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

Transcript

Carolyn bertozi was born 1966 in Boston Massachusetts USA she was awarded a PhD PhD in from the University of California at Berkeley in 1993 and is now active as the anti and Robert M bass professor at Stanford University where she's also an investigator of the house use Howard Hughes Medical Institute so by that please welcome me in welcome and pl... Read More

Summary

Dr. Bertozzi, a pioneer in the field of chemical biology, shares her journey in developing bioorthogonal chemistry and its applications in imaging cell surface glycans. She explains how bioorthogonal reactions are critical for performing chemistry in living systems like cells, animals, and even humans. The first bioorthogonal reaction she developed was the staudinger ligation, which enabled the attachment of imaging probes to sugars on cell surfaces. Later, she and her team discovered the copper-free click chemistry, using strained cyclooctins and azides, which accelerated the reaction rate. This breakthrough allowed for the imaging of various biological molecules, such as proteins, nucleic acids, and lipids, in living systems. The applications of bioorthogonal chemistry have expanded into drug development and diagnostics for human diseases. Dr. Bertozzi emphasizes the importance of curiosity-driven basic science in driving innovations and applications in the field.

Questions & Answers

Q: What is bioorthogonal chemistry and why was it developed?

Bioorthogonal chemistry refers to reactions among components that do not interact with or interfere with biological systems. It was developed to enable chemical reactions in living systems, where traditional chemical reactions control every parameter, are not feasible. The goal was to perform chemistry in complex reaction vessels like live cells, organisms, or even humans.

Q: How did Dr. Bertozzi and her team develop the staudinger ligation?

The staudinger ligation was developed by modifying the classic staudinger reaction, which reacts triphenylphosphine with azides. To overcome the hydrolytic sensitivity of the resulting azaleid product, a methyl ester group was introduced to the triphenylphosphine. This modification allowed the formation of a stable phosphorus-nitrogen bond through intramolecular reaction, making the staudinger ligation a viable bioorthogonal reaction.

Q: What was the significance of introducing the azide into cell surface sugars?

Introducing the azide into cell surface sugars allowed the attachment of imaging probes to sugars in their native habitats. This enabled the study of changes in cell surface glycans, which are associated with various biological states and diseases. For example, studying the overproduction of cyalic acid in cancer cells compared to healthy cells provided insights into cancer development and progression.

Q: How did Dr. Bertozzi and her team expand the applications of bioorthogonal chemistry?

Dr. Bertozzi's team demonstrated that bioorthogonal chemistry could be used to label and image various other biological molecules beyond sugars. They developed methods to introduce azides into amino acids, nucleosides, and lipids, allowing for the imaging of proteins, nucleic acids, and lipids in living systems. This expansion of applications sparked the interest of researchers and led to further advancements in the field.

Q: How did the development of copper-free click chemistry accelerate the reaction rate?

Copper-free click chemistry, inspired by the discovery of copper-catalyzed azide-alkyne cycloaddition, utilized strained cyclooctins and azides to achieve a fast reaction rate. The incorporation of two fluorine atoms near the triple bond of the cyclooctin greatly increased its reactivity, allowing the cycloaddition to occur rapidly at room temperature without the need for toxic metal catalysts like copper.

Q: How did Dr. Bertozzi and her team apply bioorthogonal chemistry to image sugars in living animals?

In collaboration with other researchers, Dr. Bertozzi's team used bioorthogonal chemistry to label and image sugars in living zebrafish embryos. They fed the embryos azido sugars, which were metabolized and appeared on the cell surfaces. Then, through copper-free click chemistry, they attached fluorescent dyes to the azido sugars in a live animal, enabling the visualization and mapping of sugar distribution during development.

Q: What other applications have emerged from bioorthogonal chemistry?

Bioorthogonal chemistry has found applications in various fields. One significant application is in the development of antibody drug conjugates, where bioorthogonal chemistry is used to attach drugs to specific antibodies for targeted cancer treatment. It is also being used to create vaccine conjugates and targeted degraders of extracellular molecules. The versatility and potential for new applications make bioorthogonal chemistry an exciting field of study.

Q: How does curiosity-driven basic science contribute to innovations and applications?

Dr. Bertozzi emphasizes the importance of curiosity-driven basic science in catalyzing innovations and applications. The foundational knowledge built by earlier chemists who made curious observations about exotic molecules provided the basis for bioorthogonal chemistry. These chemists could not have foreseen the current applications of their work, but their curiosity-driven research set the stage for advancements in techniques like bioorthogonal chemistry, which now has significant implications for human health and medicine.

Q: What support and funding sources have enabled Dr. Bertozzi's research?

Dr. Bertozzi acknowledges the support and funding provided by the Royal Swedish Academy of Sciences, the Nobel Foundation, her institution UC Berkeley, and her current institution Stanford. She also mentions the financial support from the National Institutes of Health and the Howard Hughes Medical Institute from the beginning of her research. These organizations and institutions played a crucial role in facilitating her groundbreaking work in bioorthogonal chemistry.

Q: Who are the key contributors to Dr. Bertozzi's research?

Dr. Bertozzi acknowledges her students, postdocs, and colleagues as the key contributors to her research. She expresses gratitude for their dedication and fearlessness in pushing the boundaries of bioorthogonal chemistry. She also recognizes the institutions, funding agencies, and her family for their support throughout her career.

Q: How has bioorthogonal chemistry impacted medicine and diagnostics?

Bioorthogonal chemistry has made significant contributions to medicine and diagnostics. It has been utilized in the development of antibody drug conjugates, vaccine conjugates, and targeted degraders of extracellular molecules for cancer treatment. The ability to image and track biological molecules using bioorthogonal chemistry has also improved diagnostics and understanding of diseases. This chemistry holds great promise for advancing healthcare and finding new therapeutic strategies.

Takeaways

Dr. Bertozzi's groundbreaking work in bioorthogonal chemistry has revolutionized the field of chemical biology. The development of the staudinger ligation and copper-free click chemistry enabled the imaging of sugars and various other biological molecules in living systems. This versatile chemistry has found applications ranging from basic research to drug development and diagnostics. Dr. Bertozzi highlights the importance of curiosity-driven basic science in driving innovations and applications. The foundational knowledge established by previous researchers played a fundamental role in the advancements made in bioorthogonal chemistry. The impact of bioorthogonal chemistry in medicine and diagnostics signals a bright future for this field, with ongoing exploration and the need for new innovations and reactions.