Carolyn Bertozzi also holds the Anne T. and Robert M. Bass Professorship in the School of Humanities and Sciences at Stanford University and, by courtesy, is a professor of chemical & systems biology and radiology.
Chemical Glycobiology and Bioorthogonal Chemistry
Although sugar often gets a bad rap in the popular press, some sugars actually play beneficial roles in the human body. For example, the sugar molecules that stud cell surfaces control how those cells interact with their surroundings. Cells add sugars to proteins or other molecules through a process called glycosylation. Changes in glycosylation occur during normal development, but these changes are also associated with cancer, inflammation, bacterial infection, and other illnesses. Carolyn Bertozzi’s lab team is developing chemical tools and strategies for probing glycosylation in biological systems, in hopes that these technologies will open new avenues for diagnosing and treating disease.
Some of the lab’s approaches fall in the realm of bioorthogonal chemistry – a field Bertozzi is credited with founding – which allows researchers to chemically modify molecules in living cells without interfering with native biochemical processes. In one technique developed by Bertozzi’s team, cells are “tricked” into using artificial sugars as carbohydrate building blocks. Once the artificial molecule gets incorporated into the cell’s usual collection of surface carbohydrates, the researchers use a nontoxic chemical reaction to attach small organic labels to it. Bertozzi and her colleagues have used this method to label and image carbohydrates in animal cells to see how sugar modifications change during aging and disease progression.
Certain types of sugar changes have also been identified as hallmarks of cancer, and the magnitude of glycosylation often correlates with a tumor’s aggressiveness. To better understand the functional significance of these changes, Bertozzi’s lab is engineering cancer-associated sugars on the surface of cellular membranes. With this approach the researchers have discovered that certain carbohydrates help tumor cells evade surveillance by innate immune cells. Her group is also exploring possible cancer therapy approaches that override these carbohydrate immune evasion tactics.
Grants from the National Institutes of Health provided partial support for these projects.
Carolyn Bertozzi is exploring ways to reengineer cell surfaces with the goal of controlling the cells’ interactions. Ultimately, her work may allow investigators to target cancer cells for diagnosis and treatment, for example, or to detect pathogenic bacteria in biological fluid samples.
Although Bertozzi grew up immersed in science – her father was a nuclear physicist at MIT, where she attended summer day camps and later had summer jobs – she seriously considered a career in music (having won awards for compositions and accompanying musicals during her high-school years) before her leanings toward math and science won out. As a Harvard undergrad biology major, Bertozzi discovered the thrill of organic chemistry during her sophomore year. “I wouldn’t go out on weekends because I just wanted to read the book and see if I could work the problems,” she says. Realizing her calling, she switched her major to chemistry and graduated summa cum laude.
Today, Bertozzi’s research is centered on glycosylation – the normal cellular process by which sugars are added to proteins or other molecules. For more than 20 years, scientists have known that changes in glycosylation are associated with cancer, inflammation, bacterial infection, and other illnesses. Bertozzi reasoned that if she could develop a way to monitor glycosylation and measure it quickly, simply, and noninvasively, the results would deepen researchers’ understanding of how cell surface sugars contribute to both health and illness and could open avenues for diagnosing and treating disease.
Toward this goal, she and her colleagues developed a chemical reaction that adds a marker molecule to cell surface sugars, a technique they refined for use in living animals. Their innovative approach uses reagents that react with one another but not with naturally occurring cell surface molecules. Thus, the reagents do not interfere with the sugars’ ability to carry out their normal signaling functions. Bertozzi’s team has used the reaction to attach tracers to sugar molecules on cell surfaces in mice. The sugars they targeted are produced in elevated amounts by cancer cells and by inflamed cells.
The team’s work suggests that this technique could potentially be used to attach tracers to diseased cells in patients, allowing doctors to pinpoint location of the cells in the body and perhaps even target therapy. The techniques developed by Bertozzi also are being used in the biopharmaceutical industry to generate engineered protein drugs including antibody-drug conjugates.
Bertozzi’s enthusiasm for her research and her talent for communicating science in the classroom has been recognized with multiple teaching awards. She likens teaching to telling a story, and her goal for each lecture is to tell a memorable anecdote. For example, in the class she teaches most frequently, an introductory chemistry course for nonchemistry majors, she explains that her philosophy is to “recapture in each lecture the thrill I felt when it was revealed to me that molecules are as diverse as human beings.”