Physicians and researchers regularly use magnetic resonance imaging (MRI) to peek inside the body. But existing MRI applications and equipment present only a big-picture view since they lack the capability to study biological processes at the microscopic level. Such a capability would be incredibly useful: Rather than taking small tissue samples and examining them beneath a microscope, as doctors do now, cellular activity in a patient could be examined while the patient is inside an MRI machine.
That capability now appears to be within reach. At a conference in March, researchers from the California Institute of Technology demonstrated an MRI system that can see three-dimensional images of genes inside a live cell. The imaging technology could someday be used to diagnose disease, deliver drugs, and survey how well treatments are working, as well as help figure out what unknown genes actually do. For example, oncologists could observe a tumor as it subdivides and its cells multiply inside a living creature.
CONTRAST AGENTS. MRI has been around since the early 1980s. It works by using a strong magnetic field to force protons on water molecules -- most of the human body is made up of water -- to spin in the same direction. The MRI unit then shoots pulses of radio waves through the body. Those waves affect the direction of the protons' spin. Complex computer-imaging systems capture the results and translate them into incredibly detailed internal images of the body. To enhance the image, a "contrast agent" such as gadolinium, is sometimes injected into the patient.
Until now, these contrast agents have worked only on a large-scale level. Now scientists are catching a glimpse of how they can use them to image the very workings of cells and genes at a microscopic level. In the latest study, CalTech researcher Thomas Meade and his colleagues injected a modified form of gadolinium contrast agent into tadpole cells.
The gadolinium they used was chemically designed to remain dark unless a certain gene emits an enzyme indicating that it's active. When the gene "turns on," the gadolinium lights up only in that specific area. Specialized contrast agents could be designed to light up in response to many different genes. Meade's efforts are a huge step toward microscopic MRIs. "It adds a whole new layer of information," he says. "The only reason you can see the images is because [the genes] are being turned on."
APPLICATIONS ABOUND. To commercialize the imaging technology, Meade founded a company called MetaProbe in 1997. Based in San Diego, the outfit was largely a virtual operation until about a year ago. Even today, it's still a very early-stage operation with only seven employees, according to MetaProbe Chief Operating Officer Doug Bakan. But the MRI market is hardly small potatoes: MRI contrast agents alone currently bring in about $550 million in annual revenues, even though only about 15% of MRI scans use them. Bakan thinks that, if MetaProbe's contrast agents prove to be safe and effective, they could significantly expand that market.
The company is interested in applying microscopic-imaging technology to diagnose a host of ailments, including cancer, inflammation, autoimmunity, cardiovascular disorders, and neurodegenerative diseases. Doctors could use this technology to determine if a tumor is activating a gene that makes the cancer more likely to spread throughout the body. The test result would be weighed when considering whether or not to proceed with an aggressive treatment regimen. Or, since calcium levels are higher in injured heart or brain cells, it might be possible to judge the severity of the injuries associated with heart attacks and strokes.
Bakan also thinks the pharmaceutical industry could use microscopic imaging to accelerate drug development, since a company could see if a compound was blocking -- or boosting -- a gene's activity in a live animal. The most pie-in-the-sky application at this point would be in genomics and proteomics to exploit the deluge of information being derived from the human genome. Bakan speculates that MRI microscopic imaging could help scientists figure out what individual genes actually do by showing where, when, and under what circumstances they're turned on.
PROMISE AND PERILS. But hurdles remain. Observing tadpole genes was relatively easy because the contrast agents were injected directly into the cells, explains Meade. Getting this to work will be harder in a more complex animal like a mouse or a human. Right now, for systemic views, MRI contrast agents need only be placed in the circulation system and are easily flushed out of the body. But modified agents must get into the actual cells, and then be removed when no longer required. In a human, foreign matter in cells is a potentially serious health problem.
Bakan says his company is making progress, and he's optimistic it could have at least one product in the near future. MetaProbe currently has enough backing to bring two compounds to Phase I trials, he says. Plus, most work on imaging genes in action is being done in academic labs -- something that makes Metaprobe one of the few companies in the game. Should Meade's research continue apace, MetaProbe could someday be a hit with patients and investors alike. By Alka Agrawal