“[We] have heard over and over these debates about what’s more important, [basic or translational science],” Carolyn Bertozzi said. “The truth is, if you don’t do curiosity-driven basic science, you have nothing to translate.”
From Feb. 24 to 26, Bertozzi — Baker Family Director of Stanford ChEM-H, professor of chemistry at Stanford University and a recipient of the 2022 Nobel Prize in Chemistry — took the stage for the Pomona College Chemistry Department’s 61st annual Robbins Lecture Series.
Alongside another scientist, Bertozzi was the only woman awarded a Nobel Prize in the sciences in 2022 as well the first out queer recipient of a Nobel Prize in the sciences.
Bertozzi shared the scientific journey of how she helped create an entirely new field of chemistry, called bioorthogonal chemistry, and pioneered its wide-ranging applications.
The goal of the Robbins Lecture Series is to help increase students’ access to world-renowned scientists, which was made possible by a donation from Frederick Robbins, according to Professor Charles J. Taylor, chair of the Pomona Chemistry Department.
“I really hope that people will walk away from tonight’s talk realizing the importance of science and the diversity of scientific problems that people approach,” Taylor said.
While traditional chemistry requires controlled environments that would destroy living tissue, bioorthogonal chemistry operates by creating chemical reactions that function within living systems.
“Healthy cells have a well-manicured garden of sialic acids (sugars),” Bertozzi explained. “But cancers have a tropical jungle.”
This difference creates an opportunity: If we could see these sugar jungles in the body, we could detect tumors earlier and more accurately.
For decades, this challenge remained unsolved — until a chance encounter set Bertozzi on the path to change that.
”My advisor at the time was supposed to go to England to give a talk at the Irish Joint Anatomical Society,” she said. “As the date approached, he realized he did not want to go, and asked who in the lab wanted a free trip to Europe, so I raised my hand.”
Although she said that most of the conference left her bored, Bertozzi was captivated by one presentation by Dr. Werner Reutter about how cells build sugar molecules in a method akin to an assembly line.
The assembly line method, or how biosynthetic machinery sugar is produced within a cell, inspired Bertozzi’s idea: modify starter molecules with special “handles” that cells would process normally until they reach the cell surface. Then, attach imaging molecules to these handles, making them visible in medical scans.
In developing their first method for attaching imaging molecules, her team initially turned to a century-old reaction, the Staudinger reduction (1919), but it was not fast enough to react in living beings.
“Once you’re in the body of an animal, it’s not an equilibrium system,” she explained. “In a round-bottom flask, you can mix chemicals with a stir bar and have a reaction happen in a few hours. But a rat is metabolizing. The reactions have to be really fast.”
Around this time, chemists Morten Meldal and K. Barry Sharpless — the other two recipients of the 2022 Nobel Prize in chemistry — had independently discovered that adding copper could dramatically speed up certain chemical reactions in what became known as “copper-catalyzed click chemistry.”
Meldal and Sharpless’ findings revolutionized how chemists could join molecules. Bertozzi realized that by harnessing molecular strain instead of copper, she could create a similar reaction that worked inside living cells.
“We thought these guys had solved our problem, but copper catalysts are toxic to living cells. Nonetheless, these guys shared the Nobel Prize with me,” Bertozzi said with a laugh.
Bertozzi expanded on their work by developing a version of catalysts that don’t need copper, making it safe for living cells. Her final breakthrough came from an unexpected source: teaching her sophomore organic chemistry class about ring strain, an instability in molecular structures.
Bertozzi wondered if molecules with ring strain could speed up reactions without the toxic copper that could threaten living cells.
“I called my graduate student while on a layover in Chicago and asked him to check if anyone had ever tried this approach,” she recounted. “By the time I landed in San Francisco, he found a paper from 1961 by a German chemist named Georg Wittig.”
“This is why we need to support basic science. You never know which seemingly obscure discovery might save lives a century later.”
The paper was in German, which Bertozzi couldn’t read, but one phrase jumped out — “Phenylazid mit cyclooctin explosionsartig” — describing the reaction she was interested in. This became the foundation for her Nobel Prize-winning work.
Attendee Jake Cole PO ’26 was intrigued by the scientific discovery process.
“Imagine your breakthrough coming from basically just seeing ‘explosion’ in some paper you can’t even read. That’s real science right there, not textbook stuff,” Cole said.
Bertozzi’s team developed several versions of these “strained ring” molecules. The new molecules allowed scientists to image sugar molecules in living organisms. Imaging transparent zebrafish, for example, or creating antibody-drug conjugates, vaccines and cell therapies. Bertozzi discussed these applications during Tuesday and Wednesday’s lectures.
Attendee Kevin Ye PO ’27 was fascinated by how biochemical research could translate to the development of therapeutic methods.
“It is not common to have a chance to listen to a Nobel Laureate’s lecture,” Ye said. “Just cutting down specific types of glycoproteins could [help] develop powerful immunotherapies.”
At the intersection of basic science and clinical research, Bertozzi’s lab has done significant work on making a faster, more accurate tuberculosis test that can detect whether cells are alive or dead.
“Not only could you tell a patient ‘you’ve got tuberculosis,’ you could also tell them an hour later, we think these drugs are healing you,” she said.
Transformative science often begins with nothing more than curiosity, chance encounters and asking simple questions.
“This is why we need to support basic science,” Bertozzi said. “You never know which seemingly obscure discovery might save lives a century later.”
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