Comment; Is it possible that something as simple as increasing intake of l-Serine can help stave off neurodegenerative diseases? Inexpensive, harmless, available without a prescrption. I also like the work of Dr. Dale Bredesen. I suspect Serine + Bredesen = success.
Big Pharma has spent billions and gotten nowhere. Here’s what we could learn from a new theory.
By Rick Tetzeli
January 18, 2019
bear (holding a beaker, naturally) just above the front portico. You might even spot a
wealthy local patron wearing one of the lab’s “Serine Dipity” sweatshirts. That’s a
wordplay on L‐serine, an amino acid that serves critical functions in the central
nervous system, among other things. That’s the second strange part of this story: How
extraordinarily unlikely and yet wonderful would it be if Cox and his colleagues were
right—and the best prevention for some of these terrifying diseases turns out to be a
naturally occurring protein building block rather than a high-priced drug?
You can buy a kilo of powdered L-serine for $53 on Amazon. A Serine Dipity
sweatshirt, on the other hand, will cost you a $150,000 donation to Cox’s lab. Which
leads us to the third twist in this marvelously odd tale. The sweatshirt buyers (and
Cox’s wealthy backers) seem to believe just as fervently in the man’s innovative
research model as they do in his purported cure. Indeed, it’s fair to say that whether
or not Cox’s theory pans out, the style of medical investigation he’s pioneering is
gaining fans—even in some traditional and elite academic quarters. So if Cox and his
colleagues do push the science forward on Alzheimer’s, ALS, or any other
neurological disease even a little, it may have an added benefit of offering the culture
of medical research a fresh model to emulate.
And that—in a nutshell—is what the Paul Cox story is all about.
Cox’s interest in neurodegeneration began when he set out to solve a puzzle that had
bedeviled researchers for decades: Why did an extraordinary number of the Chamorro
people of Guam develop an odd hybrid of ALS and Alzheimer’s symptoms? Cox’s
answer: They had been poisoning themselves every time they indulged in their
greatest culinary delight, a bat boiled in milk—eyeballs, wings, and all. That was 16
years ago. Since then, Cox has been trying to see if that insight could eventually lead
to some kind of treatment against brain diseases.
Working on a tiny budget, Cox has built a consortium of 50 scientists from a wide
range of disciplines, who share their unpublished research with one another and push
Cox’s theories in directions he never would have anticipated. Within this loose-knit
group, the spirit of inquiry seems to thrive, uninhibited by strictures that rein in
scientists in academic research centers and pharmaceutical labs. “He’s a visionary,”
said Deborah Mash, who runs the Brain Endowment Bank at the University of Miami’s
Miller School of Medicine and who has worked with Cox on several experiments. “I
was a skeptic. But he’s a fiercely intelligent man. The way he’s pushed this forward is
unbelievable.” Cox’s “virtual pharma,” as he calls it, has fostered a more innovative,
organic, and patient-focused form of scientific research than what’s often found at
the world’s leading drug companies, its members say.
Those companies have failed miserably in their own efforts to attack Alzheimer’s. The
FDA has approved just five treatments for Alzheimer’s, and they provide only limited,
temporary relief. The agency hasn’t signed off on any new ones since 2003, despite
more than 500 clinical trials of Alzheimer’s drugs. In 2018 alone, trials of once-high-
profile drugs made by AstraZeneca, Eli Lilly, Johnson & Johnson, Merck, Takeda, and
others collapsed or faded away in a statistical whimper. Some big companies,
including Pfizer, have completely abandoned the field. (For more on this epic
washout, see “Can Biogen Beat the Memory Thief?”)
Paul Cox at a cemetery in Umatac Village, Guam, 2003.Courtesy of Dr. Paul Cox
What do these serial failures have in common? The great majority of the drugs were
built on a single idea, the “amyloid hypothesis,” which posits that clumps of protein
fragments called beta-amyloid—which are found in the brain of every Alzheimer’s
patient—are the primary cause of the disease. (Another hallmark is the presence of
neurofibrillary tangles of a protein called tau.) The amyloid theory is based on
decades of perfectly good science, and the idea that if you eliminate those plaques
you might also slow or reverse the disease still holds sway. But it’s not the only
science—and targeting these plaques directly may not ultimately be the best (or only)
way to fend off or treat Alzheimer’s.
For decades, though, Big Pharma hasn’t been very interested in less conventional
theories. Seeking an enormous payout of perhaps $10 billion a year in sales, they have
thrown thousands of scientists and billions of dollars at this one idea, again and
again, with no luck.
“You know that definition of insanity?” Cox asked, the first time we met. “Doing the
same thing over and over again despite getting the same results? Each trial is a billion
bucks; each targets the same thing. None have worked. It seems to me that if you’d
put in a billion bucks and failed, you’d say, ‘Let’s try something else.’ ”
If there is any good news about Alzheimer’s, it might be this: After three decades of
cureless consensus, the scientific community may finally be ready to seriously
consider alternative approaches. One sign of change has been the entreaties in top-
tier journals ranging from The New England Journal of Medicine to Brain to Frontiers in
Neuroscience to rethink the orthodoxy. (As a New England Journal editorialist put it:
“We may very well be nearing the end of the amyloid-hypothesis rope, at which point
one or two more failures will cause us to loosen our grip and let go.”) Another sign,
perhaps, is the willingness of scores of scientists to sign on to the exploration of a
bizarre moonshot of a theory born in the rain forests of Guam.
The epiphany came while Cox was reading a book, The Call of Service, by Robert
Coles. “Coles writes that when your experience, interest, and talents are orthogonal
to a societal need, you are hearing a call,” Cox explained to me in Jackson in 2016. We
had repaired to the foyer of a bed and breakfast near his lab. Cox was tired after seven
hours of meetings with his board of directors, and he sank into a wingback chair,
yellow legal pages full of scribbled notes threatening to escape from the binder on his
lap.
His mother had died of cancer in 1985, and Coles’s call to arms offered a way forward
apart from grieving. So he grabbed some paper and began jotting down his
experiences, interests, and talents. “I’m fluent in a couple of Polynesian languages,
I’m a marine forest biologist, I’ve studied with the world’s greatest ethnobotanist, and
I really want to defeat disease,” he recalled. “If I become an oncologist, maybe I can
help dozens of people. If I could discover a new drug, I could help millions of people.
What are the chances of that? Oh, about next to zero. But why not give it a shot?”
Two months after his mother’s death, he, his wife, Barbara, and their three kids set off
for Falealupo, a tiny village on Savai’i, a Samoan island where they would live, off and
on, for several years. The funding came from a 1985 Presidential Young Investigator
Award, presented by President Reagan.
Cox didn’t discover a cure for cancer in Samoa. He did, however, find a substance in
tree bark that local healers ground into a salve, which Cox suspected might have
activity against HIV. (He later licensed the compound to the AIDS Research Alliance
of America, but it was never developed into a drug.) He also brokered a deal that
helped save 30,000 acres of Samoan rain forest—home to many native species,
including Pteropus samoensis, a flying fox, or genus of bat, whose wingspan can
stretch nearly three feet wide. Cox and a tribal chief named Fuiono Senio were
awarded the Goldman Environmental Prize for the rain forest agreement.
A flying fox on a cycad.Courtesy of Dr. Paul Cox
Cox’s interest in bats led him to Guam, and to the mysterious ailment the Chamorro
people called lytico-bodig. In the years after World War II, the Chamorro were up to
100 times as likely as people elsewhere in the world to develop symptoms often
associated with neurodegenerative diseases like ALS, Alzheimer’s, and Parkinson’s:
slurred speech, facial paralysis, loss of motor skills, immobility and dementia.
Believing that this cluster might hold essential clues to neurodegeneration, scientists
advanced several theories. Some targeted a toxin found in the seeds of local cycad
trees. Called BMAA, it killed nerve cells in lab tests and induced symptoms of lytico-
bodig when fed to monkeys. The Chamorro cleaned the seeds thoroughly before
grinding them into a flour for their version of tortillas. But later research suggested
that humans would have to ingest, literally, a ton of cycad flour each month for the
toxin to have any effect, and the purported BMAA link fell out of favor.
Cox approached the mystery through the lens of ethnobotany—examining the
Chamorro not in the clinic, but in their culture. “And we discover that the flying fox is
the most important item in their whole diet,” he said. “They identify themselves as
the hunters of flying foxes. One village elder told me, ‘You don’t get this. I would not
sell one of those for any price. If I had one, I would lock the door, bolt the windows,
cook it, and eat it, and people would be trying to break in to get some.’ ”
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Cox believed that this culinary predilection might explain lytico-bodig. One clue was
that only older generations of the Chamorro got ill. They had hunted the native bats
into extinction. Young Chamorro, who hadn’t grown up feasting on those flying foxes,
weren’t getting sick. A second clue was that the Guam bats lived on cycad seeds. If, as
Cox believed, BMAA (or another noxious substance) accumulated and magnified over
time in bat fat, then every bowl of flying fox stew was toxic. In 2002, he and Oliver
Sacks, the late neurologist and author of such books as Awakenings and The Man Who
Mistook His Wife for a Hat, published a paper in the journal Neurology that laid out his
theory.
Over the next two years, Cox set out to confirm his thesis with Sandra Banack,
another bat-loving biologist, and Canadian chemist Susan Murch. In Neurology, they
reported finding massive levels of BMAA in museum specimens of the bat. They
subsequently discovered BMAA in the brain tissue of Chamorro who had died of
lytico-bodig—and also, notably, in the brains of Canadian Alzheimer’s victims. (The
toxin, meanwhile, was nowhere to be found in the brains of Chamorro and Canadians
who had died of other causes.) The team even made a discovery that seemed to link
lytico-bodig to brain diseases around the world. Cycad trees get their sustenance via
strange, coral-like, aerial roots. Cox found cyanobacteria, the oldest organism on
earth, in those roots.
Cyanobacteria, which are often referred to as blue-green algae, are all around us, in
oceans and lakes, in puddles and ponds, even under the crust of deserts from Kuwait
to Arizona. And cyanobacteria are loaded with toxins, including BMAA. The Chamorro
were just getting ultrahigh doses of a toxin that the rest of us are exposed to all the
time. If Cox was right, every green stinky body of water around the world might
harbor an insidious source of neurological disease. “It was like staring into the abyss,”
he said.
While Cox undertook this initial research, he also had a day job: director of the
National Tropical Botanical Garden, a group of five preserves in Hawaii and Florida
set aside by congressional mandate for research and conservation. Cox kept his
employers abreast of his investigations, and eventually, Doug Kinney, a retired
investment banker who chaired the garden’s board, decided that he should move on.
“Paul was okay as a garden director,” Kinney told me. “But spending time thinking
about who would take care of a particular plot of nasturtiums is not what a great
scientific mind ought to be doing.”
“I would not sell one of those for any price,” a village elder said to the Chamorro bat
delicacy. “If I had one, I would lock the door, bolt the windows, cook it, and eat it.”
Kinney and a couple of friends, including Bill Egan, the former EVP of Johnson &
Johnson’s worldwide consumer products division, told Cox they’d fund a lab where he
could research his theory linking the BMAA toxin and neurological disease. They
wouldn’t hobble the lab with the red tape typically faced by researchers at
pharmaceutical companies and academic labs. Cox and his researchers would decide
what experiments to conduct, they’d get new equipment when they asked for it, and
neither the board nor Cox would expect any commercial return. The scientist, in turn,
promised he’d be efficient; the lab, which was launched in 2006, has an annual budget
of around $2.5 million.
Kinney, Egan, and the other initial funders weren’t the only people fascinated by
Cox’s tale of the Guam puzzle. Cox is a good storyteller—at Harvard, he twice won the
prestigious Bowdoin Prize for essay writing (other winners include Ralph Waldo
Emerson and John Updike). And he has attracted a fair amount of publicity, including
from Time magazine, which once named him one of 11 “Heroes of Medicine.” Early
on, criticism accompanied the attention, often from scientists accusing him of
dubious methods and bad science. “Every time [he] comes up with another award or a
big glossy story about him, we all just cringe,” one told The New Yorker in 2005. I tried
to contact several of his critics for this story, but none returned my emails or phone
calls.
Cox, who earned a Ph.D. in biology from Harvard and undergraduate degrees in
botany and philosophy from Brigham Young University, acknowledges such
skepticism—and seems even to welcome it. Doubt and derision are helpful reminders
for scientists—reminders not to be trapped by your own ideas and certainty: “It’s
really important, as a scholar and a scientist, to have a contour map of your
knowledge,” he told me. “And it’s just as important to have a contour map of your
ignorance.”
As he pursued his scientific inquiry on BMAA, he began cobbling together a group of
scientists that could fill in the many gaps in his own training. He started with
neurologists at the Karolinska Institute in Stockholm. Since then, he told me, “I’ve
gone to over 50 people in 28 labs in a dozen countries with the same pitch: ‘Hi, please
stop what you’re doing. Help us solve Alzheimer’s and ALS.’”
By all accounts, he’s persuasive. “In 2008, he came to meet us in Sydney,” said Rachael
Dunlop, a molecular biologist in Australia. Cox was trying to understand just how the
toxin BMAA did its damage in the brain. He believed that it insinuated itself into
protein chains in place of one of the 20 standard amino acids, causing misfolding that
can trigger the death of neurons. He didn’t know which of the 20 was being displaced,
although he suspected glutamate, an important neurotransmitter. Dunlop and her
then boss, Ken Rodgers, were expert on this kind of misincorporation, so Cox asked
them if they’d investigate. “It’s so gripping when he tells you the story about Guam
and Oliver Sacks and the Chamorros and cyanobacteria—how could you not want to
work on the project, right?” says Dunlop. “It’s the ultimate scientific detective story.
That’s what did it for us.” The research she and Rodgers conducted for Cox proved
critical—and also proved him wrong. BMAA was passing for L-serine, not glutamate.
Rodgers and Dunlop had handed Cox a potential treatment to combat his toxin.
Dunlop eventually went to work for Cox in Jackson, while Rodgers now directs a lab at
Sydney’s University of Technology.
Molecular biologist Rachael Dunlop (right) talks with research colleague Sandra Banack at the Brain Chemistry Labs in Jackson Hole.Theo Stroomer for
Fortune Magazine
Cox is the consortium’s ringleader, emcee, flack, and switchboard operator. He says
he’s on email or phone calls with a handful or two of the scientists every week,
learning about new research, suggesting new avenues to pursue, and connecting them
to others in the group. The consortium gathers once a year, often in Jackson but
sometimes in places like Johannesburg or Stockholm. “We’re all in different fields,”
marine biologist Larry Brand told me. “We all present our results and try to connect
the dots on everything from causes of algae blooms to medical problems to possible
prevention and treatment.” Brand’s work has evolved as a result of these
collaborations. A decade ago, when he first joined the consortium, Brand was trying to
understand what causes the huge algae blooms that Florida sees so often. Now he’s
trying to figure out how much BMAA is getting into the food chain via crabs, shrimp,
and other marine life that can be found in those blooms. “Paul’s something of a
Renaissance man,” Brand told me. “He’s very knowledgeable in a lot of different
fields, and he’s very good at connecting the dots.”
Neurologist Aleksandra Stark, who runs the Alzheimer’s clinic at the Dartmouth-
Hitchcock Medical Center in Hanover, N.H., attended her first conference last
October. “It’s unbelievable,” she said. “All these brilliant people get together and talk
about their research around BMAA and cyanobacteria. There was stuff on zebra fish,
on cyanobacteria carried by different species of butterflies, on all the various toxins
found in blue-green algae. It spanned all domains of science. It was kind of ridiculous
—in a good way.”
Cox’s own work has now been cited by other researchers more than 12,000 times in
scientific journals. But it’s the consortium as a whole that has really turned his initial
insight about the Chamorro into an expansive body of research:
• In Sweden, neuropharmacologist Eva Brittebo revealed that rodents dosed
with high levels of BMAA develop neurofibrillary tangles and behavioral
aberrations—but only once they become adults, mimicking the long latency
period seen in humans who develop Alzheimer’s.
• Dartmouth neurologist Elijah Stommel pinpointed epidemiological clusters of
ALS around certain lakes in New England that have had cyanobacteria blooms.
• ALS expert Walter Bradley traveled with Cox to Qatar, where they found
swaths of blue-green cyanobacteria laden with BMAA under the desert crust.
They believe this might help explain a reported spike in ALS among U.S.
veterans of 1991’s Operation Desert Storm. They have since found
cyanobacteria under desert crust in Arizona and Utah.
• Algae biologist Larry Brand discovered that certain blue crabs off the coast of
Florida that are commonly eaten by humans had levels of BMAA as high as the
bats in Guam. “If BMAA were a man-made chemical,” Brand told me, “I don’t
think it would ever be allowed to be added to food.”
• Cleveland Clinic neurologist Erik Pioro has plotted 1,000 cases of ALS in the
northwest corner of Ohio, near Lake Erie, which is polluted with BMAA and
several other neurotoxins.
All this research has inspired other scientists as well. A Norwegian team, for example,
has looked at how BMAA affects proteins in zebra fish. In Canada, researchers have
shown that BMAA is released from algae blooms as the cyanobacteria die. And in
2016, Chinese scientists showed that rats injected with BMAA developed ALS-like
symptoms.
Despite such findings, the consortium’s work is far from accepted science. A 2017
review of the literature on BMAA by scientists at an EPA lab in North Carolina’s
Research Triangle Park concluded that “the hypothesis of a causal BMAA
neurodegenerative disease relationship is not supported by existing data.”
Undeterred, Cox has steered the focus of the Jackson lab to L-serine, which he
believes could significantly delay the onset of Alzheimer’s and the progress of its
symptoms. The FDA has previously approved the use of L-serine as a safe dietary
supplement, and doctors sometimes prescribe it for chronic fatigue syndrome. The
Cox team believes L-serine may play a neuroprotective role.
When I met with Cox recently in New York City, he was quick to share some newly
published lab research on the role L-serine plays at the cellular level. We spoke over
breakfast at the dreary Times Square hotel he frequents when courting funders or
accompanying his wife, Barbara, to Broadway shows. “Here’s what we now think is
astonishing about L-serine,” Cox said. “It appears to be neuroprotective against all
possible protein misfolding. It basically turns on a system in our brains that looks for
unfolded proteins and is quickly poised to act on them.”
For Cox, the most powerful illustration of L-serine’s potential is a 2016 study he and
the University of Miami’s Mash oversaw on St. Kitts in the British Virgin Islands. A
team at an animal research lab there fed bananas loaded with BMAA, L-serine, or a
combination of both to vervet monkeys who have a gene that is thought to increase
the risk of Alzheimer’s in humans. (The control group got bananas with rice flour.)
Monkeys given BMAA showed both the plaques and tangles common to Alzheimer’s
patients. But those given an accompanying dose of L-serine had 80% to 90% fewer
tangles in their brain tissue, the study found. The results astounded Mash and Cox, so
they repeated the effort with another 140 vervets and got comparable results. Their
findings were published in the Proceedings of the Royal Society.
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Early in 2017, Cox published the results of a six-month clinical trial of L-serine given
at varying doses to ALS patients. The Phase I trial, conducted by independent labs in
San Francisco and Phoenix, showed once again that L-serine is safe for humans. One
piece of data dangled alluringly from the paper, which was published in a respected
ALS journal. The four patients who received the highest doses of L-serine (30 grams
per day) saw the progress of their symptoms, as measured on a widely used scale
known as ALSFRS-R, slow by 85%. The number of patients, in this case, was too small
for the finding to reach statistical significance, but if further clinical trials replicate
anything close to that percentage, L-serine would slow the progress of symptoms far
more than any existing drug, potentially buying patients years of life. (The average
ALS patient dies 21⁄2 years after diagnosis.)
Such “ifs” can be tantalizing and dangerous, particularly if the driving hope behind
them masks self-deception or persistent blind spots in the science. In the case of the
L-serine conjecture, though, we should at least get a little more evidence, one way or
another, next year. That’s when a pair of clinical trials currently underway in Hanover,
N.H., are due for completion. Dartmouth’s Elijah Stommel is overseeing a Phase II
trial of ALS patients taking 30 grams of L-serine a day, while his colleague Aleksandra
Stark supervises a Phase II trial of Alzheimer’s patients receiving the same dosage.
Starck is 39 and has been seeing Alzheimer’s patients since her neurology residency
at University of North Carolina in 2011. “Ultimately, I am hopeful and optimistic,” she
said. “There will be some kind of meaningful slowing of the progression of
Alzheimer’s within a decade, even if a cure seems like wishful thinking.”
“This is where we stand,” Cox told me. “We think that chronic exposure to BMAA is a
risk factor for ALS and Alzheimer’s. It’s not deterministic. It’s like tobacco and lung
cancer: If you smoke, you might not get it, and if you don’t smoke, you still might get
it. With L-serine, it’s possible that it could significantly reduce our risk of these
diseases. It’s cheap and it’s safe, so it could prove to be the molecule of choice for
disease prevention. If the research pans out, we could possibly provide L-serine to all
people who are deemed at risk of developing the disease in the future.”
Then he added: “There’s lots of L-serine in bacon. Did I mention that?”
By 2002, when Cox and Sacks first proposed their Guam theory, leading
pharmaceutical companies were well into their massive, collective bet on the amyloid
hypothesis—a theory that, at least in part, dates back more than a century. In 1906,
when Alois Alzheimer examined the brain of a woman who had suffered from
dementia and died at 51, he found plaques and neurofibrillary tangles (twisted fibers
of protein that may impede a neuron’s normal function). These plaques and tangles
are the pathological markers of the disease that came to bear his name. In the
mid-’80s, researchers identified amyloid-beta as the misfolded protein in plaques and
tau as the misfolded protein in tangles. By the end of that decade, many scientists had
settled on the accumulation of amyloid as the primary cause of Alzheimer’s.
Many in the field (and perhaps even most) argue that this remains the case—and that
the serial failures of drugs targeting this plaque is simply bad luck. Or perhaps blame
is owed to faulty measures in the clinical trials that don’t quite capture the drugs’
beneficial effects. Or perhaps the dosing has been wrong—or the therapy given too
late in the game. “The evidence for the amyloid hypothesis has continued to
strengthen,” I was told by Daniel Skovronsky, chief scientific officer at Eli Lilly. “There
is very strong genetic evidence. And imaging data has made clear that amyloid is
there in the brain years before the onset of symptoms. If you have amyloid, you’re at
risk of developing Alzheimer’s. If you don’t, you’re not.”
Others, however, see the same data points—hundreds of billions of dollars spent,
countless hours of human effort, tens of thousands of patients in ineffectual trials—
and see a failure of the drug development process, starting in the academic research
institutions. “The problem is the way science is done and funded,” said Zaven
Khachaturian, editor-in-chief of trade journal Alzheimer’s & Dementia who formerly
directed Alzheimer’s research across the National Institutes of Health, during one of
several long phone calls. “It’s populated by people who follow the orthodoxy. To get
continuous support, scientists must follow existing orthodoxies. Everybody says they
value the individual or the maverick, but nobody will fund them because they say it’s
a fishing expedition.” Research has shown that evaluators on panels that award
government funding to scientists at research universities regularly give higher scores
to conservative proposals than to those trying to break new ground.
Caution is rewarded at the corporate level as well. Pharmaceutical companies trying
to move a drug from discovery to approval face a daunting and expensive process.
After discovery of a molecule that might have disease-altering potential, pharma
companies are required by the FDA to vet their compound with a Phase I clinical trial
(to test safety), at least one Phase II trial (to establish potential efficacy), and a
massive Phase III clinical trial—often involving thousands of patients tracked over
two or more years—to verify its effectiveness and prove its safety for a wide market.
The process can take a decade or even two and cost hundreds of millions of dollars or
more. The great majority of tested compounds don’t make it through.
Dr. Paul Cox poses for a portrait at Grand Teton National Park near Jackson Hole, Wyoming on October 24, 2018.Theo Stroomer for Fortune Magazine
You could argue, as many have, that the system works, in that unsafe drugs are
unlikely to make it through all these hurdles. However, the time and expense can
discourage innovation. Pharmaceutical companies believe it’s safer for them to bet on
marginal improvements to an existing therapy than to gamble on an unconventional
drug. Repeated failures deter exploration even more: ClinicalTrials.gov, the NIH’s
official registry for clinical trials, lists just 215 active studies in Alzheimer’s disease in
the U.S., vs. nearly 7,000 directed at cancer, where a variety of treatments have
successfully lowered age-adjusted death rates.
There’s been a hefty cost to Big Pharma’s fearful orthodoxy on Alzheimer’s. “Billions
of dollars have been spent pushing bad drugs into clinical trials,” said Michael Gold,
VP of developmental neurosciences at AbbVie. “There’s the opportunity cost—every
dollar that you sink into one program, you can’t sink into something else,” he
continued. “Drug discovery programs have been terminated. Expertise has been lost.
And some of the biggest companies with the best track records of drug development
in neuroscience have left the space.”
By betting so heavily on the amyloid thesis, Big Pharma has slighted other approaches
that might hold more promise. There has been much less focus, for example, on the
tau protein, even though recent studies suggest that tau is a better indicator than
amyloid of when symptoms are going to start seriously affecting patients. Of 19
disease-modifying agents now in Phase III Alzheimer’s trials, 10 target amyloid. Just
two focus on tau (though there are additional studies now in Phase II).
In the absence of a cure, the pool of Alzheimer’s patients will soar: while 47 million
people worldwide live with Alzheimer’s today, 141 million may have the disease in
2050, according to the Alzheimer’s Association. In the U.S. alone, the financial cost of
caring for today’s 5.7 million patients is a staggering annual $277 billion. By mid-
century, Americans may spend $1.1 trillion annually on Alzheimer’s, a crippling blow
to a reeling health care system.
The ultimate cost, of course, is that we are no closer to curing Alzheimer’s than we
were 20 years ago. Alzheimer’s still looms as a kind of living death for so many of us.
One of every two people over 85 gets the disease, and since Alzheimer’s patients don’t
develop new memories, its onset seems like a premature termination of the
experience that is supposed to give meaning to our final years. “If you look at this as a
public health issue, in terms of are we solving the problem of reducing the disability
of patients, we haven’t made a dent,” said Khachaturian, the Alzheimer’s & Dementia
editor. Since the beginning of this century, annual deaths from heart disease, stroke,
and HIV have gone down. Annual deaths from Alzheimer’s disease have increased by
89%. As I was told several times while reporting this story: “Nobody knows an
Alzheimer’s survivor.”
Wherever Paul Cox’s exotic-sounding theories might lead, it’s hard not to see in his
grassroots international consortium a research model that’s more flexible, responsive,
curious, and humbly collaborative than the siloed, conservative approach of the
pharmaceutical industry. It would seem a no-brainer that better collaboration among
scientists—across disciplines, companies, and countries—is critical to solving this
ancient biological mystery. “We have a lot of exciting facts. But they are isolated, and
we haven’t connected the dots,” Khachaturian told me. “A model that brings different
perspectives from biology, genetics, pharmacology, psychiatry—even physics and
chemistry—that’s the kind of thing that’s needed to solve the big problem, the
problem of reducing disability caused by dementia. One doesn’t have to judge
whether [Cox’s] idea is good or not. His process is important.”
Read: A Trail of Disappointment for Big Pharma
Neurologist Dale Bredesen, a professor at UCLA’s Geffen School of Medicine and
author of The End of Alzheimer’s, agrees. “Paul’s work is exciting,” he told me. “Step 1,
he’s found a contributor, BMAA. Step 2 is to figure out how you address the insult,
and he’s developed L-serine to do that.” Like Cox, Bredesen believes that the amyloid
plaques in the brains of Alzheimer’s patients are symptoms of the disease, rather than
the cause.
In fact, the steady, accretive science of the Brain Chemistry Labs consortium has
become a fixture of academic journals for so long that, to some, it no longer feels so
unusual. As physician and author Andrew Weil put it succinctly: “Cox’s work doesn’t
feel so far off the mainstream now.”
Far off or not, the globe-trotting ethnobotanist seems forever to be far away. “I’ve
gone to every place where we knew there was an increase in neurological disease,”
Cox told me during one of our long, rambling conversations in Jackson. “Then one day
I thought, ‘Why don’t we go to places that don’t have any record of Alzheimer’s or
ALS at all?’ Where are those places? Well, they must be places where people have
intact motor neuron systems, which means they can grow to old age. So we went to
the village in Japan which has the oldest people.”
Ogimi is an isolated village of fewer than 4,000 people in the Kunigami district of
Okinawa, on the northern side of the island. Ogimi advertises itself as the Village of
Longevity; it has the most centenarians per capita, according to the World Health
Organization. Scores of researchers and reporters have descended on the hamlet,
searching for the secrets of a healthy old age. They’ve fingered any number of factors:
years of exercise, an intimate community, a matriarchal society, and a diet rich in tofu
and sweet potato.
Cox has now visited Ogimi six times. “These people are mind-blowing,” he said. “I go
to interview them, and I say, ‘Tell me about the war.’
‘Which war?’ they say.
‘The World War.’
‘Which World War?’
“These women, they move like ballerinas. A 98-year-old who can bend over and touch
the mat with her palms. I met a 54-year-old who came to the village from mainland
Japan when she married a matriarch’s son. She looks like she’s 19. On a hunch, I ask if
she has a sister. She says yes, and when she brings out the photograph, it’s like
looking at the portrait of Dorian Gray!” Cox clapped his hands together.
“I got dead serious about looking at their diet,” he said. Cox interviewed dozens of
locals, most often over breakfast, lunch, or dinner. He went to the market and bought
samples of all the local produce. He even walked the beach to collect seaweed after
observing locals doing that at sunset. He shipped it all back to the lab, where his
colleagues analyzed the molecular makeup of the Ogimi diet.
“Wouldn’t you know it! The Ogimi people are getting three to four times the level of
L-serine that Americans get in their average daily diet,” Cox said. “They have the
highest L-serine content of any population that I’ve ever measured. They look
unbelievable. And they live forever!”
A version of this article appears in the February 2019 issue of Fortune with the headline
“Paul Cox Has A Radical Theory For What’s Causing Alzheimer’s .”
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