Nano MRI

Researchers at IBM's Almaden Research Center working with a team at Stanford University have extended magnetic resonance force microscopy (MRFM) to give them a volume resolution 100 million times better than is possible with conventional MRI systems. The technology could herald unprecedented single-cell and nanoscale imaging with applications in biomedical research, electronics, and nanotechnology.

"MRI is well known as a powerful tool for medical imaging, but its capability for microscopy has always been very limited," says Dan Rugar of IBM and Stanford University. For more than a decade he and his colleagues, C. L. Degena, Martin Poggio, H. J. Mamin, and C. T. Rettner, have been experimenting with new ways to improve the resolving ability of MRI technology. MRFM combines the highly sensitive silicon cantilever approach of force microscopy techniques such as atomic force microscopy with the nuclear magnetic spin-flipping phenomena associated with MRI and NMR spectroscopy.

Writing in the journal Proceedings of the National Academy of Sciences (USA), Rugar and colleagues explain how MRFM could represent a significant step towards molecular biology and nanotechnology tools for studying complex 3D structures on a much smaller scale than ever before. With a resolution down to 4 nanometres, the technique seems perfectly suited to studying cells and viruses. Indeed, the researchers demonstrated proof of principle using the laboratory favourite, tobacco mosaic virus (TMV), as a test subject. TMV particles are about 18 nanometres across.

"We would like to improve the technique so that we can eventually determine the atomic structures of proteins," Rugar, who is a consulting professor at Stanford and project leader at IBM explains, "To understand how these proteins function as little nanomachines in your body, you have to understand the structure."

Co-author Poggio, a former Stanford postdoctoral researcher, explains the potential further: "Armed with this new structural information, biologists would have unprecedented insight into how and why proteins perform their biological function," he says.

In extending MRFM, the team has coupled the hybrid technique to laser interferometry. This allows them to track the movement of the cantilever as it oscillates ever so slightly due to the flipping magnetic spins of hydrogen nuclei in the sample. By scanning in three dimensions and measuring the force on the cantilever at 8000 different points around the surface of TMV, the team could then use computer analysis to build up a three-dimensional image from those vibrations.

The approach has several advantages over other microscopic techniques in that it is chemically specific. "For example, if you wanted to see where the DNA is, you can tune into the phosphorus," says Rugar. In addition MRFM can see details below surfaces and, unlike electron microscopy, is non-destructive to sensitive biological or other materials. The team also suggests that the technique could sidestep one of the big problems facing X-ray crystallography of proteins, in that it does not require often intractable proteins to crystallise before they can be imaged.

The only obvious disadvantage of the technique is that each scan takes several days and must be conducted in a super-cooled vacuum. But, such details can be overcome with further research. Future developments of this extension to MRI could ultimately be powerful enough to home in on the interactions between proteins and their substrates as well as allowing next-generation integrated circuits to be characterised on the nanoscale.

"I envision a machine, similar to the one we have today," says Poggio, "in which we load a new protein or molecule, whose structure we don't know, every month or so. In that time we make a detailed atomic-scale image of the protein or molecule."

"This technology stands to revolutionize the way we look at viruses, bacteria, proteins, and other biological elements," adds IBM Fellow Mark Dean, vice president of strategy and operations for IBM Research.

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.