In Pursuit of Memory

by Joseph Jebelli

  Inspired by Wagers’s findings, another Stanford neurologist named Tony Wyss-Coray decided to take things further, and investigate if young blood had any bearing on people with Alzheimer’s.

  In a single day, human blood travels through 96,000 kilometres of capillaries, veins and arteries–enough to encircle the globe four times. It passes through every organ in the body, but a hefty 25 per cent of its volume flows solely through the brain. Why? Because it’s doing a lot more than ferrying oxygen. Besides red and white blood cells, blood carries more than 700 proteins in its plasma, the fluid portion of blood. What many of them do is completely unknown. But like everything else, they change as we age: some fade away while others appear more. What, then, asked Wyss-Coray, might those changes mean for the brain, and could they affect memory?

  To find answers, Wyss-Coray began by using blood plasma from young mice. First, he set up a unique type of water maze that tests spatial memory. Known as the Morris water maze, the animal is placed in a pool of water and can only escape by swimming around until it remembers the location of a small hidden platform. A young mouse will usually find the platform quickly, whereas older animals struggle to remember its whereabouts and thus take longer (it’s a bit like trying to find your car in a busy car park after a long day of shopping). Remarkably, when Wyss-Coray injected young plasma into old mice they fared just as well in the maze as their younger counterparts.6

  Emboldened, Wyss-Coray moved on to investigate what was occurring at the cellular level. In mammals, especially humans, learning and memory are linked to brain circuits found in the cerebral cortex and hippocampus. The number and strength of cells in these regions–strength here being LTP, the neural analogue of memory I discussed in chapter three–essentially determines how good these higher cognitive faculties are. And so, after performing parabiosis on pairs of old–young mice, Wyss-Coray got his team to stain thin slices of their brain tissue with a dye that binds new-born neurons. Amazingly, the older mice had three to four times as many new neurons in their hippocampus as their younger counterparts. What’s more, the young mice showed the opposite effect, displaying a stunted birth of neurons instead. Wyss-Coray then decided to focus on the dentate gyrus, an area of the hippocampus that regulates the formation of new memories. What he found stunned him. The neurons in the older animals were generating more synapses and demonstrating enhanced LTP. Their memories were improving. And the younger animals, again, showed the exact opposite.

  Why was this happening? He suspected it had something to do with how neurons are born in the adult brain. In the developing brain, the birth of new neurons–dubbed neurogenesis–is highly active. It was once thought neurogenesis is restricted to the embryo, until research in the 1980s showed it also occurs in adults via a population of adult stem cells known as neural stem cells (NSCs). The hippocampus is one of the few brain regions where nurseries of NSCs reside. These nurseries, it turns out, also happen to live right next to blood vessels. And that got Wyss-Coray thinking.

  In an earlier paper he had noted that ‘diminished neurogenesis during ageing may be modulated by the balance of two independent forces: intrinsic [brain]-derived cues, and cues extrinsic to the [brain] delivered by blood’.7 So what was it about old blood that had such profound anti-neurogenesis effects? To find out, he compared over sixty different blood proteins between old and young mice, and one protein stood out. It was called eotaxin, and it was far more abundant in older animals. It belonged to a family of molecules known to have roles in brain development and, strangely, asthma. Beyond that, not much was known about it. To rule out the chance that increased eotaxin was harmless, Wyss-Coray injected the protein into young mice, only to get the same results: decreased neurogenesis, decreased LTP, impaired learning and memory in the water maze.

  That was in 2011, and the results seemed too good to be true. Indeed, when the group first submitted the work for publication the reviewers rejected it on that very basis. So the scientists spent a year repeating the experiments at a different facility. Again, the data checked out. And so, by 2012, Wyss-Coray started investigating what was happening at the genetic level.

  In the aged animals, young blood was activating a master gene called CREB. Since the early 1990s, CREB had been well known for its clear role in stabilising long-term memories. Exactly how it does that isn’t clear, but good evidence suggests it does so by controlling how other genes are activated. But whatever the mechanism, the discovery plainly showed that young blood has a deep and powerful effect on memory. Wyss-Coray published those findings in June 2014, and they immediately hit the press. The authors suddenly found themselves having to turn down lucrative requests from old-aged billionaires, exclusive invitations to celebrity dinner parties, and, of course, a deluge of emails from patient relatives, imploring them to test it on their loved ones.

  It could have ended there–with Wyss-Coray’s team mining blood, imaging hippocampi and timing mice in the water maze. After all, they still had a kaleidoscopic range of blood proteins to investigate. But a chance encounter with the grandson of a Chinese businessman made them drastically reconsider their next step.

  Mr Li Wei was ten years old when he left school to work for a silk merchant. The eldest son of a destitute family in the Zhejiang province of mainland China, his starving siblings gave him little choice. In his early teens he moved to Shanghai and worked his way into a position where he became the protégé of wealthy investors and business tycoons, learning everything he could so that he might one day return home to save his family. By the age of twenty, he had helped get his father’s dying textile business back on its feet, and by twenty-six had moved to Hong Kong to start his very own cotton-spinning factory. That was in 1949. Today, his company is worth just shy of $5 billion.

  During his life, Li expanded his business into real estate, shipping and finance, gave generously to Buddhist charities and philanthropic organisations, got married, and raised two daughters. According to his grandson, Alex, now in his early thirties, he was an intense, energetic man who slept only four hours a night, shunned holidays and hobbies, and saw making money more like a game than making a living. ‘Working was his life,’ said Alex, sitting opposite me in a conference room on the top floor of the company’s Hong Kong skyscraper. Below and across the street lay Victoria Harbour, with the frenetic mix of tower blocks, designer brands, teahouses and temples of Kowloon beyond. ‘He was our role model, the foundation of all we have. So seeing his decline was painful.’

  The family first suspected something wasn’t right when Li started becoming unusually aggressive during family dinners. Looking back, they think that was some time in the late 1990s; it’s hard to give an exact date, because Li was so passionate about work that for a while the family thought he was simply having bad days at the office. But by the mid-2000s it was obvious. Gaping holes in Li’s short- and long-term memory emerged; suddenly, he couldn’t remember where he had been the previous night, or the names of fellow business associates he’d worked with for years. His one and only pastime of Xiangqi (Chinese chess) was becoming a total enigma; unwittingly, he started making up his own rules to compensate. Terrified at the prospect of losing the man Alex described as their ‘Superman’, the family employed a group of private nurses and looked into every available treatment.

  This was done quietly. In China, and many other Far Eastern Asian nations, Alzheimer’s is still deeply stigmatised. ‘The Chinese translation for Alzheimer’s is something along the lines of “elderly retardation disease”,’ Alex confessed, while his assistant poured us a glass of warm water (a Chinese tradition). ‘Recently it’s been renamed “regression of the brain” disease, but it’s always been a taboo. And nursing homes are not very popular here, because to the Chinese you really are supposed to take care of your parents until they pass. Putting them in a nursing home is almost viewed as an irresponsible act.’

  For years the family struggled to hide Li’s condition from outsiders, afraid of what people–especially his
business partners–would think. But in 2009 something extraordinary forced them to speak out. Li, then aged eighty-six, was coming to the final stages of Alzheimer’s. He slept most of the day, was spoon-fed, scarcely recognised his family, and was in and out of hospital for other medical conditions. During one such hospital visit, he received a blood plasma transfusion as part of a routine procedure. The result was miraculous.

  ‘Before the transfusion he didn’t say anything; he was like a child of one or two years old,’ Alex explained. ‘After, however, he looked at my mom and said, “I want to go home.”

  ‘She said, “Okay, let me call the chauffeur.”

  ‘Then he said, “Okay fine, let’s go downstairs and wait for him.”

  ‘To which my mom said, “Why don’t you just wait here, because the nurses might be coming.”

  ‘And he replied, “Okay, why don’t we do this: you wait here, and I will wait downstairs for the car.”

  ‘They were having a dialogue!’ Alex exclaimed in disbelief. ‘He was negotiating. To us, that was a huge jump.’

  It didn’t end there. Li remembered old faces and old staff members. He even spoke to them about business and current affairs. He experienced moments of ‘pure lucidity’, said Alex, which lasted as long as four days. It wasn’t much, but for the family, that felt like an eternity.

  It was no fluke, either. Li had the procedure a further three times and each time yielded a similar result. The hospital doctors were baffled. They didn’t want to explicitly say that Li’s improvements were caused by the young plasma, lest they give a potentially false sense of hope. So Li’s family gratefully accepted what they’d been given, and surreptitiously documented the events should a time come when it might prove useful. They knew nothing of the experiments going on in America–until, one day in spring 2013, Alex decided to share the story with a family friend and scientist named Karoly Nikolich.

  ‘I immediately told him about Tony Wyss-Coray’s work,’ Nikolich said, sitting in his home office in Palo Alto, California. I’d just asked him to recount the inception of this radical new therapy, and he was beaming. It was 5 a.m. for him–the time he usually starts his day–and we were talking over Skype. He was easy-going and casually dressed, and yet had the face of a stern industrialist. ‘Afterwards I rang Tony and said, “Can you believe this!?” He said it was the first time he’d ever heard of a human situation where this may actually be helpful. We were fascinated.’

  Alex had told the Hungarian professor about his grandfather over lunch in Hong Kong. Though Nikolich worked primarily at Stanford, he also acted as a scientific adviser for the family’s occasional investment forays in biotechnology. Soon after their conversation, the pair started brainstorming over how best to move forward. A government-funded trial was out of the question: funding was hard enough to come by as it was, let alone funding for something based on the anecdotal observations of a single patient. So Alex agreed to fund it himself, providing $3 million for Nikolich and Wyss-Coray to establish their very own company. They called it Alkahest, after the mythical substance that chemists in the fifteenth century thought had the power to cure all disease.

  Since January 2014, Alkahest has enrolled a small number of people with mild to moderate Alzheimer’s. ‘So far we’ve done about sixty infusions,’ Nikolich revealed to me, ‘and we haven’t seen any adverse effects. This isn’t an official report, but I think we’re comfortable with the safety.’ Understandably, he was reluctant to tell me whether they had actually seen any cognitive improvements. Optimism can be a dangerous thing in science. There’s already a black market for body organs, and Wyss-Coray now gets emails from people offering to bleed children for his research. But the pair have a more basic concern at the moment–supply. A simple calculation shows that the entire planet’s young plasma supply would only be enough for 3 per cent of the world’s Alzheimer’s patients.

  Alkahest’s ultimate goal, therefore, is a pill containing purified blood proteins. It may only take a few; Nikolich thinks three to five proteins should do the job. But before he continued, my impatience got the better of me.

  ‘How long?’ I asked.

  He smiled. ‘It’s too early to say.’

  Unsatisfied with that answer, I did more research and discovered that others have put it at fifteen to twenty years. I almost wished I hadn’t looked. There’s a maddening quality to being both a scientist and a patient relative. One part of you knows to leave emotion out of it; the other is furious at the sheer indifference of when nature chooses to reveal its secrets. But I found something else while digging, too. In early 2015 a Spanish chemical company called Grifols put nearly $40 million into Alkahest for a 45 per cent share in the company. Victor Grifols, the company’s eponymous CEO, announced that the collaboration would finally address ‘the major unmet medical need of this century’. I made a note to call the company in one year’s time–and every year thereafter.

  In the meantime, I was eager to hear Nikolich’s thoughts on what caused Alzheimer’s. He’d taken such a left-field approach to curing the malady, I wondered if he could even class himself as a Bapist, Tauist, or E4ist.

  ‘I’m not in any camp, actually. My gut feeling is that this probably has deeper roots.’ Wanting to offer me something constructive, he leaned back in his chair and rummaged through a nearby bookshelf, pulling out books and papers by other unconventional thinkers. He told me about a group in Seattle, Washington, who are studying brain ageing in domestic dogs–the rationale being that because dogs share our living space and also succumb to dementia, they may hold a clue that mice and humans do not. He also spoke about a substance found in the soil of Easter Island by Canadian scientists in 1964, called Rapamycin, which has been shown to extend the lifespan of mice by 14 per cent.8

  Amid all these arresting developments, though, Nikolich stressed a crucial message: the mission, he said, is extended healthspan, not lifespan. Because even if we all live to 150, ‘nobody wants to live long as a vegetable,’ he bluntly concluded.

  But some believe this is a false dichotomy. Aubrey de Grey, an eccentric computer scientist and gerontologist at Cambridge University, thinks the only way to extend healthspan is by radically extending human lifespan. Repairing the molecular damage of ageing, he claims, should eventually allow us to live healthy lives well into our hundreds if not thousands. Adults could be sixty chronologically, but remain in their thirties biologically. As the technology advances the gap would then stretch out over centuries, with the knock-on effect of eradicating all age-related diseases–including Alzheimer’s. In Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime, de Grey predicts a time when

  we might take a regular sequence of anti-amyloid vaccines, not unlike the standardized series now given in regular succession over the course of our childhood; we would get a ‘booster shot’ of some every few years, while others would be administered only a few times in each century of a greatly expanded lifespan. Each time we took one of these vaccines, our cells and organs would once again live and function free of a specific species of molecular bindweeds [i.e. plaques and tangles], returning them to the literally unbound potential of youth.9

  Approaching seventy himself, Nikolich admitted that healthy ageing is fast becoming his obsession. But his memory is as good as ever: through the bright glow of my computer screen, he recalled the hardships of growing up in a communist satellite of the Soviet bloc, and how his parents had to scrape together makeshift chemistry sets to better educate him about science and the wider world. Now, it seemed, fate had put him, Li Wei and Wyss-Coray together to revive and realise an ancient fantasy.

  On a less grandiose note, there’s a plain and important lesson to be learned from the events of this chapter, aptly stated by Alex before I left him in Hong Kong. ‘For us, this was really just an observation of my grandfather. If every caretaker of patients who’ve been through medical procedures could just document things more, that’s already a significant step. A
nd it’s simple, right?’

  In the rigorous, dispassionate realm of academia, anecdotal evidence is often given short shrift. It suffers mainly from having no experimental ‘control’–no objective means of comparison, that is–to minimise variables and increase scientific objectivity. We depend on controls to infer whether two things are causally linked. But as Alex and Li have demonstrated, anecdotes sometimes have another power. They can lead to new hypotheses. They can take what seems absurd and use it to arouse creativity. No one would seriously consider bleeding the young to restore the old. And yet, something valuable was hiding within such an absurdity all along. It just took a perceptive relative to shake it loose.

  16

  Seeds of Dementia

  The fox knows many things, but the hedgehog knows one big thing.

  Archilochus, Greek proverb

  BY THE TIME I finished my doctorate at University College London, half the scientists in the department were entranced by a new lead. When I first heard about it, though, I felt a troubling coalescing of intrigue and dread. Naturally we all had our own pet hypothesis about what caused Alzheimer’s. It was not unusual for a group of us to meet in the kitchen over tea or coffee and quiz each other about our respective ideas; such encounters were welcome and–for the most part–civil. But something about this one went too far. It made us question everything we thought we knew. Whether that was reasonable scepticism or insecure pride, I don’t know. But when I buttonholed one of its advocates boiling the kettle one day, and forced him to explain it to me, the story he told almost made me want to wear a hazmat suit to work.