By Rohan D. ’25
The 2022 Nobel Prize in Chemistry was awarded on Wednesday, October 5, 2022, to Dr. Carolyn Bertozzi of Stanford University, who will be sharing the prize with Morten Meldal of the University of Copenhagen and K. Barry Sharpless of Scripps Research Institute. The Nobel Prize honors the scientists for the creation of click chemistry and bioorthogonal chemistry.
Click chemistry, first developed by Sharpless and Meldal, enables molecular building blocks to be assembled and connected quickly and efficiently. One of the most prominent examples of click chemistry was a copper-catalyzed reaction called an azide-alkyne cycloaddition (CuAAC), which was first described in 2001 by Meldal and colleagues.
This copper-catalyzed reaction attracted intense scientific attention because it was easy to execute and afforded extraordinary flexibility across different building blocks. Interest soon developed in extending the CuAAC reaction into biological systems; however, copper ions are toxic to living cells. In 2004, Dr. Bertozzi described a copper-free approach called strain-promoted azide-alkyne cycloaddition (SPACC). Combining learnings from her previous work in cell surface engineering with the SPACC approach, Dr. Bertozzi was able to take human cells, trick them into incorporating non-natural carbohydrates that resembled natural carbohydrates sufficiently to be “undetectable,” and then conjugate tags for the modified glycoproteins (proteins with a sugar attached). Critically, her approach did not interfere with the underlying physiology of the cell itself, coining the term “bioorthogonal.” Imagine building a car where a subtly modified side mirror with a tiny basket is introduced to the manufacturing process. If the basket were small enough to be accommodated by the assembly line without issue but large enough to carry a flag, one could now tag cars with different flags at will. Dr. Bertozzi had done this for the first time in a human cell.
Dr. Bertozzi had not always planned to be a chemist. In fact, she had originally planned to pursue medicine as an undergraduate student at Harvard. However, Harvard’s “Chemistry 17: Principles of Organic Chemistry” class inspired her to seek a career in chemistry. She decided to pursue her Ph.D. at the University of California at Berkeley, where the vanguard of chemical biology was being advanced. After completing her Ph.D., she became a postdoctoral fellow at UCSF and then returned to Berkeley, where her seminal discoveries that ultimately garnered the Nobel prize were made. In 2015, she went to Stanford University. She continues to study cell surface oligosaccharides, dissecting their roles in how cells recognize one another.
Great scientific advances often invite their own inquiry as to how they occurred. Why was Dr. Bertozzi so successful? Interviews with five of the researchers in her laboratory (Dr. Mark Breidenbach, Dr. Ryan Flynn, Dr. Anjali Ganguli, Dr. David Nierengarten, and Mr. Shivam Verma) paint a story. Like many great innovators, she was comfortable taking risks, even as a young faculty member with few resources. Dr. Nierengarten stated that Dr. Bertozzi was “brave and vocal and let her scientific interests take her on her own path. She didn’t care too much about the opinions of others on what she was doing because she was convinced of the value of her work.” Mr. Verma stated, “She doesn’t dismiss things as impossible or too far out there; it was never a question of if it’s possible but what do we need to get there. I think that mindset is incredibly powerful and has taught me a lot honestly. It’s that kind of mindset that I wanted to learn in Carolyn’s training of: “No mountain is too big, what do you need to cross it?’”
Former trainees of Dr. Bertozzi (from left): Dr. Mark Breidenbach, Dr. Ryan Flynn, Dr. Anjali Ganguli, Dr. David Nierengarten, Mr. Shivam Verma | Sources (from left): Oppenheimer, Harvard Medical School, Endless Frontier Labs, Wedbush, Bertozzi Group
With initial early success, she proved to be gifted at communicating scientific results and their implications and then translating that into additional research support. “She was masterful at describing her research and convincing people to fund it,” according to Dr. Breidenbach, one of her former postdoctoral associates.
Ample resources and a relentless commitment to examining big questions enabled her to attract some of the most elite trainees in the world to her lab, many of whom came from outside the traditional domains of organic chemistry and brought with them specialized knowledge sets. Over time, this knowledge was standardized, for example, with experimental protocols that were sufficiently robust that anyone could perform them. While sometimes laboratories going through explosive personnel growth falter from their original promise, Dr. Bertozzi was also skilled at creating “pods” of expertise where members of the pod could help one another even as her own bandwidth compressed.
Despite the lab’s meteoric rise, Dr. Bertozzi still made time for her trainees, engaging with them deeply in fields outside of her direct expertise and ultimately emerging as a skilled mentor. Dr. Flynn stated, “She was high-yield when you talk to her, and she could quickly and deeply engage with you even if it is not her expertise; she would still be able to talk to you, think critically about it, give advice, and she had the ability to quickly understand what’s going on.” She was able to be supportive when needed, but possessed a “light touch” otherwise. Dr. Breidenbach discussed how Dr. Bertozzi was “very informal and a great motivator. She would never be heavy-handed and allowed you to do your project without interfering [with her] hands-off management.” Dr. Ganguli said, “She tries to make you and her peers rather than mentor vs mentee, and she always had her door open or to hang out, always around the lab and accessible for students, […], and she tried to form strong connections. She didn’t have a specific roadmap for anyone, and always helped you pursue whatever you wanted.”
Perhaps another secret to Dr. Bertozzi’s success was something as intangible as personality. Dr. Neirengarten described that in the early days of the lab, laboratory meetings would be accompanied by Oreos. Even when the stakes were high, her wry sense of humor could be on full display. Mr. Verma stated, “Carolyn has her gimmicks. The number of times that I have had meetings with her in which she has been just subsisting on a diet of candy is ludicrous…there is a joke going around the lab that the reason she is so smart is because she survives solely off of glucose.” Similarly, while in Dr. Bertozzi’s lab, Dr. Flynn made a textbook-disrupting discovery showing that RNA could be glycosylated, shattering the long-understood dogma around modified RNA. But before that discovery was made, it was considered almost impossible to complete. Dr. Flynn recalled Dr. Bertozzi encountering him in various corridors and halls, asking “Is that glycoRNA still a thing?” Like many ideas before for Dr. Bertozzi and her laboratory, that glycoRNA idea was indeed a “thing,” and now a very big thing.