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Of Mice & Magnets

BY FRANK STEPHENSON


See also:Toxic Taste

See also:The Troubled Case for Magnetic Therapy

We do not deny the possibility of there being invented some day magnets enormously more powerful than any yet known to us, which may produce effects upon the nervous system perceptible to some of the sensory organs".

For the time, the comment might well have been taken as a magnanimous concession by learned men of science to noisy boosters of using simple magnets to cure the sick.

Surely stung by the final conclusion reached by the writers—their research equated the benefits of using magnets as medicine to those of being treated with a block of wood—at least the advocates of magnetic therapy had gotten their day in scientific court.

The year was 1892. The experiment, conducted at the Edison Laboratory in Orange, New Jersey, was aimed at testing claims made by "adherents and earnest promulgators" of using magnets to treat various human ailments. Dr. Frederick Peterson, chief neurologist at the New York College of Physicians and Surgeons, and A.E. Kennelly, the Edison lab's chief electrician, had reached their findings after exposing frogs, a dog and finally a boy to the strongest magnetic field ever used in such a test—a field 300 times stronger than Earth's own magnetic field.

Peterson and Kennelly were unequivocal. If magnets of such great power had no observable effects on living things, then it surely followed that the ordinary magnets in the hands of dubious medical practitioners of the day had none either. It was a skeptic's holiday.

Turn the clock up a century, and picture Peterson and Kennelly standing in front of a typical, experimental magnet within the National High Magnetic Field Laboratory in Tallahassee, Florida. Imagine their awe at seeing a live frog levitated, afloat on invisible forces strong enough to defy gravity; or seeing magnetically drawn pictures of the insides of a living brain.

Or seeing what happens to a Tom Houpt rat.

Last year, Houpt, a young Ph.D. from Harvard and an FSU biologist only since 1997, shared a genuinely rare moment in science with colleague and veteran researcher Jim C. Smith as the two men followed up on a hunch.

Houpt had already published one paper with Smith and others on the interesting results of experiments with rats given lengthy exposures to super-strong magnetic fields. Rats were placed head-first in a plastic tube that was inserted into the bore of an upright (vertical) superconducting magnet where for a half-hour they were subjected to a field strength of 9.4 Tesla (T). A standard measure of the strength of magnetic fields, a single Tesla is roughly 20,000 times stronger than Earth's magnetic field.

The experiment was designed to test some ideas Houpt had kicked around with Smith years before, when Houpt was still a post-doc researcher at the Bourne Laboratory, a part of Cornell University's med school. Smith, a behavioral psychologist whose long career at FSU had produced fundamental work on the curious relationship between radiation and taste aversion, was a friend of Houpt's mom and dad, both Ph.D. research veterinarians at Cornell. In the 1970s, Smith had shared his experience in taste aversion research with Houpt's mother, Kathy, who was studying the phenomenon in large farm animals. Over the years, Smith kept up with son Tom's rising interest in a career as a research scientist.

When an opportunity to join FSU's biology faculty opened up in 1997, Smith talked Tom into applying. He suggested to Houpt that their mutual interests—and the ready availability of big magnets at the NHMFL—might make for a fresh new approach to studying the neurological basis of animal behavior, or put more simply, how the brain works.

By the mid-60s, Smith's discoveries about the effects of radiation (primarily gamma and beta radiation) on animal behavior were well known. He's one of the first scientists to document that rats can develop strong taste aversions after being zapped by gamma rays. The phenomenon is almost as puzzling to scientists today as it was when it was discovered, primarily because no one has come up with a good explanation of how it works, Smith says. Even very low doses of radiation can put a rat off a particular diet for days, months, even years, and yet without the slightest, perceptible change in its internal organs or nervous system.

If gamma radiation had this effect, what about electromagnetic radiation? Could you get rats to develop a taste aversion just by shutting them up for awhile in the confines of a big magnet?

Conventional wisdom among scientists would say no. After all, magnetic resonance imaging—better known as MRI—has been one of the most powerful diagnostic tools in medicine for more than two decades. Patients typically don't complain of aversions to food as a side effect of MRI treatment, or for that matter, any side effect at all—even after treatment in machines generating fields as high as 3 T, the limit so far approved by the federal Food and Drug Administration. In fact, to this day, no MRI study conducted on animals or humans has ever turned up any hard evidence for any sustained, biological effect whatever.

Still, Houpt and Smith were curious, and between them they figured that if any team had what it took for such an experiment, it was them. Smith's nearly five decades as a researcher had earned him world-class stature as an animal behaviorist. He had a reputation for knowing how to design and run double-blind experiments that squeeze as many variables out of animal testing as is humanly possible.

Houpt, on the other hand, is an expert in tracking brain activity of animals through a technique that analyzes the pattern of genes being switched on whenever a part of the brain is being used. Known by the name of the set of genes it targets, or c-fos, the technique can pinpoint sites being stimulated within animals' brains, thus providing clues to the hardwire links between behavior and brain activity.

Results of the first tests proved to be better than either Houpt or Smith expected. Rats were given a very tasty, sweet drink (a solution of glucose and saccharin), and then exposed for 30 minutes in the 9.4 T field. A set of control animals got the same drink but sat in a magnet that wasn't switched on.

After the test, the control animals lapped up more of the sweet liquid the first chance they got. But the rats that got exposed wouldn't touch the stuff. In fact, these rats' aversion to the drink was so profound that days afterward, they still hated it.

Subsequent analysis of the test animals' brains revealed a dramatic difference in where and to what extent c-fos genes got turned on, or expressed, during the experiment. Rats that had been exposed to the magnetic field showed particularly high neural activity in the area of their brains that control their visceral organs—their stomachs, intestines and so forth—and also, somewhat surprisingly in the region that controls their inner ear, which maintains the sense of balance. The control rats showed little if any change in either region.

So, the test had proven that rats could be made highly sensitive to foods by exposure to a high magnetic field. Here was incontrovertible proof that animal behavior could be significantly altered by magnetism. Peterson and Kennelly surely would have been impressed.

But the real show stopper lay just ahead.

In their write-up of the experiment, Houpt and Smith noted something peculiar. When the rats that got the real magnetic bath were returned to their cages, they immediately began a rapid, nose-to-tail circling—and all in a counterclockwise direction. Some of the animals rotated 30 or more times before settling down. None of their control counterparts exhibited anything like that.

The gene expression analysis had clearly suggested that the inner ears of the exposed rats were being affected by the magnetic field. Perhaps this explained the curious circling behavior—like kids wobbling off a merry-go-round, the rodents were just plain dizzy. This squared, too, with anecdotal reports of nausea and vertigo from MRI technicians and others having to work near big magnets.

The circling itself was interesting, but why the consistent direction? Why did all the dizzy rats rotate counterclockwise?

For answers, Houpt and Smith studied the design of their experiment. To keep a lid on the variables, they had made sure all the rats were inserted into the magnets precisely the same way—with their heads pointed toward the ceiling. This meant the animals' heads were consistently aligned with the magnet's internal southern pole.

On a whim, the researchers decided to try the experiment again, but this time with the rats turned upside down. Magnet-wise, this time all animals were facing north. When the animals were returned to their cages, every one of them began turning.

Clockwise.

"You could have heard us yelling across the street," Smith recalls. "We knew we were seeing something no one else had ever seen—or might ever believe."

But as repeated tests since last October have shown, the bizarre phenomenon is the genuine article. Rats oriented toward the south poles of the vertical magnets always circle in a counterclockwise direction; those facing the north poles do exactly the opposite. No exceptions.

The finding stunned not only Houpt and Smith—it was met with courteous skepticism by mag lab personnel who had been aware of what the two were up to. Frankly, when they heard the news, they didn't believe it for a minute.

But they soon would. Smith and Houpt had their doubting mag lab friends expose the rats themselves and hand them over. Without knowing how the animals were oriented—toward the south or North Pole—Houpt and Smith made the correct calls every time.

"We've been trying to be our own worst critics," Houpt said. "We've tried to think of every possible way this (phenomenon) can't be (the result of) the magnetic field."

The videotape he and Smith produced, which demonstrates the phenomenon, has won over a lot of skeptics, says Houpt. "It's a remarkable finding, to say the least," says Houpt. "This presents a lot of questions which we're looking forward to investigating in the years ahead."

One of the first on their list: What effect would there be on rats exposed in a horizontal plane? All the work so far has been done in vertical machines.

"We may see 'em roll over," quipped Smith.

All jokes aside, the implications of their findings are just now beginning to sink home. Magnetism was a supreme mystery to the ancients, who didn't have the advantage of modern physics' exquisite explanations for the phenomenon. But what Houpt, Smith and a few other investigators have done is help put into fine relief the vast ignorance still out there.

The FSU findings are the latest to call into question a basic assumption made by mainstream biologists for a hundred years—namely, that living organisms aren't significantly effected, adversely or otherwise, by magnetic fields, high-power or low.

"For so long, it's been a common belief among scientists that magnetic fields, whether weak or strong, have no significant effect at all on living tissue," Houpt said. "Now we know for certain that a magnet can turn on a brain, and apparently in very interesting ways."

But how is the big question. Houpt and Smith are hopeful that their discoveries will persuade other investigators to wade into what can still be largely characterized as alien waters in research.

What research has been done has primarily focused on low-power magnetic effects in biology. In the early '90s, concern over the safety of electromagnetic fields (EMFs) generated by powerlines surfaced briefly, followed since by a flap about cell phones and cancer. Research has largely put both issues to rest, at least in the U.S.

But in general, over the years there's been comparatively little scientific interest in studying the effect of magnetic fields on living tissue, says Benjamin Greenebaum, editor of the Journal of the Bioelectromagnetic Society.

Bioelectromagnetics, or BEM, is a field that traces its roots to research into magnetic and electric fields done in the 18th Century, Greenebaum said. Most BEM researchers focus on the effect of low- to medium-strength fields on biological systems.

Given today's trend in MRI technology to build ever-more powerful machines—to say nothing of a now global magnetic therapy industry—Greenebaum said it might seem logical that there would be lots of heavy-gauge research going on into the safety and efficacy of magnetic-field applications in medicine and elsewhere. But that's not the case, he said, and the reason is fairly simple—most scientists still think the whole idea, like Peterson and Kennelly concluded in 1892, is hogwash.

"But you can bet your bottom dollar that eventually these safety issues on high-field MRIs are going to surface," Greenebaum predicted.

In their introduction to the first paper on what Houpt's c-fos analysis revealed about rats' exposure to a 9.4 T field, Houpt and his colleagues briefly discussed the issue of where MRI technology may be headed. They wrote: "Although there is evidence that lower vertebrates can detect small gradients in weak, earth-strength magnetic fields...little is known about the sensory or physiological effects of high-strength, static magnetic fields on mammals."

After seeing how easily the odd circling behavior of their rats can be manipulated just by changing their polar orientation in the high field, Houpt and Smith believe there's even more justification for research aimed at determining safe upper limits to the field strengths of MRI machines.

One of the reasons they feel that way is what they've found out about repeated exposures of rats to the high fields. Extensive testing since October has shown that rats gradually quit circling after repeated trips to the magnet. A rat that circles 30 or more times after its first exposure may circle only half that a few days later. After only the third or fourth experiment, almost all the rats quit circling entirelythe third or fourth experiment, almost all the rats quit circling entirely.

Are the animals simply getting used to being dizzy, or is there something else going on? It's quite possible that just like astronauts who train in centrifuges to get used to the disorientation of zero G, the rats are automatically adapting to the novelty of magnetically induced dizziness.

But another explanation is equally plausible, says Houpt. It could be that the magnetic field is altering, possibly damaging, the animals' inner ears. Rock concert-goers often find the music getting quieter the more they go, says Houpt, and physicians have known why for some time. Tiny hair cells in the ears get literally blown apart by the amplified decibels, a well-documented phenomenon that can lead to permanent hearing loss. Could the magnum doses of magnetic fields be doing something similar?

Only more research will answer the question, of course. This spring, Houpt and Smith won modest support from the National Institutes of Health and a special grant from FSU's Office of Research to keep their work going for at least another three years.

"We're hoping to get enough papers published to convince the MRI people to take this seriously," Houpt said. "The magnets we're using are a little big for human clinical use, but they're already using machines of this size for experimental work (in humans). I think we'll soon see a push on to get FDA approval for 10T machines or higher."

To be sure, MRI developers are well along in testing super-strength MRI devices on rats and other animals for pilot studies aimed at applications in humans. At present, the FDA-approved limit on MRI machines for clinical use in human "whole-body" examination is 3 T. But machines up to 8 T already are being tested for whole-body work in humans, says Steve Blackband, of the University of Florida's Brain Institute.

Last year, the Brain Institute, an affiliate of the NHMFL, took delivery of a 24-ton, 11.7 T machine that was billed as the world's most powerful research MRI magnet. Blackband, with the institute's Advanced Magnetic Resonance Imaging and Spectroscopy Facility, said the $2.4 million machine, still in the tweaking stage, will "greatly aid" his work in studying brain and nervous system damage caused by stroke.

A physicist, Blackband has extensive experience in applied MRI research. He's met Houpt and Smith, seen their videotapes, and acknowledges the need for more research that would help define the safest upper reaches of MRI diagnosis in humans.

"We don't really know what that limit is yet, and that's really what much of our work is about," he said. "At the moment, we claim that there are no (adverse) effects at the strengths we use. We certainly haven't found any so far."

The primary health concern in beefing up MRIs, says Blackband, is the limits on another component of the machines—their radio pulses. While being subjected to a magnetic field, MRI patients also are bombarded with high-frequency radio waves. Unlike magnetic fields, radio waves carry a lot of energy that--as any microwave oven user knows—can heat up organic material (e.g. flesh and bone) in a flash. If no power limits were set on MRIs' radio transmitters, patients would boil.

But it's clear that technology is on track to test the limits of MRI magnetic fields for use in health care, says Blackband. Higher fields mean greater resolution of images generated from examining bodily tissues. A typical machine today can easily look at blood vessels and nerves, but a 17 T machine is theoretically capable of determining the health of individual cells. Speculation is that if such a machine were approved for use in humans, it could help physicians detect the early onset of such brain disorders as Parkinson's and Alzheimer's diseases.

Ultimately, MRI strengths in health care will be determined by whatever risks are balanced by benefits, the same principle that guides the development of radiation therapy, says Blackband. Aside from their uses—for the moment at least, MRI remains strictly a diagnostic tool while most applications of radiation in medicine are for therapy—the main difference between these two technologies is a conspicuous gap in scientific understanding. Blackband agrees that high magnetic fields hold great potential for medical applications, but such technology is still in its infancy, along with the research needed for advancement.

Meanwhile, Tom Houpt and Jim Smith are deep into designs for clever new experiments. They fully expect their line of research to lead to a better understanding of the magnetic sensibilities of animals, and possibly even shed light on what they were looking for in the first place—physiological evidence of how the brain processes information to learn things. "Every time Tom and I sit down and talk we design 20 more experiments that we want to do," says Smith, grinning. "This is a moving target, and we're excited."