In Pursuit of Memory

by Joseph Jebelli

  Deep in the tropical rainforest of Papua New Guinea, in the Okapa region along the Eastern Highlands above the Lamari River, lies a row of small, thatched huts lashed together by bamboo stems and grass. It’s a village called Agakamatasa. Few go there. It’s home to a prehistoric tribe called the Fore: a tribe that once, according to anthropologists, indulged in ritualistic cannibalism.

  But in March 1957 an American paediatrician called Carleton Gajdusek did go there. Gajdusek was thirty-three, a workaholic with lively blue eyes and a renowned love of conversation. (Once, when asked before a lecture if he was nervous, he replied, ‘No, I am only nervous when I am not talking.’) The son of a Slovakian butcher, he grew up in New York and studied at Harvard, where his charismatic energy earned him the nickname ‘atom bomb’. Soon tiring of American life, Gajdusek elected to pursue infectious diseases in primitive cultures. As an army medic he travelled the globe to study rabies, plague, scurvy and haemorrhagic fevers. It wasn’t long before he heard about the Fore tribe in New Guinea, who were suffering from a mysterious illness they named kuru, a word meaning ‘to shake’.

  Kuru wasn’t pleasant. Its victims suffered wild spasms and slurred speech, followed by ominous fits of laughter, which culminated in a slow, sometimes year-long, gut-wrenching demise. The ruling Australian government called it the Laughing Death. It affected nearly 200 people a year, threatening to eradicate the roughly 35,000 Fore altogether. They believed kuru was the work of sorcerers from rival tribes; some would even hire local counter-sorcerers to fend off the illness with chants and protective herbs. Gajdusek, however, was eager to discover the real cause, and so decided to move to Agakamatasa and stay a while.

  He established a makeshift laboratory in a large, circular hut, gathered as many samples as he could, and performed post-mortems. Though wary of his curious instruments and outlandish concepts, the Fore grew fond of Gajdusek. They called him ‘Doctor America’.

  Because kuru mainly affected movement, Gajdusek tracked its source to the brain–where, sure enough, something was terribly wrong. It was freckled with numerous sponge-like holes. Perplexed, Gajdusek shipped some samples to his colleagues. Despite being similarly mystified by its cause, they were struck by its resemblance to Creutzfeldt-Jakob disease (CJD), the human form of ‘mad cow disease’. CJD is a freakish, fatal condition that usually arises spontaneously in people’s sixties. It causes a rapid loss of memory and cognition, abnormal movements and muscle stiffness, visual problems and slurred speech, and most patients lapse into a coma and die within a year. But kuru also bore an uncanny likeness to scrapie, a disease that caused sheep to shake and compulsively scrape their skin against trees or fences.

  It turned out that all three afflictions were transmissible: CJD could pass from person to person during medical procedures; scrapie infected other sheep by close contact; and kuru, they realised, was spread by cannibalism. Since 1890 the Fore had staged funeral rituals where family members were cooked and eaten. Nothing was wasted–especially the brain, which they considered the seat of the soul. Eating it, they believed, gave the dead eternal life. But what was the infectious agent? A virus? A bacterium? Perhaps some kind of parasite? It had to be one, but the evidence was non-existent.

  The truth, when it arrived twenty years later, was a scientific heresy that changed our view of Alzheimer’s for ever.

  It came from a neurologist named Stanley Prusiner. Prusiner was not a popular man: during the mid-1980s, at the defining point of his career, he was called ‘impulsive’, ‘presumptuous’, ‘reckless’, ‘aggressive’, ‘manipulative’ and ‘egotistical’. But Prusiner uncovered something that baffled some and downright incensed others. The agent for kuru, CJD and scrapie was not a micro-organism: it was a protein, an infectious one that survived and reproduced without DNA–violating every rule in the book.

  Prusiner dubbed these weird new particles ‘prions’, a tweaked portmanteau of protein and infection (in fact prions were so weird, they later became the inspiration for Kurt Vonnegut’s ‘Ice-nine’–an infectious crystal that kills by hardening the body’s water into ice–in his science fiction novel Cat’s Cradle). Most disturbingly, Prusiner soon discovered that healthy brains make prions all the time. The only reason everyone didn’t have kuru or CJD was because prions live a shadowy double life. In normal brain cells a prion is harmless and actually has a function: according to recent evidence, it helps insulate neurons. But every so often a neuron will accidentally manufacture a prion with a deformed three-dimensional shape. A protein with a deformed shape is as useless as a mangled house key. Usually our cells spot these biochemical mishaps and either refold the protein into its normal shape or, failing that, destroy it.

  But somehow, in the brains of those with kuru, the prion’s deformed rogue twin evades these fail-safe mechanisms. Worse, it then corrupts copies of normal prions until they too become deadly rogue twins. If enough normal prions are recruited this way, a chain reaction ensues, and pernicious hordes of prions rise and spread like cancer. That prions are capable of this without using DNA is baffling because every other known infectious agent needs a genome to construct fresh copies of itself.

  The existence of such an insidious entity was deeply concerning. More unnerving, however, were the similarities between prion infections and Alzheimer’s. In the early 1990s a German anatomist named Heiko Braak looked at thousands of patient brains and described how beta-amyloid and tau spread through the brain in a strikingly prion-like fashion.1 Tangles start at the base of the brain, he said, then creep into the hippocampus before eventually fanning out to the rest of the cortex. Plaques do the same, only in the opposite direction. It was almost as if Alzheimer’s had been seeded.

  And there was more. During his training, Prusiner met a patient called George Balanchine. The founder of the New York City Ballet, Balanchine was a renowned choreographer and ballet master but began complaining of ‘unsteadiness’ in September 1978. Before long his balance problems worsened and he started to experience severe memory loss and confusion. By February 1983 he was unable to speak and died one month later. A post-mortem finally revealed the cause. It was CJD. But bewilderingly, Balanchine’s brain was filled with dark clumps of protein, just like the plaques seen in the brains of Alzheimer’s patients.

  It begged a question with huge implications: is Alzheimer’s a prion disease? Prusiner thought about this for a long time. He knew the possibility of Alzheimer’s being something one could ‘catch’ was highly unlikely, because attempts to transmit it from humans to animals had proved unsuccessful.

  Until 2006, that is.

  Mathias Jucker told me he’s wary of speaking to the public about his work. He doesn’t want to cause alarm. Alzheimer’s is not infectious, he stressed, and the best way for me to understand the prion link was to imagine dominoes. ‘When the first domino falls, the others fall too. The seed is the first domino,’ he asserted in his deep German accent. ‘And I want to catch it before it falls.’

  Jucker is handsome and athletic-looking, with short grey hair and a marvellous excess of candour. In September 2006, on the hundredth anniversary of Alzheimer’s ill-famed lecture, and only a short train ride from the notorious Frankfurt asylum, Jucker reported a shocking new transmission of the substance that plagued Auguste Deter all those years ago. Taking brain tissue from deceased Alzheimer’s patients, Jucker injected it into the brains of young mice and then waited to see if anything happened. Within four months, seeds of beta-amyloid had sown in the hippocampus, before spreading–like weeds–to other parts of the animals’ brains.2 They were behaving just like prions. ‘We’d long anticipated that other proteins would behave like prions, so we just looked at what the prion people were doing and did the same,’ Jucker explained, as if it were obvious. His desire to understand how amyloid seeds function like prions is not merely academic; it will help to design small molecules that can stop the proteins dead in their tracks. ‘Mouse hosts are good because they allow us to do the experiment fast. But now
everyone’s trying to find out what the initial seed is in humans. And the idea of an initial seed is a beautiful thing to say to the public, because if it’s true I could just develop antibodies and make sure that I get rid of this one seed. But of course, it might be that there’s more than one; that many dominoes can fall at the same time.’

  Jucker’s primary obstacle is a pitfall all researchers must face: the divide between in vitro and in vivo, Latin for ‘within the glass’ and ‘within the living’, respectively. In vitro is good for scrutinising nature at the microscopic level; single molecules surrender their secrets far more readily when isolated from the body, a system so complex it often drowns out meaningful data with background noise. But there’s a catch: the very act of isolating such molecules can change their behaviour. And so that in vitro clue–which in Jucker’s case takes the form of beta-amyloid seeds extracted from post-mortem brain tissue–may in fact be a perversion of what’s actually happening in the living brain. It’s arguably the biggest hurdle facing drug developers. If it were easy to surmount, ‘drug discovery would be as reliable as drug manufacturing,’ notes Pfizer Pharmaceuticals veteran Christopher Lipinski.3

  Since 2006 Jucker has been trying to extrapolate his findings to living humans by searching for beta-amyloid seeds in bodily fluids. His team had got proof it was a lead worth chasing when, in November 2010, they showed that injecting beta-amyloid into a mouse’s belly triggered plaque formation in the brain.4 It took five months and appeared to have created tangles to boot. How this happened, they don’t know. It’s possible the seeds were ferried into the brain through some undiscovered cell-to-cell transport mechanism. If proven, that will be a serious blow to stem cell research, for how can a stem cell therapy ever succeed if seeds of beta-amyloid can circle the body like vultures, waiting to inflict dementia all over again?

  If Jucker does identify the first falling domino (or dominoes), as he so eloquently puts it, a Nobel Prize is on the cards. Meanwhile, a few inconvenient truths kept the question of Alzheimer’s prion ancestry alive. For one thing, different strains of prions cause different prion diseases, all of which display a wide variety of symptoms; it’s possible, therefore, that different ‘strains’ of beta-amyloid and tau account for variations in the symptoms of Alzheimer’s sufferers. For another, Jucker’s breakthrough coincided with a breakthrough by a group of Cambridge University researchers, who had demonstrated Alzheimer’s transmission in primates–a mammal uncomfortably close to us.5 And so, feverishly, scientists persevered at unlocking the connection. Thankfully, human-to-human transmission of Alzheimer’s pathology had never been seen.

  What happened next almost caused a serious public health scare. Reporting in the September 2015 issue of Nature, John Collinge, a world-renowned prion researcher at University College London, offered the first evidence that beta-amyloid may very well be transmitted between people.6 His team were investigating the brains of eight people who’d died from CJD. Aged between thirty-six and fifty-four, the patients had received pituitary growth hormone thirty years earlier; it was a routine treatment for children with dwarfism or stunted growth. Until 1985 the hormone was sourced from human cadavers. An estimated 30,000 children were treated with cadaveric growth hormone and most lived–and are living–full, healthy lives at a normal height. But a small percentage of children contracted the lethal prion disease during surgery. The tragedy was especially common in France, where surgeons unwittingly used older cadavers, more likely to be reservoirs of prions because the risk of CJD increases with age. As a consequence, 125 children died–and in a Parisian courtroom in October 2010 two French doctors narrowly avoided charges of involuntary manslaughter.7

  As if the hormone recipients’ problems weren’t bad enough, Collinge found that six of the eight brains under scrutiny were also teeming with beta-amyloid. How had this happened? None had any genes for early-onset Alzheimer’s, nor were they old enough to have so much amyloid in their brains. The most plausible explanation, according to Collinge, is that the protein ‘piggybacked’ its way in on the growth hormone during their injections. Worryingly, he might be right. Beta-amyloid sticks to metal like industrial glue, and unlike bacteria or viruses, you can boil, bake, desiccate and even irradiate it without ever totally eliminating it. In fact, the required decontamination conditions are so intense that many surgeons don’t meet them for fear of damaging the tools themselves.

  Of course, the patients in Collinge’s study didn’t have Alzheimer’s. They may never have got it. So Collinge considered other possibilities. Maybe CJD somehow made the patients’ brains more vulnerable to Alzheimer’s. Maybe the CJD prions seeded the growth of beta-amyloid; prions can do this by a mysterious process dubbed cross-seeding. But in every other CJD case Collinge’s team examined, none had comparable levels of beta-amyloid. Plus, both seeds were found physically far apart, which was hardly convincing evidence for one corrupting the other.

  When word of Collinge’s discovery got out, people started worrying they might catch Alzheimer’s after seeing their dentist. CAN GOING TO THE DENTIST GIVE YOU ALZHEIMER’S? proposed the UK’s Daily Mail newspaper. Fortunately, that scenario seems far-fetched, and this small, inconclusive study certainly shouldn’t make you cancel your next dental check-up or hospital appointment.8

  Nevertheless, until the human source of these patients’ amyloid is confirmed, similar transmission events can’t be ruled out. So in a desperate bid to learn more, Collinge and others are still searching for the original growth hormone extracts, prepared decades ago at various locations. If found, all they need to do to prove human transmission is follow Mathias Jucker’s lead, i.e. inject an animal with it and then see if it develops Alzheimer’s pathology. From this strange coupling emerged an inescapable question. Alzheimer’s could be spontaneous. It could be genetic. Could it also be acquired?

  John Collinge, seated in his office at the National Prion Clinic in London, his desk covered with issues of Nature and government reports, told me that he doesn’t want to scare anyone. Alzheimer’s is not contagious, he assured me. But–and there is undoubtedly a ‘but’–it may be transmissible under certain circumstances. ‘Prions are lethal pathogens,’ he said in a quiet, measured tone, ‘and I don’t think that beta-amyloid is a lethal pathogen that passes from person to person in the same way. But the idea that amyloid seeds is not speculative. It seeds by definition.’

  Collinge is a mild-mannered man with deep-set eyes, bushy eyebrows, and a stratospheric intellect. He’s been studying prions for more than thirty years. He was one of the early investigators showing that they’re transmissible. When the UK’s bovine spongiform encephalopathy (BSE, or ‘mad cow’) epidemic manifested in humans as CJD–so-called variant-CJD–in the 1990s, the government appointed him as their go-to guy to defuse a potential prion time bomb and thwart another epidemic. And it really was a time bomb: scientists had discovered that prions could incubate in humans for decades without producing any symptoms–providing yet another ominous unknown. Funded by the Department of Health, Collinge set up a National Prion Clinic in 1998 and used patient post-mortems to amass a natural history of the pathogens.

  Although CJD was his primary focus, he was acutely aware of the implications for other neurological disorders, and always saw Alzheimer’s as ‘part of the mission’. The conspicuous features of rare diseases, he knew, give clues to common diseases. ‘That’s the way I’ve always seen prion diseases,’ he said. ‘If proteins can do this, it isn’t just going to be about CJD; it’s going to open the door to so many things, and at the top of that list is Alzheimer’s.’

  One of the first things the UK government wanted Collinge to do was investigate better ways to sterilise surgical tools. Politicians were slowly catching up with what scientists were seeing and were understandably worried about the risk of hospital-acquired infection, given how seemingly indestructible prions are. So they invested more than £10 million in Collinge and other researchers to devise a potent decontamination technology.
Seven years, 400 combinations of detergents and enzymes later, Collinge had done just that. He’d made a biological washing powder that eliminated prions from metal by a million-fold, below all limits of detection. The technology was commercialised by the American chemical company DuPont, a cheap disinfectant product called RelyOnTM was manufactured, and a UK scientific advisory committee recommended that the government use it.

  Blood transfusion was the next big concern. Without any blood test for prions, it was impossible to know how they were circulating in the population. It was an invisible mystery, with a bad track record: in the 1980s and 1990s, UK blood transfusions led to over 4,000 haemophiliacs contracting hepatitis C and 1,200 infections of HIV, resulting in over 2,000 deaths. Since prions can lurk in the body for decades before any symptoms emerge, a good blood test was even more urgent. And so Collinge delivered yet again. In February 2011, by exploiting the prions’ affinity for metal, he invented an ingenious test that uses metal powder to detect prions in the blood. With a sensitivity of one part per 10 billion, it was 100,000 times more sensitive than every other method. Again, a panel of experts recommended the government use it.

  It had been hard, expensive, but we’d got ahead of this one. The mistakes of the past weren’t going to be repeated. Reason and prudence and science had prevailed.

  But astonishingly, the British government chose to use neither the disinfectant nor the blood test. When it came to using the disinfectant in a hospital setting, they put up so much red tape that DuPont was only allowed to conduct one trial (which was a success). Then the same advisory committee that recommended the disinfectant told DuPont that the British National Health Service simply wouldn’t use it; after all, who would bother with an additional sterilisation step when the prion prevalence in the population was still unknown? As for the blood test, when Collinge sought to try it on 20,000 UK and 20,000 US blood samples–for £750,000–the government rejected the proposal. At a House of Commons Science and Technology Committee session in 2014, Sally Davies, the government’s Chief Medical Officer, said that ‘the government had limited budgets for healthcare, public health and research,’ adding that it had already ‘given a lot of money to this area of prion research, particularly to Professor Collinge’.