Physicists Shine Some Light on the Brain
Biologists and physicists are seeing the mind as never before. Amber Dance explores how sliced-up brains and X-rays could help scientists understand diseases like Parkinson’s. Illustrated by Laura Randall and Heather Gordon.
Illustration: Laura Randall
Uwe Bergmann explains his take on science with an old joke:
A guy comes home one night, really drunk, only to discover he’s lost his house key. He looks for it in the small circle of light surrounding a lamppost. A passerby asks him, “Do you really think you left your key there?” “I don’t know,” the drunk replies, “but it’s the only place with light.”
For Bergmann, an X-ray specialist at the Stanford Linear Accelerator Center (SLAC) in Menlo Park, California, science is like that. “We often look in places where we have some light,” he says.
Bergmann’s light is a hair-thin beam of sizzling X-rays, shed by a 75-meter-across circular tube called a
synchrotron. In recent years, he’s become SLAC’s resident guru for anyone who wants to put something unusual in the beam line—from ancient manuscripts to body parts to fossils. For his next trick, Bergmann is focusing his rays on preserved brain tissue, sliced like a loaf of bread.
The brain research is a collaboration with
Helen Nichol, a cell biologist at the University of Saskatchewan in Canada. Together, they have put together detailed maps of the metals in a healthy and diseased brain. Bergmann’s beam shed light on Nichol's field of study: how metals contribute to diseases like Alzheimer’s and Parkinson’s.
For Nichol, the research has a personal element. Before graduate school, she cared for her father, who had Parkinson’s-like symptoms, and two aunts with Alzheimer’s disease. Her inheritance from those relatives allowed her to pursue her doctorate in her 40s. Now a professor, she studies how metals, like iron and copper, can build up in a patient’s
snarled brain tissue like a clog in a drain. It’s important to Nichol that she makes a contribution to medical research. But, she says, science also is “a license to play.”
With Bergmann, she gets to play with some fancy toys. Their secret is speed—Bergmann’s X-rays can scan a brain slice one thousand times faster than other scanning technology. Armed with maps of different diseases, scientists will now know where to look for the problems that metals can cause. “I don’t know how the heck you would find that by any other means,” Nichol says.
Mental metal
While scientists have known for decades that metals are associated with disorders like Alzheimer’s, they still don’t know whether the metals cause the disease or result from it.
A healthy brain needs metals. Iron, in particular, is necessary for neurons and their communication. The brain stores iron in a large protein molecule: a soccer-ball-shaped cage called ferritin. As iron atoms follow channels to the center of the cage, they get oxidized—essentially, they rust. A single ferritin can hold 4,500 iron atoms. It sequesters extra iron, out of the way in the rusted form, so it can’t interfere with the brain’s chemical reactions.
One section of the brain that uses lots of iron is the
substantia nigra—“black stuff,” named for its dark pigment. It sits at the base of the brain, between the ears at the center of motion control. The substantia nigra uses iron to produce dopamine, the pleasure hormone that rewards the brain for activities like eating and sex. Dopamine also helps to control movement. In people with Parkinson’s, dopamine-making cells bloat and die, and patients struggle to control their bodies.
In Parkinson’s and similar diseases, the brain seems to lose control of iron. Ferritin can’t hold it all, and iron spills out into brain. Unchecked, it starts oxidizing everything in its path. “If you crack an egg and the white part of the egg starts to solidify, that’s an oxidation reaction,” says
James Connor, a neuroscientist at the Hershey Medical Center in Pennsylvania. “Think of that egg white as a membrane in your cell.” As the membranes stiffen, the neuron can’t function and it dies. Reactive iron can also form dreaded free radicals, which damage DNA and interfere with other chemical reactions.
In Alzheimer’s, excess iron is often mixed up with the plaques—big globs of unorganized protein—characteristic of the disease. In this case, the misplaced iron may pull other iron atoms away from the neurons that need them, Nichol speculates. “You end up with brain cells that are almost starving for metal,” she says.
Until now, scientists have only been able to study small pieces of brain. They use chemical stains to color metals in ultra-thin slices, but that labels only one kind of metal at a time. Or, they dissolve small chunks in acid or grind them up. They don’t have a whole brain map of metals from any single patient, just bits and pieces from different brains.
Jon Dobson, a biophysicist at Keele University in the United Kingdom, uses X-rays to analyze fingernail-sized bits of brain. He hopes to find brain areas that collect extra iron when diseased, and to use the information to diagnose Alzheimer’s in its early stages. Some of the excess iron forms magnetite; he figures it should be possible to see it in living patients with magnetic resonance imaging.
But looking at the brain a centimeter at a time is like trying to appreciate the Mona Lisa with a penlight. Dobson’s group might take all day to run a single sample at Argonne National Laboratory in Illinois or the Diamond Light Source in South Oxfordshire. Time on the synchrotron is expensive and hard to get, Dobson says, so speed is valuable in this kind of research.
Better, faster, stronger
Enter Bergmann and his team of physicists and engineers. They’re all about speed. For a project to reveal ancient text written by Archimedes (see sidebar), SLAC researchers developed the hardware to scan faster with X-rays. Instead of taking a picture, moving the beam, and repeating those steps, they can now scan smoothly along the sample. It’s like graduating from a still camera to video. They also wrote software to track the beam’s position and process the rapid-fire stream of data.
Bergmann, 44, is a lanky, athletic German who strides across SLAC’s campus at the pace of a speed walker. He’s also a self-described “synchrotron junkie.” A senior scientist at SLAC, he specializes in developing X-ray techniques to study matter at the atomic scale. His primary research is on the water-splitting center in photosynthesis, which ultimately powers life on this planet. With that work and his collaborations, he keeps the X-rays zipping. “I do compete, sometimes, for my own beam time with myself,” he says.
His beloved synchrotron houses a river of electrons, circling at nearly the speed of light. Traveling electrons spit out X-rays as the beam bends. The tube, about an inch thick, is surrounded by a set of warehouse-like buildings crammed with scientific equipment. At 25 stations around the synchrotron ring, scientists tap those X-rays for their experiments. The X-rays from the synchrotron bounce through a set of mirrors to be focused on the sample.
Bergmann aims his X-rays with high precision. He forces them through a metal straw with a 50-micron hole—about the width of a fine human hair. It’s too thin to see lamplight through the tube. “It always takes some time to fiddle the beam through that thing,” Bergmann says.
Once aimed, the X-rays hit Bergmann’s sample. The sample—be it brain, parchment, or otherwise—sits in a frame that can move up-and-down and side-to-side, so the physicists move the sample through the beam as they scan. A regular medical X-ray scan wouldn’t work because there is so little metal to image, so the scientists have to get fancy. When an X-ray hits a bit of metal, it sparks the metal to spit out an X-ray of its own. Then, they collect those secondary X-rays.
“The detector is one of the real pieces of magic we have here,” says Martin George, a SLAC programmer who wrote the code to make their baby run. When the secondary X-rays hit the germanium atoms in the detector, they produce a spurt of electrons. The computer translates the electrical signals into an image. With this setup, the team can take pictures of anything that’s got metal atoms in it.
With the new equipment, Bergmann first trained his beam on the
Archimedes Palimpsest. Nichol was using X-rays to scan fly brains at that point. When she heard about Bergmann’s setup, she wanted in. “I thought, well, heck, if he can do a whole sheet of paper, the brain is smaller than a sheet of paper,” she recalls.
They’ve got brains at SLAC
Nichol asked a pathologist for slices of preserved brain from people who’d donated their bodies to science, one Parkinson’s and one healthy sample. Preparing the brains for imaging was easy—they simply sandwiched the squishy tissue between two plastic sheet protectors, like you might find at any office supply store. The tricky part, Nichol says, was finding a brand that didn’t include any metal in the plastic. Only Itoya brand sheet protectors would do. Then, Nichol FedExed the brains to SLAC. “Pretty gross,” was Bergmann’s reaction to the package’s contents: a pale pink slice about an inch thick, with its lobes splayed out like petals on a flower.
Although SLAC houses cutting-edge research from every kind of science, Brain Day was an exciting event at the synchrotron lab known as SSRL. George remembers that Saturday: After dropping his wife off at the airport, he just had to stop by the lab. “Hey, there’s slices of brain at SSRL—I’ve got to take a look,” he recalls.
At SSRL, one can stroll the catwalk and look down into what one of Bergmann’s collaborators described, quite accurately, as an “electronics junkyard.” Wires and foot-thick pipes snake across the room. Cobbled-together devices sprout dozens of plugs, and power strips line up in ranks of six or more. Racks of electronics gear lurk around every corner, blinking their many lights. Much of the equipment hides in a snug coat of aluminum foil, as if trying to ward off alien brain waves. (Actually, the foil insulates the gear and protects it from dust.) The occasional physicist stares into a computer terminal or laptop.
At each station, the X-rays shoot off the synchrotron into a hutch, a sort of walk-in closet holding a table for the instruments. Closing the equipment in the lead-lined hutch protects the scientists from the X-rays, which can cause cancer in high doses.
When it’s time to fire up the detector, Bergmann and his colleagues haul their equipment from the corner where it squats, covered in a plastic sheet, to the hutch. Carefully, and with the help of some duct tape, they set up the gear amid a riot of brightly colored wires.
Bergmann’s detector is a million-dollar piece of equipment that looks like something out of a low-budget sci-fi flick. It’s a tube a little wider than the brain itself, covered in foil. “Even though it may look like it’s been put together with tape and string—it has—that doesn’t necessarily mean we’ve been careless with what we do,” George says.
In fact, Bergmann is a perfectionist who refuses to even look at an image until he’s checked all the equipment. “I really get my hands dirty,” he says.
With everything just right, they close the hutch door and start the scan. A few hours later they’ve got a map, not just of iron, but also of a host of other metals. The X-ray beam hits each spot for a few milliseconds, crisscrossing the sample so fast that it isn’t even damaged. Nichol can return the brain to the pathologist unharmed—an important factor if she wants to image rare samples.
As expected, the substantia nigra of the Parkinson’s patient was black indeed, clogged with iron. Nichol also saw halos of iron surrounding the blood vessels in the diseased tissue. Scientists had suspected blood vessels were involved in disease, but they had never seen this evidence before. In future studies, Nichol hopes to identify which form of iron surrounds the blood vessels—whether it’s reactive or rusted.
To Nichol, most surprising was the relationship between iron and zinc. In both brains, areas high in iron were low in zinc, and vice versa. Some zinc-containing proteins bind to dangerous metals and protect against oxidative damage, so scientists think they might block the symptoms of Parkinson’s disease. Nichol intends to follow up on this finding as well.
A brain a day
Those first pictures proved to the scientists’ satisfaction that the technique works. SSRL administrators also were pleased. “They’re very keen on this,” Nichol says, because of the health implications. She expects to get more beam time, and she has permission to look at ten more samples.
Nichol is starting by imaging brains with a variety of diseases. The most exciting discovery, she says, would be to find a role for metals in a disease for which no one has yet considered them. In that case, she says she’d need about a dozen brains to convince other scientists. With equipment that scans a brain every six hours, that is now something she can envision doing. And the technique is not limited to brains—any metal-containing organ could eventually get its turn in front of the X-rays.
Another possible application is animal research. Scientists trying out new drugs, for example, could use the speedy scans to look for neurological effects. In just two days, Nichol estimates, they could get through 25 mouse brains.
At the time of writing, Nichol had not yet shared her results with other biologists. However, scientists have wished for this kind of data. “Complete maps of individual patients are not available,” James Connor and co-authors wrote in a 2004 article. “Moreover, data on iron in some areas that are seriously impaired in Alzheimer’s disease and Parkinson’s disease are still missing.” With Nichol’s brains and Bergmann’s machine, those maps may come out soon.
Nichol expects the new maps will help scientists understand neurological diseases, and perhaps reveal ways to slow or halt the damage metals can do in the brain. One possibility is
chelation therapy. Chelators are molecules that act like sponges for metal atoms, sopping them up and keeping them from causing trouble. The molecules cage metal ions with more than one chemical bond. The kidneys and liver then remove the chelator-metal pairings from the bloodstream. Chelation treatments are used for heavy-metal poisoning and Wilson’s disease, in which a person’s body has too much copper.
In the 1980s, scientists tried chelation therapy for Alzheimer’s disease, but the project fizzled. The treatment required painful intramuscular injections, says
Mark Smith, a neuroscientist at Case Western Reserve University in Cleveland. “I’ve heard, anecdotally, that patients who have thalassemia [a disorder including iron overload] would prefer to die of thalassemia than have the treatment,” he says.
Chelation therapy for neurodegenerative disease may get a second chance. Pills have replaced the painful shots, and an Australia-based company, Prana, is doing clinical trials. No chelation treatments have yet made it to the pharmacy shelves. “The problem so far has been that the chelators are too good,” Connor says. “They don’t differentiate good and bad iron.”
Any potential treatment coming out of Nichol’s research is years away. “We are just telling them where to look,” Bergmann says. For scientists who used to squint at tiny parts of the brain, suddenly the floodlights are on, and there’s so much to see.
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Sidebar: 21st Century Look at a B.C. Book
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Illustration: Heather Gordon |
The monk Johannes Myronas needed parchment. He wished to construct a prayer book.
But in 1229, parchment was expensive and hard to get. So Myronas recycled an old scroll, scraping off the dark iron gall ink and writing his prayers on top. The practice was called “palimpsesting,” from the Greek for “scraped again.” And in that moment, musings by the famous mathematician Archimedes of Syracuse, who lived in the third century BC, were nearly lost forever.
Eight centuries after Myronas obliterated them, it took a modern scientist to unveil those thoughts. Uwe Bergmann, an X-ray specialist at the Stanford Linear Accelerator Center, used his ultra-fast scanner to map traces of iron from the erased ink.
The book had traveled from the monastery, through the hands of forgers who damaged it, to Christie’s auction house in 1998. An anonymous buyer offered the book to scholars, who partnered with Bergmann. “You can imagine that if you tell some owner of a two-million-dollar book that we will put this book into a beam a million times brighter than the sun, he will be very delighted and give it to you right away,” Bergmann says. “And in fact, he was.”
Using the synchrotron’s powerful rays, Bergmann’s technique lit up the iron atoms in the ink. This allowed scholars to read the original writings: at least seven treatises by Archimedes and work by others. Of these, two Archimedes works had survived nowhere else. The palimpsest contained the only known text of the "Stomachion," in which Archimedes describes his favorite puzzle game. The object is to use different-shaped tiles to build other shapes, such as people or animals.
In addition, Bergmann’s beam illuminated the only copy of Archimedes’ letter to his friend Eratosthenes, the librarian in Alexandria. In it he describes his “Method of Mechanical Theorems,” in which he used mechanical metaphors to do mathematical calculations.
The Archimedes project brought Bergmann’s X-ray scanner to the attention of other scientists. In addition to his work on brains, he plans to scan a fossil
Archaeopteryx, the feathered dinosaur that bridges the divide between reptiles and birds. He and his collaborators hope to learn about the animal’s skin by studying the elements it left behind.
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Biographies
 Amber Dance
Sc.B. (biology with honors) Brown University
Ph.D. (biology) University of California, San Diego
Internship: Nature (Washington, DC)
The FBI tour guide stopped in front of a window to a molecular biology lab and asked whether anyone knew what the letters “DNA” stood for. The adults shook their heads, but a small voice from a 12-year-old piped up:
“De-oxy-ribo-nucleic acid.” That 12-year-old was me, a science nerd from the beginning. I also devoured any writing in front of me—whether magazines, adult novels my mom never should have let me read, or the backs of cereal boxes.
I followed my love of science to a biology degree and a Ph.D. But somewhere in the middle of an endless search for mutant bacteria, that love withered. I’m thrilled to trade my pipette for a pen, and I hope to recapture my fondness for science while letting someone else do the tedious mutant hunts.
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 Laura Randall
I studied Ecology & Systematic Biology, with a concentration in wildlife biology at California Polytechnic State University, San Luis Obispo. Coursework, research experience, and job experience as a veterinary assistant further cultivated my love and understanding of the natural sciences. Following graduation from Cal Poly with a B.S. I entered the Science Illustration program through UC Extension, Santa Cruz. After 9 months of intense instruction, artistic growth, and lots of fun I received my post graduate Certificate in Science Illustration. I am now relocating to San Diego to pursue an internship in the entomology department of the San Diego Natural History Museum.
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 Heather Gordon
BA, Literature/Creative Writing, University of California, San Diego
“But it is of course easier, when we have previously acquired, by the method, some knowledge of the questions, to supply the proof than it is to find it without any previous knowledge.”
—Archimedes (to Eratosthenes), from The Method
Maybe the same could be said about the relationship between scientific and aesthetic discovery…. Anyway, it has been my pleasure to consider. And to draw. Enjoy!
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