The creation of a microscopy tool with ultrahigh resolution, combined with an advanced 3-D image reconstruction technique, has enabled scientists to demonstate magnetic resonance imaging (MRI) on biological objects such as viruses. The achievement stands to affect the study of materials – from proteins to integrated circuits – for which a detailed understanding of atomic structure is essential. This artistic view depicts the magnetic tip (blue) interacting with the virus particles at the end of the cantilever. (Images: IBM) The microscope created by IBM Research scientists, working in collaboration with the Center for Probing the Nanoscale at Stanford University, has volume resolution 100 million times finer than conventional MRI, giving it the power and potential to unravel the structure and interactions of proteins. That could pave the way for advances in personalized health care and targeted medicine. The research results, published in the Proceedings of the National Academy of Sciences (PNAS), signal a significant step forward in tools for molecular biology and nanotechnology by offering the ability to study complex 3-D structures at the nanoscale, the scientists say. An electron micrograph shows the end of the silicon cantilever with several virus particles attached. (Adapted from Figure 1 of the PNAS article.) “This technology stands to revolutionize the way we look at viruses, bacteria, proteins and other biological elements,” said IBM Fellow Mark Dean, vice president of strategy and operations for IBM Research. The advancement was enabled by a technique called magnetic resonance force microscopy (MRFM), which relies on detecting ultrasmall magnetic forces. Besides high resolution, the technique is chemically specific, can “see" below surfaces and, unlike electron microscopy, is nondestructive to sensitive biological materials. This is a basic setup for nanoscale MRI using a magnetic resonance force microscope. An ultrasensitive silicon cantilever with the virus attached to its end is shown hovering over a magnetic tip. A high-frequency magnetic field applied through the “microwire” underneath the tip is used to manipulate the hydrogen nuclei in the virus sample, but only in the region of the “resonant slice.” Rapid flipping of the hydrogen nuclei causes the cantilever to vibrate very slightly because of the magnetic forces between the hydrogen nuclei and the magnetic tip. The cantilever vibration is detected using a laser interferometer. By scanning the magnetic tip in a 3-D raster pattern and applying a sophisticated image reconstruction algorithm, a 3-D image of the sample is obtained. (Adapted from Figure 1 of the PNAS article.) For more than a decade, IBM scientists have been making advances in MRFM. Now, the IBM-led team has dramatically boosted the sensitivity of MRFM and combined it with an advanced 3-D image-reconstruction technique. This allowed them to demonstrate, for the first time, MRI on nanometer-scale biological objects. The technique was applied to a sample of tobacco mosaic virus and achieved resolution down to 4 nm. (1 nanometer is one-billionth of a meter; a tobacco mosaic virus is 18 nm across.) On the left is a 3-D reconstruction of the hydrogen density for virus particles sitting on the cantilever. The uniform bright layer results from a naturally occurring hydrocarbon layer below the virus particles, which are visible in the upper layers. On the right, one plane of the reconstruction shows the hydrogen in several virus particles. (Adapted from Figure 4 of the PNAS article.) “MRI is well-known as a powerful tool for medical imaging, but its capability for microscopy has always been very limited,” said Dan Rugar, manager of nanoscale studies for IBM Research. “Our hope is that nanoMRI will eventually allow us to directly image the internal structure of individual protein molecules and molecular complexes, which is key to understanding biological function.”The new device does not work like a conventional MRI scanner, which uses gradient and imaging coils. Instead, the researchers use MRFM to detect tiny magnetic forces as the sample sits on a microscopic cantilever – essentially a tiny sliver of silicon shaped like a diving board. Laser interferometry tracks the motion of the cantilever, which vibrates slightly as magnetic spins in the hydrogen atoms of the sample interact with a nearby nanoscopic magnetic tip. The tip is scanned in three dimensions and the cantilever vibrations are analyzed to create a 3-D image. For a video of the technique, click here. For more information, visit: www.research.ibm.com