Microscopycell Development

Gene Scenes

New magnetic resonance imaging lights up cells when their DNA turns on

CLEVELAND—Imagine that you are an alien commissioned to decipher a football game. Equipped with nothing more than a Polaroid camera and a truckload of film, could you accurately explain the sporting event given that, to your otherworldly sensibilities, the halftime show carries just as much importance as the kickoff? That scenario depicts the challenge facing researchers who track cells during the development of embryos and tumors. Outfitted with scalpels and microscopes, investigators must try to explain the workings of biology by killing embryos or removing tissue samples, fixing them on slides and piecing together the "snapshots" taken over time. And there is no way to tell what is meaningful to the game and what is halftime fluff.

Chemist Thomas J. Meade and his colleagues at the California Institute of Technology may have found the engineering equivalent of a video camera and an on-field microphone. This past May at a National Academy of Engineering meeting in Cleveland, Meade unrolled stunning videos of frog embryos unfolding from egg to tadpole stages. With unprecedented detail and cellular-level resolution, the images showed the creatures' cells at work communicating with one another during development.

The three-dimensional shots came from magnetic resonance imaging (MRI), which detects vibrations in the hydrogen atoms of water that are induced by an intense magnetic field. To enhance contrast, researchers add an element, such as gadolin ium, that speeds and amplifies hydrogen's signal emission. But typical contrast agents report only the topography of soft tissue. They cannot, for instance, distinguish between dead tumor tissue and robust, newly developing cancers nor track specific cells—and their daughter cells—in a developing embryo. In a way, MRIs give anatomical information akin to a video


DEVELOPING FROG EMBRYO glows when a particular gene is activated.

camera projecting pictures without sound.

To add the audio, Meade employed a novel contrast agent that lights up specific cells as their genes turn on. Meade started by fashioning a molecular basket for each gadolinium ion out of clawlike molecules called chelators, and he latched the basket shut with a sugar called galactopyranose. The only way to lift the lid was through an enzyme that chewed up the sugar specifi cally. In the first experiments, Meade's graduate student Angelique Y. Louie injected the caged gadolinium into both cells of a two-celled frog embryo and then injected one of those cells with the gene for a lid-digesting enzyme. Real-time MRI then produced a video of the developing embryo with half its cells lit up as the gene turned on, encoded the enzyme and permanently lifted the lids of the gadolinium cages. The exposed metal interacted with the water and shot off a bright signal.

"This is the platform for a whole slew of enzymatic processes," says Meade, who first reported the work in the March Nature Biotechnology. Indeed, by changing the latch so that it becomes the substrate for any enzyme—for example, one produced only by live cancer cells or by cells that spur new blood vessel growth—the technique can be tweaked to monitor tumor growth or to track the fate of any number of cells and their contents down to 10 microns in size. Figuring out ways to provide such functional information "is one of the most interesting areas in magnetic resonance imaging now," comments biomedical engineer David L. Wilson of Case Western Reserve University.

At the meeting, Meade presented his team's progress in chemically weaving a gadolinium basket that opens and shuts based on intrinsic calcium levels. Such a basket could track, in fine detail, brain or nerve activity, both of which involve sending impulses via calcium fluctuations. Other ongoing projects include hooking up drugs to the basket handles that are activated when a normal cell enzyme clips them off. That would be a breakthrough in the local delivery and detection of chemotherapy agents at a tumor site, for example, because it would distinguish between dead tissue and live cells. "Now," Meade says, "we have a powerful toolbox." —Trisha Gura

TRISHA GURA is a freelance science writer based in Cleveland.


Magnetic Anomalies

^^ What are magnetic fields doing in the middle of nowhere?

The next time you visit deep space, don't forget to pack a compass. It might not be much use for navigation, but it will be one of the few ways you can take in one of space's sublimities, the magnetic fields. The lines of magnetic force twist and wind through the interstellar miasma and arch over millions of light-years of intergalactic wilderness. They are, astronomers have gradually realized, one of the great shaping forces of the universe. Now it seems that even the outermost of outer space—the chasms between clusters of galaxies—is pervaded by magnetic fields of unforeseen power and unknown origin. "These magnetic fields are the dominant free energy of the universe," says astrophysicist Stirling A. Colgate of Los Alamos National Laboratory.

Magnetism had long been considered a side attraction in astronomy—hard to measure, hard to master, seemingly easy to neglect. The basic trouble is that the fields are invisible. To infer their presence, astronomers must make do with such compasses and filings as nature has haphazardly provided, including dust grains and charged particles. By aligning dust grains or diverting the paths of electrons, for example, a magnetic field can effect the emission of polarized radio waves or skew the polarization of light passing through a region of space, rather like a weak pair of polarizing sunglasses.

Gradually astronomers have deduced that the Milky Way has a magnetic field of roughly five microgauss, generally directed along the galaxy's spiral arms. (By comparison, the earth's north-pointing magnetic field is about 500,000 micro-gauss.) If you had a compass sensitive to this field, in our corner of the galaxy it would point toward the constellation Cygnus. Other galaxies have similar fields.

When researchers began to look for fields in between galaxies in the late 1980s, their expectations were low. After all, cosmic magnetic fields are embedded in plasmas, which are much thinner in in-tergalactic than in interstellar space. According to x-ray telescopes, even the thickest intergalactic plasmas—found in the cores of galaxy clusters—are a hundredth as dense as interstellar plasmas. So it came as a surprise in 1990 when Philipp P. Kronberg and Kwang-Tae Kim, both then at the University of Toronto, announced the first magnetic readings of the interstices of the Coma cluster. The cluster's field is nearly as strong as the Milky Way's.

Puzzled theorists took refuge in the thought that Coma was a fluke. But that escape hatch slammed shut when Kronberg, Tracy Clarke of Toronto and Hans Bohringer of the Max Planck Institute for Extraterrestrial Physics in Garching, Germany, reported their latest findings at a meeting of the American Physical Society this past April. The 24 other clusters they

VERY ATTRACTIVE: Magnetic fields suffuse the space in and around the Coma cluster of galaxies. The fields are traced out by 74-megahertz radio emissions (blue is strongest, red weakest) from the cluster, unrelated galaxies and unknown sources.

probed all have galactic-strength fields, too. Such fields are as potent as other cosmic forces, so they can no longer be ignored in models of galaxy formation and other celestial goings-on.

Kronberg also unveiled new measurements of the space beyond clusters of galaxies, made with a special low-frequency radio receiver installed two years ago on the Very Large Array telescope in Socorro, N.M. Kronberg and the rest of his team— Torsten A. Ensslin of the Max Planck Institute for Astrophysics in Garching, Richard A. Perley of the National Radio Astronomy Observatory and Namir E. Kassim of the Naval Research Laboratory—found that magnetic fields just outside the Coma cluster are 0.01 to 0.1 microgauss, also too strong for many theorists' comfort.

Explaining cosmic magnetism has never been easy, and now the task is even more daunting. A galactic field must somehow be generated from scratch, amplified to the strength now observed, ejected into intergalactic space and further amplified there. Each stage poses problems. And some worry that ordinary galaxies simply lack the oomph to magnetize the huge space between them. Colgate and his colleague Hui Li think it is a job for the biggest guns in astronomy, the black holes at the heart of so-called active galaxies. "The only place where you have that much energy is a supermassive black hole," Colgate says.

For all the questions they raise, the in-tergalactic fields might resolve a separate mystery: the origin of ultrahigh-energy cosmic rays. None of these superparticles has come from the direction of a plausible source, such as the nearby active galaxy M87. But, as Glennys Farrar of New York University and Tsvi Piran of Hebrew University of Jerusalem argued in Physical Review Letters in April, sufficiently strong intergalactic fields would deflect the particles' paths. If so, M87 can't be ruled out after all.

Alas, the proposal immediately ran into controversy. The Milky Way is not part of a cluster, and magnetic fields in its vicinity have yet to be measured. Arnon Dar of the Technion in Haifa, Israel, argued that the fields cannot have the requisite strength, as that scenario would contradict other observations. Kronberg thinks the same process that amplifies the intergalactic fields might also be responsible for the particles. In any event, it looks like cosmic magnetic fields will retain their lure for some time to come.

—George Musser

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