To answer the really big questions in biology, scientists sometimes need to think small — very small. That's because the molecules of life — bundles of DNA, for example, and proteins — are tiny: generally less than one millionth of an inch long.
Now researchers have developed a microscope with resolution about 10 times better than the previous state of the art. The technology allows visualization of molecules with a resolution of roughly one nanometer, or about 40 billionths of an inch.
Achieving better resolution in this range is crucial, scientists said, because many of the molecules they are interested in are about the same size as the previous resolution limit, so earlier studies couldn't reveal details about their structures.
The improved instrument, described Thursday in the journal Nature, doesn't quite reach the resolution of some other imaging methods, such as X-ray crystallography and electron microscopy, but it has a huge advantage. Unlike these two techniques, it can look at molecules in a relatively natural, wet environment — even, potentially, inside living cells — and it can watch those molecules in action, providing insight into the moving parts of these minuscule machines.
"It's kind of like developing the Google Earth view of the cell — we're sort of zooming in to the street level now, where you can see the people and the cars," said Joe Gray, director of the life sciences division at Lawrence Berkeley National Laboratory. Gray is collaborating on applications of the technology with the report's senior author, U.S. Energy Secretary Steven Chu, who still runs a lab at UC Berkeley.
Researchers not involved with the report said there are countless biological questions that could be answered with this type of technology.
"This is a very significant milestone in bio-imaging," said Harvard biophysicist Xiaowei Zhuang, who along with other researchers said she is likely to implement some of the technical optimizations into her own microscopes.
Chu and Gray already are using the super-resolution microscope to investigate why some people don't respond to certain breast cancer drugs. These drugs block an assembly of proteins that promotes the growth of cancer cells. The researchers hope that the new instrument will provide insight into this complex and that differences in the detailed pictures could reveal why the drugs aren't effective for everyone.
Stanford biologist Axel Brunger, another of Chu's collaborators, is using the technology to answer questions about how nerve cells work. Signals traveling through the nervous system rely on large clusters of certain proteins, but researchers are still trying to unravel the details about how they function.
The resolution improvement was achieved by ridding existing technology of two errors. First, the team found that light detectors on microscopes are not perfectly consistent in the way they handle light rays that hit them at different points; this results in fuzzy images that make it difficult to distinguish two spots that lie within a few nanometers of each other. The researchers developed software to fix this problem. They also used a laser to stabilize the microscope stage, further sharpening the images.
The researchers said they are working toward experiments in an even more realistic environment: a living cell. Previous studies using this and related technologies to study biological molecules in action were done under conditions thought to mimic a cell, but whole cells are much more complex and delicate.
Chu commented that running a lab doesn't affect his work as secretary of Energy. He takes care of his research in his leisure time, he said.
"The first 70-plus hours of my time go to being secretary of Energy; it's a day-and-night job," Chu said. "After you've done all your real work, what do you turn to? Some people watch a movie, other people read a novel. I do this."