Long for This World

by Jonathan Weiner

  Sparrow explained, very cautiously and carefully, that my question about lipofuscin had indeed been debated for years in her field. Because the lipofuscin in the retina glows in the dark, most specialists now do believe that in macular degeneration, at least part of the problem might be these molecules of lipofuscin. “We’re trying to understand if they’re negative,” said Sparrow. “We think it’s increasingly apparent they are.”

  Aubrey nodded. “The case isn’t closed. But it sure ain’t gonna do any harm, getting rid of them!” I had a strong feeling that he wasn’t speaking to Sparrow or to me. He was speaking to my notebook and pen, and through them to the world. “And if we restore everything,” he said, “then we’re done!”

  Chapter 8

  THE METHUSELAH WARS

  “Vermiculate questions,” Francis Bacon called them, “fierce with dark keeping.”

  Controversies—niggly, bookwormy controversies—bedevil scholars in every age. Every field of study has battlegrounds that burn up scholars’ time and energy. To the casual bystander it’s all academic squabbling and logic-chopping. To the scholars themselves it is almost life-or-death. Aubrey’s work is contentious at least in part because it keeps him darting around in the no-man’s-land between battlefields. And yet if you take a long view of the Methuselah wars, you can see that they may be winding down, and you can see that Aubrey, or certain key positions of Aubrey’s, may just survive.

  In the science of life today, the biggest battlefield lies between biologists who study life whole and those who analyze its working parts. They’re the “skin-out” people and the “skin-in” people. In the skin-out camp you have the naturalists, the ecologists, the field biologists, the evolutionary biologists. In the skin-in camp you have the cell biologists and the molecular biologists, experts on gadgets and widgets that are too small to see through a microscope.

  Those who study nature whole and those who study it at the level of molecules rarely see eye to eye. Skin-out people look at the big picture and skin-in people look at the microscopic or submicroscopic picture. Skin-out people tend to think about the panorama of history, and skin-in people tend to think about the meshing of molecular gears. Francis Crick once scolded Stephen Jay Gould: “The trouble with you evolutionary biologists is that you are always asking ‘why’ before you understand ‘how.’” Meanwhile the evolutionary biologists blame the molecular biologists for asking how and never why.

  The evolutionary biologists are tied to Darwin and nineteenth-century natural history. The molecular biologists are tied to Watson and Crick and twentieth-century physics and chemistry. Darwin was the greatest life scientist of the nineteenth century; Watson and Crick made the greatest breakthrough of the twentieth century, and from the beginning they’ve seen themselves as ringing out the old and ringing in the new. They see the skin-out biologists as describers, anecdotalists, stamp collectors. In universities, molecular biologists get most of the grant money, the new buildings, and the power. They’ve relegated the evolutionary biologists, ecologists, and naturalists to the corners of the old buildings and the natural history museums. The dustbins.

  It has been an epic rift. The skin-in people tend to be excited about the engineering projects they can do. They study the body’s works and wonder how much of their new knowledge they can translate into how much power to improve or save human lives. The skin-out people, the evolutionary biologists and ecologists, tend to worry about what we’re doing to the rest of the planet, and what we can do to save the other ten or twenty million species that live on it.

  In the early years of the molecular revolution, the skin-in people weren’t very interested in the problem of aging, because they didn’t think there was much they could do about it. One of the young revolutionaries, Leslie Orgel, a collaborator of Francis Crick’s, argued that aging is probably caused by damage to DNA. Our DNA is continually jostled and shaken by cosmic radiation from outer space, and by the agitation of the living molecules around it in our own bodies, and these collisions—along with a thousand and one other accidents—can cause mutations. If mutations occur in the egg and sperm cells, they can cause problems for the next generation. If the mutations occur in other cells, they can cause problems for our own bodies, because DNA contains information that is crucial for the cell in all of its manufacturing processes. When the wrong genes get the wrong mutations, you could say that a cell no longer knows how to live. Orgel argued that cells with mutations would make defective molecular machinery, and the defective machinery would then behave badly around the genes, and eventually the cell’s production lines would get hopelessly, viciously snarled. Errors would pile on errors. Orgel called this the Error Catastrophe.

  Many skin-in biologists found this hypothesis intriguing. After all, DNA is precious. Genes can’t be repaired as simply as the rest of the cell’s apparatus. When genes are corrupted or destroyed, the cell has lost priceless information. It’s bad to lose a cake; it’s worse to lose the recipe. If mutations in cells can lead to cancer, maybe they also cause the many kinds of deterioration that we call aging. So the skin-in people were drawn to Orgel’s idea; but few of them worked on it. The Error Catastrophe is a difficult hypothesis to test. Each cell contains six feet of DNA, tightly spooled, with about three billion letters of genetic code on the spool. As the cell ages, it gets typos in unique, random places along those six feet of DNA, as well as typos in the elaborate machinery that reads the DNA. How would you keep track of all those typos and prove that they’re aging the cell? We all do have days when aging feels like an Error Catastrophe. But it is an ugly hypothesis to study. It would be very messy to prove; and even if you could prove it, what could you do about it?

  By and large, then, the skin-in people left the problem to the skin-out people and their arguments about the evolution of aging. To skin-in people, those arguments were not really science at all. If you couldn’t understand a problem at the level of molecules, you weren’t a biologist; you were just a philosopher.

  Then, in the 1980s and 1990s, both camps began to realize that aging might be malleable. Naturally, each camp assumed that the other side’s work had to be wrong. But each camp figured out how to make Methuselahs: creatures that live much longer than the rest of their kind.

  The molecular work was started by a researcher named Michael R. Klass at the University of Houston. Klass reasoned that at least some of the sources of our longevity have to be in the genes. So he decided to go looking to see if he could find a longevity gene by making mutants in the laboratory and looking for Methuselahs. For his search he used the tiny round nematode worm Caenorhabditis elegans. He bred lots of mutant worms by feeding them a toxic compound called ethyl methanesulfonate. Then he grew them in petri dishes, where he let them graze like sheep or cows on lawns of bacteria. Every day he would collect the worms, put them on a nice fresh bacterial lawn, and see how many were still alive. Through the microscope he zoomed in on the worms’ throats, one by one, to see if they were still alive, still swallowing bacteria.

  Klass created one thousand different strains of mutant worms. Out of that thousand he found just one strain that he considered to be Methuselah mutants. But he noticed that if he put those worms on a little lawn of bacteria in the center of a petri dish, they would wander off the lawn and try to graze on the bare glass. Apparently that strain seemed to have trouble smelling its food. So those worms were hungry. Probably those wandering worms weren’t getting enough food, he decided, and that was why they lived a long time. If they lived a long time because they were half-starved, that was not news—they’d be living longer because of calorie restriction. He was looking for a worm that lived longer purely because a mutation had extended its life span. He decided that he had failed. And after doing so much work, Klass concluded, reasonably enough, that aging genes must be very, very rare, if they exist at all. So Klass abandoned the experiment.

  Not long afterward, a biologist named Tom Johnson asked Klass if he could look at that last mutant more closely
. Johnson looked at the worms through the microscope. He thought they ate fine. Their calorie intake was not restricted. So after a great deal of work Johnson traced the gene that had mutated and made that mutant strain live so long. He named the gene age-1. Johnson found that when he raised age-1 worms in petri dishes at the warm, humid, Floridian temperature of 25 degrees C (77 degrees F), their maximum life span was more than doubled: it increased by 110 percent. A few strains did even better. Their average life spans increased by 120 percent.

  At that time, most experts on the biology of aging mistrusted this work. They were evolutionary biologists. They thought it was impossible that a single gene could do very much for life span. According to the line of argument that ran from Darwin to Medawar to Williams to Kirkwood, when bodies age they just fall apart. The disintegration is not programmed. It is not written in our genes. So how could a single gene make so much difference? Something must be wrong with the experiments.

  A few years later, a third molecular biologist, Cynthia Kenyon, decided to take up the search for longevity mutants. There was still so little interest in the subject of aging, and the study was thought to be such a backwater, that she had trouble finding a student she could persuade to work on it. When she did, at last, she found a mutant worm that she thought was perfectly beautiful. Under the microscope, ordinary old C. elegans worms look granular and ugly, as if they were made of cottage cheese. But these mutants stayed smooth and elegant almost to the end of their lives. Cynthia Kenyon published her first studies of Methuselah mutants in 1993, ten years after the first paper by Klass.

  Kenyon’s mutants caused a sensation among molecular biologists. The science that grew out of Watson and Crick’s “secret of life” had now found the secret of the fountain of youth. If they could make a Methuselah worm, soon they’d be able to genetically engineer a human Methuselah. Whether or not that was true, the link between the gene and the long life of the worms was very clear, news of Kenyon’s mutants traveled fast, and here and there other molecular biologists began to enter the field of gerontology. I happened to be present one afternoon at the lab of a grand old man of molecular biology when a young scientist gave a seminar about longevity mutants. Seymour Benzer, one of the founders of the field with Watson and Crick, was fascinated. He seemed astonished to think that we really might be able to understand aging at the level of the genes. He began looking for longevity genes in fruit flies the way Klass, Johnson, and Kenyon had in worms. When he was eighty years old, Benzer discovered a Methuselah fly. He used to talk about that fly in an almost shady way, lowering his voice, making it thin and quiet, as if he and his listeners were convicts in neighboring cells, as if he had to drop his voice and turn it edgewise to slip a scribbled message between prison bars.

  The evolutionary biologists remained skeptical about the molecular biologists’ Methuselah mutants. To the skin-outs it still seemed impossible that a single gene could matter that much to the life span. Disposable soma theory predicted that there should be many genes that go wrong with age. Aging was a Hydra with at least nine heads. You couldn’t kill it with just a single kick. According to disposable soma theory, the Methuselah mutants should not exist. I once talked about them with John Maynard Smith, a grand old man of British evolutionary biology, who worked out some of the mathematical theory that flows from present thinking about aging. He and I met on one of the upper floors of New York’s American Museum of Natural History. Maynard Smith was a brilliant scientist who had started out as an aeronautics engineer. He’d helped improve the fighters and bombers of World War Two, the planes that the young airmen of the RAF flew over London and Berlin after burning their initials into the ceiling of the Eagle. After the war, Maynard Smith had done both theoretical and experimental work on the science of longevity. Now he was nearing the end of his life. When I asked him about the biologists who thought it might be possible to engineer a human Methuselah, he shook his head. He said that something seemed to happen when serious people approached the problem of aging and death. They just seemed to go mad.

  As a software engineer with a wide range of interests in biology, Aubrey de Grey is in the camp of the molecular types, the genetic engineers, and also in the camp the evolutionary biologists. Still, he’s a proud engineer at heart. When I told Aubrey what Maynard Smith had said, he smiled. “John Maynard Smith? I have the greatest respect for his intelligence. But he’s an evolutionary biologist. He finds it hard to think in an engineering-type way.”

  That’s the way the two camps flame each other. They fire off those killing salvoes again and again. Once I was talking with a famous biologist—a molecular biologist—who had just joined Rockefeller University, and I asked him if he had ever heard of Maria Rudzinska. He looked blank. I described her work to him, how she had been trying to understand death and dying without looking at genes and molecules, just by watching aging cells through a microscope.

  “There used to be a lot of deadwood around this place,” he said.

  In the 1980s, while the skin-in people were making Methuselah mutants, the skin-out people made their own Methuselahs. They did it the old-fashioned way: not through genetic engineering but through Darwinian breeding experiments. At about the same time that Klass engineered the first Methuselah worm, a young evolutionary biologist named Michael Rose bred Methuselah flies. Typically fruit flies breed at the age of a week and a half. Rose watched carefully and selected only the flies that kept breeding in old age, and he bred those. It was work that could have been done in the nineteenth century just as well as in the twentieth. And it didn’t violate the disposable soma theory, because Rose assumed that many, many genes would be involved in making a Methuselah.

  It was very hard work. Rose bred millions of fruit flies, and each experiment took between thirty and fifty fly generations. But he found that it was possible to play with a fly’s length of days. When he allowed only older flies to breed, generation after generation, they evolved longer life spans; when he allowed only the younger flies to breed, they evolved shorter life spans. Rose and his thesis adviser, Brian Charlesworth, announced the creation of the first of these evolutionary Methuselahs in 1983.

  Again, unlike the Methuselahs of the molecular biologists, Rose’s were acceptable to the evolutionary biologists. These populations of fruit flies represented the same miracle that has happened again and again in the wild. See, for instance, the bats, the flying squirrels, the flying lemur of the Philippines, all of which are Methuselahs. Any population of living things that finds itself in conditions in which it is able to breed at later ages will begin to evolve longer life spans. Since Rose could replicate that miracle again and again quickly in the laboratory, he argued that adding years of vigorous healthy life must be comprehensible at the level of the genes. He didn’t know which genes had changed; evolutionary theory predicted that the change must have been produced by a constellation (or cluster or galaxy) of genes. Evolutionary biologists thought they understood the why of aging, and according to evolutionary theory the existence of a single powerful Methuselah gene was impossible. Even so, changes in life span could not happen so quickly and so repeatedly, both in the wild and at his laboratory bench, unless it was a relatively simple trick to bring off.

  Rose championed the evolutionary Methuselahs and tended to brush aside the molecular Methuselahs. He dismissed those Methuselahs as Johnny-come-latelies. In his memoir, The Long Tomorrow, Rose writes, “It is always entertaining when molecular biologists rediscover findings from evolutionary biology. They have such an appealing naiveté, like the moment when my son Darius gleefully discovered at the age of one that gravity would help him knock over a glass of milk.”

  To the outside world, of course, the battlefields of biologists weren’t very interesting. What was interesting was the creation of all these Methuselahs. Cynthia Kenyon, who put the Methuselah worms on the map for molecular biologists in the 1990s, was not only a gifted scientist but young, photogenic, buoyant, and articulate on camera. She was invited o
n dozens of television shows and news shows to talk about them. When people asked her, Wouldn’t it be weird to have adult grandchildren? she would shoot back a snappy answer to the interviewer’s questions. “I think every grandparent wants to live to see the grandchildren grow up.” She made the study of mutant worms sound sexy. “They are like eighty-year-olds who look forty.” And, “I can make your dog live forever!”

  Michael Rose also got a lot of press. A generation before, at mid-century, Peter Medawar had dared to imagine that the total span of human life might be lengthened by “stretching out the whole life span symmetrically, as if the seven ages of man were marked out on a piece of rubber and then stretched.” Rose declared that ambition too modest. What if we could stretch out the time we spend young without stretching the time we spend withered and decrepit? If we learn to control the genes that govern life span, we could do that. Who knows? We could make youth last threescore and ten years, and age last only one or two years. Certainly we could prolong youth without prolonging age. We could open that door with a few twists of the skeleton key.

  These twin victories on either side of the trenches in the Methuselah wars helped revive the field of gerontology. The skin-ins and the skin-outs still don’t get along. Skin-out biologists still doubt that you can kill aging with a single gene. Skin-in biologists are still playing with single genes to make more Methuselahs. (“My rule of thumb is to ignore the evolutionary biologists—they’re constantly telling you what you can’t think,” Gary Ruvkun of the Massachusetts General Hospital told a reporter from the New York Times not long ago.) Even so, more people on both sides are entering the field, and a resolution of the paradox is beginning to emerge. This battle is beginning to die down.