A fluorescent micrograph showing the nuclear envelope of an amphibian cell breaking up in preparation for cell division (Image: Visuals Unlimited/SPL)
Watching individual memories form in brain cells, DNA in action and plaques form in Alzheimer’s disease are all now possible thanks to advances by two Americans and one German that today earned them this year’s Nobel prize in chemistry
The award is shared by Eric Betzig of the Howard Hughes Medical institute in Ashburn, Virginia, William “W. E.” Moerner of Stanford University in California – and Stefan Hell of the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany.
Their ingenuity has given biologists an otherwise impossible window into the nanoscale world of living things, turning the microscope into a “nanoscope”.
To succeed, they had to overcame a natural barrier called Abbe’s diffraction limit, discovered a century ago, which makes all objects smaller than 0.2 millionths of a metre blurred when viewed through a conventional microscope.
Beyond the limit
Their efforts culminated in the development of super-resolved fluorescence microscopy, a method of routinely viewing living objects tinier than the Abbe limit, including viruses, proteins, small organic molecules and tiny chambers within cells.
“The work of the laureates has made it possible to observe living processes in real time,” said Måns Ehrenberg of Uppsala University in Sweden.
“It means we can watch DNA as it’s read and turned into proteins, how proteins related to disease aggregate in brain diseases including Alzheimer’s, and even changes in neurons in the brain during learning processes,” said Ehrenberg.
Hell said that the method has made it possible in theory to view all objects, however small. “It shows the cell at a molecular scale, which is very important to understanding how the cell works and what goes wrong if the cell is diseased,” he said, calling in to the announcement. “So it’s very important for understanding physiology and disease.”
Seeing proteins at work
The problem of completely bypassing Abbe’s limit was finally cracked in 2005 by Eric Betzig, who demonstrated his solution by producing dramatic images of individual proteins working in the lysosome, the chamber in cells where cellular debris is broken down and recycled.
Betzig tagged millions of native molecules in the membrane of the lysosome with an extra molecule from jellyfish called the green fluorescent protein, discovery of which earned a Nobel prize in 2008 . When exposed to certain wavelengths of light, the proteins temporarily give off a bright green glow that reveals exactly where they are.
By taking images of small subsets of tagged proteins then merging the images together, Betzig produced a composite image that overcame the Abbe limit.
Breakthroughs by the other researchers paved the way for Betzig’s eventual solution. In 1989, for example, Moerner became the first scientist to detect a single fluorescent molecule, rather than the collective fluorescence from a test tube full of molecules. This opened the door to fluorescence tagging of individual proteins in living things, the technique ultimately applied by Betzig with the help of the green fluorescent protein.
Hell, meanwhile, was the first to break through the limit in 1994 with a technique that relied on making natural molecules in a biological sample fluoresce by exposing them to blue laser light within a tight “sleeve” of red laser light. The sleeve kept the image from the blue light tightly focused to a single spot beyond the Abbe limit, and by painstakingly running the beam over an entire bacterial cell, Hell built up an image of Escherichia coli bacteria three times more detailed than any previous microscope image.
Now the technique forms the mainstay for studying all living cells and the processes within. Hell has focused mainly on watching connections form between brain cells, while Moerner has studied how proteins aggravate Huntington’s disease, a degenerative brain condition, and Betzig has been investigating cells dividing in embryos.
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