Profile: Dr. Carolyn Bertozzi

Doctor Carolyn Bertozzi joined Stanford in 2015 as a professor of chemistry in the School of Humanities and Sciences. She earned a B.A. in chemistry from Harvard and a Ph.D. from UC Berkeley. She is also an investigator at the Howard Hughes Medical Institute,¹ and among her many honors, Dr. Bertozzi is a member of the Royal Society and the Academies of Sciences of Germany and the US. She has won the Lemelson-MIT Prize in 2010, the Arthur C. Cope Award of the American Chemical Society in 2017, the Wolf Prize in Chemistry in 2022, and the Nobel Prize for Chemistry in 2022—an honor she shared with American chemist Karl Barry Sharpless and Danish chemist Morten Peter Meldal. As an open lesbian in academia, Bertozzi is a role model for all future LGBTQ+ scientists to come³. She has a wife and three sons, and resides in Palo Alto, California. Bertozzi describes herself as a chemical biologist, and her current focus is on the role of glycoproteins in cancer.⁹

Background

Carolyn Ruth Bertozzi was born October 10, 1966 in Boston, Massachusetts⁴, and little did she or her parents know at the time that she would go on to make significant contributions to the field of chemistry. She grew up in Lexington, Massachusetts, the second of three girls, and of Italian-American ancestry. Her father was a nuclear physicist at MIT, and her mother a secretary in MIT’s physics department. Her family had a history in the sciences—all four of her father’s siblings were born in Italy, immigrated to the US, went into a branch of science and excelled. As a high schooler, she played soccer, though she ultimately quit to devote herself to academics.⁹ 

After high school, she chose to attend nearby Harvard and almost majored in music, before her pre-med track ultimately led her to declare herself as a biology major at the end of her first year. “‘I didn’t really enjoy the general chemistry class in my freshman year,’ she claims. ‘It was just a box I had to check.’”⁷ She realized her love for chemistry in her second year organic chemistry class, and switched her major. Throughout college she continued to play keyboard and sing backing vocals in a rock band called “Bored of Education” in the 1980s, and the lead guitarist of the band she was in ultimately ended up forming the band “Rage Against the Machine”.⁷ Bertozzi ultimately graduated summa cum laude in 1988 and worked at Bell Labs for a few years. Her main research at Harvard centered around working with a professor on the design and construction of a photoacoustic calorimeter—a tool that studies the properties of molecules by “listening to them” as they decay.

When she arrived at UC Berkeley for grad school, she got a position designing molecules for studying biology in the lab of Mark Bednarski, who she met at Harvard. In her third year, Bednarski was diagnosed with colon cancer, and when he took a leave of absence, Bertozzi and her labmates continued the experiment and finished their PhDs without supervision in 1993 (something that would not be possible today after the introduction of more safety measures). During her subsequent postdoc in an immunology lab at UCSF, she realized how frustrating it was to study glycoscience in biological systems, and this fueled her mission once she took on a professor position back at Berkeley—a mission that would eventually lead her to invent the field of bioorthogonal chemistry,⁷ a term she coined in 2003.

Content and Contributions

What is bioorthogonal chemistry? Bioorthogonal chemistry represents a class of high-yielding chemical reactions that proceed rapidly without interfering with the cell’s natural biology. They are selective transformations not commonly found in biology. Bioorthogonal chemistry overlaps with the field of “click chemistry”, which studies high-yielding chemical reactions that are wide in scope and simpler to perform.⁸ Bertozzi ultimately went on to win the Nobel Prize in Chemistry in 2022 for her contributions to the fields of click chemistry and the invention of bioorthogonal chemistry.

How did Bertozzi discover this field? During her postdoc studies, she investigated the role of carbohydrates in inflammation by mapping a specific glycan—type of carbohydrate found on the surface of cells—that specializes in attracting immune cells to lymph nodes. She used click chemistry to generate a ring-shaped molecule that would bind to a modified sugar called sialic acid on the glycan. Bertozzi described the reaction between the modified sugar and the ring-shaped molecule as bioorthogonal.⁴ Bioorthogonal chemistry has a diverse range of applications, and has contributed to advances in cancer drug development, molecular imaging, medicinal chemistry, protein synthesis, and more. 

Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality¹¹

One of the main ways for scientists to achieve bioorthogonality is via protein modification. There are multiple methods to modify proteins: classic protein bioconjugation, metal-mediated transformations, and modification of the N-terminus are just a few. Classic protein bioconjugation involves reactions that target the functionality of the side-chains of proteinogenic amino acids. Of those, cysteine and lysine are the most commonly modified. Metal-mediated transformations have been used to target tyrosine and tryptophan residues, which are rarer on protein surfaces, and thus offer the opportunity for a controlled, single-site modification. The chemical modification of the N-terminus of a protein is done because the N-terminus has a unique, pH dependent reactivity that allows for selective acylation or alkylation.¹¹ It connects to what was studied in CHEM131, because the pH dependent reactivity of the N-terminus has to do with the differing pKa value of different amino acids, and we studied the pKa and used it in formulas last semester.

Biomolecules that are less amenable to modification can be tagged by metabolically labeling their bioorthogonal chemical receptors, namely, the functional groups that have a unique reactivity orthogonal to the reactivity of natural biomolecules. Once a chemical receptor is incorporated in the target biomolecule, it is treated with a probe molecule that has a complementary bioorthogonal functionality. This selectivity is important for the chemical reaction because with the right combination, reagents can be used at low concentrations and still bind their targets are reasonable rates. Thus, optimizing the kinetics of the bioorthogonal reaction reduces the concentration of chemicals required for labeling of different biomolecules.

Glycans in cancer and inflammation — potential for therapeutics and diagnostics⁶

Bertozzi’s current focus is on glycans, and their role in cancer. She published an article in 2005 discussing the role of glycans in cancer, and how it could be possible to exploit the glycans for therapeutic strategies. Glycans decorate all eukaryotic cell surfaces and undergo changes due to cancer that ultimately mean they play a role in the progression of the disease, specifically in tumor formation and metastasis (cancer’s tendency to spread throughout the body from the original tumor).⁶ In mammals, glycans are constructed from nine connected monosaccharides that form on protein or lipid scaffolds. 

In her research, in a process named Metabolic Oligosaccharide Engineering, Bertozzi explains how unnatural sugars bearing bioorthogonal functional groups can be metabolically introduced into cellular glycans. This was adapted for the cell-surface display of glycans bearing azido groups. The azide is not a natural part of the biological system and is inert to biological components, but it will react with other bioorthogonal functional groups like phosphine in a selective manner. The reaction between azide and phosphine can chemically tag specific sugars in animals, which can be used to tag specific, cancer-affected glycans. Changes in this glycan expression can then be used to track the progression of cancer.

Bibliography

1. Larson, Erik J., and PhD. “Top Influential Chemists Today | Academic Influence.” academicinfluence.com, n.d. https://academicinfluence.com/rankings/people/most-influential-chemists-today.
2. chemistry.stanford.edu. “Carolyn Bertozzi | Department of Chemistry,” n.d. https://chemistry.stanford.edu/people/carolyn-bertozzi.
3. NOGLSTP. “2007-01-21: NOGLSTP to Honor Bertozzi, Gill, Mauzey, and Bannochie at 2007 Awards Ceremony in February – NOGLSTP Is out to Innovate,” January 21, 2007. https://noglstp.org/publications-documents/announcements/2007-01-21-noglstp-to-honor-bertozzi-gill-mauzey-and-bannochie-at-2007-awards-ceremony-in-february/.
4. Gregerson, Erik, and Kara Rogers. “Carolyn R. Bertozzi | Biography, Bioorthogonal Chemistry, Nobel Prize, & Facts | Britannica.” http://www.britannica.com, n.d. https://www.britannica.com/biography/Carolyn-R-Bertozzi.
5. Bertozzi Group. “Bertozzi Group.” Accessed February 12, 2023. https://bertozzigroup.stanford.edu/.
6. Dube, Danielle H., and Carolyn R. Bertozzi. “Glycans in Cancer and Inflammation — Potential for Therapeutics and Diagnostics.” Nature Reviews Drug Discovery 4, no. 6 (June 2005): 477–88. https://doi.org/10.1038/nrd1751.
7. Houlton, Sarah. “Carolyn Bertozzi.” Chemistry World, January 12, 2018. https://www.chemistryworld.com/features/carolyn-bertozzi/3008380.article.
8. Scinto, Samuel L., Didier A. Bilodeau, Robert Hincapie, Wankyu Lee, Sean S. Nguyen, Minghao Xu, Christopher W. am Ende, et al. “Bioorthogonal Chemistry.” Nature Reviews Methods Primers 1, no. 1 (April 15, 2021): 1–23. https://doi.org/10.1038/s43586-021-00028-z.
9. James, Amanda. “Italian American Scientist Carolyn Bertozzi Wins the Nobel Prize in Chemistry.” La Voce di New York, October 5, 2022. https://lavocedinewyork.com/en/news/2022/10/05/italian-american-scientist-carolyn-bertozzi-wins-the-nobel-prize-in-chemistry/.
10. Navals, Pauline. “ONE on ONE with CAROLYN BERTOZZI.” Acs.org, 2022. https://cen.acs.org/biological-chemistry/One-on-one-with-Carolyn-Bertozzi/100/i12.
11. Sletten, Ellen M., and Carolyn R. Bertozzi. “Bioorthogonal Chemistry: Fishing for Selectivity in a Sea of Functionality.” Angewandte Chemie International Edition 48, no. 38 (September 7, 2009): 6974–98. https://doi.org/10.1002/anie.200900942.