Magnetic resonance imaging, or MRI, is a mainstay of medicine and neuroscience research. It can noninvasively probe deep inside tissues and gives information on the presence of specific chemicals. But because the magnetic forces that it detects are so tiny, MRI isn’t very sensitive: it typically reveals structures on the millimeter to submillimeter scale.
Nano needle: Affixed to the tip of this nano-sized silicon cantilever is a small sample of tobacco mosaic virus. When hydrogen nuclei within the sample interact with a nearby magnet, the cantilever vibrates slightly. By monitoring these vibrations via laser, researchers can construct a 3-D image of the viruses. This technique, called magnetic resonance force microscopy, is a massively scaled-down version of MRI.
Now researchers at IBM Almaden Research Center, in California, have developed an MRI scanner with resolution 100 million times better than that–good enough to image individual viral particles. With further refinements, the technique could one day be used to generate 3-D images of individual molecules.
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“The dream of imaging a single molecule is something that keeps chemists up at night,” says John Marohn, an associate professor of chemistry and chemical biology at Cornell University. “If you had this tool, there’s no end of things that you could do with it, and there’s no end to the good that would come of it.”
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MRI makes use of the fact that the nuclei of some elements, such as hydrogen, act like tiny magnets. When an external magnetic field is applied, these nuclei rotate around the direction of the field at characteristic frequencies, generating tiny magnetic fluctuations. In a typical MRI scanner, an electrical coil detects these fluctuations and uses them to map the spatial distribution of hydrogen nuclei, generating an image of the scanned tissue.
Because MRI is so good at creating 3-D images of internal structures, scientists would like to harness it for imaging much smaller biological samples, such as individual proteins. But the detection coil doesn’t scale down very well–the smaller the coil, the lower the sensitivity–leaving smaller samples and finer resolution outside the scope of conventional MRI.
The new scanner developed by IBM harnesses an emerging technology called magnetic resonance force microscopy (MRFM). MRFM circumvents the limitations of MRI by using a physical, rather than electrical, detector to pick up on the minuscule magnetic forces generated by rotating nuclei.
“It’s a much more sensitive way of detecting the magnetism from the nuclei,” says Dan Rugar, manager of nanoscale studies at IBM Almaden Research Center and leader of the team that developed the new device.
Rugar and his colleagues place the sample to be imaged on the tip of a tiny, exquisitely sensitive silicon cantilever. Near the tip is a very small magnet. Using a microscopic wire, the researchers generate an oscillating magnetic field that causes the hydrogen nuclei within the sample to flip back and forth between attracting and repelling the magnet. The resulting physical vibrations in the cantilever are detected by a laser and used to construct an image.
Miniature MRI: A schematic of the scanning device developed by IBM. The sample is placed at the end of an ultrasensitive silicon cantilever and positioned near a tiny magnetic tip. A microwire produces an oscillating magnetic field that causes hydrogen nuclei in a thin section of the sample–the resonant slice–to flip back and forth between attracting and repelling the magnetic tip. As a result, the cantilever vibrates slightly. These vibrations are measured using a laser inferometer and translated into a 3-D image of the sample.
The oscillating field is precisely tuned so that only the nuclei in a very small sliver of the sample, called the resonant slice, respond. By scanning the magnet in a three-dimensional pattern, the researchers can move the resonant slice throughout the sample. It is this precision that allows the device to create such a high-resolution image.
Other forms of high-resolution imaging, such as scanning tunneling microscopy and atomic force microscopy, can only see the surface of a substance. Because of the resonant slice, MRFM can penetrate deep into the sample, building a 3-D picture of its internal structure.
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MRFM first emerged in the early 1990s, and IBM has been a consistent leader in the field. In a landmark experiment in 2004, Rugar and his colleagues used the technology to detect the spin of a single electron. More recently, they generated images of a nonbiological sample with resolution as good as 90 nanometers–far better than conventional MRI, but not nearly sensitive enough to model individual biological structures.
Now, after years of painstaking incremental advances, Rugar’s team has achieved nanometer-resolution imaging of a biological sample. The team chose to use the hardy, well-understood tobacco mosaic virus as a proof of concept and saw details as small as four nanometers. .
“This is actually the first time this technique has been used on a biological sample,” says Rugar. “We wanted to show it really could do biology, because after all, that’s our overall goal.”
This successful experiment opens the door to a wide range of biological applications, says Rugar. In particular, he would like to be able to image individual proteins in order to determine their internal three-dimensional structure.
“You have thousands of proteins in your body that have no known structure, because there’s no technique to determine their structure,” says Rugar. Right now, the gold standard for solving protein structure is x-ray crystallography, which is limited to proteins that can be crystallized.
The nano-MRI scanner would not be subject to that constraint. In theory, with further improvements in resolution, it would be possible to examine proteins in their native state by rapidly freezing them. MRFM must be carried out at a very low temperature–barely above absolute zero–to minimize the noise created by thermal vibrations.
“The real significance of this is it shows that the limits of MRFM haven’t been reached, and they’re still on the way to doing an atomic imager,” says Jonathan Jacky, a research scientist at the University of Washington. “An atomic-scale imager would be one of the most significant scientific instruments ever. It would be on the same level as the telescope or the light microscope. That’s what’s really exciting about this.”
