inescapable death—and they haunted Aubrey in the starkest possible form.

  Aubrey worried about cancer until early in the spring of 2002, when he went to a scientific meeting in Ravenna. He was abstracted during the meeting; in his mind, he kept returning to the problem of cancer. Afterward his hosts organized a tour of the ancient city, and along with the other biologists, Aubrey, still distracted and far away, trooped through the churches, beneath the legendary golden mosaics. He did not know it—he does not care much about history—but Ravenna has inspired leaps into immortality for thousands of years. Julius Caesar collected his army there before crossing the Rubicon. Dante finished the Divine Comedy there in the last years of his life; the mosaics inspired some of his visions of eternity, like candles lighting candles. Yeats made a pilgrimage to Ravenna. Years afterward, when the poet felt repulsively old, “a tattered coat upon a stick,” he remembered the place; he implored all the saints and sages of the past to help him write immortal verse; he saw them standing before him “in God’s holy fire / As in the gold mosaic of a wall,” and he begged them to gather him “into the artifice of eternity.”

  After the tour, Aubrey set out for home. He took a bus alone to nearby Forlì and got out in the center of town. Forlì is one of those small Italian towns where you can walk from the bus station to the airstrip. It was a warm day, for March, and when Aubrey had almost reached the airport he stopped at a café to drink and think.

  He was sitting alone at his table, when suddenly it dawned on him what to do about cancer. As he lifted his glass of beer, he hit upon what he called a proper cure. He saw a way to fix the weakest link in our mortal chain.

  Aubrey thought of the tips of the cell’s chromosomes, the telomeres. Everyone in the field of gerontology knows that the telomeres wear away a bit each time a cell divides. According to present thinking, that is why our cells cannot divide indefinitely. We do have an enzyme for repairing the telomeres, called telomerase, but cells run out of it as they age. Then their chromosomes fray, and they come to the end of their tether.

  For years, gerontologists have wondered how we could supply our aging cells with more telomerase, and live longer. At the same time, many cancer researchers have wondered about the opposite problem. They would like to find ways to eliminate telomerase from tumors, so that cancer cells would cease to multiply. Cancer cells carry mutations that allow them to make plentiful supplies of telomerase, and that is one of the reasons they have become immortal.

  In his first thoughts about SENS, Aubrey too had hoped to eliminate telomerase from cancer cells. But there is a problem with that approach, as there is with every attack on tumors. As long as our bodies carry the gene for telomerase,
a cancer cell can always find a way to make more of it. Somewhere in the course of the innumerable random mutations that take place in our trillions of cells, there will always be one rebel that chances upon the trick, makes itself immortal, and multiplies out of control.

  Aubrey’s insight was this. If we were to eliminate just one gene from the body—the gene for telomerase—then every cell in the body would be unable to repair its telomeres. No renegade cell could rediscover and re-create telomerase. “Creation of a new gene out of nothing does of course occur on evolutionary timescales,” as Aubrey has written; “but that takes many, many generations.” Even if our bodies lasted thousands of years, we would not have enough cells or enough time to achieve it. The secret of regeneration would be lost. No cell could ever build a tumor, because it could not divide often enough to get out of control. Eliminate that single gene from a human being, and not even our stem cells would have telomerase. Stem cells normally have plenty of it; they need it to replenish our bodies with young cells as our old cells wear out. Without telomerase, even stem cells would reach their limit early. That way they could not run wild with cancer. In a sense, every cell in the human body would be sterilized.

  We could maintain tissues like blood, gut, and skin by periodically reintroducing new stem cells. None of them would have telomerase, either. We would reseed the body with them, and repeat the operation again ten years later. “Then we’d have to do it again, indefinitely,” Aubrey says. “But the point is, we’d never introduce a cell that had the capacity to mutate into a cancer.”

  That was his eureka in Forlì: take the telomerase gene out of the body!

  In many ways this is a desolating vision, a disastrous idea, because without telomerase the body could no longer regenerate itself in the places that need regeneration most. Our skin and the lining of our gut, our outer and inner linings, are always repairing and replacing themselves because they get the most wear. At regular intervals we would introduce stem cells into the body to rebuild those outer and inner linings. We would insert stem cells that we had genetically engineered, cells with abnormally long telomeres. And before those stem cells began to wind down, we would just top up our tissues with more of them. That might not be an easy procedure. No one knows how to do it now. But eventually it would be just one more medical routine for the young, healthy immortals of our boundless future. When cells escape into cancer, they become immortal. We would prevent the birth of those cells and become immortal ourselves.

  Aubrey calls this plan, his cure for the “seventh deadly thing,” Whole-Body Interdiction of Lengthening of Telomeres (WILT). It is an ugly idea, as Aubrey himself is the first to admit. Not everyone will find it attractive. He writes, “The idea of eliminating from the body a function known to be essential for survival is a conceptual leap that takes substantial justification even to contemplate, let alone implement.” He believes most of us will not see its appeal until medicine has managed to cure the other diseases of old age—until we have figured out how to prevent heart attacks, strokes, Alzheimer’s disease, Parkinson’s disease, and diabetes. At that point, however, so many people will be living long enough to get cancer that we will be willing to undergo something even this traumatic.

  In the WILT procedure, patients would undergo periodic bouts of chemotherapy to kill all the cells in the bone marrow. Then they would receive injections of bone marrow in which the cells had no telomerase. Aubrey estimates that they might need new bone marrow transplants every ten years or so. They would need replacements of their skin stem cells every ten years or so, too. The same is true of the innermost layer of the lung; but “there is no reason to think that we won’t make quick and relatively painless progress on this front once we put our mind to it,” Aubrey writes in Ending Aging. Getting fresh stem cells into the gut might be more difficult but could be accomplished by the same general tools and techniques that people endure when they get a colonoscopy.

  By adding fresh stem cells wherever and whenever they were needed, we would keep reseeding the body.

  Of course, we would have to denude the body of native stem cells first. That would require high doses of chemotherapy. The treatment would get rid of the cancer and clear the body of all its fertility, which we would then continue under new management. It would be a far more brutal treatment than a radical mastectomy. But, then, think of the painful and expensive procedures that many people are willing to go through just to look young, Aubrey argues; many people pay for chemical or laser “peels” of skin even if the benefit is merely cosmetic. His denuding of native stem cells would allow people to continue to be young, not just look young. Since we have no way of curing cancer now, and can’t imagine a way that would be foolproof, or evolution-proof, and since the better we do at living longer, the more cancer will attack us, Aubrey thinks we should start working on WILT.

  Might cancer cells find some surprising way to escape even this attack? Cells seem to be able to lengthen their telomeres with enzymes other than telomerase. But if that happens, Aubrey says, we will figure out what those enzymes are, and delete them, too.

  The transformation of the human body to a totally WILTed state would have to be performed gradually. We would have to endure the rigors and horrors of all that chemo. Men might become permanently sterile and might want to set aside sperm first, to be frozen and stored in fertility clinics. But our risk of cancer would no longer rise with age; it would actually decline.

  Not long after he got home from Italy, Aubrey convened a panel of experts to consider WILT. One of the participants in his WILT summit, Nicola Royle, a senior lecturer in the Department of Genetics at the University of Leicester, refused to have her name attached to the paper that resulted. But Aubrey puts a positive spin on that. It wasn’t that Royle didn’t think his idea would work. She was bothered only by the goal itself, the creation of nearly immortal human beings.

  Aubrey had now gone from his starting point to the very limit. He’d begun by imagining that we might keep aging bodies alive by clearing away debris. With WILT, he was envisioning an overhaul of the body. To do what he was describing would be to remove from the body its own powers of rejuvenation and to assume this power and responsibility, entirely and permanently, for ourselves.

  “Now, it’s critical to remember, we’re talking about a proper cure,” Aubrey said. “Not just to postpone cancer by ten years. We’ve got lucky here, with evolution having given us this window of simplicity in the middle of a highly complicated cause of events. Cancer is compositionally simple and we have that window to get rid of it.” All we have to do is kill one gene—the gene for telomerase.

  People have never thought in these terms before, he said, because people have always thought of the body as requiring its own powers of rejuvenation. “The epidermis does constantly renew,” said Aubrey. “And it renews from stem cells at the bottom. And those cells do express this gene telomerase. If they didn’t have it they’d conk out, and we’d end with no skin. The same is true of the blood, and the same is true of the gut. The same is true of quite a lot of tissues that we rather rely on.

  “So this seems like a bit of a showstopper on the face of it.” But really, again, all it would take is the subtraction of one gene.

  “Why cure cancer that well?” Aubrey asked me, when he first laid out his vision of WILT. “Because if you can cure cancer—I mean really cure it—then you’ve actually done the hardest thing there is in curing aging.”

  And how soon did he think we could take over the body’s powers of rejuvenation?

  “It could take ten years; it could take twenty years; but it’s not a century away.”

  From the moment Aubrey told me about WILT, I knew that I would have to see the place where he had his vision. I thought it would make a wonderful story that he had found his path toward eternal life after wandering in Ravenna. For his part, Aubrey was perfectly happy to lead me to the place where he’d had his eureka moment. He was pleased that I was willing to take WILT so seriously, beca
use most of his colleagues in gerontology thought the idea was crazy. In fact, they thought WILT was by far the weakest link in his scheme. Their objections were numerous. How would you eliminate the gene? How would you deal with the side effects? How would you carry out the necessary procedures: reseeding the bone marrow, the gut, the skin, the lungs? It would be far, far worse than conventional chemotherapy. Cure the disease and kill the patient. Biologists who hear Aubrey’s idea for the first time often become furious. “WILT is clearly nonsense and the main reason why so few scientists take him seriously,” says Jan Vijg, the cancer specialist and gerontologist at the Albert Einstein College of Medicine, who is one of Aubrey’s strongest supporters among established gerontologists. “This has nothing to do with disliking Aubrey or seeing him as a competitor or whatever. WILT is just sheer nonsense.”

  But this is the point at which Aubrey feels that conventional scientists reveal their fatal lack of imagination. What they don’t understand, what they don’t factor in, is the way medicine will begin to accelerate once we achieve our first modest successes in the war against aging. Once we realize that Aubrey is right in broad principle, and aging can be cured, there will be no stopping us. There will be no obstacle we can’t leap over. That is why he has no patience with the pessimism of the gerontologists or the modest optimism of the demographers. When demographers say that during the next century we may gain another decade or two or three in life expectancy, they merely extrapolate from the history of human health in the nineteenth and twentieth centuries. Aubrey calls them “extrapoholics.” If we move fast enough, with each researcher building on the work of the immediately preceding researchers, then we will achieve what Aubrey calls escape velocity. Escape velocity, he’s written, is “the point when improvements to the comprehensiveness and safety of human life-extension treatments are being made faster than people are aging: that is, when the remaining average life span of those who are receiving the latest therapies, and who are of the age that derives the most benefit from those therapies, begins to increase with time even though they are getting chronologically older.” In other words, we achieve escape velocity when science is adding to our life expectancy faster than we are living it—or, in Aubrey’s metaphor, when the engines of biomedicine are lifting us upward faster than the forces of decline and decay are dragging us down.