Summary

The Royal Swedish Academy of Sciences announced today that HHMI Investigator Carolyn Bertozzi of Stanford University, Morten Meldal of University of Copenhagen, and K. Barry Sharpless of Scripps Research Institute are the recipients of the 2022 Nobel Prize in Chemistry for the development of click chemistry and bioorthogonal chemistry.

© 2010 The Regents of the University of California, Lawrence Berkeley National Laboratory

The development of ingenious tools for building new molecules has earned three scientists the 2022 Nobel Prize in Chemistry.

Carolyn Bertozzi, a Howard Hughes Medical Institute (HHMI) Investigator at Stanford University, Morten Meldal of University of Copenhagen, and K. Barry Sharpless of Scripps Research Institute have received the award for their work on the development of click chemistry and bioorthogonal chemistry.

Sharpless and Meldal laid the foundation for a functional form of chemistry – click chemistry – in which molecular building blocks snap together quickly and efficiently. Bertozzi has taken click chemistry to a new dimension and started utilizing it in living organisms.

The Royal Swedish Academy of Sciences announced the news at a press conference earlier today. “This year’s Prize in Chemistry deals with not overcomplicating matters, instead working with what is easy and simple. Functional molecules can be built even by taking a straightforward route,” says Johan Åqvist, Chair of the Nobel Committee for Chemistry.

Bertozzi has been an HHMI Investigator since 2000.

Bertozzi explores ways to reengineer cell surfaces with the goal of controlling the cells’ interactions. Ultimately, her work may allow investigators to target cancer cells for diagnosis and treatment, for example, or to detect pathogenic bacteria in biological fluid samples.

“Carolyn is a role model, mentor, and inspiration to budding chemists everywhere,” said Leslie Vosshall, vice president and chief scientific officer at HHMI. “What is terrific about Carolyn is that she effortlessly bridges curiosity-driven basic research and therapeutic translation. Her creative application of chemistry to biology has led to rapid development of these ideas to future clinical interventions.”

She grew up immersed in science – her father was a nuclear physicist at MIT, where she attended summer day camps and later had summer jobs. Still, she seriously considered a career in music (having won awards for compositions and accompanying musicals during her high-school years) before her leanings toward math and science won out.

As a Harvard undergrad biology major, Bertozzi discovered the thrill of organic chemistry during her sophomore year. “I wouldn’t go out on weekends because I just wanted to read the book and see if I could work the problems,” she said. Realizing her calling, she switched her major to chemistry and graduated summa cum laude. (She did find an outlet for her music – at Harvard, she played keyboard with guitarist Tom Morello, founder of the rock band Rage Against the Machine.)

After Bertozzi finished her PhD in organic chemistry in 1993 at the University of California, Berkeley, she did something risky. She accepted a postdoctoral fellowship in a cell biology lab, not a chemistry lab. In the decades since, chemists have embraced the value of studying biology by total immersion.

Sugar studies

One of Bertozzi’s research interests is glycosylation, the normal cellular process by which sugars are added to proteins or other molecules.  Scientists have known for decades that changes in glycosylation are associated with cancer, inflammation, bacterial infection, and other illnesses. Bertozzi reasoned that if she could develop a way to monitor glycosylation and measure it quickly, simply, and noninvasively, the results would deepen researchers’ understanding of how cell surface sugars contribute to both health and illness and could open avenues for diagnosing and treating disease.

Toward this goal, she and her colleagues developed a chemical reaction that adds a marker molecule to cell surface sugars, a technique they refined for use in living animals. Their innovative approach, which Bertozzi dubbed bioorthogonal chemistry, uses reagents that react with one another but not with naturally occurring cell surface molecules. Thus, the reagents do not interfere with the sugars’ ability to carry out their normal signaling functions. Bertozzi’s team has used the reaction to attach tracers to sugar molecules on cell surfaces in mice. The sugars they targeted are produced in elevated amounts by cancer cells and by inflamed cells.

The team’s work suggests that this technique could potentially be used to attach tracers to diseased cells in patients, allowing doctors to pinpoint location of the cells in the body and perhaps even target therapy. The techniques developed by Bertozzi also are being used in the biopharmaceutical industry to generate engineered protein drugs including antibody-drug conjugates.

Luke Lavis, a chemist at HHMI’s Janelia Research Campus first heard about Bertozzi’s work while he was working in industry. “It was clear that this idea of bioorthogonal chemistry was going to be a major part of the then-nascent field of chemical biology,” he says. At the time, Lavis synthesized the first commercial lot of some of Bertozzi’s molecules. Now, he says, “the many reactions her lab developed permeate every corner of modern chemistry.”

High risk, high reward

Bertozzi prides herself on choosing projects that many other chemists would consider too risky. “We like to do things that some people might say are really ‘out there,’” she said. In 2021, her team reported the surprise finding that sugar-coated RNA molecules decorate the surface of cells. In what Bertozzi describes as “probably the biggest scientific shock of my life,” she and her now-former postdoc Ryan Flynn showed that the so-called glycoRNAs poke out from mammalian cells’ outer membrane, where they can interact with other molecules.

The researchers’ work upended the current understanding of how the cell handles RNAs and glycans. Flynn is now running his own lab at Boston Children’s Hospital and Harvard University and plans to study how – and if – glycoRNAs are involved in immune signaling.

Bertozzi says the freedom to pursue an unlikely observation made the glycoRNA discovery possible. “That’s what HHMI provided,” she said. “If I were a junior scientist who stumbled into this and put out an NIH grant, we’d get laughed out of the study section.”

Her enthusiasm for research and her talent for communicating science in the classroom has been recognized with multiple teaching awards. Bertozzi likens teaching to telling a story, and her goal for each lecture is to tell a memorable anecdote. For example, in a class she has taught frequently – an introductory chemistry course for non-chemistry majors – she has explained that her philosophy is to “recapture in each lecture the thrill I felt when it was revealed to me that molecules are as diverse as human beings.”

Bertozzi, Meldal, and Sharpless will split the 10 million Swedish kronor (roughly $900,000) for this year’s prize.

Bertozzi is the eighth woman to be honored with a Nobel Prize in Chemistry. The first was Marie Curie in 1911, for her discovery and work on the radioactive elements radium and polonium.

Bertozzi is now one of 34 current or former HHMI scientists who have won the Nobel Prize. In 2021, HHMI Investigator Ardem Patapoutian shared the 2021 Nobel Prize in Physiology or Medicine with David Julius for their discoveries of receptors for touch and temperature. In 2020, HHMI Investigator Jennifer Doudna shared the Nobel Prize in Chemistry with Emmanuelle Charpentier for developing a method of genome editing known as CRISPR-Cas9.

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