‘Sue Daniel and Andrew Lees and their colleagues at the Parkinson’s Brain Bank have wondered whether these diseases are, in fact, related – perhaps even the same disease, a viral one, which could take three different forms.
‘These are very similar to the neurofibrillary tangles to be found in Alzheimer’s disease,’ John went on, ‘though in Alzheimer’s there are not as many, and they occur in a different distribution. So we have tangles – like little tombstones in the nervous system – in four major neurodegenerative diseases. Perhaps the tangles contain vital clues to the process of neu-rodegeneration, or perhaps they are relatively nonspecific neural reactions to disease – we don’t know.’
As we got back in his car to return to Umatac, John continued to sketch the history of the lytico-bodig. Another dimension was added to the problem as the 1960s advanced, and a curious change was observed in the natural history of the disease: cases of bodig, which had been much rarer than cases of lytico in the 1940s and early ‘50s, now came more and more to outnumber them. And the age of onset was also increasing – there were no more teenage cases (like the nineteen-year-old youth with lytico whom Kurland had seen), and almost no cases in their twenties.
But why should a single disease present itself chiefly as lytico in one decade, and then predominantly as bodig the next? Did this have something to do with age? – bodig patients, by and large, were a decade older than those with lytico. Did it have something to do with dose – could it be that the most severely exposed patients had their motor neurons knocked out in the 1950s, producing an ALS-like syndrome; whereas those exposed to less of the agent (whatever it was) were then caught by the slower effects of this on the brain, which might cause parkinsonism or dementia? Would most patients with lytico, were they to survive long enough, go on to develop bodig years later? (This, of course, was an impossible question, because lytico in its acute form cuts short the course of life. But Tomasa, still alive after twenty-five years of lytico, showed not a trace of bodig.) All of these questions were posed – but none of them could be answered.
Kurland had always felt that the possibility of cycad toxicity, however odd it seemed, should be investigated as carefully as possible, and to this end, he had organized, with Whiting, a series of major conferences starting in 1963 and continuing for a decade. The first of these were full of excitement, hopes of a breakthrough, and brought together botanists, nutritionists, toxicologists, neurologists, pathologists, and anthropologists to present research from all over the world. One constituent of cycad seeds was cycasin, a glycoside which had been isolated in the 1950s, and this was now reported to have a remarkable range of toxic effects. Large doses caused death from acute liver failure; smaller doses might be tolerated by the liver, but later gave rise to a variety of cancers. While cycasin did not seem to be toxic to adult nerve cells, it was one of the most potent carcinogens known.
There was renewed excitement when another compound found in cycad seeds was isolated – an amino acid, beta-2V-methylamino-levoalanine (BMAA), very similar in structure to the neurotoxic amino acid beta-N-oxalylamino-levoalanine (BOAA), which was known to cause the paralysis of neuro-lathyrism. Was BMAA, then, the cause of lytico-bodig? It had been administered in many animal experiments, John said, but none of the animals developed anything like lytico-bodig.
Meanwhile there were two further discoveries of an epidemiological sort. In 1962 Carleton Gajdusek, who had been working on the cause of kuru, a fatal neurological disease in eastern New Guinea (work for which he was later awarded a Nobel Prize), now found an endemic lytico-bodig – like condition among the Auyu and Jakai people on the southern coastal plain of western New Guinea.[65] This proved indeed to be an extraordinarily ‘hot’ focus, for the incidence of disease here was more than 1,300 per 100,000, and thirty percent of those affected were under the age of thirty. At about the same time, in Japan, Kiyoshi Kimura and Yoshiro Yase discovered a third focus of a lytico-bodig – like disease on the Kii Peninsula of the island of Honshu. But in neither of these places did they find any cycads.
With these new findings, and the inability to produce an animal model of the disease, the plausibility of the cycad hypothesis seemed to fade. ‘The cycad proponents thought they had it,’ said John, somewhat wistfully. ‘They thought that they’d cracked the lytico-bodig, and it was a real loss to let the cycad hypothesis go. Especially as they had nothing to replace it; they were left with a sort of conceptual vacuum.’ By 1972 only Kurland continued to consider it a possibility, but for most of the researchers, the cycad hypothesis had died, and attention turned elsewhere.
John had arranged to take me that evening to a Japanese restaurant in Agana. With our huge tourist trade, he said, we get the best Japanese food in the world here, outside Japan. As we sat down and studied the enormous, exotic menus before us, I was interested to see fugu, puffer fish, listed; it was ten times as expensive as anything else on the menu.
‘Don’t try it!’ said John, adamantly. ‘You have a one in two hundred chance of being poisoned – the chefs are highly trained, but sometimes they make a mistake, leave a trace of skin or viscera on the fish. People like to play Russian roulette with the stuff, but I think there are better ways to die. Tetrodotoxin – a ghastly way to go!’
On Guam, John continued, warming to his theme, the most common form of toxic seafood illness was ciguatera poisoning – ’It’s so common here, we just call it fish poisoning.’ Ciguatoxin is a powerful neurotoxin produced by a tiny organism, a dinoflagellate called Gambierdiscus toxicus, which lives among the algae that grow in channels on the coral reefs. Herbivorous fish feed on the algae, and carnivorous fish in turn feed on them, so the toxin accumulates in large, predatory fish like snapper, grouper, surgeonfish, and jack (all of which I saw on the menu). The ciguatoxin causes no illness in fish – they seem to thrive on it – but it is very dangerous to mammals, and to man. John is something of an expert on this. ‘I first saw it when I was working in the Marshall Islands twenty years ago – a fourteen-year-old boy, who became totally paralyzed, with respiratory paralysis as well, after eating a grouper. I saw hundreds of cases in those days. There were fifty-five different species of fish we found which could carry the ciguatoxin. There is no way a fisherman can tell whether a particular fish is toxic, and no way of preparing or cooking it that will deactivate the toxin.
‘At one point,’ he added, ‘people wondered if the lytico might be caused by some similar kind of fish poisoning – but we’ve never found any evidence of this.’
Thinking of the delectable sushi I had looked forward to all day, I was conscious of a horripilation rippling up my spine. ‘I’ll have chicken teriyaki, maybe an avocado roll – no fish today,’ I said.
‘A wise choice, Oliver,’ said John. ‘I’ll have the same.’
We had just started eating when the lights went out. A groan – ’Not again!’ – went around the restaurant, and the waiters quickly produced candles, which they lit. ‘They seem very well prepared for power outages,’ I said.
‘Sure,’ said John, ‘we have them all the time, Oliver. They’re caused by the snakes.’
‘What?’ I said. Did I mishear? Was he mad? I was startled, and for an instant wondered if he had somehow eaten some poison fish after all, and was beginning to hallucinate.