Nobel Prize lecture: Carolyn Bertozzi, Nobel Prize in Chemistry 2022

Carolyn Bertozzi introduces herself, her academic background, and her current role at Stanford University and the Howard Hughes Medical Institute. She discusses the development of bioorthogonal chemistry, a field she pioneered, which allows chemical reactions to occur within living organisms without interfering with biological processes. The concept was inspired by the need for new technologies in chemical biology and medicine, and the goal was to create reactions that could take place in complex environments such as living cells or organisms. Bertozzi explains the fundamental principle of bioorthogonal reactions, which are reactions that do not interact with or interfere with biological systems, thus expanding the 'reactivity space' beyond what is found in biological systems.

Dr. Bertozzi delves into the specific unmet need that led to her lab's focus on bioorthogonal chemistry: the study of changes in cell surface glycosylation. She explains that alterations in cell surface carbohydrates are associated with diseases like cancer and that there was no existing technology to image these sugars. Her lab aimed to develop a method to profile and image cylic acid, a sugar that is often overproduced in cancerous cells. Bertozzi recounts a pivotal conference where she learned about the potential to metabolically incorporate chemically altered sugars into cells, which sparked the idea of using bioorthogonal chemistry to attach imaging probes to these sugars.

Bertozzi describes the development of the first bioorthogonal reaction, the Staudinger Ligation, which was inspired by a classic reaction between triphenylphosphine and azide. The challenge was to make this reaction work within the aqueous environment of living systems. Her student Eliana Saxon solved this by modifying triphenylphosphine with a methyl ester, leading to a stable ligation product. This breakthrough allowed the introduction of azide groups into various cell surface sugars, enabling their imaging via Staudinger Ligation with a complementary imaging probe.

The talk continues with the successful application of bioorthogonal chemistry in living mice by Bertozzi's former students, Jen Prescher and Danielle Dube. They demonstrated that sugars with azide groups could be metabolized in mice and then reacted with a phosphine probe to attach imaging labels, marking a significant advancement in the field. This showed that bioorthogonal reactions could be well-tolerated by living systems, opening up new possibilities for in vivo imaging and drug delivery.

Bertozzi discusses the need for faster bioorthogonal reactions for practical biological applications. She explains the discovery of click chemistry by Sharpless and colleagues, which greatly accelerated the azide-alkyne cycloaddition reaction with a copper catalyst. However, the toxicity of copper in biological systems necessitated the development of copper-free alternatives. Her team explored the use of strained ring systems, like cyclooctynes, which could undergo azide-alkyne cycloadditions rapidly at room temperature, paving the way for more efficient bioorthogonal reactions.

The development of copper-free click chemistry enabled the imaging of cell surface sugars in live zebrafish embryos by Jeremy Baskin and Scott Laughlin. They used cyclooctyne-based probes to label and visualize sugars in developing zebrafish, allowing the study of sugar distribution and dynamics during embryogenesis. This work showcased the power of bioorthogonal chemistry for live imaging in whole organisms and revealed the role of glycans in cellular processes such as mitosis.

The field of bioorthogonal chemistry expanded with the development of new reactions and reagents, moving beyond the initial azide-cyclooctyne pair to include tetrazines and strained alkenes. This diversification of the toolkit has been crucial for the broader application of bioorthogonal chemistry in various areas of biological research and for the development of new medicines and diagnostic tools.

Bertozzi highlights the translational potential of bioorthogonal chemistry, with applications ranging from antibody-drug conjugates for cancer treatment to targeted degraders of extracellular molecules. She mentions her involvement with companies that are harnessing bioorthogonal chemistry for novel therapeutic approaches, emphasizing the importance of this chemistry in the development of new medicines and diagnostics.

In conclusion, Bertozzi reflects on the importance of curiosity-driven basic science, tracing the origins of bioorthogonal chemistry back to the foundational work of early 20th-century chemists. She emphasizes that their initial observations, made out of pure curiosity, have led to transformative applications in modern medicine and diagnostics. Bertozzi's narrative underscores the unpredictable yet profound impact that basic scientific research can have on applied sciences and human health.

Bertozzi expresses her gratitude to the institutions, funding bodies, and individuals who have supported her work, from her students and postdocs to the National Institutes of Health and the Howard Hughes Medical Institute. She acknowledges the role of her family and the audience for their support. The talk concludes with a celebration of the achievements made possible by the curiosity and dedication of those in the scientific community.