1996 - The Island of the Colorblind

by Oliver Sacks

  Gajdusek and his group, meanwhile, had also been trying to produce an animal model for lytico-bodig and had been maintaining a number of macaques on a low-calcium, high-aluminum diet. The monkeys developed no clinical symptoms in the four years of the trial, but autopsies showed many neurofibrillary tangles, as well as degenerative changes in the motor neurons, throughout the neuraxis. These changes seemed to resemble those of lytico-bodig or the presymptomatic changes described by Anderson and Chen, and it was speculated that a longer period of calcium deficiency, or higher doses of toxic metals, might have led to overt clinical disease. And though Gajdusek had told John in 1983 that he thought the lytico-bodig was dying out in Guam, he has continued to investigate it in Irian Jaya, where in 1993 he found it still had a remarkably high incidence. He and his colleagues continue to see aluminum neurotoxicity as the cause of lytico-bodig and indeed of a wide range of other conditions.

  While Spencer, for his part, was greatly encouraged by his own success in inducing neurological disorders in primates with BMAA, he soon developed reservations. The disorders shown by his monkeys were dose-related, came on promptly, and were acute and nonprogressive (they resembled, in this way, the neu-rocycadism of cattle); whereas human lytico-bodig, it was abundantly clear, had a very long latency or incubation period, but once it had become symptomatic, was almost invariably progressive. Was it possible, Spencer speculated, that another factor was involved besides the BMAA, which might not predispose to overt disorder for many years? Slow viruses had been described by Gajdusek; could there not be, analogously, a slow toxin? Spencer did not have any clear idea, at this stage, of how such a toxin might work, or any way of validating the concept.

  Though Gajdusek might have been expected to be sympathetic to the idea of a slow toxin, he argued passionately against it in a sternly titled paper, ‘Cycad Toxicity Not the Cause of High-Incidence ALS⁄Parkinsonism-Dementia on Guam, Kii Peninsula of Japan, or in West New Guinea,’ asserting that such a hypothesis was, first, redundant; second, without precedent; third, without support; and fourth, impossible:

  No neurotoxin has been demonstrated to give rise to fatal central nervous system disease, neurological signs and symptoms of which first start to be detectable years after exposure to the neurotoxin has ceased. In fact, we have no example of any toxin producing progressive damage to any organ years after last exposure to the substance…Only hypersensitivity disorders, slow infections, and genetically-timed disorders have given rise to this pattern of long delay.

  Spencer, undeterred, saw Gajdusek’s words as a challenge (indeed he has cited them in several of his own papers), and continued to see his task as the search for a new kind of toxin, a new kind of toxic mechanism, hitherto unrecognized in medicine. A great deal of attention was focused, in the sixties and seventies, on carcinogenesis, the appearance of cancers, in some cases, years after an initial exposure to the carcinogen, whether radioactivity, a toxin, or a virus. It had been established, in Kur-land’s original cycad conferences, what a potent carcinogen cycasin was, capable of inducing liver cancers and colon and kidney malformations. It had been observed, moreover, that if infant rats were fed cycasin-high diets, the still-dividing Purkinje cells of the cerebellum might develop bizarre multinucleated forms and ectopic ‘nests,’ and such findings had also been reported, on occasion, in cases of human lytico-bodig.

  What then might be the effect of cycasin, Spencer wondered, on adult nerve cells, which are no longer capable of dividing?

  He and Glen Kisby have postulated recently that cycasin (or its component, MAM, or methazoxymethanol) may be able to form stable compounds with the DNA in nerve cells (such adduct formation is believed to underlie the overt carcinogenic and teratogenic effects of cycasin elsewhere in the body). This aberrant DNA in the nerve cells, he thinks, could lead to subtly but persistently altered metabolic functions, the nerve cells finally becoming oversensitive to their own neurotransmitters, their own glutamate, so that this itself could act as an excitotoxin. No external agent would be needed to provoke a neurological disaster at this point, for in this pathologically sensitized state, even normal neural functioning would now overexcite neurotransmitter receptor cells and push them toward their own destruction.

  The notion of such a gene toxin is not as outlandish as it seemed a decade ago, and Spencer and Kisby have now observed DNA changes in tissue cultures of cells exposed to cycasin which suggest that such a mechanism may be at work in lytico-bodig. Such a gene toxin would actually alter the genetic character of the nerve cells it affected, producing, in effect, a genetically-based form of hypersensitivity disorder.

  Now that Spencer was pondering the possible effects of cycasin on adult nerve cells, he had new analyses made of traditionally prepared cycad flours and found (contrary to what John had found earlier) that the Guam samples, even though low in BMAA, contained substantial amounts of cycasin. The highest levels of cycasin, indeed, were found in samples from villages with the greatest prevalence of lytico-bodig, lending strong circumstantial support to the hypothesis of cycasin toxicity.72

  John is a very vivid storyteller, and as he told me this story – a story not just of a scientific odyssey, but of his own most passionate hopes and disappointments – he seemed to relive it with almost unbearable intensity. He had enjoyed a cordial relationship with Kurland and Gajdusek, he thought, and a passionate one with Spencer – but when, in 1990, he gave up on the cycad hypothesis (as four years earlier he had given up on the mineral hypothesis), a sense of intense isolation gripped him; he felt he was out in the cold, seen as an apostate by them all. In the early 1990s, he toyed with a viral hypothesis (this was very much in his mind when we first met, in 1993). But as a primary physician, a general practitioner, living and working amidst the whole affected community in Umatac, he has been forced to think in terms of the entire families or clans with lytico-bodig under his care – no external cause alone, it seemed clear, could adequately account for such a pattern of distribution. Had a genetic theory been thrown out prematurely? Much had changed since Kurland and Mulder first considered, then rejected, this in the 1950s. The classic Mendelian patterns of inheritance had now been joined by concepts of complex inheritance involving the presence of multiple genetic abnormalities and their interactions with each other and with environmental factors. Further, it was now possible to directly examine the genetic material with molecular biology, using technologies and concepts not available to the early investigators.

  Working with Verena Keck, an anthropologist, John started to collect pedigrees of every patient he had seen – pedigrees of unprecedented accuracy and detail, including medical histories going back fifty years. The more pedigrees he obtained, the more he became convinced that there had to be some genetic predisposition, or perhaps several predispositions – for it looked as though the lytico and the bodig had different patterns in different families. Sometimes one saw a family in whom the affected members had only the lytico, sometimes a family in which the clinical expression was always bodig, and sometimes, more rarely, a family with both. The similarity of the pathological pictures in lytico and bodig, he started to feel, might have been misleading them all; genealogically, they seemed to be two separate diseases.

  Recently John has embarked on a new series of studies, collecting DNA samples from all of his patients and sending them out for genetic analysis. He has been very excited by preliminary results indicating the presence of a genetic marker in several cases of bodig – a marker which seems to be absent in lytico and normal controls. His immediate reaction has been one of exuberance: ‘I feel the excitement coming again, and it’s a feeling I have not had since ‘86, when I was captivated by Spencer’s hypothesis.’ But it is an exuberance tempered by considerable caution (‘I don’t quite know what it means’). The search for genetic markers is extraordinarily laborious and difficult – it took more than a decade of incessant work to find a marker for Huntington’s chorea – and John is not sure whether these preliminary results will
be borne out. (And even if a clear genetic basis is established for lytico and for bodig, John feels, this will indicate no more than a vulnerability or disposition; he has never doubted that some external agent is also necessary.)

  It is now a third of a century since he and his colleagues delineated progressive supranuclear palsy in the early 1960s and perceived it as a unique yet exemplary disease which might shed some light on neurodegenerative disease in general. The similarity of the clinical picture of lytico-bodig and postencephalitic parkinsonism to PSP continues to intrigue him. He had been struck from the start by the fact that supranuclear palsies could also be observed in some patients with lytico-bodig, and on occasion in those with post-encephalitic syndromes too (on a recent trip to New York, he was intrigued to meet one of my post-encephalitic patients who has had a supranuclear palsy for more than thirty years). But he is not yet sure how to interpret these affinities.

  He has been fascinated, as well, by the similarities of the neurofibrillary tangles which are so characteristic of lytico-bodig, post-encephalitic parkinsonism, and PSP with those of classic Alzheimer’s disease and has been investigating this with Patrick McGeer, a neuropathologist in Vancouver. The tangles themselves are virtually identical, as are the areas of inflammatory reaction about them (though there are other features of Alzheimer’s, most notably the presence of so-called ‘plaques,’ which one does not see at all in the other three diseases). At an immediate and practical level, the presence of these inflammatory reactions around the tangles makes him wonder whether anti-inflammatory agents can be helpful in lytico-bodig. Their use in Alzheimer’s disease is under study, and John is eager to see if they can help his own patients, if only to retard the course of a fatal disease. This is one of the few thoughts which gives him a brief sense of therapeutic optimism or hope, as he does his daily rounds among chronically ill and ever-deteriorating patients. And he is concerned by the steadily rising incidence of classic Alzheimer’s and Parkinson’s disease – which rarely if ever occurred on Guam before the Second World War – even as the native disease, the lytico-bodig, declines.

  After forty years of research, then, we have four (or more) seemingly divergent lines of thought and research – genetic, cycadic, mineral, viral (Alma’s money is on prions) – each with some support, but with no overwhelming evidence for any of them. The answer will not be a simple one, John now feels, but a complex interaction of a variety of genetic and environmental factors, as seems to be the case in many diseases.73

  Or perhaps it is something else, as Ulla Craig, one of John’s research colleagues, muses. ‘I’m not sure what we are looking for – though, like John, I have the feeling of some sort of virus that came and went. Some mutant virus, perhaps, with no immediate effect, but affecting people later, as their immune systems responded. But I am not sure. I am afraid we are missing something – this is the value of a fresh mind, seeing things in a new way, someone who may ask the question we have not asked. We are looking now for something complex, but it could be something we have overlooked, something very simple.’

  ‘Back in the 1940s and ‘50s,’ John mused, ‘there was a sense that we would find the cause of lytico-bodig in a matter of months. When Donald Mulder came here in ‘53, he thought he might have the problem solved by the time Kurland arrived six weeks later – but after forty-five years, it remains a complete enigma. Sometimes I wonder if we will ever decipher it. But time is running out: the disease may vanish before we can understand it… This disease has become my passion, Oliver, and my identity.’ If it is John’s passion and identity, it is Kurland’s, and Spencer’s, and many others’ as well. A colleague of mine, who knows and respects them all, says, ‘Guam has been a tar baby for all of them – once they get stuck, they can never let go.’

  The disease is indeed dying out at last, and the researchers who seek its cause grow more pressured, more vexed, by the day: Will the quarry, hotly pursued for forty years now, with all the resources that science can bring, elude them finally, tantalizingly, by disappearing at the moment they are about to grasp it?

  ‘We’re on our way to see Felipe,’ John said as we climbed into his car once more. ‘You’ll like him, he’s a very sweet man. And he’s been touched by at least four different forms of lytico-bodig.’ He shook his head slowly.

  Felipe was sitting on the patio at the back of his house, as he does most days, staring out, with a faint fixed smile, at his garden. It was a lovely garden, full of native plants, and the patio itself was shaded by banana trees. He has spent most of his life in Umatac, fishing and farming. He raises cockerels, and has a dozen of them, gorgeously colored, and all very tame. My neurological examination of Felipe was punctuated by the crowings of cockerels, a sound which he imitated, very loudly, to perfection (this was in striking contrast to his poor vocal volume when talking), by their perching on both of us during the exam, and by the affectionate nuzzling and occasional barking of his black dog. This was all delightful, I thought – rustic neurology, rural neurology, in the backwoods of Guam.

  Felipe spoke movingly of his life and the past. He enjoyed fadang occasionally (‘we all did’), but he was not, like many other Chamorros, forced to subsist on it during the war. On the contrary, he spent the war as a sailor with the U.S. Navy, stationed part of the time in Portsmouth, Virginia (hence his excellent English), and he was part of the Navy force which retook Guam. He himself had to take part in the bombardment of Agana, a heartbreaking business, for it was the destruction of his native town. He spoke movingly of friends and family with lytico-bodig. ‘And now,’ he said, ‘I have it too.’ He said this quietly, simply, without a hint of self-pity or drama. He is sixty-nine.

  His memory, intact for the past, has become severely eroded for recent events. We had in fact passed his house and stopped to say hello the previous day – but he had no memory of this, showed no recognition now we had come to visit again. When John told him the Chamorran version of his name (John Steele translates as ‘Juan Lulac’), he would laugh, repeat it, and forget it within a minute.

  Though Felipe had an inability to register current events, to transfer them from short-term to permanent memory, he had no other cognitive deficits – his use of language, his perceptual powers, his powers of judgment, were all fine. His memory problem had worsened, very slowly, for about ten years. Then he had developed some muscular wasting – the thinning of his once thick and powerful farmer’s hands was striking when we examined him. Finally, a couple of years ago, he had developed parkinsonism. It was this, in the end, which had so slowed him down, taken him out of active life, made him a retiree in his garden. When John had examined him last, a few months before, the parkinsonism was entirely confined to one side, but it had progressed apace, and now affected both sides. There was very little tremor, just an overall immobility, a lack of motor initiative. And now, John showed me, there were the beginnings of a gaze palsy too, an indication of yet a fourth form of lytico-bodig. Felipe’s civility, his character, was perfectly preserved despite his disease, along with a sense of rueful insight and humor. When I turned to wave goodbye, Felipe had a cockerel perched on each arm. ‘Come again soon,’ he said, cheerfully. ‘I won’t remember you, so I’ll have the pleasure of meeting you all over again.’

  We returned to Umatac, this time stopping at the old graveyard on the hillside above the village. One of John’s neighbors, Benny, who tends the graveyard – he cuts the grass, acts as a sexton in the little church, and as grave digger when needed – showed us around. Benny’s family, John told me, is one of the most afflicted in Umatac and one of the three families which especially caught Kurland’s attention when he came here forty years ago. It was one of his forebears, in fact, at the end of the eighteenth century, who was cursed after stealing some mangoes from the local priest, and told that his family would contract fatal paralyses generation after generation, until the end of time. This, at least, is the story, the myth, in Umatac.

  We walked slowly with Benny among the limest
one grave markers, the older ones crooked and sunken with time, the newer ones in the shape of simple white crosses, often embellished by plastic statues of the Virgin Mary or photographs of the deceased, some with fresh flowers on them. As Benny led the way, he pointed out individual stones: ‘Here’s Herman, he passed away from it…and my cousin, that one here…another cousin is the one down here. And one of the couple here, the wife, passed away from that…yeah, they all passed away from the lytico-bodig. And up here – my sister’s father-in-law passed from the same disease…my cousin and her dad and mom, the same thing…the mayor’s sister, same problem…got a cousin here passed away too. Yes, here’s another cousin, Juanita, and her dad, they both had it. My uncle Simon, right here – he was the oldest in the family who passed away from the lytico-bodig…and another cousin, he just passed away a couple of months ago. Another uncle, same problem – and the wife, same disease; I forget his first name. I didn’t really know him, he just passed away before I got to know him.’

  Benny went on, leading us from one grave to another, continuing his endless, tragic litany – here’s my uncle, here’s my cousin, and his wife; here’s my sister, and here’s my brother…and here (one seemed to hear, intimated in his voice, necessitated by the tragic logic of it all), here too I will lie, among all my family, my community of Umatac, dead of the lytico-bodig, in this graveyard by the sea. Seeing the same names again and again, I felt that the entire graveyard was devoted to lytico-bodig, and that everyone here belonged to a single family, or perhaps two or three interrelated families, which all shared the same curse.