A picture might be worth a thousand words—but inventing a way to take nanoscale pictures is worth US$3-million. The inventor of a ‘super-resolution’ microscopy technique that biologists are using to reveal the hidden molecular structures of cells is one of six big winners of this year’s Breakthrough Prizes—the most lucrative awards in science and mathematics. The winners were announced on 17 October.

The microscopy method’s lead inventor, Xiaowei Zhuang, is a biophysicist at Harvard University in Cambridge, Massachusetts, and an investigator at the Howard Hughes Medical Institute (HHMI) in Chevy Chase, Maryland. She was awarded one of four prizes in the life sciences for developing stochastic optical-reconstruction microscopy—known as STORM—just over a decade ago. The technique was one of the first to break a fundamental resolution limit of conventional light miscroscopy and is now used widely in the biology community.

“To receive this major award is a very rewarding feeling,” says Zhuang. “I was thrilled to receive the phone call.”

“This is wonderful research,” says Allard Mosk, an optical physicist and specialist in microscopy at Utrecht University in the Netherlands. “Zhuang contributed several results that really got the super-resolution revolution started in biological microscopy.” (The 2014 Nobel Prize in Chemistry was awarded to the developers of other super-resolution methods.)

Conventional light microscopy’s resolution limit—which is propotional to the wavelength of optical light used—was first identified in the nineteenth century and makes it seemingly impossible to distinguish objects that are less than 200 nanometres apart. “The images of two objects that overlap spatially will bleed together into one blob, so how do you separate these out?” says Zhuang. “Our answer with STORM was to separate them in the time dimension.”

The trick involves tagging overlapping molecules with ‘photoswitchable’ fluorescing compounds that may or may not glow when bathed with light. Biologists cannot control which particular molecules will fluoresce—different ones light up at random each time.

When a tagged biological sample is illuminated under a low-intensity laser, only a tiny, random fraction of the molecules will glow, allowing researchers to obtain distinct images of that subset of molecules, which in turn allows the molecules’ positions to be determined precisely. The process is then repeated multiple times, each round focusing on a different random subset. Biologists can then layer the snapshots to build a complete picture.

The technique has led to a slew of discoveries. Among them, Zhuang’s team has used STORM to peer at the molecules just underneath the membrane of neurons, and discovered that the cytoskeleton—a cell’s structural framework—is consists of repeating elements. “It’s a beautiful and surprising structure,” says Zhuang, “almost like the ribs of a literal skeleton you see at Halloween.”

She has since developed another imaging technique, and aims eventually to create a “Google Map of every cell in our body—especially in the brain”.

Physics and mathematics

The Breakthrough prize for fundamental physics was awarded to Charles Kane and Eugene Mele at the University of Pennsylvania in Philadelphia for their work predicting the existence of a type of exotic material known as a topological insulator. The interiors of these materials are electrical insulators, yet their surfaces conduct electricity. They could one day be used to make more-energy-efficient electronic devices and to make quantum computers.

Kane recalls trying to calculate the possible properties of the atom-thick carbon material graphene in 2005, and predicting theoretically that the counterintuitive effect could occur. The predicted effect was so small, however, that it could not be confirmed experimentally in graphene, and Kane admits nearly giving up on the idea. “There was a voice in my head saying, ‘This is stupid,’” he recalls. But the effect was later confirmed by other researchers in mercury telluride in 2007, and has since been seen in other materials. “I guess I am glad I stuck with it,” says Kane.

“Kane and Mele rewrote condensed-matter physics from the fundamentals up,” says Judy Cha, who studies topological insulators at Yale University in New Haven, Connecticut. She recalls that when the materials were discovered, the “excitement in the atmosphere was palpable”, in the physics community. Researchers this year also found that, surprisingly, as many as one-quarter of materials might have the potential to exhibit topological features.

Chromosomes and immunology

Three other life-sciences awards were also announced. C. Frank Bennett of Ionis Pharmaceuticals in Carlsbad, California, and Adrian Krainer at Cold Spring Harbor Laboratory in New York were recognized for developing an effective therapy to silence the gene that causes neurodegenerative spinal muscular atrophy in children.

Angelika Amon of the Massachusetts Institute of Technology in Cambridge and HHMI won for determining how an abnormal number of chromosomes can disrupt cell repair, leading to consequences such as Down’s syndrome or miscarriage. And HHMI-investigator Zhijian Chenat the University of Texas Southwestern Medical Center in Dallas was awarded a prize for discovering the DNA-sensing enzyme cGAS, which is involved in triggering immune and autoimmune responses.

Vincent Lafforgue of the French national research council, the CNRS, in Grenoble, France, received the Breakthrough mathematics prize for his contributions to the Langlands programme. Often referred to as a ‘grand unified theory of mathematics’, the programme, the programme involves deriving a set of conjectures connecting the far-ranging fields of algebra, number theory and analysis.

The Breakthrough prizes, awarded each year by a committee, were launched in 2012 and are funded by entrepreneurs including Internet entrepreneur Yuri Milner and Facebook chief Mark Zuckerberg. The announcement of this year’s annual awards follows a special prize announced by the committee in September for astrophysicist Jocelyn Bell Burnell of the University of Oxford and Durham University in the United Kingdom for her discovery of pulsars.

This article is reproduced with permission and was first published on October 17, 2018.