QnAs with Carolyn R. Bertozzi

The 2022 Nobel Prize in Chemistry (1) was awarded to three scientists for the development of click chemistry and bioorthogonal chemistry, two innovations that have had a significant impact on chemistry. Click chemistry, which involves simple molecules that quickly and selectively bond or “click” together like building blocks, was independently developed by two of the prize recipients, K. Barry Sharpless and Morten Meldal. This groundbreaking innovation has improved the speed and efficiency with which pharmaceuticals and other chemicals are synthesized. Carolyn Bertozzi, the third prize recipient, set the precedent for later applications of Sharpless’ and Meldal’s click chemistry in biological systems by inventing a class of reactions she named bioorthogonal chemistries. Bioorthogonal chemistries have enabled researchers to observe the inner workings of cellular processes. The techniques Bertozzi pioneered are being developed for diagnostic and therapeutic applications. Bertozzi, a professor of chemistry at Stanford University and a member of the National Academy of Sciences, spoke with PNAS about her Nobel prize-winning work.

Carolyn Bertozzi. Image credit: Do Pham, Stanford University.

PNAS: What is bioorthogonal chemistry?

Bertozzi: Bioorthogonal chemistry is chemistry that neither interacts with nor interferes with a biological system. You can do those reactions in living systems, in cells, in model organisms, and now it is happening in human patients. To do chemistry in living systems requires that you have reactants that can react with each other and form a bond, regardless of being surrounded by incredibly complex, richly functionalized biological molecules. It puts a very high demand on the selectivity of the chemistry and the orthogonality. The functional groups cannot have any side reactivity with anything in a natural system. So, that means these are functional groups that do not exist in nature. These are functional groups that we humans invented. They have no reactive counterparts in nature, but they do react with each other. It is like having a whole dimension of chemical reactivity that is occurring in the environment of a biological system, but there is no interaction between that dimension and the biological dimension.

PNAS: Much of your research has focused on glycans, which are a group of sugar molecules found on the surfaces of cells and proteins, including an article (2) published in PNAS in 2007 on the development of bioorthogonal click chemistry to image glycans in living cells. What is the importance of studying glycans?

Bertozzi: Cell surface glycans are an information-rich dataset that allows cells to communicate with the outside world. Those patterns of cell surface glycosylation undergo changes when cells transform to a different state. I first got interested in this because there was so much literature pointing toward altered glycosylation on cancer cells in the tumor microenvironment. That is something you would like to be able to image in living systems for diagnostic purposes or to study the functions of these glycans.

I started as a synthetic chemist focused on carbohydrate synthesis, and then, I worked in an immunology lab as a postdoc. That is where I really became interested in studying the role of glycosylation in cancer and in the immune system, but the tools were primitive back then. It was difficult to ask questions about glycans compared to some of the other biopolymers that you could study with genetics tools. For me, the intersection between chemical biology, technology development, and glycobiology is rich with unanswered questions and therapeutic opportunities.

I think chemical tools have been transformative for glycoscience, maybe even more so than for other areas of biology. Glycans are not directly encoded in the genome, so you cannot easily manipulate them using molecular biology tools. You need chemistry. So, chemists can have an outsized impact in glycobiology. Cancer is an important disease class [that] involves glycobiology (3), but it is not the only one. When I was a postdoc, I worked on chronic inflammatory diseases (4). My current lab also works on infectious diseases: tuberculosis (5) and COVID-19 (6), for example. Glycoscience touches on every aspect of human health and human disease. So, whatever disease you study, you would like to have a glycoscientist in the room.

PNAS: The bioorthogonal chemistry described in the same PNAS article (2) allowed you to create time-lapsed and multicolored images of cell-surface glycans. What insights did you gain by observing the dynamics of glycans?

Bertozzi: You can actually see what these molecules are doing, how they are moving during rounds of cell division. We were able to see a total redistribution of certain types of cell surface glycans that was coordinated with the cell cycle. That is biologically meaningful, but you could not have seen that without the imaging tools. We saw different types of glycans being biosynthesized at different time points in very early development. It was like throwing open the telescope to the galaxy and seeing things for the first time.

PNAS: What therapeutic applications are being developed using bioorthogonal chemistry?

Bertozzi: Various new types of therapeutic molecules have been constructed using bioorthogonal chemistry. One company I advise has a phase I/II clinical trial underway in soft tissue sarcoma using in vivo bioorthogonal chemistry for drug delivery. They are doing the chemical reaction in the human cancer patient, in their body, as a mechanism to release a toxic drug locally in a tumor microenvironment. Antibody–drug conjugates, another type of cancer therapy, have been constructed with bioorthogonal chemistry. I cofounded a company named Redwood Bioscience that has put a bioothogonal chemistry-derived antibody–drug conjugate into clinical trial and has another handful lined up for clinical testing in the next year or two. There are other companies that have made various bioconjugates with bioorthogonal chemistry, including vaccine conjugates, that are in phase II clinical testing right now.

PNAS: What does the recognition of your work with a Nobel Prize mean to you?

Bertozzi: I am a chemical biologist, and bioorthogonal chemistry is very much a product of chemical biology. It is literally chemistry we invented to use in biological settings. Having an invention from chemical biology recognized with a Nobel Prize is big for our field. More traditional fields like biology, biochemistry, and organic chemistry have long histories and are well understood. By contrast, chemical biology is a fairly new discipline and less well understood by scientists outside the field. This prize casts a spotlight on chemical biology that will hopefully increase its visibility across physical life sciences. And although the prize was not given to me for glycobiology in name, it was the unmet needs in glycoscience that drove the invention of bioorthogonal chemistry. Also, my corecipient Morten Meldal is well known for his work in glycopeptide synthesis. This prize therefore helps to enhance awareness of glycoscience as a venue in which new inventions from chemistry can advance biology.