A toolkit for assembling molecules like Lego building blocks has won the Nobel Prize in Chemistry 2022.
Chemists Carolyn Bertozzi from Stanford University, Morten Meldal from the University of Copenhagen, and Barry Sharpless from the Scripps Research Institute in La Jolla, Calif., will equally share the prize for the development of click chemistry and bioorthogonal chemistry, the Royal Swedish Academy of Sciences announced on October 5 at a press conference in Stockholm. These tools allow scientists to easily construct complex molecules in the laboratory and inside living organisms.
“The good thing about this discovery is that it can be used for almost anything,” said Olof Ramström, a chemist at University of Massachusetts Lowell and a member of the Nobel Chemistry Committee. 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 will revolutionize medicine in many areas.”
About 20 years ago, Sharpless introduced “click chemistry” – a way to simply and quickly attach two compounds using certain connecting molecules. But finding these Lego-like connecting molecules that can bond together in a chemical reaction hasn’t been easy. Working independently, Sharpless and Meldal discovered a solution.
By adding a little copper to a mixture containing two other small molecules – called azide and alkyne – scientists were able to quickly assemble the two molecules into a ring-shaped chemical. Without the copper, the molecules would eventually combine, but slowly, Ramström said.
The reaction “quickly sparked huge interest in chemistry and related fields,” he added. Although scientists would later discover a handful of other molecules that could assemble in the same way, this first reaction is considered the “crown jewel of click reactions”.
But while catalyzing reactions with copper can work well in a glass beaker, the metal can damage living cells. Bertozzi has discovered a way to do click chemistry without copper, so scientists can now engineer chemical reactions inside organisms without disrupting their normal cellular functions.
Bertozzi tricked the cells by incorporating a chemical click into the sugars decorating the cell surface. When scientists expose these cells to a different chemical click, a type of alkyne, the two can come together, much like the molecules in the Sharpless and Meldal reactions. By linking the alkyne to green molecules, scientists can illuminate the surface of cells.
“Imagine being able to attach glowing molecules to biomolecules in a living cell. Then you could follow them under a microscope and see where they are and how they move. That’s what Carolyn Bertozzi did. said Johan Åqvist, a theoretical chemist at Uppsala University in Sweden and chairman 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 Rockefeller University in New York who is vice president and chief scientific officer of the Howard Hughes Medical Institute. . Simple 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 example, Bertozzi and his colleagues were able target and deactivate sugars that helped tumor cells hide from T cells in the body (SN: 03/21/17).
Bertozzi, an HHMI investigator, is the 59th woman to win a Nobel Prize since 1901, and just the eighth to receive a chemistry prize. In 2021, Emmanuelle Charpentier and Jennifer Doudna were the last women to win Nobel Prizes in Chemistry, for their work on the gene editing tool known as CRISPR (10/07/21).
“Carolyn is…one of the few amazingly women in chemical biology,” Vosshall says. “Her laboratory was a generative place that inspired women chemists and brought them into the world.”
When woken by the news around 3 a.m. PT, Bertozzi said, “I am absolutely stunned. I’m sitting here and I can barely breathe. To call the middle of the night phone call a shock is an understatement, she added. “I’m still not quite sure it’s real, but it’s getting more real by the minute.”
Bertozzi, Meldal and Sharpless will share the prize – 10 million Swedish crowns, or around $917,000. The prize is the second Nobel prize for Sharpless, who shared the prize in 2001 for his work on develop catalysts for oxidation reactions.