An Idea with Mettle

Once fodder for alarmist health scares, the notion that metals contribute to degenerative diseases of the brain is gaining new respect.

Back in the early to mid-1980s, when health-scare stories spread by word of mouth rather than by multiply forwarded e-mails, one of the most alarming rumors to make the rounds concerned a possible link between aluminum and Alzheimer's disease. A handful of studies had merely hinted at a connection. But before you could say "Reynolds Wrap," people were tossing out perfectly good pots and pans, eyeing their soda cans suspiciously, and becoming foil phobic.

Without additional evidence, the furor died down--in scientific circles at least--and the notion that metal might cause brain degeneration was buried as deeply as cast-off cookware in a landfill. But the idea has recently resurfaced. Backed by solid research, it now appears that iron, zinc, and copper--not aluminum--might harm the brain. A paper published in the 27 March issue of Neuron suggests that excess iron in the brain contributes to Parkinson's disease, a degenerative disorder that causes tremors, muscle stiffness, and an unsteady gait. Furthermore, a suite of other studies published over the past 4 years fingers copper and zinc as culprits in Alzheimer's disease. Although aluminum is out of the picture, the reprise of the metal hypothesis highlights a larger issue: How do scientists know when to keep mining a research area for worthwhile nuggets and when to move on to different territory?

The metal hypothesis wasn't completely junked when the aluminum connection lost its luster. In the late 1980s, researchers discovered that some metals are present at abnormally high concentrations in the brains of people with certain neurodegenerative diseases, says neuroscientist Julie Andersen of the Buck Institute for Age Research in Novato, California. For example, in people with Parkinson's disease, the iron concentration is elevated specifically in the substantia nigra, an area of the brain that is destroyed in patients with the disease. "This evidence suggested that iron could be involved in the cellular degeneration associated with Parkinson's disease," says Andersen. "But there's been a raging debate as to whether the iron was contributing to the condition or was just a byproduct of the cell death that occurs with the condition."

To determine whether iron accumulation is a cause or a consequence of Parkinson's disease, Andersen studied mice that show many of the classic signs of the illness, such as loss of cells in the substantia nigra and movement problems. When she treated the animals with a drug that takes the metal out of commission, cells in the substantia nigra were protected from damage, and the mice moved better--findings that strengthen the case for iron's causative role in the disease.

Other research bolsters Andersen's finding that controlling metal concentrations can alleviate disease. Harvard Medical School neuroscientist Ashley Bush, who has doggedly pursued the metal connection since the late 1980s and is a co-author on Andersen's Neuron paper, has uncovered links between copper, zinc, and Alzheimer's disease. A small clinical trial designed by Bush and his colleagues showed that clioquinol, a drug that binds metals, slows Alzheimer's progression.

No one knows how metals wreak havoc in the brain, but reactive molecules called free radicals might play a key role. Mounting evidence suggests that free radicals drive many of the maladies associated with aging, including Alzheimer's and Parkinson's diseases. Like a lonely guy in a singles bar, a free radical is looking for action and will interact with any molecule it bumps into, including DNA and proteins. In the process, these molecules damage the cell and set off a chain reaction that produces more marauding free radicals. Metals such as iron and copper exacerbate the problem by kicking off the production of free radicals and amplifying the chain reaction.

Although metals are involved, the recent work is not a rehash of the old aluminum theory, Bush stresses: "It is not a story of toxic exposure." Iron, zinc, and copper are all normally found in the body's cells. They play a role in disease only when they accumulate improperly. Even so, Bush says he has been "tarred with an aluminum brush." Colleagues, reviewers, and mentors kept reminding him that the aluminum theory had been debunked, and they advised him to stop wasting his time. His steely resolve to understand how metals might damage the brain kept him plugging away, and his diligence paid off. But his situation raises the question of how funding agencies can encourage that kind of tenacity without wasting money and talent on fruitless pursuits.

It's a tricky balance, says neuropathologist John Trojanowski of the University of Pennsylvania Medical School in Philadelphia, who has both pursued unpopular research and scoffed at seemingly shaky hypotheses that later turned out to have merit. In general, solid work proceeds and kooky ideas wither, he says. "But scientists are human beings, and we're moved by the fashions of the time." It's easy to get locked into the prevailing view and ignore nonmainstream ideas. Perhaps a smarter approach is to behave like a savvy investor and diversify, he says, keeping a number of lines of research open, especially when attacking diseases such as Alzheimer's and Parkinson's that seem to be influenced by multiple, interacting factors, such as age, genetics, and environment.

Funding organizations can--and do--encourage unconventional research, says Trojanowski. Although the National Institutes of Health (NIH) funds investigations into some provocative hypotheses, "foundations can take more risks," he says. "They can launch new ideas that will mature and go on to get regular NIH funding."

Brainstorming sessions that gather researchers who are pursuing disparate paths, such as an NIH workshop that assembled Parkinson's experts in 2000, can point out holes in hypotheses and boost bright ideas that otherwise might languish, says Trojanowski: "Thanks to that workshop, a lot of new issues got put on the research agenda for scientists to focus their minds on. This was an example of very creative bureaucracy, and in this case, that's not an oxymoron."

Perhaps such approaches will keep unorthodox ideas from being dumped before getting their due. The biggest health scare, after all, is the prospect that a potential cure might end up in the scrap heap with all of those old aluminum pans.

Nancy Ross-Flanigan has written about science and health for 20 years. She never throws away perfectly good pots and pans.