2024 Priestley Medalist Carolyn Bertozzi has built a unique culture

It would be hard to find a chemist better known to the field than Carolyn Bertozzi—the subject of a Lego figurine and a Spanish-language comic book and the recipient of a dizzying list of scientific honors.

Bertozzi’s work in bioorthogonal chemistry has become a cornerstone of the field of chemical biology. To solve a problem specific to a niche research area, probing the cell surface, Bertozzi and her team came up with a type of chemistry that was celebrated by the 2022 Nobel Prize in Chemistry and has become ubiquitous, even in biology laboratories that otherwise do no chemistry at all.

And Bertozzi hasn’t stopped. She has made major discoveries in basic glycobiology and spun off numerous companies that are moving her lab’s discoveries into clinical practice for cancer and rare diseases. She leads an interdisciplinary research institute at Stanford University and a large lab within it and is the founding editor in chief of the journal ACS Central Science.

She has also received just about every award in her field, including the American Chemical Society’s highest honor, the Priestley Medal. (ACS publishes Chemical & Engineering News but is not involved in editorial decisions.)

Today, the field of chemistry celebrates her as one of its very best practitioners. But when she began her career, Bertozzi’s field barely tolerated a person like her. Bertozzi epitomizes an ongoing cultural shift in chemistry: from professor as resident of the ivory tower to professor as entrepreneur, from scientific silos to interdisciplinary research and team science, and from an old boys’ club to an environment that values diversity of background in all its forms.

Becoming a scientist

A few days after the Royal Swedish Academy of Sciences announced that Bertozzi had won a share of the 2022 chemistry Nobel Prize, Bertozzi gave off-the-cuff remarks to an outdoor gathering at Stanford University. She spoke about how diversity of background had been key to creating the culture of her lab and key to its success in creating new types of chemistry. A video of the speech went viral.

But it was nothing Bertozzi hadn’t been saying for years. Inclusivity in science is personal for her. “If I was born even 10 years earlier . . . I’m not getting an academic job as a woman in chemistry. And as an open lesbian—are you kidding?” she says. Timing, Bertozzi observes, is everything. She entered the field through doors that were just beginning to open.

Raised in an intensely academic household, Bertozzi fell in love with organic chemistry in college. But she couldn’t land a summer research position in any of the male-dominated organic chemistry labs that hired her Harvard University classmates. Perhaps, she has since concluded, that’s a good thing. “Toxic masculinity would have probably driven me out,” Bertozzi says. “I might have never become an organic chemist.” Instead, she joined a physical chemistry lab and thrived.

The consummate scientist, Bertozzi sometimes says in interviews that she can’t tell for sure whether discrimination has affected her career, because the control experiment is impossible to run. Occasionally, she has pointed out that she may have had it easier than straight women in her cohort because men tended to view her as a colleague rather than a dating prospect.

But being gay in the late 1980s had its hardships. In graduate school at the University of California, Berkeley, her floor lacked a women’s restroom; the building had been designed for a male workforce. When she went downstairs, fellow graduate students lobbed homophobic insults at her as she walked past.

The verbal abuse had happened before, but one day she returned to the lab particularly upset. Graduate adviser Mark Bednarski overheard her talking to a lab mate—she wouldn’t have told him otherwise, she says. But when he heard what had happened, he marched downstairs and excoriated the bullies.

“That was the first time, actually, somebody in a position of authority had my back,” Bertozzi says.

Bednarski was a difficult boss in some ways. He held group meetings at 10:00 p.m. on Saturdays and was so full of ideas that his students scrambled to keep up with new research directions. But what he did to support her has stayed with her. As has his enthusiasm for carbohydrate structure and function, which sparked an interest in sugar chemistry that has defined Bertozzi’s research.

Bednarski left Berkeley during Bertozzi’s third year of graduate school after a cancer diagnosis. Suddenly without a principal investigator, she talked the academic administration into letting her finish her degree unsupervised, an unconventional training that included writing grant renewals and convincing journal editors to publish her work.

“It was a crisis when my boss quit—and on the other hand, it felt like doors opened because I was no longer constrained by the mainstream mindset,” she says.

When the time came for a postdoctoral position, senior chemists advised Bertozzi that without a big-name champion from her graduate days, she’d need a well-known postdoctoral mentor. Despite their advice, Bertozzi was guided by her scientific curiosity. She wanted to study carbohydrate receptor binding in the immune system and so joined the lab of immunologist Steven Rosen at the University of California, San Francisco.

“She’s a chemist, but she knew the essentials of the biology, and she identified . . . absolutely the right problem,” Rosen says. At the time, his UCSF lab was studying how a carbohydrate-binding protein called L-selectin on white blood cells recognizes glycoproteins on cells in blood vessels, allowing the white blood cells to migrate into tissues where they are needed.

On arriving in Rosen’s lab, Bertozzi was struck by a few cultural differences between chemistry and biology. One was the ability to be closer to patients, since she worked at the UCSF medical center. Another was being surrounded by more women colleagues. She also found that her new colleagues knew of “big names that were just as big to them as my big names were to me—but we didn’t know any of the same people.”

The observation eroded some truisms of chemistry at the time. “I was like, ‘Wow, all of this is artificial. There is no big name; there’s just a bunch of scientists working in little silos . . . and creating their own culture.’ ”

Bertozzi’s knowledge of carbohydrate synthesis let the team compare an L-selectin ligand with synthetic standards and thereby determine its glycan structure. How glycans mediate cell recognition and signaling, especially in the immune system, has become a through line in Bertozzi’s career. Her postdoctoral work set Bertozzi apart from peer chemists when she looked for a first faculty job. She was, Rosen says, “the only person I’ve ever known to be simultaneously recruited by UCSF, UC Berkeley, and Stanford.”

Still, she knew that at least Stanford’s offer was influenced by the Chemistry Department’s being under pressure to hire more women—the hiring committee told her so. “Back then . . . you had to take opportunities,” she says. “You ate whatever scraps people threw at you and just tried to make the most of it.”

Things start to click

At UC Berkeley, Bertozzi ran her lab differently right from the start. In her first year, her lab group consisted entirely of four women, at a time when only about a third of chemistry graduate students in the US were women. “People would dump on my students, make jokes,” she says.

Former student Jennifer Prescher, who was in the lab in those early days, says Bertozzi never made her students feel like the diversity lab. “She never let on to us that we were anything other than awesome,” and working on important problems.

In her remarks at Stanford in 2022, Bertozzi said that her team’s diversity “created an environment where we felt we didn’t have to play by the same old rules as scientists. We could do things like organic chemistry in living animals—why not?”

Specifically, in the early 2000s, Bertozzi’s lab was looking to develop a reaction so selective that the two reactants would not be sidetracked by the cacophony of other molecules in a biological system. The researchers called this then-radical aim bioorthogonal chemistry.

Leaving old rules behind was risky. Science runs on the esteem of peers: without convincing a panel of colleagues, a researcher will never land a grant or get a paper published. And as Bertozzi points out, unconscious bias makes peer reviewers less likely to appreciate research in an area they’ve never heard of. “The headwinds that come with being in a field that’s underappreciated are substantial,” she says. “But at the same time, there’s a huge opportunity to make new discoveries in a field that’s underpopulated . . . without stepping on each other’s toes.”

Fringe at first, bioorthogonal chemistry soon began to get noticed. The team published several papers in high-profile journals, describing reactions between a series of reagents: first an azide and a phosphine, then an azide and an alkyne, which later became a strained cyclic alkyne. These reagents react very specifically, enabling ligations in a living cell, or even a living animal, without cross-reactions with the rest of the complex cellular environment. This was the work that the Nobel Prize later recognized. During the period when it was being published, Bertozzi landed a Sloan Research Fellowship, was named a Pew biomedical scholar, received a MacArthur Fellowship, and joined the faculty at the Howard Hughes Medical Institute.

Bioorthogonal click reactions have become ubiquitous. “All these biologists who just don’t think about chemistry at all—they know how to click things,” says former trainee Jennifer Kohler of the University of Texas Southwestern Medical Center.

Bioorthogonal chemistry also placed the Bertozzi lab squarely in the burgeoning field of chemical biology—a discipline that uses the tools and principles of chemistry to study and manipulate biological systems.

According to John Jewett of the University of Arizona, who joined Bertozzi’s lab from an organic chemistry PhD program, the culture in chemical biology contrasts with the lingering machismo of organic chemistry. Many chemical biologists are at the fringes of fields in their home departments and used to having colleagues challenge their work, he says. As a result, “chem bio is a pretty accepting community.”

People are a scientist’s biggest asset

During brief remarks to the Swedish royal family and guests at a Nobel banquet in December 2022, Bertozzi made the usual mention of how much she and her fellow laureates owe to their students. She paused, smiling, and then repeated herself, looking expectantly across the hundreds of gala attendees in their tailcoats and gowns. This time, they applauded. Bertozzi nodded in satisfaction and went on to acknowledge the laureates’ postdocs, staff, and supportive families, to more applause.

Bertozzi’s generosity, and her habits of always advancing her students and crediting their work, inspires great loyalty in return. “She gets along with her peers wonderfully, but she especially is revered among the people who work with her,” says Frances Arnold, a fellow Nobel laureate in chemistry. “She has very high expectations, but she manages to get tremendous respect—and love, really—from the people that work with her. I think that’s marvelous.”

Vanderbilt University glycoscientist Steven Townsend recalls Bertozzi’s advice to him on running a lab: “You’ve got to crush it when it comes to research. Aim high. Go after tough problems. But you should put equal effort into making sure people are comfortable—that they can exist in their own skin—because that’s going to maximize what they can do in the lab, and then doing well in the lab will enhance their self-image.”

Prescher recalls that when she started her lab at the University of California, Irvine, Bertozzi told her that people are a scientist’s greatest asset—so they deserve the greatest investment of her time. Though Bertozzi is busy and hands off when it comes to technical troubleshooting, many of her former trainees say, she finds the time for them when it’s important. She once spent an hour on the phone with a former trainee puzzling through a major career decision while also navigating a family trip to the grocery store.

Besides career advice, she also gives parenting advice. And she’s open about her own challenges, Jewett says. That humanity is “one of the reasons people are drawn to her.”

Meanwhile, Bertozzi also maintains a panoramic view of glycobiology and a strategic sense of where both the lab and its projects are headed. Cornell University chemical biologist Jeremy Baskin, a Bertozzi lab alum, says Bertozzi students often feel as if “we’re just walking in a field with 6 ft high grass, but she’s up in a propeller plane.”

Bertozzi’s research group meets every Thursday afternoon. Each week, a different speaker presents. Once a year, Bertozzi takes her turn. “That’s an opportunity for me to remind everybody that ‘Here’s what I value; this is how I think science is best done. It requires collaboration and teamwork and generosity and listening skills,’ ” she says.

One of the lessons she imparts is that friendship is more important than authorship. Relationships built in grad school can become lifelong collaborations, she says, so “disrupting a potential future collaborative relationship over some authorship order is . . . bad math.”

Catherine Leimkuhler Grimes, a professor and codirector of the Chemistry- Biology Interface Program at the University of Delaware, recalls an ACS conference around 2012 where she learned that Bertozzi’s lab—a well-established powerhouse—was investigating labeling bacterial cell walls along a line similar to that of Grimes’s newly founded lab. Nervous that Bertozzi would scoop her fledgling research program, Grimes approached Bertozzi to ask where her project was headed next. If their goals were the same, Grimes planned to find a different line of research.

She still remembers how compassionately Bertozzi allayed her concern that the whole Bertozzi army was working on this project. But only a single graduate student, Sloan Siegrist, was working on the project—and Bertozzi offered to put the two in touch.

“She did not need to do that,” Grimes says. “She could have just been like, ‘I’m going to crush you.’ ” Instead, Bertozzi connected Siegrist and Grimes after the conference, and they remain collaborators and friends. “I think that speaks volumes to her as a scientist and a person,” Grimes says.

Bertozzi says she doesn’t remember this episode. Still, it illustrates a guiding principle. “If I discover that another lab is doing something very similar to what we’re doing . . . my first instinct is, let’s communicate. Let’s share what we’re doing. Is there a way that we can leverage what we’re doing together and be more than the sum of our parts?”

If that doesn’t work—after all, she can’t control other people’s decisions—she encourages her own group to pivot, she says. “There are so many mysteries that we haven’t solved and so many questions to ask. . . . There’s just no reason for two labs to work on the same thing.”

Leaving Berkeley and directing ChEM-H

In 2015, Bertozzi moved her lab from UC Berkeley to Stanford and became a founding member of a research institute called Sarafan ChEM-H. According to Kathryn “Kam” Moler, former vice provost and dean of research at Stanford, the institute “embodies this new way of doing research, where things are more team centered,” and Bertozzi has been key to setting its direction.

“Carolyn Bertozzi is the avatar of team science,” Moler adds.

Some years earlier, Bertozzi had turned down a similar invitation to join the Broad Institute of MIT and Harvard—a choice she came to regret when she became a member of its advisory board and saw what Broad researchers were accomplishing. “I remember thinking, ‘This is a lesson,’ ” she says. So when Bertozzi was invited to a well-funded institute at Stanford whose mission of multidisciplinary translational research was still being defined, she had a certain sense of déjà vu. She has directed the institute since 2020.

If you ask academic administrators today about the importance of diversity, equity, and inclusion, many hesitate, mindful of a backlash that includes the Supreme Court’s outlawing of affirmative action in admissions and the ousting of several university presidents.

Bertozzi, however, is plainspoken about her values. “I think people know me well enough now that if there’s something they’re going to do that’s offensive or objectionable, they just don’t do it in front of me,” she says.

As an institute director a step outside the usual departmental hierarchy, she says, she has more latitude to make public statements too—as she did after the 2020 murder of George Floyd. While a few colleagues suggested that she tone it down, she asked: “Do I have to?” The way she saw it, answering the concerns of students at ChEM-H was part of her primary responsibility. Supporting students is what she calls “the heart and soul of my job.”

Spinning off companies

Working at Stanford, with its busy medical center and entrepreneurial mindset, also gives Bertozzi more opportunity to translate her research into the clinic. As industry has become more daring and the old norm that a professor should be unsullied by commercial interests has waned, Bertozzi has launched a small flotilla of companies. Since she moved to Stanford in 2015, 11 start-ups have emerged from her lab.

There’s a risk inherent in entrepreneurship—one that Bertozzi was quite familiar with. Her first company, cofounded with postdoctoral mentor Rosen and two other colleagues, went bankrupt in 2005. Juggling crystallography, antibody development, and small-molecule screening for enzymes involved in carbohydrate sulfation, the company ran out of money before identifying a candidate molecule to advance. “It didn’t take too many years of hindsight to realize that we had bitten off way too much,” Rosen says.

Bertozzi proceeded with pared-down ambitions for her second company, Redwood Bioscience, which developed a chemical biology approach for site-specific protein tagging and was later bought by Catalent. “Carolyn always learns from her mistakes,” Rosen says. “I didn’t form a second company. But Carolyn, within a year or 2, formed a second company and has had the energy to go on.”

One of Bertozzi’s most advanced companies, and the one that academic colleagues seem most excited about, is Palleon Pharmaceuticals, which is developing drugs to edit cell-surface glycans.

Palleon’s platform is based on a long-observed oddity of cancer cells: the glycans on their surface are much richer in sialic acid than the average cell’s. Bertozzi and her team had the insight that these atypical glycans might shield cancer cells from immune surveillance, just as immune checkpoint signaling proteins do. Kamil Godula, a former Bertozzi postdoc, says the conceptual link is a great example of Bertozzi’s ability “to connect fundamental discoveries in the laboratory to long-standing problems in medicine and biology.”

Checkpoint inhibitor drugs are usually monoclonal antibodies. But since the Bertozzi team wasn’t sure which specific sialic acid–containing molecule was most important—or even that there was only one in play—it tried something new, targeting cells with an enzyme that cleaves sialic acids from glycans. On the strength of a prototype enzyme, Palleon raised $47.6 million for a launch in 2015, the same year Bertozzi moved to Stanford. Palleon plans to begin human trials of a sialidase drug later this year.

Since Palleon’s launch, Bertozzi has spun a further 10 companies out of her lab, and more possibilities are burbling in stealth mode.

In a paper published last year, Bertozzi’s team reported that a single specific glycopeptide on a cell-surface protein can calm T cells. This finding clinched the concept of an immune checkpoint (Proc. Natl. Acad. Sci. U.S.A. 2023, DOI: 10.1073/pnas.2215376120). The researchers have developed a prototype protease to cleave that motif from cells.

Bertozzi is also interested in exploring click reactions that could build drugs in living people. Such reactions might make it easier to design a drug without being forced into the molecular trade-offs that define medicinal chemistry, like sacrificing desirable activity so a compound can be given orally, diffuse across membranes, or dodge metabolism in the liver.

One reason for Bertozzi’s prolific entrepreneurship, she says, is that being a cofounder enables her to support students’ career ambitions. “If they want to do it, I’m on board with it because that’s my job,” she says.

Risky science

In addition to developing new potential drug modalities, scientists in Bertozzi’s lab have continued to make fundamental observations about how biology works. Even though she has a bigger reputation to protect now than ever before, she’s still game for a risky project—such as the lab’s provocative 2019 preprint (a paper posted before peer review) showing that a subset of the glycosylated molecules on the surface of a cell are RNA.

Biologists had thought that RNA was never in the same cell compartment as glycosylation enzymes and certainly never on the surface of a cell. So when she first saw the data, Bertozzi says, “I was like, ‘This is impossible. It’s an artifact.’ ”

For 2 years, then-postdoc Ryan Flynn ran one control experiment after another to rule out spurious reasons that RNA and glycan might have stuck together as he prepared cells for glycomic analysis. Bertozzi says, “Every day I would joke, ‘Hey Ryan, is RNA still glycosylated today?’ ”

Eventually, the scientists convinced themselves—and a panel of five peer reviewers for the journal Cell (2021, DOI: 10.1016/j.cell.2021.04.023)—that the molecule they were observing, a glycosylated RNA, was truly present on the surface of the cells.

But many in the community remained skeptical off the record. In the past, plenty of scientists have believed that they’ve made a completely novel discovery only to turn out mistaken. And more than a few professors have lost face when major claims from their labs fell apart under scrutiny.

These days, Bertozzi says, the more people publish on RNA glycosylation, the more relief she feels. “Biology is complicated. . . . It’s important to know that people are seeing the same thing.” Still, she adds, “I wouldn’t be surprised if 50% of people out there might be like, ‘I don’t buy it.’ Because again, it flies in the face of dogma.”

To Bertozzi, the allure of mapping out the new dogma is just as strong as it was when she was an assistant professor on the fringes of the chemistry department, contemplating the unsolved questions of the glycome.

“There’s all these cool mysteries now that are implied by this idea,” she says enthusiastically. Her lab has contributed to at least one study investigating the chemistry of the RNA-sugar conjugation, but she’s clear that she does not plan to compete with Flynn’s new lab.

After all, there are plenty of other mysteries to explore.