Priestley Medal address 2024: Bringing chemistry to life, literally

The American Chemical Society has shaped my professional life since my days as a student. I am deeply grateful for 30-plus years of engagement with the ACS mission and humbled to be situated among the list of Priestley Medalists, which includes many heroes and role models.

My story begins in Lexington, Massachusetts, where I was the second of three daughters born to my father, Massachusetts Institute of Technology physics Professor Emeritus William Bertozzi, and my mother, former MIT Physics Department secretary Norma Bertozzi. They were children of immigrants from Italy and Nova Scotia, respectively, who met in their 20s while my father was a graduate student in the department that eventually hired him onto the faculty.

My father idolized his mother. She ran a strict household where he was the youngest of five children. Having fled Italy during Mussolini’s regime, my father’s mother had an abundance of survival skills that served the family well during the Great Depression. She taught the family to respect education as the ticket out of poverty in America. So my father and his siblings studied hard, earned college scholarships and advanced degrees, and in one generation the family found their places among the middle class.

My mother also prized education: it meant self-sufficiency and independence for her daughters. Although she was a star student in high school, there was little support for her dream of going to college. Instead, she worked part-time jobs and put herself through secretarial school at Boston University. My mother was resolved that her daughters would have the educational and career opportunities that she had been denied in her youth. Decades later she attended Wellesley College, graduating with a bachelor’s degree at age 65.

You might think that we had been tracked into science since birth, but it didn’t feel that way. My older sister, Andrea, was a childhood math whiz, so her destiny was clear. But my younger sister and I were still searching for our passions into adulthood. I entered Harvard University in 1984 with the idea of pursuing music while also majoring in biology and taking all the premed requirements as a concession to my parents’ pragmatism. Imagine my surprise when the course my premed classmates found most intimidating, organic chemistry, turned out to be the one I loved most. David Evans was teaching first-semester organic chemistry to us premeds. He presented the subject with such clarity, elegance, and beauty, I couldn’t get enough. I spent every evening in the Harvard chemistry library hunkered between the shelves reading book after dusty faded book. By the end of my sophomore year, I knew that organic chemistry was my educational and career destiny.

My first action item was to explore whether I should officially change my major from biology to chemistry. I sought advice from 2007 Priestley Medalist George Whitesides, who was teaching my organic chemistry class that semester. I asked, “Professor Whitesides, I am thinking of switching my major from biology to chemistry. Is that a good idea?” His answer left an indelible mark: “Carolyn,” he said, “all of biology is either chemistry or dull.” The message was clear: becoming a chemistry major was an excellent idea, especially if you are interested in biology!

My next action item—finding a summer research position in an organic chemistry lab—was less straightforward. The field of organic chemistry in the 1980s was rather unwelcoming to women. I learned this the hard way, searching for a lab position and finding all doors closed. Studying organic chemistry from lectures and books was fun, but it wouldn’t amount to much if I couldn’t practice the art with my own hands.

The frustration dissipated when a young physical chemist, assistant professor Joe Grabowski, offered me an unexpected opportunity. I was taking his class, and after lecture one day he approached me out of the blue and asked if I would like to join his lab for the summer. In shock, but with good instincts, I immediately said yes. Then after a pause, I asked what exactly his group worked on. Turns out he was looking for a student to build a photoacoustic calorimeter. It wasn’t organic chemistry, but I was thrilled to have the opportunity and resolved to make the most of it.

My experience in the Grabowski lab transformed me. Joe was patient and helpful and respectful of me as a colleague. I built the machine, collected the first datasets, trained my successors, and coauthored a paper (Anal. Biochem. 1992, DOI: 10.1016/0003-2697(92)90003-P). In hindsight, working in a supportive lab where I was challenged and valued was more important to my development as a scientist than the details of the subject I researched.

Still, I was determined to find my way to organic chemistry in graduate school. The University of California, Berkeley, seemed like a promising destination, as they had a cadre of organic chemists who were applying their tools to study biological molecules—complex natural products, proteins, and nucleic acids—in all kinds of creative ways. And I saw women graduate students in those labs, a refreshing image to behold.

I arrived at UC Berkeley at the same time as new assistant professor Mark Bednarski. Coming from his own training with Sam Danishefsky and George Whitesides, Mark introduced me to the wild world of glycoscience, and I was hooked. More to the point, he was an organic chemist who was willing to give me my big break in the field I had dreamed of pursuing. I was finally synthesizing molecules with my own hands, carbohydrate analogs called C-glycosides, and also learning about their fascinating biology (J. Am. Chem. Soc. 1992, DOI: 10.1021/ja00052a072). Mark saw no boundaries between fields. He was an idea factory with no hesitation to launch projects outside our comfort zone. I wish he and I could have known each other as peers. But Mark was diagnosed with cancer during my third year of grad school, and his life was ultimately cut short. I centered my own career on glycoscience to honor his vision.

My years in graduate school, 1988–1993, were also marked by the AIDS crisis. I had many friends succumb to this scourge, an experience that solidified my dedication to LGBTQ+ rights activism and motivated me to pursue postdoctoral work in immunology. But in the early ’90s, it was not yet fashionable for chemists to cross over into biology labs or vice versa. I applied to five labs for postdoctoral positions, and only one professor gave me an interview—Steven Rosen at the University of California, San Francisco. His mind was open to my case that a chemist’s perspective could be valuable in a biology lab. I worked on a family of carbohydrate-binding receptors called selectins that help immune cells traffic to sites of infection or inflammation.

Being immersed in that environment matured my thinking about important problems in biology that only a chemist could solve. For example, great strides were being made in the development of imaging technologies to study proteins and nucleic acids in living systems. But the molecules we were studying, cell-surface glycans, were inaccessible to those tools. I had an inkling that chemistry might solve this problem, but I didn’t yet know how.

It was pure serendipity when, at a conference Steve sent me to, I met German biochemist Werner Reutter (ChemBioChem 2017, DOI: 10.1002/cbic.201700277). His lab was studying the biosynthesis of an important sugar called sialic acid, which often caps the complex glycans projecting from the cell surface. They discovered that unnatural modifications of the N-acetyl group of the metabolic precursor sugar N-acetylmannosamine (ManNAc) were tolerated by the biosynthetic enzymes. So when they fed cells or animals an unnatural N-acetylmannosamine analog, the corresponding modified sialic acid was produced and incorporated into cell-surface glycans.

Reutter’s talk gave me an idea for how to image cell-surface glycans: (1) feed cells a modified sugar bearing a reactive chemical handle, (2) rely on metabolism to incorporate the unnatural sugar into cell-surface glycans, and finally (3) perform a chemical reaction with an imaging probe bearing a complementary reactive functional group. A few months later, I proposed this idea in my academic job applications and landed an assistant professorship at UC Berkeley.

Returning to Berkeley in 1996 was a smooth transition. I already knew the landscape and had mentors in place. I leaned on Bob Bergman, Paul Bartlett, Judith Klinman, and Jon Ellman for critical advice and wisdom in those early days. Brilliant students and postdocs joined my lab, and we set off on a quest to advance the field of chemical glycobiology, with an initial focus on molecular imaging. The strategy outlined above could rely on professor Reutter’s precedents for parts 1 and 2, but part 3 was as yet unattainable. That part of the plan would require a pair of mutually reactive functional groups that would neither interact nor interfere with the biological systems we sought to image—live cells and ultimately live animals. No such chemistries existed at that time; we would have to invent them.

This is the origin story of what we later called bioorthogonal chemistry, i.e., chemical reactions that can be performed in living systems. Our playbook was to take inventory of biocompatible functional groups that don’t exist in nature, then work within this chemical space to find mutually reactive partners. Our first big conceptual breakthrough was identifying the azide as an ideal bioorthogonal functional group, as it is stable in biological systems while possessing selective reactivity as a soft electrophile or 1,3-dipole. My familiarity with azides (J. Org. Chem. 1991, DOI: 10.1021/jo00013a053; Tetrahedron Lett. 1992, DOI: 10.1016/S0040-4039(00)79826-1) from my graduate work gave me conviction that this was the right place to start.

A few years later, we published the first bioorthogonal reaction, the Staudinger ligation of azides with triaryl phosphines to form amide-linked adducts (Science 2000, DOI: 10.1126/science.287.5460.2007). This reaction unleashed the notion that complex biological systems, even live animals, could be vessels for reliable, high-yielding chemical transformations (Nature 2004, DOI: 10.1038/nature02791). We also learned during this period—the early 2000s—that many in vivo applications, including glycan imaging, would require faster reaction kinetics. We still had work to do.

Around this time, the labs of Barry Sharpless (Angew. Chem., Int. Ed. 2002, DOI: 10.1002/1521-3773(20020715)41:14<2596::AID-ANIE2596>3.0.CO;2-4) and Morten Meldal (J. Org. Chem. 2002, DOI: 10.1021/jo011148j) published on the now-storied Cu-catalyzed cycloaddition of azides and terminal alkynes to form triazole adducts. This paragon of click chemistry was fast and compatible with biological molecules like proteins and glycans in vitro. But the Cu catalyst was toxic to cells and animals, so this form of click chemistry would not fulfill the mandates of in vivo bioorthogonality.

Our solution was to accelerate the azide-alkyne cycloaddition via ring strain, a concept as old as the field of organic chemistry itself. This form of copper-free click chemistry involved the reaction of azides with strained cyclooctynes (J. Am. Chem. Soc. 2004, DOI: 10.1021/ja044996f) and possessed the bioorthogonality needed for use in living systems, including cells (Proc. Natl. Acad. Sci. U.S.A. 2007, DOI: 10.1073/pnas.0707090104), zebrafish (Science 2008, DOI: 10.1126/science.1155106), and mice (Proc. Natl. Acad. Sci. U.S.A. 2010, DOI: 10.1073/pnas.0911116107). Sharpless, Meldal, and I were awarded the 2022 Nobel Prize in Chemistry based on the impact of click and bioorthogonal chemistries as tools for biological research, drug development, and beyond. I am deeply grateful to UC Berkeley’s College of Chemistry for providing me with the perfect environment and talent to realize our vision.

A career story should have more than one chapter, and for me, the next big adventure started with a phone call from Chaitan Khosla at Stanford University in the summer of 2013. He asked if I would like to help them build a new institute that brings together chemistry, engineering, and medicine for the benefit of human health, summarized with the acronym ChEM-H. It seemed like a perfect fit to my interests, which had been shifting ever more toward therapeutic development and translational science. I moved to Stanford in 2015, and since then, my lab has developed new therapeutic modalities, such as antibody-enzyme conjugates (Nat. Chem. Biol. 2020, DOI: 10.1038/s41589-020-0622-x) and extracellular targeted protein degraders (Nature 2020, DOI: 10.1038/s41586-020-2545-9). These concepts have been translated to clinical candidates in companies I cofounded. It has been an incredible journey integrating chemistry and biology, and I hope we can ultimately make a positive impact on human health.