Techniques that allowed scientists to peer inside nerve cells, track proteins that cause disease and watch cells divide in living embryos have earned three researchers this year’s Nobel prize in chemistry.
Two Americans and a German received the prestigious award and share equally the 8m Swedish kronor (£690,000) winnings from the Royal Swedish Academy of Sciences “for the development of super-resolved fluorescence microscopy”.
Stefan Hell, 51, at the Max Planck Institute for Biophysical Chemistry, Göttingen, William Moerner, 61, at Stanford University in California, and Eric Betzig, 54, at the Howard Hughes Medical Institute in Virginia, laid the foundations for powerful new microscopes that are used to study tissues at the level of single molecules.
Hell was quietly checking a scientific paper when the phone rang with what he thought was a prank call. “It was a total surprise, I couldn’t believe it. The first moment I thought it was perhaps a hoax,” he told the Nobel Foundation.
In a series of breakthroughs, the scientists overcame what many regarded as a fundamental barrier to improving the resolution of optical microscopes and showed that it was possible to see features at the scale of billionths of a metre. Now there is theoretically no structure too small to be studied.
“Their groundbreaking work has brought optical microscopy into the nano-dimension,” the Nobel jury said. “Today, nanoscopy is used worldwide and new knowledge of the greatest benefit to mankind is produced on a daily basis.”
For more than a century, the level of detail that could be seen through optical microscopes was thought to hit an immovable limit at around a fifth of a micrometre. The apparent barrier emerged from work by a microscopist called Ernst Abbe who in 1873 showed that optical microscopes could never see features smaller than roughly half the wavelength of visible light.
The Nobel prizewinners refused to believe the orthodoxy. After a decade spent trying to sidestep Abbe’s theoretical limit, Stefan Hell demonstrated his breakthrough. In 2000, he revealed the first stimulated emission depletion (STED) microscope images of an E coli bacterium. The resolution was unprecedented. Before taking the pictures, Hell prepared the bug by tagging it with fluorescent proteins that glowed when light was shone on them. The microscope flashed laser light onto the samples in a way that allowed only a tiny region to glow at a time. By combining hundreds of snapshots of the glowing sample taken from slightly different positions, he built up a picture with a resolution far below the 200 nanometre limit.
Hell’s ideas met with substantial scepticism from the scientific community. “People believed ‘this barrier has been around since 1873 and the resolution is what it is and doing something about it is kind of crazy, not very realistic’,” he said.
“But it was my view that so much physics had happened in the 20th century. I felt there must be something, some kind of phenomenon that leads you beyond the barrier.”
“I’ve always enjoyed doing challenging things and challenging common wisdom,” he added.
Moerner and Betzig took a similar approach. Their own breakthrough came when they discovered fluorescent proteins that could be turned on and off at will. With these in hand, they developed single-molecule microscopy. The technique uses weak pulses of laser light to make only a fraction of the fluorescent tags light up. The microscope takes a picture of these glowing tags, then fires another shot of laser light. This time, a different fraction of tags light up, and another picture is taken. By repeating the process hundreds of times and then superimposing the images, the scientists created pictures with higher resolution than Abbe ever thought possible.
Moerner said that on hearing the news that he’d won a Nobel, “I was incredibly excited and thrilled and of course your heart races.” Betzig said he felt an equal measure of happiness and fear. “The fear is your life being changed. I really like my life the way it is now!”
“It’s ironic in a way because, trained as a physicist, as a young man I would look down on chemists,” he added.
“It’s no exaggeration to say that super-resolution fluorescence microscopy has revolutionised imaging, so this year’s Nobel Prize in Chemistry is very well deserved. The resolution in microscopy had been limited to 200 nanometres – about the size of the smallest bacteria – for several hundred years,” said Stefanie Reichelt, head of light microscopy at the Cancer Research UK Cambridge Research Institute.
“The new imaging developments suddenly gave us a more than tenfold increase in resolution and we can now see individual components of cells in great detail. But these are much more than just pretty images – at this resolution, we can begin to understand much more clearly what is happening in important biological processes.”
Dominic Tildesley, president of the Royal Society of Chemistry, said: “Betzig, Hell and Moerner’s work to improve the resolution of traditional light microscopy has enabled scientists to bring their understanding of physiological process into much sharper focus – right down to the molecular level. Using the cutting-edge spectroscopic techniques they have developed, we are now able to see molecular processes in real time, including the study of live cells such as bacteria and important biological processes such as the transcription and translation of DNA to make proteins.”
He added: “Super-resolution fluorescence spectroscopy is now enabling scientists to peer inside living nerve cells in order to explore brain synapses, study proteins involved in Huntingdon’s disease and track cell division in embryos – revealing whole new levels of understanding as to what is going on in the human body down to the nanoscale.”
