by Oliver Sacks
In the nineteenth century, when a powerful mind could still take all of nature for its subject, the great naturalist Alexander von Humboldt, after a lifetime of travel and scientific research, embarked in his mid-seventies on a grand synthetic view of the universe, bringing together everything he had seen and thought into a final work, Cosmos. He was well into its fifth volume when he died at eighty-nine. In our own time, when even the largest minds must narrow their gaze, the evolutionary biologist Ernst Mayr recently gave us, in his ninety-third year, This Is Biology, a marvelous book on the rise and scope of biology that combines the spaciousness that a lifetime of thought brings with the eager immediacy of the boy who passionately tracked birds eighty years before. Such passion, as Mayr writes, is the key to vitality in old age:
The most important ingredient [for a biologist] is a fascination with the wonders of living creatures. And this stays with most biologists for their entire life. They never lose the excitement of scientific discovery…nor the love of chasing after new ideas, new insights, new organisms.
If we are lucky enough to reach a healthy old age, this sense of wonder can keep us passionate and productive to the end of our lives.
*1 . Caring for someone else, especially if that someone is already quite demented and is inexorably going downhill, can involve backbreaking physical exertion as well as a constant, almost telepathic sensitivity to what is going on in a mind now less and less able to communicate its thoughts, less and less able to have clear thoughts. People with dementia may get terrifyingly confused and disoriented. Such a burden can make the caretaker ill with stress. As a physician, I see this all too often—sometimes an elderly husband or wife will sacrifice their own health and die before the incapacitated loved one they are caring for; this is why outside help is crucial.
*2 . Such dissolution was very clear, Jackson thought, in the processes of dreaming, delirium, and insanity, and his long 1894 paper “The Factors of Insanities” is full of fascinating observations and insights in this regard.
*3 . As Henry James was dying, with pneumonia and a high fever, he became delirious—and it is said, as I wrote in Hallucinations, that though the master was raving, his style was “pure James” and, indeed, “late James.”
Kuru
In 1997, I saw a patient in New York, an eighty-seven-year-old woman who had been physically active, intellectually intact, and seemingly in good health until the beginning of that year. In the last days of January, however, she became strangely excited, then agitated—“Something terrible is happening to me,” she said. It was difficult for her to sleep: the curtains and the corners of the room seemed peopled by ghostly faces, and what sleep she had was broken by vivid dreams. On the fifth day, periods of confusion and disorientation began to appear. A medical disturbance was suspected—perhaps a urinary infection, a chest infection, some toxic or metabolic disturbance—but her attending physician could find no fever, nor any abnormality in her blood or urine. CT scans of her brain appeared normal. A psychiatric opinion was sought—depression in the elderly can sometimes present itself as confusion—but this notion became increasingly untenable as, within days, the initial confusion deepened.
By the middle of February, myoclonic jerks of the muscles convulsed her limbs, her abdomen, and her face. Her speech lost coherence and intelligibility from day to day, and an increasing spasticity took hold. By the third week of her illness, she no longer recognized her own children.
Towards the end of the month, she started to alternate between states of stuporlike sleep and a restless, twitching delirium, in which a light touch might bring on violent jerks of her whole body. She died on March 11, emaciated, rigid, in a coma, less than six weeks after the onset of her first symptoms. We sent a tissue sample from her brain to the pathologist, for the overwhelming possibility was that she had Creutzfeldt-Jakob disease. The pathologist, indeed, was visibly uneasy; no pathologist is quite comfortable dealing with the tissues of such patients.
Neurologists see incorrigible diseases all the time, and yet this case threw me to an unusual degree, with its devastating clinical course, the almost visible day-to-day destruction of the brain, the racking myoclonic spasms of the body, and our manifest inability to do anything for the patient.
Creutzfeldt-Jakob disease is rare—its incidence is about one in a million per year—and I had seen it only once before, in 1964, when I was a neurology resident. The unfortunate man afflicted with it then was presented to us as a case of a highly unusual degenerative brain disease. There was discussion of its typical features: a rapidly advancing dementia; sudden, lightning myoclonic jerks of the muscles; and a peculiar-looking “periodic” electroencephalogram. These, we were told, constituted the diagnostic triad for CJD. Only about twenty cases had been reported since the original account by Creutzfeldt and Jakob in 1920, and we were excited at encountering such a neurological rarity. At that time, neurology was still largely descriptive, almost ornithological, and CJD was seen as a rara avis, along with Hallervorden-Spatz disease, Unverricht-Lundborg syndrome, and other such exotic, eponymous rarities.
We had no idea in 1964 of the truly singular nature of CJD, its affinities with other human and animal diseases, or that it would turn out to be the archetype, the epitome, of a whole new order of disease. We never for a moment thought of it as infectious; indeed, we took blood and spinal fluid from this patient nonchalantly, as from any other, not dreaming that an inadvertent needle stick, the accidental implanting of a grain of tissue, might cause us to share his fate. It was only in 1968 that CJD was shown to be a transmissible disease.
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IN 1957, CARLETON GAJDUSEK, a brilliant young American physician and ethologist who had already done notable work exploring disease “isolates” elsewhere in the world, went to New Guinea to investigate a mysterious neurological disease decimating the villages of the Fore people. It seemed to affect women and children almost exclusively, and it had apparently never occurred before the present century. The Fore called it “kuru” and ascribed it to sorcery. The clinical course of kuru was one of rapid and remorseless neurological deterioration—falling, staggering, paralyses, and involuntary laughter—ending fatally within a few months. The brains of those who died showed devastating changes, some areas having been reduced to a virtual sponge, riddled with holes. The cause of this disease was exceedingly puzzling—genetic factors, toxic factors, disease agents of the usual sort were all considered and found irrelevant. It required original work, much of it in the difficult field conditions of western New Guinea, for Gajdusek to trace the disease to the transmission of a new kind of agent, one that could rest for years in the tissues of those affected without causing any symptoms and then, after this huge latent period, begin a rapidly fatal process. He used the term “slow virus” for this singular agent, and he demonstrated that it was the practice of cannibalism as part of funeral rites (specifically, the eating of infected brain tissue) that caused its spread among the Fore. He went on to show that the agent could cause a similar disease when it was given to chimps and monkeys. For this work he received a Nobel Prize in 1976.
Richard Rhodes, in his 1997 book Deadly Feasts, has told the kuru story with psychological insight and dramatic force, virtually reliving the early days of this investigation—a time of fear, bewilderment, great ambition, and intellectual discovery.
From its prelude in New Guinea, Rhodes’s chronicle opens out, steadily, to wider and wider prospects, showing how connections with other human diseases and with various animal diseases were laboriously pieced together. Not the least of his book’s many excellences is Rhodes’s depiction of the great role that chance and luck and unexpected encounters play in the all too human business of science. A most crucial serendipity came in 1959, when an English veterinarian, William Hadlow, saw an exhibit of photographs—Gajdusek’s “kuru show”—then on display in the Wellcome Historical Medical Museum in London. Hadl
ow was instantly struck by the similarities of the clinical and pathological picture of kuru to that of a fatal sheep disease, scrapie, which had affected isolated flocks of sheep in England and elsewhere since the early eighteenth century. (It had been endemic in Central Europe before that, and spread to the United States in 1947.) And scrapie, as Hadlow pointed out in a letter to The Lancet, was known to be transmissible. Gajdusek had briefly thought about an infectious basis for kuru, but had then discarded the notion; now he was forced into reconsidering it—indeed, into seeing that kuru must be infectious, and that any similar human diseases would almost certainly be infectious, too. Demonstrating this experimentally took years of patient and difficult work that involved injecting chimps with kuru- and CJD-infected tissue—work made more difficult by the long incubation periods of these diseases.
All of these diseases—kuru, CJD, scrapie, and various rarer ones like fatal familial insomnia and Gerstmann-Sträussler-Scheinker syndrome—are relentlessly progressive and rapidly fatal. All produce devastating spongy changes and cavitations in the brain—hence they are referred to collectively as the transmissible spongiform encephalopathies, or TSEs. The disease agents in each of these are very difficult to isolate, smaller than viruses, and, ominously, capable of surviving the most drastic conditions, including extreme heat and pressure as well as chemicals like formaldehyde and all the usual sterilization procedures.
Bacteria are autonomous and multiply by themselves; viruses use their genetic material to subvert the host’s cells to replicate—but the TSE disease agents show no evidence of containing any RNA or DNA at all. How, then, could they be characterized, and how could they cause disease? Gajdusek named these agents “infectious amyloids.” (They are now known as “prions,” the name given to them by Stanley Prusiner, who was awarded a Nobel Prize for his work in identifying this new class of pathogen.) But if prions could not replicate like viruses, how did they multiply and spread? One had to envisage a wholly new form of disease process—one akin not to biological replication but to chemical crystallization, whereby the tiny prions, which are actually deviant, pleated forms of a normally present brain protein, act as “pattern-setting nucleants,” or centers of recrystallization, causing rapidly spreading transformations of the surrounding crystalline proteins. Such nucleation is seen in the patterning of ice or snowflakes, and an apocalyptic form of this was imagined years ago by Kurt Vonnegut in Cat’s Cradle, where the world is ended by a sliver of a substance that transforms all water into unmeltable “ice-nine.”*
Prions infect us not by lodging in us as invaders but by evoking a disturbance in our own brain proteins. It is for this reason that there is no inflammation or immune reaction to the prions, for our own proteins, normal or abnormal, are not perceived by the immune system as foreign. It is the helplessness of the organism in the face of its own subversion, allied to the near indestructibility of prions, that makes the TSEs potentially the deadliest diseases on earth. While the TSEs may be extremely rare in nature, arising only from a very occasional, stochastic transformation of brain protein (this seems to account for the remarkably constant one-in-a-million incidence of sporadic CJD throughout the world each year), cultural practices—eating brains or feeding offal or animal remains to cattle—may radically alter the picture and cause a galloping transmission of these diseases.
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IN THE EARLY DAYS it was often thought that kuru was no more than, as Rhodes puts it, “a tragic curiosity” confined to a few Stone Age cannibals at the other end of the earth. But Gajdusek insisted from the first on its much wider potential relevance. It was Gajdusek and his colleagues at the National Institutes of Health who showed, in 1968, that CJD was a transmissible spongiform encephalopathy, like kuru, and who warned that this disease might be transmitted accidentally by surgical or dental procedures. Exactly this happened in the early 1970s, following corneal transplantation in one patient and neurosurgery (with autoclaved but still infected instruments) in others.
A greatly heightened incidence of disease was seen in the 1990s in patients who had received human growth hormone (extracted from cadaveric pituitary glands) as children: of some 11,600 patients who were given it, at least 86 developed CJD. Fortunately, synthetic growth hormone became available in the mid-1980s, forestalling further disasters.
Around that time, too, a new disease appeared among some cattle in Britain, causing them to act strangely, stagger, and rapidly die. It was dubbed, popularly, “mad cow disease”; scientists referred to it as bovine spongiform encephalopathy, or BSE. Cattle, of course, are normally vegetarians, but increasingly they have been fed on a high-protein meat-and-bonemeal mix, a slaughterhouse by-product sometimes containing, among other things, the offal of diseased cattle and sheep—perhaps including brain tissue from scrapie-infested sheep. Whether the cannibalistic eating of cattle brains amplified a previously rare and sporadic disease (like the cannibalism among the Fore did) or whether scrapie prions from sheep crossed the species barrier to infect cattle is unclear. But the use of meat-and-bonemeal feed soon brought about a disaster.
More than a dozen young people died of a CJD variant in Britain in the late 1990s, and it seems likely that they acquired their disease from eating infected meat products. The clinical picture in these cases—early behavioral changes and incoordination—was more reminiscent of kuru than of “classical” CJD (and this was true of the pathological changes, too).
But the incubation period, as the Fore people showed, can be many decades, and in the United States and elsewhere there are large reservoirs of TSE in sheep and mink, as well as in some wild deer and elk, and continuing use of meat-and-bonemeal feed for pigs, chickens, and cattle. And it may be, as Gajdusek theorized, that no source of food can be considered safe from infection by prionlike agents. Meat-and-bonemeal waste and animal by-products are even used sometimes to fertilize organic vegetable crops, and animal fat and gelatin are widely used in food, cosmetics, and pharmaceuticals.
Such practices have now been banned in several countries.
* Prions were seen first as “slow” viruses, then as “unconventional” ones, but if we categorize them as “viruses” or “alive,” we must radically redefine what we mean by either term, for they seem to belong, in many ways, to a purely crystalline world. (Gajdusek, indeed, entitled one of his early papers “Fantasy of a ‘Virus’ from the Inorganic World.”)
A Summer of Madness
“On July 5, 1996,” Michael Greenberg starts, “my daughter was struck mad.” No time is wasted on preliminaries, and his memoir Hurry Down Sunshine moves swiftly, almost torrentially, from this opening sentence, in tandem with the events it tells of. The onset of mania is sudden and explosive: Sally, Greenberg’s fifteen-year-old daughter, has been in a heightened state for some weeks, listening to Glenn Gould’s Goldberg Variations on her Walkman, poring over a volume of Shakespeare’s sonnets till the early hours. Greenberg writes:
Flipping open the book at random I find a blinding crisscross of arrows, definitions, circled words. Sonnet 13 looks like a page from the Talmud, the margins crowded with so much commentary the original text is little more than a speck at the center.
Sally has also been writing singular, Sylvia Plath–like poems. Her father surreptitiously glances at these and finds them strange, but it does not occur to him that her mood or activity is in any way pathological. She has had learning difficulties from an early age, but she is now triumphing over these, finding her intellectual powers for the first time. Such exaltation is normal in a highly gifted fifteen-year-old. Or so it seems.
But on that hot July day, she breaks—haranguing strangers in the street, demanding their attention, shaking them, and then suddenly running full tilt into a stream of traffic, convinced that she can bring it to a halt by sheer willpower. (With quick reflexes, a friend yanks her out of the way just in time.)
In an unpublished draft of his Life Stud
ies, Robert Lowell described something very similar in an attack of “pathological enthusiasm”:
The night before I was locked up I ran about the streets of Bloomington Indiana….I believed I could stop cars and paralyze their forces by merely standing in the middle of the highway with my arms outspread.
Such sudden, dangerous exaltations and actions are not uncommon at the start of a manic attack.
Lowell had a vision of evil in the world, and of himself, in his “enthusiasm,” as the Holy Ghost. Sally had, in some ways, an analogous vision of moral collapse, seeing all around herself the loss or suppression of God-given “genius,” and of her own mission to help everyone reclaim that lost birthright. That it was such a vision which led to her passionate confrontation with strangers, her bizarre behavior imbued with a sense of her own special powers, her parents learn when they quiz her the next day. Greenberg writes:
She has had a vision. It came to her a few days ago, in the Bleecker Street playground, while she was watching two little girls play on the wooden footbridge near the slide. In a surge of insight she saw their genius, their limitless native little-girl genius, and simultaneously realized that we are all geniuses, that the very idea the word stands for has been distorted. Genius is not the fluke they want us to believe it is, no, it’s as basic to who we are as our sense of love, of God. Genius is childhood. The Creator gives it to us with life, and society drums it out of us before we have the chance to follow the impulses of our naturally creative souls….
Sally related her vision to the little girls in the playground. Apparently they understood her perfectly. Then she walked out onto Bleecker Street and discovered her life had changed. The flowers in front of the Korean deli in their green plastic vases, the magazine covers in the news shop window, the buildings, cars—all took on a sharpness beyond anything she had imagined. The sharpness, she said, “of present time.” A wavelet of energy swelled through the center of her being. She could see the hidden life in things, their detailed brilliance, the funneled genius that went into making them what they are.