Carolyn R. Bertozzi

Carolyn R. Bertozzi
Institutions	Stanford University, Howard Hughes Medical Institute, University of California, Berkeley
Occupation	Chemist
Awards	Nobel Prize in Chemistry (2022)
Known for	Bioorthogonal chemistry
Field	Bioorthogonal chemistry, Chemical biology, Glycobiology
Wikidata	Q7442

Carolyn Ruth Bertozzi (born October 10, 1966) is an American chemist known for creating bioorthogonal chemistry – chemical reactions that can occur inside living organisms without disrupting normal biology. She served as a professor of chemistry at the University of California, Berkeley, and later at Stanford University, where she holds appointments in chemistry and biomedical fields. Bertozzi’s innovations for labeling and tracking molecules in cells transformed glycobiology and chemical biology. In 2022 she shared the Nobel Prize in Chemistry (with K. Barry Sharpless and Morten Meldal) for her work on click chemistry and bioorthogonal chemistry. Her methods now underpin new diagnostics and targeted therapies in medicine.

Early Life and Education

Carolyn Bertozzi was born in Boston, Massachusetts, in 1966 and raised in Lexington, Massachusetts, in a family of scientists. Her father was a physicist at MIT and several relatives pursued science careers. As an undergraduate she attended Harvard University, earning a chemistry degree summa cum laude in 1988. Initially interested in biology and even music, she became fascinated by chemistry in her sophomore year. After Harvard, Bertozzi worked briefly in industrial research and as a teaching assistant, then began graduate studies in chemistry at the University of California, Berkeley. There she earned her Ph.D. in 1993 under Professor Mark Bednarski. During her Ph.D. research she began tackling problems at the chemistry–biology interface, such as designing molecules relevant to immunology.

Following her Ph.D., Bertozzi conducted postdoctoral research in immunology at the University of California, San Francisco (UCSF). There she became keenly aware of the challenges in studying complex biological surfaces like cell membranes and their sugar coatings (glycans). In 1996 she joined the UC Berkeley faculty as an assistant professor of chemistry. She served on the Berkeley faculty until 2015, also holding appointments at Berkeley Lab. In 2015 Bertozzi moved to Stanford University, where she became the Anne T. and Robert M. Bass Professor of Chemistry and led Stanford’s chemical biology initiatives. She is also an Investigator of the Howard Hughes Medical Institute. Throughout her career she has combined chemistry training with insights from biology, and her interdisciplinary approach has defined modern chemical biology.

Bertozzi has also been a prominent advocate for diversity in science. She is openly gay and serves as a role model for LGBTQ+ scientists. In her personal life she is married and has three children.

Major Works and Ideas

Carolyn Bertozzi’s most famous contribution is founding bioorthogonal chemistry. The term “bioorthogonal” refers to chemical reactions that can occur inside living cells or organisms (in vivo) without interfering with any native biochemical processes. In other words, the reactants (and resulting products) are “invisible” to the cell’s normal chemistry. This idea builds on the concept of “click chemistry” (introduced by K. Barry Sharpless and others), which describes reactions that are fast, reliable, and easy to perform. Bertozzi extended click chemistry to living systems by developing new reactants and reactions that are biocompatible.

A key requirement is to use chemical functional groups not found in biology. For example, Bertozzi’s lab made extensive use of the azide group (N₃). Azides are very small, inert molecules that do not generally react with natural cellular components. By attaching an azide onto a biomolecule (for instance, embedding it into a cell-surface sugar), one creates a “tag” that will only react with a specially designed partner molecule. In 2000, Bertozzi and her collaborators reported a pioneering reaction called the Staudinger ligation, which links an azide to a modified phosphine reagent. This reaction covalently attaches a probe to the azide-tagged molecule, allowing it to be labeled or modified. Importantly, the ligation is “traceless,” meaning it does not leave any large chemical scar on the biomolecule. The Staudinger ligation was one of the first demonstrations that covalent tagging of biomolecules could be done in aqueous, cell-like conditions without harming cells.

Bertozzi’s group took bioorthogonal chemistry further by solving practical challenges. A major advance came in 2004 when her team introduced a strain-promoted azide–alkyne cycloaddition (SPAAC), a copper-free version of the click reaction. Traditional “click” chemistry between an azide and an alkyne requires a copper(I) catalyst, but copper is toxic to living cells. Bertozzi replaced it by using a specially strained cyclic alkyne (a cyclooctyne) that reacts with azides rapidly without any metal catalyst. In practice, cells are fed an azide-containing sugar, which they naturally incorporate into their surface glycans; then a fluorescent or affinity-labeled cyclooctyne can be added to react in situ with those azides. This copper-free click reaction proceeds under physiological conditions with no apparent harm to live cells SPAAC dramatically sped up labeling reactions and became widely used for live-cell imaging.

Bertozzi also pioneered metabolic oligosaccharide engineering. Instead of adding labels directly to cells, she had the idea of feeding organisms chemically altered sugar precursors. Cells naturally metabolize these precursors and incorporate them into their glycans on proteins and lipids. By using sugars bearing an azide or other bioorthogonal handle, her group could install the “clickable” tag throughout the cell’s glycan layer. For example, Bertozzi showed that an azide-modified version of the sugar sialic acid can be taken up by cells and attached to their outer membrane glycans. Later, this azide can be detected and labeled by bioorthogonal reagents such as phosphines or cyclooctynes. This strategy allows researchers to visualize and track complex sugars on living cells and even in live animals. In one famous 2004 study, Bertozzi’s team demonstrated chemical remodeling of cell surfaces in live mice: they fed mice an azido-sugar and then tagged the azide-bearing glycans in the animals using a fluorescent Staudinger ligation, enabling imaging of tissues.

Bioorthogonal techniques have illuminated many aspects of biology that were previously hard to study. For instance, Bertozzi’s lab used these methods to investigate how cancer cells differ in their glycan patterns, how immune cells migrate in the body, and how pathogens (bacteria and viruses) interact with host cells. Her work showed that certain disease states involve unusual sugar structures, and by tagging these sugars one can create better diagnostics. Notably, her research inspired new classes of therapies. For example, her group developed novel therapeutics called “Lysosome Targeting Chimeras” (LYTACs) which use sugars to drag disease-causing proteins into the cell’s degradation pathway. This effort led to a startup (Lycia Therapeutics) aimed at drug delivery and targeted protein degradation.

In summary, Bertozzi’s major ideas include:

Coining and building bioorthogonal chemistry – introducing the term in the early 2000s to describe chemical reactions in living systems that do not disturb biology
Developing new chemical ligations – especially the Staudinger–Bertozzi ligation (azide plus phosphine) and copper-free click (strained alkyne plus azide). These enable covalent tagging of biomolecules inside cells with high specificity.
Metabolic glycan labeling – feeding cells modified sugar precursors (bearing azides or other tags) and then selectively detecting them. This revealed the roles of cell-surface carbohydrates (glycans) in inflammation and disease
Applications to diagnostics and therapy – using bioorthogonal chemistry to create new imaging probes, pathogen tests, and targeted drugs. Her lab tied fundamental chemistry to practical medical problems.

These contributions established chemical methods that work in vivo, opening a new way to study and manipulate biology with precision.

Research Methods

Bertozzi’s research blends synthetic organic chemistry with cell/molecular biology. A hallmark method is the chemical reporter strategy: one introduces a small, non-disruptive functional group into a biological system, then uses a second molecule to tag or modify that group. In practice, this often means the first step is metabolic engineering – feeding cells modified substrates that get incorporated into biomolecules. For example, cells may be cultured with an azido-modified sugar or amino acid. The cell’s own biosynthetic machinery mistakes it for a normal nutrient and builds it into glycoproteins on the surface. Crucially, the azide tag does not affect the molecule’s normal function in the cell; it merely sits there waiting for detection.

The second step is the bioorthogonal reaction: a probe molecule carrying a complementary functional group (phosphine, cyclooctyne, etc.) is added. Only that probe and the tagged biomolecule react with each other – nothing else in the cell. This covalently links a reporter (such as a fluorescent dye or an affinity handle) to the biomolecule of interest. By choosing different reporter molecules, Bertozzi’s lab can visualize where the biomolecules are (via microscopy) or isolate them (via pull-down methods).

Bertozzi also employs high-throughput screening and directed evolution in developing reagents. For instance, her group designs new cyclic alkynes with improved solubility or reactivity for the copper-free click reaction. She collaborates with cell biologists, immunologists, and translational researchers to apply these chemistry tools to problems like tumor imaging or vaccine development. In sum, her method is highly interdisciplinary: it requires organic synthesis to make specialized molecules, cell-culture and animal models to apply them, and advanced imaging or molecular analysis to interpret the results.

Influence and Impact

Carolyn Bertozzi’s influence spans chemistry, biology, and medicine. Her introduction of bioorthogonal chemistry created a new subfield of chemical biology; today thousands of laboratories use her techniques to study biomolecules in situ. By allowing scientists to “light up” and manipulate sugars and other cell-surface molecules inside organisms, her methods have become standard tools in molecular imaging and diagnostics. For example, researchers can monitor how immune cells traffic through the body, or how bacteria invade tissues, by labeling specific molecular markers originally developed in Bertozzi’s group.

Her discoveries have also catalyzed new biotechnology. Bertozzi co-founded several startups (such as Redwood Bioscience, which commercialized glycan labeling diagnostics, and Lycia Therapeutics, developing LYTAC drugs) to translate glyco-chemistry into products. Her ideas paved the way for a “glycoscience” industry focused on the sugar-coated cell surface (glycocalyx). Pharmaceutical companies now routinely explore glycan-binding drugs and site-specific antibody–drug conjugates, building on concepts she helped introduce.

Within academia, Bertozzi has been a mentor and leader. She has guided hundreds of graduate students and postdocs, many of whom have become professors or biotech leaders. She serves on advisory boards (for example, pharmaceutical company Alnylam) and recently took roles such as Director of Stanford’s Bio-X center (later renamed ChEM-H) to foster collaboration between chemists and biomedical researchers. She has also brought attention to the importance of carbohydrates in biology, a field once considered arcane. Science journals and conferences frequently highlight her work, and she is often invited to speak worldwide. Bertozzi’s Nobel Prize has further elevated the profile of chemical biology.

Her influence extends beyond science. Bertozzi actively promotes diversity in STEM fields. She has spoken publicly about being an LGBTQ scientist and works to make academic environments welcoming. She has won awards not just for research but for teaching and mentorship, such as Berkeley's Distinguished Teaching Award. Her career is often held up as an example of how basic chemistry research can lead to medical breakthroughs, inspiring a generation of interdisciplinary scientists.

Critiques and Challenges

Bioorthogonal chemistry, while powerful, is not without limitations. Early reactions like the Staudinger ligation worked well in principle but were slow and sometimes yielded low yields. The phosphine reagents could be hard to synthesize and oxidized readily in air, which limited practical use. Similarly, although copper-free click chemistry solved the toxicity issue, some cyclooctyne reagents were initially large and hydrophobic, making them hard to deliver inside living tissues. Over the years, Bertozzi and others have designed improved reagents (faster reacting, more water-soluble cyclooctynes, new ligations like tetrazine–norbornene cycloadditions) to address these concerns.

Some critics also note that no bioorthogonal system is perfect. In practice, very high selectivity and fast kinetics are ideal but hard to achieve simultaneously. For certain applications (such as imaging very fast cellular dynamics), even the fastest bioorthogonal reactions might not keep pace. Moreover, introducing unnatural sugars or probes into an organism can alter metabolism or immune responses if done in excess. Care must be taken in experimental design to ensure the tags truly remain “invisible” to the system as intended.

On a broader level, some biologists initially doubted the usefulness of chemistry tools in living systems. It took years of successful applications for the field to catch on. Even now, translating bioorthogonal methods into clinical practice (e.g. as approved medical diagnostics or therapies) is challenging due to regulatory hurdles and the complexity of working in humans. For example, using modified sugars or enzymes in patients raises safety questions that researchers must answer. These are active areas of research and development. In short, while Bertozzi’s methods have opened many doors, scientists continue to refine them to make reactions faster, safer, and easier to use in complex biological settings.

Legacy and Future Directions

Carolyn Bertozzi’s legacy is already vast and will grow further. The term “bioorthogonal chemistry” is now a standard part of the chemical education lexicon, and her papers remain highly cited. Textbooks on chemical biology discuss her discoveries as fundamental breakthroughs. Many laboratories worldwide continue to adopt and extend the reactions she introduced, applying them to fields as diverse as neuroscience, immunology, and even environmental science.

She has also helped elevate glycobiology to a “first-tier” field. Carbohydrates and glycoproteins are now recognized as critical in health and disease, in no small part due to tools her lab developed. For instance, cancer immunotherapies often seek to block or exploit tumor cell glycan shields; this strategy is built on understanding glycan biology, which her work helped map. In medicine, diagnostics for pathogens sometimes use carbohydrate markers – again reflecting the impact of her research on infectious disease testing.

Moreover, as one of the few Nobel laureates active in chemical biology, Bertozzi is paving the way for future innovations. She continues to run an active research group at Stanford, exploring new bioorthogonal reactions and applications. Her entrepreneurial ventures (companies, consultancy) suggest that her ideas will keep influencing biotech pipelines. She is also likely to inspire policy and funding support for interdisciplinary science.

In recognition of her role, Bertozzi has received some of the highest honors in science: membership in the US National Academy of Sciences and National Academy of Medicine, the American Academy of Arts and Sciences, and foreign academies, as well as major awards such as the MacArthur “Genius” Fellowship (1999), the Lemelson-MIT Prize (2010), and the Wolf Prize in Chemistry (2022). These underscore her broad and international impact.

Legacies are built over generations; Bertozzi’s contributions have set the stage for new therapies envisioned today – for example, targeted cancer drugs, improved imaging agents, and novel vaccines – that may come to fruition in years ahead. Her career shows how fundamental chemical insights can translate into tangible societal benefits.

Selected Works

Saxon, E.; Bertozzi, C. R. “Cell surface engineering by a modified Staudinger reaction.” Science 2000, 287, 2007–2010. (Introduced covalent tagging of azide-labeled cell-surface sugars in living cells.)
Sletten, E. M.; Bertozzi, C. R. “Bioorthogonal chemistry: fishing for selectivity in a sea of functionality.” Acc. Chem. Res. 2011, 44, 666–676. (Review article defining bioorthogonal chemistry and summarizing key ligation methods.)
Jewett, J. C.; Bertozzi, C. R. “Ca(II)-Free Click Chemistry for Covalent Modification of Biomolecules in Living Systems.” J. Am. Chem. Soc. 2004, 126, 15046–15047. (Reported strain-promoted azide–alkyne cycloaddition (SPAAC) for living cells.)
Prescher, J. A.; Dube, D. H.; Bertozzi, C. R. “Chemical remodelling of cell surfaces in living animals.” Nature 2004, 430, 873–877. (Demonstrated in vivo labeling of glycans in mice via Staudinger ligation.)
Chang, P. V.; Prescher, J. A.; Hangauer, M. J.; Bertozzi, C. R. “Imaging Cell Surface Glycans with Bioorthogonal Chemical Reporters.” J. Am. Chem. Soc. 2007, 129, 8400–8401. (Applied dual metabolic labeling and imaging of cell-surface glycans using bioorthogonal chemistry.)

Timeline of Major Events

1966 – Born in Boston, Massachusetts.
1988 – Graduated Harvard University (Chemistry, summa cum laude).
1993 – Earned Ph.D. in Chemistry from UC Berkeley.
1996 – Joined the University of California, Berkeley faculty (Chemistry department).
1999 – Awarded MacArthur “Genius” Fellowship for her innovative research in chemical biology
2000 – Published first bioorthogonal tagging reaction (Science report on “cell surface engineering” with Staudinger ligation.
2004 – Developed copper-free click chemistry (J. Am. Chem. Soc. publication) and demonstrated in vivo glycan labeling (Nature publication.
2010 – Received the Lemelson–MIT Prize for outstanding invention in chemistry.
2015 – Moved to Stanford University as Professor of Chemistry (with appointments in systems biology and radiology). Became co-director of Stanford’s chemistry-biomedical interface institute (ChEM-H).
2017 – Awarded ACS Arthur C. Cope Award for contributions to organic chemistry.
2022 – Awarded the Priestley Medal (ACS top honor) and Wolf Prize (Chemistry); announced as co-recipient of the Nobel Prize in Chemistry “for the development of click chemistry and bioorthogonal chemistry.”

Sources: Institutional profiles and award citations; press releases and news articles on Bertozzi’s work; Bertozzi’s group publications and interviews. (In-text references have been omitted as requested.)