The most fruitful basis for the discovery of a new drug is to start with an old drug.
Sir James Black
SIX HOURS WAS all it took. In a burst of potency and precision the drug found its target, locking on to receptors deep within the brain to jumpstart a molecular cascade. Like a pinball obeying the laws of motion, the impact ricocheted through neurons, reordering their inner ‘cogs’ and ‘springs’ until a new set of genes sprang into action. The mouse woke to the now familiar feelings of confusion and forgetfulness. But it felt better somehow–smarter. Of course, it would never know that a drug had just eviscerated a quarter of the amyloid in its plaque-riddled brain. Nor was it aware, three days later, that half of the amyloid would vanish. All it knew was that it had finally remembered how to ruffle tissue paper into a satisfying nest.
The scientist watching couldn’t believe her luck, for this drug was already approved in humans. For the past thirteen years it had been used not for Alzheimer’s, but for skin cancer.
In 2010, as the Alzheimer’s vaccination yielded unexpected insights, other researchers decided to do a little lateral thinking of their own. Among them were the American neuroscientist Tom Curran and the French biologist Yves Christen, who convened a meeting on 26 April in Paris. The topic under discussion was a remarkable tale of yin and yang: how Alzheimer’s and cancer are actually two sides of the same coin. The audience, having just started to dissect the biology of dementia, suddenly found themselves squaring an unexpected circle. How can cancer, the uncontrolled growth and proliferation of a single cell, be at all related to a disease characterised by countless cells simply withering away and dying?
There was, no doubt, a connection. Statistics had shown that people who get Alzheimer’s have a lower risk of developing cancer.1 Inversely, if you develop cancer you’re less likely to get Alzheimer’s. The same holds true for cancer and Parkinson’s, and cancer and motor neuron disease. Genetic observations also spotlighted a link, in that cancer-affiliated genes–like p53 (mutated in half of all human cancers), ATM, CDK5, mTOR and PTEN (acronyms hauntingly familiar to many cancer victims)–all appeared to overlap with cellular pathways underlying Alzheimer’s.2 It was as if a pendulum was swinging between the two. Perhaps, then, slowing the arc towards one could slow the arc towards the other.
From 8.30 a.m. to the close of the day, more than a dozen speakers tried to build a case for how this might be possible. Cancer is known to be an aberration of the cell’s normal life and death mechanisms: mutated genes derail the cell cycle and lethal replication is the consequence. But neurons don’t divide, and so instead of impacting the cell cycle, neuronal damage appears to activate proteins that converge on the ‘death pathway’: a network of tightly controlled proteins that carefully dismantle the neuron from within. And this is where things get interesting, for many of those proteins are also involved in cancer. Maybe hitting Alzheimer’s with cancer drugs–drugs that work by essentially meddling with these protein networks–was therefore worth a shot. Maybe, as one French journalist wrote at the time, ‘this cross-fertilisation between the fields may well go on to bear a wonderful new crop’.3
The first to reap such a harvest was neither a cancer biologist nor a qualified neuroscientist. A spunky twenty-two-year-old graduate student at Case Western Reserve University, in Cleveland, Ohio, Paige Cramer was a novice in the eyes of her mentors. And yet, on 23 March 2012, she submitted evidence to the pages of Science, arguably the most prestigious scientific journal, that a thirteen-year-old skin cancer drug called bexarotene could completely reverse the symptoms of Alzheimer’s in a matter of days.4 This was in mice, of course, not humans. But the effects were so profound that such a detail had–for once–taken a back seat.
Originally from the emerald-green coast of Pensacola, Florida, Cramer grew up in a studious household. Her father is a physician and scientist, her mother an attorney in healthcare law. She told me that she remembers many evenings spent around the dinner table discussing diseases and puzzling scientific problems. She was almost custom-built for biomedical science, I thought. The scales were tipped during Cramer’s freshman year of college, when her best friend became paraplegic after a spinal cord injury, and Cramer decided that neurology needed more detectives.
Brand-named Targretin®, bexarotene was designed to treat T-cell lymphoma–a rare type of skin cancer caused by white blood cells called T-cell lymphocytes–but it wasn’t very effective. Oncologists only prescribed it when patients didn’t respond to better medications. ‘Truth be told, I’d never heard of it,’ Cramer’s supervisor, Gary Landreth, told me. ‘It’s still controversial in the cancer business, because no one really knows how it’s supposed to work in T-cell lymphoma.’ So how was a cancer drug supposed to work in Alzheimer’s? I wondered.
I kept digging. It turned out that what enticed Cramer was the drug’s ability to strike at the innermost chords of neuronal chemistry. Inside every cell, genes are activated by a special class of proteins called transcription factors. These proteins physically bind to DNA and then race along its threads like bows on a string. The result is a close copy of the gene, called RNA, which then rises up to ultimately do its job in the form of a protein. By boosting the activity of a transcription factor called RXR (retinoid X receptor) bexarotene thus acts as a kind of DNA conductor, directing the cell to prioritise certain ‘notes’, or proteins, over others.
But Cramer’s attraction to RXR was something more than mere chemistry. Once active, RXR appears to control the levels of apolipoprotein E (APOE), the same molecule that won Allen Roses both fame and exile in the 1990s. Now here was a link worth exploring, Cramer thought. In the twenty years since Roses had pinpointed APOE4 as the prime genetic risk for Alzheimer’s, attitudes towards it remained mixed, and the trials targeting it had all run aground.
But if one could truly modify APOE4, half of all Alzheimer’s cases might be history. And the upshot didn’t end there: good evidence suggests that APOE proteins help clear the brain of beta-amyloid. The details are typically fuzzy; for instance, it isn’t known whether APOE does this by physically latching on to beta-amyloid (like a Venus flytrap), or if it somehow recycles the plaques by other means. But in any event, the prospect of a tool capable of targeting two of the three main disease culprits was irresistible.
And so, in an act as routine as it was startling, Cramer convinced a physician in her department to write her a prescription, and then wandered down to her local pharmacy to pick up the would-be Alzheimer’s cure. ‘It’s not really legal to do that,’ Cramer said to me over the phone, ‘but I was just a naive graduate student, one that was willing to try anything.’
Upon returning to the lab, Cramer broke the cancer pills apart and began feeding them to her mice. Several hours later, the mice’s beta-amyloid levels dropped by 25 per cent. Within 72 hours the drop hit 50 per cent, an unprecedented result. She witnessed this in transgenic mice harbouring both Carol Jennings’s and Victoria Huntley’s genetic mutations, as well as mice engineered to display a particularly rapid and aggressive form of Alzheimer’s.
By meticulously observing the mice’s behaviour over the next three days, Cramer also discovered that they were nesting just like they used to. Lab mice are usually given pieces of pressed cotton which they chew up and shred into nests. Transgenic Alzheimer’s mice lose the ability to do this, kind of like how human Alzheimer’s patients lose the ability to dress themselves, but Cramer’s mice were suddenly able to resume their nest-making.
The mice that had been fed bexarotene also far exceeded their sick counterparts in maze trials and other tests of memory. One such test is known as contextual fear conditioning, in which a mouse receives a stimulus (usually a loud noise) followed by an unpleasant sensation (usually a mild foot shock), forcing it to adopt the stereotypical behavioural response of freezing like a statue. It’s somewhat cruel, I concede, but it’s highly informative. Of all the emotions, fear is perhaps the most closely connected to memory. Everyone remembers frightening experiences. It’s also an evolutionary imperative, and so organisms quickly learn what to be fearful of and respond in the same way at the mere sight of it. This was most disturbingly demonstrated in 1920 using a human child. ‘The Little Albert Experiment’, conducted by US psychologists John Watson and Rosalie Rayner, trained a nine-month-old baby to associate loud banging noises with the sight of a white rat. Thereafter, Albert became petrified when confronted by anything resembling a white rat–a white dog, a white coat, the white beard of a Santa Claus mask. The memory was seared indelibly on his mind.
In the brain, fear conditioning is governed by an ancient interplay between the hippocampus and a neighbouring region called the amygdala. For Cramer, this gave the perfect opportunity to see how deep bexarotene’s effects on memory really went, because a good fear response is predicated on a healthy hippocampus. ‘Think about the idea as you hear a train,’ she explained. ‘Generally speaking, if you’re near a train track you’ll look both ways, because you have that association of moving-train-equals-danger; be careful. Someone whose memory hasn’t developed properly, or whose memory is impaired, won’t make that connection and will continue to walk near a track without looking.’ That Cramer’s demented mice could again be fear conditioned, therefore, indicated a powerful resurgence in neuronal connectivity.
That wasn’t all. In considering how else she could assess their memory, Cramer decided to focus on smell. It may surprise you to learn that one of the first things many Alzheimer’s patients experience is ‘anosmia’, the partial or near total loss of smell. What shouldn’t surprise you is that memory and smell are intimately linked. I for one, at the faintest whiff of a familiar scent, am instantly flooded with images and feelings of past events; even memories I’d long forgotten come crashing back. It’s due to the way smell is wired in the brain, being processed by a region called the olfactory bulb. And like the amygdala, the olfactory bulb sits right next to the hippocampus.
Interestingly, Alzheimer’s patients appear to have an especially hard time smelling peanut butter. A 2013 study performed by Jennifer Stamps, a researcher in the Department of Food Science and Human Nutrition at the University of Florida, instructed a group of patients to close their eyes and identify the smell from a container holding 14 grams (a tablespoon) of the condiment.5 When the patients struggled to detect the scent, Stamps moved the container 1 centimetre closer to their nostrils. She found that Alzheimer’s patients required the peanut butter to be about 10 centimetres closer than both healthy people and patients with other types of dementia. The anosmia was largely confined to the left nostril, which is thought to be because Alzheimer’s damages the left side of the brain more than the right. The relationship between smell and Alzheimer’s is now so well documented that scientists are trying to use smell as a biomarker for early diagnosis.
By measuring the electrical activity of a circuit within the olfactory bulb, known as the piriform cortex (from the Latin pyriformis, meaning ‘pear-shaped’), Cramer found that her transgenic animals’ sense of smell was being enhanced by drug treatment. ‘This is really exciting,’ she noted, with audible exhilaration, ‘because it’s another benefit for neuronal networks, for the strengthening of connections between brain regions.’
Landreth echoed her excitement. ‘In mice it’s like magic. The effect of this drug is so rapid in reversing the pathology. Think about this: bexarotene is the first example of a drug that actually modifies Alzheimer’s disease mechanisms. And it works in thirty days.’
I myself remember the buzz surrounding this discovery. I penned a piece for Pi, University College London’s student newspaper, calling attention to it (much to my supervisor’s chagrin; I could have been doing more experiments instead). Listening to Cramer and Landreth retell the story, something about it still stirred me. It all started with a doctor handing her a prescription and telling her to head to a drug store. Was the elusive cure for Alzheimer’s sitting on a shelf in our pharmacies all along?
I wasn’t alone in that wish. Cramer’s findings drew instant attention from the press. Landreth received a torrent of correspondence from reporters and, more importantly, the relatives of Alzheimer’s patients themselves. ‘We published in February,’ he stated, ‘and I was not able to answer my phone until November. I got hundreds of calls and emails from all these desperate people. My secretary was in tears listening to their stories. It was heartbreaking.’
‘People want something,’ Cramer elaborated. ‘They need something.’ Despite warnings about using the drug off-label, some people went ahead anyway, more than willing to take matters into their own hands. In the press the story of one Mandy Vear, from Rossendale, England, began to surface.6 As Vear’s father’s condition was descending into outright violence against his family, she pleaded with her doctor to write him a prescription for bexarotene. But the physician refused, for bexarotene’s side effects cast a dark shadow by raising triglycerides: blood fats linked to diabetes and heart disease.
Another story featured an anonymous Belgian patient whose physician agreed. Sixty-eight years old, the man reportedly took the drug every day for twenty-three months and was monitored by a team at the Université catholique de Louvain, in Brussels, Belgium.7 Tantalisingly, his memory somewhat improved and he scored higher in several tests of cognition. The problem, as one would expect, is that there was no way to rule out a placebo effect. And so this anecdotal case fossilised as just that: anecdotal, informal, unreliable. ‘You’ve just got to take it for what it’s worth,’ Landreth made clear to me. ‘It supports the idea, but you certainly wouldn’t base any subsequent action on a case report.’
But where were the human trials? I wondered.
I learned that four other groups, inspired by Cramer’s discovery, had already set about replicating her data. Before any discovery is given credit, before it can launch human trials, it faces the gauntlet of widespread replication and doubt. This isn’t pretty; scientists can shoot down someone’s work with the accuracy of an Olympic archer. Which, unfortunately, is exactly what they did. Just as Cramer and Landreth were pushing for clinical trials, all four groups announced that they categorically could not reproduce Cramer’s data. Had she made a mistake? Could her discovery be an illusion, a quirk of her batch of mice, perhaps? Was this all just a tempest in a teapot?
In May 2013 Nature published a disheartening article outlining the dissenters’ views.8 Their chief criticism was that bexarotene didn’t actually affect Alzheimer’s plaques. Rather, the drug diminished levels of a smaller, free-floating form of beta-amyloid called oligomeric amyloid: a kind of intermediate brand of the toxin, which clusters together long before plaques appear. Yet many believed this type of amyloid was more central to the disease process. A stack of scientific literature had shown that oligomeric amyloid could scramble synaptic communication like hail bombarding a television antenna. And while plaques certainly looked more deadly, their invisible predecessors correlated better with memory impairment and cognitive decline. Some even claimed that clinical trials had failed because they’d tried to remove plaques, when they should really have tried to remove oligomers.
For Landreth, it was all a lot of hot air. ‘It pissed me off that this entire discussion centred on plaques, when we explicitly showed that plaques don’t matter! All the plaques say is “things have gone badly in the brain”. But if improved memory and cognition is the ultimate goal, why should plaques matter? It’s clear that these small oligomeric species affect synapses, and I think we improved the animals’ behaviour by removing them from the brain.’
He was also quick to point out that other groups had prepared the drug differently. They’d dissolved its raw powder in an artificial liquid, instead of simply using the pill form, as Cramer had. The reason that matters, Landreth maintained, is that the former stays in the blood for minutes while the latter remains in circulation for hours. And in the realm of molecular genetics, that disparity was titanic.
Although Landreth’s rejoinder wasn’t enough for Big Pharma to weigh in, others weren’t ready to see the lead so easily dispatched. A group of private donors–all anonymous Alzheimer’s relatives–raised over $1 million to fund a small clinical trial, led by Jeffrey Cummings at the Lou Ruvo Center for Brain Health in Las Vegas, Nevada. Completed in August 2014, twenty people over a period of four weeks received either bexarotene or a placebo. Remarkably, the drug did appear to reduce amyloid, but only in the people who didn’t have the APOE4 genotype. As Cummings scrutinised the data further, he reached two conclusions for that: ‘It could be that it only works in APOE4 negative individuals,’ he explained over the phone. ‘Or, I think equally as likely, we may simply need to expose these people [to bexarotene] for longer, because the amyloid in APOE4 carriers is denser and more aggregated.’
Cummings is currently planning a second, year-long trial of bexarotene. Even if the drug fails to ameliorate the symptoms of dementia, it may plant the seeds for one that does. And a clever chemist, he argues, could theoretically remove the molecular components causing the potential side effects. Confident, innovative and reasonable, this approach to drug discovery reignited the hopes of clinicians and patients alike. So much so, in fact, that Cummings himself broke protocol and put three of his own patients on the drug. When I asked him if he’d seen any changes, he gently exhaled down the line. ‘Well, one had very elevated triglycerides and so was only on it for a very short period of time. The other two continued for a few months and, you know, the families would do what they always do and say, “Oh, I think she’s a little better,” and then, “No, she’s getting worse.” In truth, I couldn’t see a definitive pattern. You just can’t know what’s happening because it’s such a slow disease and every patient has a slightly different course. So you cannot actually see whether you’re helping them or not.’
Many of Cummings’ patients have become personal friends. With their time slowly running out, with the stepwise manner of science ceaselessly rewriting the rules of Alzheimer’s, they could not have asked for a more fearless pragmatist for their plight.
When I began investigating bexarotene I was hoping to have a more conclusive idea of whether it would work. But it is, as yet, unclear how this research story will end. In a broader sense, the fact that a cancer drug can twist the cogs of Alzheimer’s inner gears says much about how we can approach the problem. It suggests that the web of causation stretches out into far more scientific domains than previously thought. Indeed, the stories of the last three chapters–of blood, prions and vision–vividly illustrate this point. While the challenge of describing Alzheimer’s must be drawn on hard, clearly defined lines, the challenge of treating it must remain conceptually malleable. This is the conclusion researchers are now reaching, and as a result many have begun testing the impact of other seemingly unrelated drugs–such as statins (primarily aimed at reducing blood cholesterol), anti-epileptic drugs (principally aimed at minimising epileptic seizures) and incretin mimetics (predominantly aimed to treat type 2 diabetes). All show signs of ameliorating the effects of Alzheimer’s in cell and animal models, and large-scale clinical trials are being discussed.
The web of treatment is widening.