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‘Lego’ chemistry that joins molecules wins this year’s Nobel Prize

Researchers pioneered a technique called click chemistry that has aided the design of drugs and industrial materials

Carolyn Bertossi, Morten Meldal and Barry Sharpless are identified on a big screen during the Chemistry Nobel Medal announcements
The winners of this year’s Nobel Prize in Chemistry—Carolyn Bertozzi, Morten Meldal, and Barry Sharpless—on display during the press conference this morningJONATHAN NACKSTRAND/AFP via Getty Images
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A version of this story appeared in Science, Vol 378, Issue 6616.Download PDF

Think of it as Lego for chemistry. This year’s Nobel Prize in the field has gone to a pioneering way to join molecules together—known as click chemistry. The advance has made everything from cancer drugs to industrial materials easier to assemble, without all of the byproducts that result from traditional methods. It has also allowed biologists to map biomolecules in cells without disrupting cells’ normal chemistry, while enabling manufacturers to click new skills into materials, such as the ability to conduct electricity, capture sunlight, or fight bacteria.

Carolyn Bertozzi of Stanford University, Morten Meldal of the University of Copenhagen, and Barry Sharpless of Scripps Research will share the 10 million Swedish kronor ($915,000) prize equally.

The work of the three laureates has had “an enormous impact on science,” said Olof Ramström, a chemist at Linnaeus University and a member of the Nobel Committee, at press conference this morning. About the prize, Bertozzi told assembled journalists: “I’m still not entirely positive that it’s real, but it’s getting realer by the minute.”

Over centuries, chemists have developed a variety of tools to make ever-more-complicated molecules. But coaxing two molecules to join through a chemical reaction can often be slow and lead to a variety of products that must then be separated before scientists move on to the next stage of a complicated synthesis.

Sharpless is the rare winner of a second Nobel Prize. He won his first, along with two others, in 2001 for reactions that create mirror-image molecules. Around the same time, he set out in another direction, seeking simple molecules that would reliably snap together when needed. He described his goal as click chemistry. He argued at the time that relying on constructing carbon-carbon bonds—ubiquitous in biomolecules—was making chemists’ work too complicated.

Instead, Sharpless advocated building complex structures by taking small biomolecules and linking these together using bridges of nitrogen or oxygen atoms, which are more eager to bond. From simple molecular beginnings, he said, it should be possible to build much more complex molecules.

One linker that Sharpless eyed initially was combining an alkyne, which has two carbons linked by a triple bond, with an acyl halide. The reaction, originally discovered in 1960 by German chemist Rolf Huisgen, was efficient and produced few unwanted side reactions. But it required a large amount of heat. “A lot of organic molecules couldn’t take that,” Laura Kiessling, a chemist at the Massachusetts Institute of Technology, tells Science.

In 2001, Meldal, working to add chemical handles to short proteins, called peptides, started to experiment with the azide-alkyne combo. Almost simultaneously, in 2002 teams led by Sharpless and Meldal independently discovered that copper sped the reaction and reduced the need for adding extra heat.

Sharpless described it as the perfect click reaction: If chemists want to connect two molecules reliably, add alkyne to one and azide to the other and use copper to snap them together. “It really opened the door to the whole field,” Kiessling says.

Bertozzi’s work came at the problem from a different direction. In the 1990s, she was studying glycans, complex carbohydrates on the surface of cells that played a then–largely unknown role when viruses infect cells or the immune system is activated. Most of the tools of molecular biology at the time did not work on glycans, so Bertozzi was seeking a way to probe their roles. She wanted to add a molecular handle to the glycans so that she could then, for example, attach a fluorescent tag onto them and see where they resided in a cell. But it needed to be a handle that didn’t react with anything else in the cell, a quality she described as “bioorthogonal.”

In 2000, Bertozzi explored using an azide as that handle. She attached the azide to sugars and fed the combo into cells, where they were incorporated into glycans on the cell surface.

Sharpless’s and Meldal’s alkyne seemed the perfect way to attach other compounds to those azides on glycans. But copper is toxic to cells. So, in 2004, Bertozzi ditched the copper and remade alkynes from being linear molecules to circular. “It’s like you spring-load the bond,” making it more reactive, Kiessling says. It was a Lego-like reaction similar to Sharpless’s and Meldal’s, but without the copper catalyst that would be harmful to cells.

Bertozzi employed this click reaction to attach a green, fluorescent molecule to the glycans so they could be seen working in the cell. This led her to discover that some glycans on the surface of tumor cells protect the cells by shutting down immune cells. To block this mechanism, Bertozzi and her colleagues developed an antitumor drug candidate, joining a glycan-specific antibody to enzymes that break down the glycans on tumor cells. The drug is now undergoing human trials.

“The good thing with [click chemistry] is that this discovery system can be used for almost everything,” Ramström said. “So it has spread very widely, and it’s been used, for example, to make new drug compounds to treat illness. It’s been used to make all sorts of different materials like polymers, like gels.”

Alessio Ciulli, a chemical structural biologist at the University of Dundee, tells Science that the techniques the trio developed allowed chemists to think about molecule-joining reactions in a new way—“a way that we can do it easily, in a friendly manner, in a green manner, without any waste products, where it’s easy to control, fast and robust.”


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