Science is about getting it wrong, until you get it right. What if we're refusing to admit we're wrong about a horrifying disease?
"The hard but just rule is that if the ideas don't work, you must throw them away," wrote astronomer Carl Sagan.
But when your career and everything you’ve ever worked for is on the line, admitting you might be wrong is very hard to do.
Despite decades and billions of dollars of research, we have not developed a single drug to cure, prevent or even slow Alzheimer's disease.
In January, after spending billions on failed drug trials, Pfizer, one of the largest companies in the world, gave up and pulled out of Alzheimer's research altogether.
Leading researchers say these repeat failures are a required part of the scientific method.
But a small group claim those researchers are refusing to accept, despite decades of drug failures, that they are wrong about the causes of the disease.
More damningly, they say leading Alzheimer's theories have become dogma, blocking research into other unorthodox theories.
“It’s been 100 years of the amyloid hypothesis. The treatments that have been in development are consistently failing. There is a growing sense that maybe we need to rethink the direction of the field,” says Professor Bryce Vissel, director of neuroscience and regenerative medicine at the University of Technology Sydney.
Australia’s leading Alzheimer’s scientists do not agree. They say the evidence for what is known as the 'amyloid cascade hypothesis' is overwhelming. In interviews, a number told Fairfax that Professor Vissel was at best a fringe researcher.
And the evidence for amyloid is compelling. There is only one problem with it: a focus on it hasn't led to a single drug that stops or even slows the disease's heartbreaking progression.
The discovery of Alzheimer's
Around the turn of last century, a German doctor working in Frankfurt sent the brain of an elderly patient who suffered from memory loss and delusions to undergo a process only recently perfected: brain staining using silver dye.
When the results came back, Alois Alzheimer was stunned. They revealed the woman’s brain was filled with small sticky plaques in between the nerve cells, almost like the neurons had been gummed up.
More than 100 years later, we know more about those plaques – but not much more.
We know the plaques are made of a protein called beta-amyloid. They block neurons from talking to each other. Another protein called tau also appears to be involved, forming into "tangles" that cut off the transport system that ferries nutrients within brain cells.
Both plaques and tangles form first in the areas of the brain important to memory and learning and then gradually progress to other regions, killing neurons as they go. Patients lose their memory first, and then other functions progressively deteriorate.
Alzheimer's, which is the leading cause of dementia, can lead to immobility and problems with feeding and swallowing, which can cause pneumonia, heart failure and eventually death.
We know all this. What we still don’t know: what causes dementia, and how to stop it.
The path to successful drug treatments for any disease is often long and winding and littered with failures. But the miserable record for Alzheimer's drug development stands alone.
A study in 2014 found 99.6 per cent of all compounds tested in clinical trials between 2002 and 2012 on Alzheimer's had failed. The success rate was "among the lowest found in any therapeutic area", the researchers concluded.
And the vast majority of drugs don’t even make it to clinical testing.
Bapineuzumab, owned by Pfizer, failed to outperform a placebo in a phase three trial in 2012.
Solanezumab, an antibody designed to clear away amyloid beta proteins, failed in 2012. In 2016 it was tested again at an earlier stage of disease progression, and again failed.
Verubecestat, which was designed to interfere in the process that creates amyloid beta and was among Merck’s most promising compounds, failed at stage three trials in February last year.
What’s going wrong?
A changing of the guard?
Many academic papers are replete with scientific jargon. Professor Vissel’s big paper on amyloid reads more like a tabloid op-ed.
“A hypothesis that remains unproven yet catches the collective imagination can become, with the passage of time, so seductive that it dominates peer review opinion and arrests the development of alternative ideas. Such is the case for the amyloid hypothesis,” it begins, and does not let up from there.
Professor Vissel argues the scientific community became obsessed with amyloid because it was so simple and so compelling – a literal plaque on the brain, gumming up its functions. Yet amyloid plaques are not uncommon in healthy individuals; by some estimates 40 per cent of non-demented elderly have them. And, Professor Vissel points out, not all people with dementia have plaques.
Professor Vissel and others have been emboldened to speak out by Pfizer’s recent withdrawal from the field. But they also sense a changing of the guard.
“Any big international Alzheimer’s congress you go to these days, the audience is split down the middle. More and more, people are saying amyloid is not the only answer – it might be part of the answer, but it’s not got the prominence it once had,” says Dr Bill Ketelbey, Pfizer’s former Australian senior medical director.
Dr Ketelbey now runs his own startup, Actinogen, which is testing a novel, non-amyloid treatment for Alzheimer's.
Professor Vissel and Dr Ketelbey believe lifestyle factors contribute to Alzheimer's disease, and amyloid plaques are likely to be just one part of a complex condition.
Obesity and diabetes are both known strong risk factors for Alzheimer's. Why would lifestyle conditions lead to plaques forming in the brain, the dissenters ask, unless something else is going on here?
Both conditions are well-known for activating our inflammation system. Inflammation is the tender and painful tissue that rises up when we sprain a joint; it can also occur, unseen, inside the body.
Inflammation in the brain impairs cognitive function and memory formation. If it goes on too long, it can lead to cell death. What if our Western diets and lifestyles - which are linked to obesity and diabetes - are also leading to overactive inflammation systems, spreading to the brain and damaging it?
There is good evidence of brain inflammation in Alzheimer's patients, although critics argue this is a symptom of the damage being caused by amyloid.
All this has led some physicians to start calling Alzheimer’s "type 3 diabetes".
In studies, the brains of animals fed diets designed to give them diabetes quickly become riddled with plaques.
And a trial being funded by the UK Alzheimer's Society which uses a diabetes drug to treat the disease is showing promise in animals.
“The evidence is mounting,” says Professor Vissel. “This says there are ways of treating dementia that aren’t based on amyloid at all.
“I suspect it’s going to be the case that we work out that amyloid can be the cause in some cases, but mostly it’s going to be secondary.”
The inflammation hypothesis has its own flaws, as critics - who Professor Vissel likes to call "amyloid traditonalists" - are quick to point out.
“I think it’s very dubious,” says University of Melbourne Alzheimer’s researcher Professor Chris Rowe. “Bryce is a bit of an alternative thinker, he’s not mainstream.
“When you do imaging studies ... You only see inflammation once patients have developed dementia. It’s a late feature of the disease, not a cause”.
Where the money goes
Amyloid is "too big to fail," American researcher Rudolph Castellaini told The Times of London. “There is too much personal and financial investment."
Refusing to accept you're wrong is one thing; a scientific community that refuses to fund different ideas is quite another.
It has been extremely difficult for years to get a grant for any non-amyloid research, says Emeritus Professor Ian Clarke, an Australian National University researcher and Professor Vissel’s long-time co-author.
“The whole Alzheimer’s field in this country is very tied up with amyloid. If you don’t believe in amyloid you couldn’t get a grant for decades in this country. It’s like Galileo trying to get a grant out of the Vatican.
“Bryce is the only person I can find in this country who will even talk to me."
Professor Vissel claims after he wrote his paper on amyloid his inbox was flooded with emails from researchers thanking him for saying publicly what they were thinking privately, but were too afraid to put their name to.
“It was hard for a long time to get funding for research outside of the amyloid hypothesis. It was hard to get papers published. There has been a feeling that if you don’t publish with amyloid in your paper, you’re going to have a harder time publishing it,” he says.
At the centre of all this is a man several scientists refer to as the “the father of amyloid” or the “pope” of Alzheimer's: the University of Melbourne’s Professor Colin Masters.
Professor Masters is a giant in the field – he was the first in the world to define the key molecular and genetic pathways that produce amyloid plaques, and is one of Australia's leading scientists.
But his enormous successes have skewed the field, claims Dr Clarke. Research at odds with Professor Masters’ work became politically untenable, he says.
“I couldn’t get a grant for a decade in Australia. I applied for a similar grant in the US and got it straight away. Australia is clearly on the amyloid side – because of Colin Masters,” says Macquarie University Alzheimer’s researcher Professor Gilles Guillemin. “Too many scientists subscribe to dogma.”
Quite obviously, Professor Masters does not agree.
"We are all subject to the peer review system", he told Fairfax via email. "We have just as many hurdles to jump in convincing our peers that our approach is correct. The 'politics' is really about our peers who are poorly informed or hold non-scientific ideas about how to move the field forward."
He has a strong, simple and clear counter to the inflammation theory - one written into our DNA.
“This is what Bryce and others don’t understand,” says Professor Masters.
“We have a pretty good handle on the cause. It’s pretty much locked down. And the single most powerful argument is in genetics. Bryce or anyone else cannot argue with that.”
Here's the evidence for amyloid in a nutshell: people with genetic mutations that produce more amyloid are at very high risk of developing Alzheimer’s. People with mutations that produce less amyloid seem to be protected.
Simple. Straightforward.
“Amyloid is found in the brain of everyone with Alzheimer’s, but rarely in other brain diseases. If it’s only a byproduct, why does it only appear in these cases?” asks Professor Rowe.
In this explanation, inflammation in Alzheimer's is a reaction to the damage caused by the amyloid, much in the way the skin bruises after a blow. A symptom, not a cause.
Fairfax interviewed four of Australia’s foremost Alzheimer’s experts, including Professor Rowe, director of the Centre for Excellence for Alzheimer’s Research Professor Ralph Martins and Professor Masters.
All agreed the drugs that Pfizer and others were testing were failing because they were being given too late in the disease’s progression or given in too low a dose.
“You’re looking at a severely damaged brain by the time the patient has symptoms. The cells are dead,” says Professor Rowe.
“So in a way it’s not surprising that trying to treat a severely damaged organ is not successful, and it’s not unique to Alzheimer’s. The key is to try to prevent the damage in the first place.”
A detectable early stage biomarker of the disease would allow us to catch Alzheimer’s years before symptoms appear - and treat it. Professor Masters and Professor Martins were part of a research team that developed a potential candidate in January, yielding headlines around the world.
If early biomarkers can be found, failed drugs could be dug out of cold storage and retried when the disease first appeared.
“The field is moving toward early diagnosis,” says Professor Martins. “That’s where the future is.”
Professor Vissel, meanwhile, likes to tell the story of how Professor Barry Marshall won his Nobel Prize.
So Marshall decided to experiment on himself. He ingested the bacteria, developed an ulcer, and then took a simple antibiotic to cure it. “Everyone was against me, but I knew I was right,” he reportedly said, a few years before he was awarded the Nobel.
The reasons why Professor Vissel likes to tell this story are obvious, although he’s less confident than Marshall.
“Being a doubter has been difficult. you’d have to be an absolute fool to disregard the brilliance of the people in this field, and the weight of evidence they have.
“And whether I’m in the right camp, I cannot tell you yet.
“But there was groupthink around stomach acid. This guy said something completely different, he was ridiculed and not accepted, and for a long time it was very difficult for him. And he ended up with science’s greatest prize - because science is a living organism.”
By Liam Mannix Sydney Morning Herald's science reporter.
