The 2014 Nobel Prize for Chemistry has gone to Eric Betzig, Stefan Hell and William Moerner for developing super-resolution microscopy techniques based on the fluorescence of molecules. The prize is worth SEK 8m (£690,000) and will be shared by the three winners, who will receive their medals at a ceremony in Stockholm on 10 December.
Betzig is a US citizen and works at the Howard Hughes Medical Institute, Hell is a German citizen and is at the Max Planck Institute for Biophysical Chemistry in Göttingen, and Moerner is a US citizen based at Stanford University.
The trio won the prize for overcoming what had seemed to be an insurmountable barrier to using microscopes to see features in biological cells that are smaller than a few hundred nanometres across – the so-called diffraction limit. Hell took one approach to solving the problem, while Betzig and Moerner took a somewhat different route. Both techniques, however, involve “tagging” a relatively large biological molecule of interest with much smaller fluorescent molecules that glow briefly (or “blink”) after being illuminated with a pulse of laser light.
Suppressing fluorescence
Hell’s method involves firing two lasers at the sample. One (the exciting laser) is tuned to cause the molecules to fluoresce and the other laser is tuned to suppress fluorescence. The clever trick is that the suppressing light has a dark region in the middle of its beam, the size of which is defined by the diffraction limit. The exciting light, on the other hand, illuminates a spot with a size defined by the diffraction limit. The effect of overlapping these two beams is the emission of fluorescent light from a central region that is smaller than the diffraction limit. Indeed, the size of the region can, in principle, be made arbitrarily small by adjusting the relative intensities of the two lasers. An image is acquired by scanning the location of the central region across the sample.
The technique developed by Betzig and Moerner involves illuminating the sample with a weak laser pulse to ensure that only a tiny fraction of the fluorescent molecules will blink at a given time. This tiny fraction means that it is extremely unlikely that any of these blinking molecules are separated by distances less than the diffraction limit. Each molecule will emit a number of photons during a blink and these are detected as an intensity peak that has a normal distribution with a width that is limited by the diffraction limit. However, because the light is known to come from a single molecule, the location of the molecule can be placed with high probability at the centre of the normal distribution. Furthermore, the uncertainty in the location of the molecule falls as one over the square root of the number of photons detected. While an individual image only shows the locations of a few molecules, repeating the process many times allows a composite image of all the molecules to be created.
Well deserved
Frank Jäckel of the University of Liverpool in the UK, who worked in Moerner’s lab in the 2000s, described his former colleague as a “great researcher” and said that the prize is “well deserved”. He points out that Moerner’s discovery in 1989 that just one molecule in a sample can be detected was an important breakthrough that lead to the development of the super-resolution microscopy technique.
John Dudley, president of the European Physical Society, told Physics World that the work of Betzig, Hell and Moerner “has pushed back the accepted wisdom of the limits of optical resolution [and is] a timely reminder how we should constantly question received wisdom and pre-conceived ideas”. He added that “Sometimes what we think is impossible is possible with new technology and imagination.”
Eric Betzig was born in 1960 in Ann Arbor, Michigan. After obtaining a BS in physics from the California Institute of Technology in 1983, he received his PhD from Cornell University in 1988 for work on near-field scanning optical microscopy.
Betzig then moved to Bell Labs in New Jersey, where he continued to work on near-field optics for applications in biology and data storage. In 1994 he left Bell Labs to start a research and consulting firm called NSOM Enterprises, but two years later left to become vice-president of R&D in his father’s machine-tool company, Ann Arbour Machine Company.
Return to academia
In 2002 commercial failure left Betzig unemployed, so he founded another R&D consulting firm, New Millennium Research. Three years later he went back to academia, joining the Howard Hughes Medical Institute (HHMI) in Ashburn, Virginia, where he is currently leader of the HHMI’s Janelia Farm Research Campus.
Stefan Hell was born in 1962 in Arad, Romania. After receiving his Diplom degree from the University of Heidelberg, Germany, in 1987, he was awarded a PhD from the same university in 1990 for work on the imaging of transparent microstructures. In 1991 Hell moved to the European Molecular Biology Laboratory, also in Heidelberg, and two years later became a senior researcher at the University of Turku in Finland. In 1997 Hell moved to the Max Planck Institute for Biophysical Chemistry in Göttingen, becoming a director in 2002. Hell is also currently a division head at the German Cancer Research Center in Heidelberg.
William Moerner was born in 1953 in Pleasanton, California. In 1975 he was awarded degrees in physics, mathematics and electrical engineering from Washington University in St Louis and in 1982 received his PhD in physics from Cornell University for work on the vibrational relaxation dynamics of alkali halide lattices. After his PhD, Moerner worked at the IBM Almaden Research Center in California as a researcher and then project leader, before joining the University of California, San Diego in 1995. He – along with his research group – then moved to Stanford University in 1998.
