Multiple Steps Took Click Chemistry from Idea to Nobel-Winning Breakthrough

On October 5, 2022, when the Nobel Committee announced that K. Barry Sharpless, a chemist at the Scripps Research Institute, had won the Prize for Chemistry, I assumed that this Nobel, his second one, must be linked to the first one he won in 2001. But I learned that his 2022 Nobel was for click chemistry, an entirely different field from his Nobel two decades earlier that was for his work on chirally catalyzed oxidation reactions. His extraordinary achievement got me wondering: Why do some scientific breakthroughs gain recognition while others do not?

As I started researching this topic, I knew I had to find a mentor who could help me ask the right questions as I unpacked the problem. My mentor introduced me to three tenets of a good approach to research. First, he asked me to read like a detective and never be satisfied with what scientific authors concluded in their papers. Always ask what they chose not to test and what assumptions they left unexamined. Second, my mentor told me to distinguish between the novelty of an idea from its significance to scientific advancement. A result can be new, but what makes it matter is how many other problems it unlocks. Third, he encouraged me to observe forward-looking questions that scientists pose in their research articles; these questions provide significant clues about a field’s maturity.

To test the above three principles, I decided to trace the journey of click chemistry from the early 2000s to 2022, when Sharpless; Morten Meldal, a chemist at the University of Copenhagen; and Stanford University chemist Carolyn Bertozzi won the Nobel Prize in Chemistry. I started by exploring the critical role of copper in click chemistry reactions that both Sharpless and Meldal had independently established in 2001. Click chemistry is like a seatbelt buckle: two chemical pieces designed to snap together quickly, cleanly, and reliably. Copper acts as the helping hand that grabs one piece and holds it in place so the other slots in fast and correctly.

Thinking like a detective, I asked if there were any assumptions that everyone in the field had accepted without testing. This led me directly to Bertozzi’s research. In a paper published in 2004, she had asked why copper was necessary in click reactions.¹ Subsequently, she re-engineered the click reaction in such a way that one of the chemical pieces was built into a ring shape that's under tension. The stored tension makes the ring "eager" to react, so when the other chemical piece comes near it, they snap together on their own, without copper. Copper is toxic to living cells, so by removing it she allowed click reactions to work inside a living organism without killing it. That single constraint, once broken, made the reaction useful in ways its inventors had not imagined—in imaging tumors, tracking proteins, and delivering drugs with precision. Scientific breakthroughs, I learned, rarely travel in straight lines. They deepen the science before they widen it, and the widening, which began the moment Bertozzi questioned the use of copper in click reactions, is where the real transformation lies.

To test my mentor’s second principle of novelty versus significance of ideas, I began exploring how Bertozzi’s copper-free click reactions had impacted the field of click chemistry. I documented the geographic locations of the labs engaged in click chemistry research and drew a chronological heat map of the field’s advancement around the globe. I found that labs in Prague, Beijing, and California took Bertozzi's copper-free click reactions in directions she may not have envisaged. For example, computational chemists trained models to find entirely new click reactions. By the early 2020s, over 1,000 click-related papers had been published by research teams from labs around the world. One group used click chemistry to build self-assembling materials, and another used it to label and modify nucleic acids in ways that conventional chemistry could not. Each research team provided a result that unlocked new solutions. It became clear to me that this is how a significant idea works in practice. Scientific progress doesn’t only happen with an original insight, discovery, or invention, but rather it happens through the cascade of research and ideas that it releases across the scientific community.

I finally tested my mentor’s third principle that a researcher's most important skill is to ask forward-looking questions that the field does not yet know. Towards the end of my project, I began proposing forward-looking questions of my own before checking what the authors had proposed to see how well my instincts matched theirs. Sharpless's 2001 paper in Angewandte Chemie read like a manifesto, forward-looking but openly uncertain.² By contrast, reviews on click chemistry from 2020 read like catalogues.^3,4 That shift in tone is a sign of the advancement of the click chemistry field. Forward-looking questions had given way to discussions on real-world applications of click reactions. The Nobel Prize awarded at this stage of the discovery’s evolution amplified its legitimacy, further accelerating the journey of click reactions from academic labs to commercial products.

Tracing the journey of click chemistry over two decades has taught me that transformational science is rarely the effort of a single genius. It occurs through the willingness of strangers to build on the ideas of other scientists. I learned that the greater the degree of co-creation in any scientific field, the more the idea is likely to get remembered. The most important question isn't always who had the idea first. It's who kept it all clicking.

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