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Was Lou Gehrig’s ALS Caused by Tap Water?

• January 05, 2012 • 4:00 AM

A toxic molecule found in pond scum may trigger neurodegenerative diseases such as ALS and Parkinson’s. Could a group of scientists, led by a botanist, hold the key to a cure?

Rudyard Kipling called it “Hell’s Half Acre,” a geothermal wonderland where people could fall through the Earth’s thin crust or be poached by steamy hot springs and geysers. Most visitors to Yellowstone National Park’s Midway Geyser Basin stroll the wooden boardwalks, but a few hike a short, steep side trail that reveals a bird’s-eye view of the entire valley, including Grand Prismatic Spring, which can be fully appreciated only from above. Mustard-yellow and vibrant-orange mats spread like tentacles from the turquoise pool. “Not even the most talented artist could imagine something as beautiful as that,” muses Sandra Banack, a biologist who studies cyanobacteria, the microbes that create the colorful mats — and that hold a toxic secret.

Banack works as senior scientist at the Institute for EthnoMedicine in Jackson Hole, Wyoming, alongside the institute’s founder, Paul Cox, a botanist and conservationist. Cox’s long list of achievements includes working to preserve Samoan rain forests, for which he was awarded the 1997 Goldman Environmental Prize, and discovering one of the few compounds active against HIV, prostratin, from the Samoan mamala tree. In the early 2000s — when he directed the National Tropical Botanical Gardens in Hawaii and Florida and Banack was a biology professor at California State University, Fullerton — the two made a series of discoveries that led to the founding of the institute.

What started as a study of the island of Guam’s fruit bats and cycads, ancient seed-bearing plants that resemble palms, led to a startling hypothesis: Could cyanobacteria cause neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer’s, and Parkinson’s?

“WE NEVER WANTED TO announce a problem without some thoughtful solutions,” says Cox. He, Banack, and I met at their small institute, a building tucked on a side street near Jackson Hole’s town square two hours from Yellowstone. The institute’s two-room laboratory is stuffed with equipment and Erlenmeyer flasks filled with emerald goo — cyanobacteria from around the world.

Cyanobacteria, which sometimes form symbiotic relationships with other organisms, live in marine and freshwater habitats and even in dried desert crusts, where they spring to life with the first droplets of rain. The microbes may cover shallow lakes and ocean floors or grow over the top of coral reefs. And under certain conditions, massive blooms erupt, covering the water’s surface in a pea-green scum.

Although frequently called blue-green algae, cyanos are actually bacteria that photosynthesize, or create food from light, which is why early scientists classified them as algae. Modern genetics shows they share no evolutionary lineage with algae; the classification is as scientifically accurate as calling a dog a plant.

Cyanobacteria produce a host of nasty compounds, including neurotoxins that derail nervous systems, hepatotoxins that damage liver function, and tumor promoters. Their blooms have poisoned wildlife and caused massive fish kills. In humans they can cause rashes, numbness, vomiting, and sometimes long-term liver or nerve damage. While “death by pond scum” has never appeared in an obituary, that could change: not only are blooms increasing worldwide, but scientists predict they will worsen as the climate warms and nutrient levels rise, when, for example, fertilizers from America’s breadbasket run into the Mississippi River and down to the Gulf of Mexico. Recently, burgeoning cyano blooms in the Great Lakes have garnered attention.

Although cyanobacterial toxins are well known, until Cox started studying them, no one had documented that they can cause health problems years after exposure.

I first met Cox in 2004, when he gave a seminar at Rice University in Houston, where I was a graduate student. He told a riveting tale about following a serendipitous trail of clues that led him to discover that a tiny toxic molecule, beta-methylamino-L-alanine (BMAA), believed to be from cycads on Guam, was in fact produced by cyanobacteria, and not just on Guam, but around the world. More astonishing, he and Banack discovered that BMAA had accumulated in the brains of humans who’d died from ALS, Alzheimer’s, or Parkinson’s — but not in the brains of people who’d died from other causes. Was BMAA accumulation a cause or an effect of these diseases? And how had BMAA gotten into these individuals’ brains in the first place?

Cox and Banack theorized that long-term, chronic exposure to BMAA — from eating food, drinking or swimming in water contaminated with cyanobacteria — could trigger these neurodegenerative diseases. He suspected that BMAA accumulated in the brain, creating a neurotoxic reservoir that eventually began to attack the nervous system. He also suspected a gene-environment interaction, since many people are likely exposed, but not everyone falls ill.

A 2005 New Yorker article detailed Cox’s hypothesis, and his critics complaints that his initial studies showing BMAA in human brains had been based on small sample sizes, and that there was no plausible scientific mechanism for how it could accumulate in brain tissues. BMAA is a nonprotein amino acid — in other words, it’s not one of the 20 amino acid building blocks that make up proteins in all living organisms. “My grail now is to raise this story to the level of scientific respectability,” the article quoted Cox. And he set out, guns blazing, to do just that.

After the Institute for EthnoMedicine was founded in 2004, Banack, who had studied bats, donned a lab coat while Cox built a loose consortium of scientists — neurologists, medical scientists, analytical chemists, bacteriologists, ecologists — who could help piece together the puzzle. Although their research will provide new insights into all neurodegenerative diseases, the institute focuses on ALS both because it’s more accurately diagnosed in living patients than is Alzheimer’s and because ALS has no known cause or cure.

Called Lou Gehrig’s disease after the baseball player who died from it in 1941, ALS is a brutal disease that strikes healthy people seemingly at random. Victims are slowly paralyzed, and within two to five years most have died, usually after reaching the point where they can no longer breathe or swallow. The only therapy approved by the U.S. Food and Drug Administration offers at best two to three extra months of life. Around 5,600 Americans are diagnosed with ALS every year, and 90 percent of cases remain unexplained.

“If we’re right, we can stop these diseases — and that’s huge,” Banack says. “We can get BMAA out of people’s bodies, and out of their diets. There’s a lot of potential for good.”

DURING COX’S SEMINAR HE described the famous medical mystery of Guam. The indigenous Chamorro people suffer from what they call lytico-bodig; its symptoms include ALS-like paralysis, Parkinson’s-like shaking, and occasionally Alzheimer’s-like dementia. At the height of the epidemic, in the 1950s, Chamorros were succumbing to lytico-bodig at an astonishing rate — 50 to 100 times the normal rate of ALS worldwide.

In 1967, researcher Arthur Bell suspected lytico-bodig might be traced to the island’s cycads, and he was the first to isolate BMAA from the plants. More than 30 years later, Cox discovered that it was cyanobacteria within the cycad roots that produced BMAA, rather than the cycads themselves. On Guam, Cox also learned that the Chamorros craved stewed Mariana flying fox, consuming them whole — brains, bones, skin, and all. Perhaps, he surmised, BMAA biomagnified (or increased in concentration) as it moved up the food chain — from cyanobacteria to cycad to bat to human — much as the fat-soluble insecticide DDT once had.

Cox set out to find more collaborators. Renowned neurologist Oliver Sacks added his name to the first scientific paper outlining the hypothesis, in 2002. But others took more convincing. Banack recalls that after Cox presented his ideas before the Royal Swedish Academy of Sciences in Stockholm in 2003 “the room was totally silent. We looked at each other. Finally Lars-Olof Ronnevi, at the Karolinska Medical Institute said, ‘Your account of flying foxes has been a source of great amusement at our cocktail parties. Now that I’ve heard your research, I think you are on to something.’”

One of the major discoveries made by Cox and his colleagues, published in 2004, was that 50 to 100 times as much BMAA is bound within proteins than exists as free amino acids, which are not bound together into chains but float in the cellular or intercellular fluid. Cells build proteins by stringing together amino acids using a process called translation.

“At the time Cox first published his hypothesis,” says Walter Bradley, a neurologist and ALS expert at University of Miami Miller School of Medicine, “the scientific world thought translation was so accurate that no amino acid other than the 20 that normally make up our proteins could be incorporated into them.” Since amino acids dissolve in water, most scientists also didn’t think BMAA could biomagnify.

Cox’s ability to see solutions where others see obstacles has earned rave reviews from some of his peers. Bradley, who collaborates with Cox, calls him a polymath, a Renaissance man. A former graduate student, Renee Richer — who helped connect higher rates of ALS in Gulf War veterans with inhalation of desert crusts containing cyanobacteria — describes him as “one of those rare minds that comes along only once in a while.”

But along with the kudos are still some criticisms. A handful of scientists were skeptical of the BMAA hypothesis, before and after Cox came along. These included Douglas Galasko, director of the Alzheimer’s Disease Research Center at the University of California, San Diego; Tom Montine, a professor at the University of Washington; and Daniel Perl of the Uniformed Services University of the Health Sciences in Bethesda, Maryland. The three published two separate studies, in 2005 and 2009, that failed to find BMAA in human brains. In the first study they had looked only for free, unbound BMAA, not BMAA in protein chains in tissues. “If BMAA is incorporated into proteins, leading to protein dysfunction or an immune reaction, this would be a remarkable and novel mechanism of toxicity,” Montine and his colleagues wrote in the journal Neurology in 2005.

As well as questioning biomagnification and sample size, they asked if Cox could have been detecting an isomer, a compound with the same molecular formula as BMAA but a different structural formula.

In response, Cox and Banack published two papers, in 2010 and 2011, detailing a method for differentiating BMAA from its isomers and suggesting that other scientists standardize their research techniques so that results could be more accurately compared. In 2009, Deborah Mash, a professor of neurology at the University of Miami Miller School of Medicine, replicated Cox’s brain study, finding BMAA in the brains of ALS, Parkinson’s, and Alzheimer’s victims but not in the brains of people who’d died from Huntington’s, a neurodegenerative disease that’s linked to a specific gene. She also verified that BMAA crosses the blood-brain barrier in laboratory rats.

A 2006 paper coauthored by Susan L. Ackerman of the Jackson Laboratory in Maine, published in Nature, revealed that insertion of the wrong amino acid into a protein chain, known as misincorporation, can cause neurodegenerative disease. And research by Ken Rodgers and Rachael Dunlop in Sydney, Australia, which at press time was scheduled to be unveiled at the International Symposium on ALS/MND (motor neuron disease) in December, found that BMAA can be incorporated into protein chains within human neurons, causing proteins to “misfold” and form aggregates within the cells.

Many proteins have a highly specific three-dimensional structure in which the water-loving (hydrophilic) parts stay on the outside, and the water-repelling (hydrophobic) parts stay on the inside. “If proteins are damaged or contain a nonprotein amino acid such as BMAA, the structure of the protein can be altered so that the hydrophobic parts become exposed, and the damaged proteins can then stick together and form aggregates,” Rodgers says. What’s more, he found that the higher the concentration of BMAA, the more likely that it would be incorporated into a protein chain. When proteins misfold and stick together within nerve cells, it is thought to lead to neurofibrillary tangles, a telltale sign of neurodegenerative disease.

Much work remains to be done, but the scientists working on Cox and Banack’s hypothesis believe that normal metabolic processes should allow most people to metabolize and excrete small amounts of BMAA. But some individuals don’t metabolize or excrete BMAA, which could allow it to accumulate in their nerve cells. And that, if Cox and his team are right, could lead to ALS and other neurodegenerative diseases.

Based on recent discoveries, Phase II clinical trials are underway to see if a zinc-based drug could remove BMAA from the body and slow the progression of ALS, bringing hope to victims of a disease that has given them little reason for optimism.

WHILE BANACK SHOWS ME Banack shows me how researchers at the institute test for BMAA using a machine called a triple quadrupole mass spectrometer, my mind wanders to how I might be exposed to the toxin — in drinking water, seafood, milk from cows eating pastures irrigated with pond-scum-laden water, spirulina in my protein shakes. I ask about blue-green algae supplements. “Our official policy is that we do not test them,” she says, choosing her words carefully. She refers me to a 2008 paper by Dan Dietrich from the International Symposium on Cyanobacterial Harmful Algal Blooms; he found large quantities of BMAA in commercially sold supplements, including ones containing spirulina and Aphanizomenon flos–aquae.

Cox and Banack have tested, but not yet published, data on several food items. “We are very interested in shellfish as a possible route of exposure, because an oyster can filter 4 to 8 liters of water a minute. They’re amazing indicators of waterborne toxins. They’re like canaries in the mine shaft,” says Cox. “The danger, if there is one, is in consuming shellfish from cyanobacterially contaminated habitats. But if you’re eating from a pristine habitat, you are OK.” I point out that people usually don’t know what kind of water their seafood comes from. Cox suggests that warnings could help. The government already warns people to avoid eating fish caught in mine-tailing areas and to avoid shellfish at certain times of year because of toxins; similar warnings could work for areas with cyanobacterial blooms or high BMAA levels.

In 2009, Larry Brand, a marine biologist at the University of Miami, published a study showing extreme BMAA levels in bottom-feeding species off Florida’s coast, where a massive cyanobacterial bloom exists. Pink shrimp, blue crabs, and species that feed on the ocean floor had the highest levels; people eat some of those species. Brand and Deborah Mash have since found BMAA in the brains of dolphins as well as in fins of several shark species, organisms at the top of the food chain. Meanwhile, European researchers have documented biomagnification of BMAA in Baltic Sea aquatic life.

“As the dose goes up, our data suggests that incidence [of ALS] also goes up,” says Cox. “If people are consuming a BMAA-rich diet, there’s more chance they are going to fall ill. People need to be very careful about the water they’re drinking.” Neurologist Elijah Stommel of Dartmouth-Hitchcock Medical Center has linked clusters of ALS cases in the same zip code, or even the same street or building, to exposure to cyanobacteria-contaminated lakes in New Hampshire, Vermont, and Maine. Stommel is building a geographic database of ALS cases in the northeastern U.S.; it already includes more than 800 cases.

Do standard water-treatment methods remove BMAA? Only one study has been conducted so far. A graduate student who works with microbiologist Tim Downing at Nelson Mandela Metropolitan University Summerstrand campus in Port Elizabeth, South Africa, found that standard water-treatment methods, including sand filtration, powdered activated carbon (a bit like what’s found in a Brita filter), and chlorination, were particularly successful at removing BMAA. Flocculation, sometimes called coagulation, in which particles are allowed to settle and then made to cluster so that they can be separated from drinking water, was not as effective.

I knew that Texas’s Lake Houston, which supplies drinking water to residents of this country’s fourth largest city, including me, regularly has cyanobacterial blooms, so I collected water and sediment from the lake and mailed it to the institute. It returned positive for BMAA. Houston’s Northeast Water Treatment Plant uses coagulation, sedimentation, and sand-filtration processes, so I can only hope they remove the BMAA.

There are potentially bigger problems further north. According to Stommel’s research in New England, the rate of ALS doubles around lakes where cyanobacterial blooms have been reported. For people living around Lake Mascoma in New Hampshire, the prevalence of ALS was 10 to 25 times the normal rate. At present, no water facilities are known to test for BMAA, though in a 2005 article in Proceedings of the National Academy of Sciences, Cox and his colleagues suggested it would be prudent to monitor BMAA concentrations in drinking water contaminated by cyanobacterial blooms. Researchers at the institute have created an antibody that binds with BMAA and could be used in a simple dipstick-type water test. They’ve also developed the technology for a filter that would remove the compound. Cox hopes some company will commercialize these technologies. “We’re not a commercial lab,” he says. “We need to focus on finding a cure.”

In a world where poisons assault us from every angle — air, water, food, cosmetics — people tend to either overreact or ignore the problem. “You can cause panic pretty easily,” says Banack. “We want to urge measured caution.”

BANACK AND COX SAY they believe the paradigm is shifting in the science of neurodegenerative diseases. For the past decade or so, most funds have gone toward seeking genes that cause neurodegenerative diseases. “If there’s a gene that can cause ALS, then maybe there’s some way to block it. Everybody’s been looking at genetics,” says Banack. “There’s some good research out there, but as Cox says, scientists have been kicking the same ball for 15 years.” Given that 90 percent of cases haven’t yet been explained by genetics, more scientists have begun assessing environmental triggers.

One thing going for the institute’s research is the variety of fields represented in Cox’s consortium of scientists. Too often scientists work in disciplinary silos, “and the silos are not communicating,” says Cox. “A lot of neurologists never heard of cyanobacteria, and a lot of cyanobacterial people were not that familiar with ALS. But there have been a lot of really smart people working really hard for a long time, and there has just not been any progress in terms of discovering new therapies. It’s going to require an interdisciplinary group to approach the problem from a number of different angles.

“The paradigm here that is emerging is that there are ties between environmental health and human health,” Cox goes on. “There is a tie between cyanobacteria and human health. I think that’s pretty well accepted. And at this point we suspect there may be a tie between cyanobacterial toxins and your risk of progressive neurodegenerative disease — but it’s still a hypothesis.”

“If we can disprove it, we can go move on to something else,” adds Banack. “But so far we’ve been unable to disprove it. The data support the hypothesis.”

“We probably have some details wrong,” Cox admits. “But at this point, it’s hard to think that we, including all 20 universities focusing on it, are totally on a wild-goose chase.”

Wendee Holtcamp
Wendee Holtcamp is a Houston-based writer whose work has appeared in Scientific American, Smithsonian, National Wildlife, Audubon, Sierra and Nature. She also writes regularly about Texas water, wildlife and environmental issues for Texas Parks & Wildlife Magazine and has master's degrees in wildlife ecology and evolutionary biology from Texas A&M University and Rice University, respectively.

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