A way to snap molecules together like Legos wins 2022 chemistry Nobel

A tool kit for snapping together molecules like Lego building blocks has won the 2022 Nobel Prize in chemistry.

Chemists Carolyn Bertozzi of Stanford University, Morten Meldal of the University of Copenhagen and Barry Sharpless of the Scripps Research Institute in La Jolla, Calif., will evenly split the prize for developing click chemistry and bioorthogonal chemistry, the Royal Swedish Academy of Sciences announced October 5 in a news conference in Stockholm. These tools allow scientists to easily construct complex molecules in the lab and inside living organisms.

Chemist Carolyn Bertozzi (left) developed bioorthogonal chemistry, while chemists Morten Meldal (middle) and Barry Sharpless (right) pioneered click chemistry.L.A. Cicero; Scripps Research; University of Copenhagen

“The good thing with this discovery is that it can be used for almost everything,” said Olof Ramström, a chemist at the University of Massachusetts Lowell and a member of the Nobel committee for chemistry. Applications include building drug molecules, polymers, new materials and tracking biomolecules among cells. 

“We’re kind of at the tip of the iceberg already in terms of applications,” says Angela Wilson, president of the American Chemical Society. “I think this chemistry is going to revolutionize medicine in so many areas.”

Around 20 years ago, Sharpless introduced “click chemistry” — a way to simply and quickly attach two compounds using certain connector molecules. But finding these Lego-like connector molecules that can bond together in a chemical reaction wasn’t easy. Working independently, Sharpless and Meldal discovered a solution. 

By adding a smidge of copper to a mixture containing two other small molecules — called an azide and an alkyne — the scientists could rapidly snap the two molecules together into a ring-shaped chemical. Without the copper, the molecules would eventually combine, but sluggishly, Ramström said. 

The reaction quickly “gained enormous interest across chemistry and related fields,” he added. Even though scientists would later discover a handful of other molecules that could snap together in the same fashion, that first reaction is considered the “crown jewel of click reactions.” 

But while catalyzing reactions with copper may work fine in a glass beaker, the metal can harm living cells. Bertozzi discovered a way to do copper-free click chemistry, so scientists can now design chemical reactions inside of organisms without mucking up their normal cellular functions. 

Bertozzi tricked cells into incorporating a click chemical into sugars decorating the cell’s surface. When scientists expose these cells to a different click chemical, a type of alkyne, the two can snap together, just like the molecules in Sharpless’ and Meldal’s reactions. By linking the alkyne to green-glowing molecules, scientists can illuminate the surfaces of cells. 

“Imagine you could attach shining molecules to biomolecules in a living cell. Then you could follow them in a microscope and see where they are and how they move. This is what Carolyn Bertozzi did,” said Johan Åqvist, a theoretical chemist at Uppsala University in Sweden and chair of the Nobel committee for chemistry.

Bertozzi’s specialty has been studying sugar molecules, which “are incredibly difficult to work with,” says Leslie Vosshall, a neuroscientist at the Rockefeller University in New York City, who is the vice president and chief scientific officer at the Howard Hughes Medical Institute. Straightforward methods exist for looking at DNA, RNA and proteins, but not so much for sugars, she says. “Sugars are the dark matter of the cell.”

By targeting specific sugars on cell surfaces, scientists can develop new treatments. For instance, Bertozzi and her colleagues were able to target and deactivate sugars that were helping tumor cells hide from T cells in the body (SN: 3/21/17).

Bertozzi, an HHMI investigator, is the 59th woman to win a Nobel Prize since 1901, and just the eighth to be awarded a prize in chemistry. In 2021, Emmanuelle Charpentier and Jennifer Doudna were the last women to win chemistry Nobels, for their work on the gene-editing tool known as CRISPR (10/7/21).

“Carolyn is… one of the astonishingly few women in chemical biology,” Vosshall says. “Her lab has been a generative place that has inspired women chemists and put them out into the world.”

When awakened by the news around 3 a.m. Pacific Time, Bertozzi said, “I’m absolutely stunned. I’m sitting here and can hardly breathe.” Calling the middle-of-the-night phone call a shock is an understatement, she added. “I’m still not entirely positive that it’s real, but it’s getting realer by the minute.”

Bertozzi, Meldal and Sharpless will share the prize — 10 million Swedish kronor, roughly $917,000. The award is the second Nobel for Sharpless, who shared the prize in 2001 for his work on developing catalysts for oxidation reactions.