by Michio Kaku
Behind the optimistic promise of heading off aging in spaniels and, soon, in their owners lies a sadder reality: that even foundational research cannot always cure a fundamental problem. Despite what had seemed to be groundbreaking discoveries in the basic genetics and pathology of dementia, no cure or even promising treatment for senility, as it once was called, is in sight. Increasing numbers of people enter old age not merely reduced but ravaged by Alzheimer’s or another form of dementia, now epidemic in the richer countries that have greater life expectancies. Old Lear’s primary fear is not of age but of madness, which he imagines precisely as dementia: as the loss of mental control, of memory, and of cognition, seeing his fate mirrored in that of Poor Tom, the ranting homeless man impersonated by Edgar.
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To pass from the Harvard rejuvenators to the laboratory of Patrick Hof, at the Icahn School of Medicine at Mount Sinai, in Manhattan, is to sober up a little. Here, there is talk not of imminent innovation but of discouragingly minute work proceeding on many slow-moving fronts over decades. Where the Harvard crowd see quick fixes in the near future, Hof, an expert on the neuronal underpinnings of aging and Alzheimer’s, sees the exposure of ever more confounding complexity.
His tenth-floor office is filled with reproductions of Blake illuminations and Whistler portraits, while photographs of his children cycle on the screen saver behind him, blended with images of whales and dolphins, a particular interest of his. His nearby lab is an open space with small chapels off it, in which researchers—postdocs, junior faculty, skilled technicians—study the youthful and aged brains of many kinds of animals, with what looks like every kind of microscope: smaller viewing ones, mid-sized high-resolution ones, and a single massive electron-scanning microscope that lets his researchers see neural structure down to a dendrite’s tiny terminal spines.
“My career started at the beginning of digital microscopy,” Hof says. He is white-haired, with the soft accent of his native Switzerland. “Now we can collect terabytes of data—we can collect entire networks of neurons within a single animal brain. We do tissue staining, taking a piece of brain or an entire brain—slicing them into very thin sections, which we incubate with an antibody that labels a specific population of neurons, and we collect that. Or we can load neurons with a fluorescent dye—inject it, using a very thin glass pipette that runs right into the neuron—so then we have a fluorescent neuron!”
Hof’s laboratory is full of brains. In a large common lab outside the microscopy rooms, there are shelves holding rows of what look like hinged, dark-wooden cigar boxes. “These are all brains,” Hof says casually. He takes a box down and opens it; inside, there’s a slide with what looks like a small profile of a brain on it. “That’s a human brain. It’s a section, sliced like bread. It looks small, because it was incubated in a chemical process—we started with the entire hemisphere and then incubated it in an alcoholic treatment, and it shrinks by two-thirds. Then you stain it, and there you go.” The brain sections are kept indefinitely, Hof explains, and loaned out, like library books, from lab to lab.
Hof, who has taken to studying the brains of whales and dolphins, likes to bring visitors to an open, chilled “brain room,” a sort of rare-book collection of brains, to see a few beautiful instances. The brain room is a revelation. Here they are: human brains, monkey brains, dolphin brains—the space between brain and mind never seems so large as it does when you actually see the material of mind, curved and segmented, as ugly as an intestine, floating in a fixing solution.
The room even contains a sperm-whale brain—“the largest brain known to the planet,” Hof says. (It looks beautifully broad, with nobly large-spaced convolutions.) Finding the brains of senile cetaceans is hard, he says. “The ones that beach are young adults, and the seniors tend to die quietly at sea.” Hof hopes that insight might be found in studying neurodegeneration in the cetaceans’ more expansive, differently structured cortexes.
The study of Alzheimer’s became Hof’s special preoccupation because of its insidious destruction of normal minds and normal character. “You can’t tell any difference, even under extreme magnification, between an aging non-demented brain and a younger human one,” he says. “You have to have really fine levels of resolution to see any loss in neural organization just through aging without illness. But, holding an Alzheimer’s brain in your hand, you can see the atrophy.”
Three decades ago, Hof explains, research in Alzheimer’s linked two key proteins with the terrible dissolution of selves: beta-amyloid, which formed plaques between neurons; and tau, which formed tangled fibrils within neurons. The relative importance of the two was disputed, but many scientists concluded that those plaques and fibrils clog the brain as coffee grounds clog a drain. It seemed likely that there would be therapeutic benefits if they could be cleared away. “Now, we know that these are really downstream effects,” Hof says. “What’s happening upstream to cause them is much, much more complicated.”
With the causes unclear—debate continues over which anomalies are better seen as culprits or as bystanders—and the cure evidently far away, Hof can only enumerate the “co-morbidities” for Alzheimer’s, the conditions that correlate most strongly with its onset. They are the old-fashioned sins: obesity, a lack of exercise, bad diet—and the diabetes that these can produce. For all the cascades of research into longevity, the new science often seems to distill into old wisdom: be fit, stay thin, and you will look and feel younger longer.
“The disease is diverse and heterogeneous enough that treatment and prevention will have to move on several fronts,” Hof says. “First, just promoting healthy aging, what can you do and what can you avoid? Every elder is unique, and will have had life experiences and habits that are unique. So we’re going to have to look at that aspect, in ways that prevent or treat, to a degree, the development of something worse. Then we need to have a better understanding of the causative factors. There are leads that point to a number of interesting markers. There are proteins that play cellular roles that effect a cascade of reaction inside the cells, but it becomes very difficult to target specifically without altering other functions. None of it is easy.”
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As you take off the AGNES suit—piece by piece; the boots and then the wrist weights and the impeding gloves—the feeling is disconcerting. It’s the return of flow, the feeling of choice and possibility as you begin to move again through the world, that makes you recall that what it is to be young is not to be in a state of ecstasy but merely to be unimpeded, to be in the world without having undue consciousness of your own muscle and bone within it. It’s the same thing we experience when we remove a splinter from our foot; what we get is not happiness in a positive sense but a return to not having to think about the prison and the fact of our flesh. We forget our insides, and fold ourselves back out.
The true condition of youth is the physical ability to forget ourselves. A friend who is still creative in his eighties points out what he calls the geriatric possessive: people past eighty, he says, are expected to say, “I’m going to take my bath,” “I’m going to take my walk.” We can counterpoise that to the pediatric possessive: “You’re going to take your bath,” “It’s time for your nap.” Only in midlife do we feel secure enough to enumerate actions as existing individually outside our possession of them: “I’m going to take a bath,” “I’m going to take a nap.” A bath and a nap exist, briefly, outside our possession of them—they’re just around for the taking, we suppose, and always will be.
Glenda Jackson, now playing Lear on Broadway at the age of eighty-three, captures the indomitable egotism of the aged. Watching her onstage, we are asked to recognize not just the anger but also, eventually, the wisdom of age. The old, Shakespeare says, can become, or assist us to become, God’s spies. A decade and a half ago, a presidential council chaired by the bioethicist Leon Kass produced a report raising questions about research into extended longevity. “Might
we be cheating ourselves,” the report asked, “by departing from the contour and constraint of natural life (our frailty and finitude) which serve as a lens for a larger vision that might give all of life coherence and sustaining significance?” We do turn, after all, to the imagery of the old for comfort; we turn to work marked by the frailties of aging for consolation and enlightenment. Matisse, his hands crippled by arthritis, picks up scissors and painted paper and finds a new world of purity; de Kooning, on the edge of Alzheimer’s, paints some of his greatest pictures just as renewed simplicity breaks the hand of excessive excellence.
Swift, in Gulliver’s Travels, invented the race of the Struldbrugs in order to imagine what eternal life would be like. Eerily, they were given a precise phenotypic marker, a blemish above the left eyebrow, and were given, too, the ill temper associated with age. Promised eternal life, they were cursed with ever-progressing aging, and were the most miserable people alive. What we want—Swift’s point—is not eternal life but eternal youth, and what the new science seems to promise us is more like permanent middle age. We may indeed already be converging as a population—irascible millennials who feel dated at twenty-five and determinedly upbeat boomers who insist on feeling young at seventy—on a single American age, a kind of shared perpetual middleness, where we will dye our hair and take our pills and suddenly collapse in the midst of the dance. Right now, we live well, and then we don’t live well, and then we die. The most that science seems to offer us is this: we’ll live well, and then we’ll die.
In the past, as science and medicine annihilated old curses, we worried about losing the corresponding compensating benefits. And yet pain in childbirth, which some thought to be foundational to what we call Judeo-Christian morals, could be largely subdued without any loss to mother love; consumption was cured without lessening the romance of romantic poetry. Perhaps the loss of aging will be one more in that series, where, like all the other supercentenarians, we will dance and make love and ski, sharp-eyed, right to the edge of the still inevitable cliff. In the word cloud of concepts associated with aging that hangs in the AgeLab, the word “death” appears only in a tiny balloon, associated with the stray and bubbling thoughts of younger men—much smaller than the other words, lost among larger clouds of hope.
SARA HARRISON
Right Under Our Noses
from Wired
The dogs still make Andreas Mershin angry. “I mean, I love dogs,” says the Greek-Russian scientist, in his office at MIT. “But the dogs are slapping me in the face.”
He pulls up a video to show me what he means. In it, a black dog named Lucy approaches a series of six stations, each separated by a small barrier. At every one, a glass cup of human urine with a screened lid sits at the level of the animal’s nose. Lucy takes a brief sniff of each sample, sometimes digging her snout in to get a better whiff. She is performing a kind of diagnostic test: searching for the telltale scent of prostate cancer, which, it turns out, leaves a volatile, discernible signature in a man’s pee. Discernible if you’re a dog, anyway. When Lucy finds what she’s looking for, she sits down and receives a treat.
Among humans—whose toolmaking prowess has given the world self-driving suitcases and reusable rocket boosters—prostate cancer is notoriously difficult to detect. The prevailing method is to check a patient’s blood for elevated levels of a protein called prostate-specific antigen. But the test has a miserable track record. The scientist who first discovered PSA has described the test as “hardly more effective than a coin toss.” A false positive can lead to a prostate biopsy, a harrowing procedure that involves inserting a large, hollow needle through the wall of the rectum to retrieve a tissue sample from the prostate itself.
Properly trained dogs, on the other hand, can detect prostate cancer with better than 90 percent accuracy, and with sleek, tail-wagging efficiency. In the video, Lucy works her way through six samples in just a couple of minutes. This drives Mershin up the wall. “We have $100 million worth of equipment downstairs. And the dog can beat me?” he says. “That is pissing me off.”
Mershin is not a doctor. He’s a physicist by training. He runs a lab called the Label Free Research Group, which exists to spite the boundaries between physics, biology, materials science, and information science. In his office, Mershin keeps a pair of sunglasses that can measure brain waves, along with magazines on aviation and books on urology, the physics of consciousness, and coding in Python. He speaks rapidly in an accent that sits somewhere between his two native languages, and he changes subjects at the slightest provocation. He refuses to wear matching socks, because why should socks match? He is short and round, with a mane of strawberry blond curls that bounce when he gets excited.
Mershin’s lab, where he keeps that $100 million worth of equipment, sits a few floors down from his office at MIT. In one room, researchers are trying to invent new colors; in another, to create the lightest, strongest materials on earth. But I’m here because this facility is doing some of the most important research in the world toward developing AO—artificial olfaction.
Plenty of robots these days can see, hear, speak, and (crudely) think. But good luck finding one that can smell. In part, that’s simply because olfaction has always been deeply underrated by humans—a species of cerebral, hypervisual snobs. Kant dismissed smell as the “most dispensable” of our five senses. One 2011 poll found that 53 percent of people ages sixteen to twenty-two would rather give up their sense of smell than give up their smartphones and computers.
But in the past several years, it has become increasingly clear that smell, in the right snout, can be a kind of superpower. For millennia, humans have prized dogs for their tracking abilities; police and armed forces have long used them to sniff out bombs, drugs, and bodies. But since about the early 2000s, an avalanche of findings has dramatically expanded our sense of what dogs can do with their noses. It started when researchers realized that canines can smell the early onset of melanoma. Then it turned out they can do the same for breast cancer, lung cancer, colorectal cancer, and ovarian cancer. They can smell the time of day in the movement of air around a room; sense diabetic episodes hours in advance; and detect human emotional states in the absence of visual cues. And it’s not just dogs. Tipped off by a Scottish nurse with a highly attuned nose, scientists have recently learned that people with Parkinson’s disease begin emitting a distinct “woody, musky odor” years before they show symptoms.
All this adds up to a revelation not just about dogs but about the physical world itself. Events and diseases and mental states leave reports in the air—ones that are intelligible to highly attuned olfactory systems but otherwise illegible to science. Smell, it appears, is sometimes the best way of detecting and discriminating between otherwise hidden things out in the world. And often, the next-best method of detecting that same thing is expensive (gas chromatography/mass spectrometry) or excruciating (tissue biopsies) or impossible (mind reading).
Unfortunately, the other reason we don’t have robots that can smell is that olfaction remains a stubborn biological enigma. Scientists are still piecing together the basics of how we sense all those volatile compounds and how our brains classify that information. “There are more unknowns than knowns,” says Hiroaki Matsunami, a researcher at Duke University.
Mershin, however, believes that we don’t really have to understand how mammals smell to build an artificial nose. He’s betting that things will work the other way around: to understand the nose, we have to build one first. In his efforts with a brilliant mentor named Shuguang Zhang, Mershin has built a device that can just begin to give dogs—his panting adversaries—a run for their money.
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In May 1914, Alexander Graham Bell delivered a commencement address to some high school students in Washington, D.C. The sixty-seven-year-old inventor of the telephone gave a peculiar speech—a crotchety ode to observation, measurement, and gumshoe curiosity. He spent much of his time proposing ar
eas of investigation for his teenage audience to take up. “Did you ever try to measure a smell?” he asked. “What is an odor? Is it an emanation of material particles in the air, or is it a form of vibration like sound?” he asked. “If it is an emanation, you might be able to weigh it; and if it is a vibration, you should be able to reflect it from a mirror,” he went on. “If you are ambitious to found a new science, measure a smell.”
More than a century later, no one has yet been able to measure a smell, and there is even still some debate as to whether smell is a vibration or a chemical interaction between particles. (The vibration theory is far more controversial, but no one understands olfaction well enough to dismiss it entirely.) In fact, it wasn’t until 1991 that scientists were able to map the basic genetic and physiological building blocks of mammalian olfaction. That year, biologists Linda Buck and Richard Axel published a seminal paper; they discovered about 1,000 genes that code for about 1,000 olfactory receptors in mice, and they showed that those receptors are the beginning of a mammal’s sense of smell. They live in the olfactory epithelium, a thin piece of tissue that sits at the top of the nasal cavity, right where it meets the skull. When we take a deep breath, we suck the volatile molecules in the room up our noses toward those receptors. When the receptors interact with molecules, they set off a chain reaction that ends by sending a message to our brains.
