Carolyn Bertozzi’s glycorevolution

When Carolyn Bertozzi’s fourth grader was trying to choose an instrument to play at school, she asked him what his friends were picking. Her son ticked off the dozen or so kids playing the clarinet and the handful that went for the trumpet. OK, she pressed, but what instrument did no one else pick? You have an opportunity here to fill a niche, she explained, to be the person everyone counts on.

And so it was, last year, that Bertozzi’s son started lugging a slide trombone to school.

It’s advice that she often gives her students at Stanford University as they consider areas of science to focus on and skills to hone so they’ll be attractive to future employers. How can you be uniquely useful?

It’s also a philosophy that Bertozzi herself embraces. The chemical biologist has spent her career as an evangelist for glycoscience, a complex field long relegated to the fringes of biology. Because of the many tools she’s developed to clarify the role of the sugar structures, or glycans, coating our cells, she’s become arguably one of the most useful scientists in her field.

In 2015, Bertozzi jumped from the University of California, Berkeley, to Stanford, a move intended to push her own science—and the wider field as well—beyond biological tools and into actual products. Since then, she’s started five companies focusing on technologies ranging from diagnostics to drug conjugates, all grounded in glycans. She’s also taken on a more prominent position in the pharmaceutical and venture capital communities. Bertozzi’s entrepreneurial pivot may have laid the groundwork for something she long ago envisioned: a glycoscience revolution.

Our cells are coated with complex sugar structures that do critically important work, like giving proteins their shape or facilitating chatter between cells. But figuring out these structures’ function—not to mention synthesizing or harnessing them—can be a daunting task.

Bertozzi says this complexity often relegates carbohydrates to the sidelines of science. Glycoscience wasn’t on her radar as an undergraduate at Harvard University, but when she got clued into the field as a graduate student at Berkeley, she saw a vast opportunity for an enterprising chemist.

“I’d never even heard of this class of biomolecules that were as important as proteins and nucleic acids,” she recalls. “As a chemist, the glycoscience field was attractive because the molecules are very complex, and their synthesis was not a solved problem.” Big-name chemistry labs were chipping away at the synthesis piece, but biologists’ gaze was squarely on proteins and nucleic acids, which by then could be easily made and studied.

“I had this idea that maybe the chemists were going to power some glycoscience revolution,” Bertozzi says. If she put her energy there, she’d be in on the ground floor.

And so it was that when Bertozzi launched her lab at Berkeley in 1996, she quickly rose to prominence by devising methods for exploring the structure and function of sugars on cells. Her early work posed a simple but nontrivial question: Is it possible to do organic chemistry reactions inside a living organism?

Her answer opened up a new branch of chemical biology. Early on, Bertozzi’s group was able to coax cells into expressing a glycan—one that wouldn’t disrupt the cells’ normal routine—that became a handle for doing chemistry on the cell surface.

Those early experiments felt “blue-sky crazy,” recalls Lisa Marcaurelle, who joined Bertozzi’s group in 1997 and is now a chemistry director at GlaxoSmithKline. “She was very bold and not afraid to take on big ideas.”

The technique, which Bertozzi eventually dubbed “bioorthogonal chemistry,” offered a springboard for a wide range of applications—biological tools, of course, but later imaging, diagnostics, and therapeutic development. The work catapulted Bertozzi into the scientific spotlight. By 1999, at just 33 and with a rapidly growing group, she won a MacArthur Fellowship—often called a “genius grant.”

Her group spent the next decade producing a steady stream of techniques for imaging glycans, eventually developing ways to peek at the shifting array of sugars decorating cells in a living organism, a zebrafish. At the time, one prominent peer compared the zebrafish work to a “global positioning system for tracking carbohydrates through organisms.”

When science journalists and citation trackers, year after year, put Bertozzi on their short lists of potential winners of the Nobel Prize for Chemistry, it’s because of the impact of those bioorthogonal chemistry techniques.

Neal Devaraj, a chemical biologist at the University of California San Diego, recalls being a graduate student and seeing Bertozzi give a talk about the zebrafish work. His mind was blown. Devaraj was an electrochemist and contemplating a switch to a new field. “That’s when I decided I really wanted to be part of a movement she created in bioorthogonal chemistry,” he recalls.

Devaraj, who has gone on to become something of a chemical biology superstar, credits Bertozzi with showing it was possible to make the chemical reactions on cell surfaces robust enough and happen fast enough that they could be practically applied.

Though she was scientifically successful out of the gate, Bertozzi says she initially struggled to find her footing as a leader and principal investigator. “My first 2 years as a PI, I think I made every rookie mistake there is to make,” she says.

Little formal guidance was available for new professors at the time, so Bertozzi found herself taking cues from older faculty, who often gave her advice that was either dated or didn’t jibe with her personality. She felt pressured to apply for grants before she was ready and was confounded when people asked about her tenure strategy. Wasn’t her job just to do good science and train good scientists?

“It took a while for me to just kind of filter out the noise, figure out how to just dispose of the bad advice, and try to be authentic and myself,” Bertozzi says.

Luckily, her authentic self turned out to be an exceptional leader.

“I met Carolyn on a recruiting visit, and it sort of changed my whole world view,” says Jennifer Prescher, who arrived at UC Berkeley in 2001 and is now a chemical biologist at the University of California, Irvine. Prescher had every intention of pursuing total synthesis, but as Bertozzi laid out her vision, “I was hooked.” At the same time, Prescher, like many of Bertozzi’s earliest students, had little knowledge of biology and even less of an understanding of carbohydrate chemistry.

“I barely even knew what the amino acids were at the time, and I’d never used a pipette pen in my life,” Prescher recalls. She admitted all that to Bertozzi, who replied breezily, “What better place to learn?”

Many of Bertozzi’s early students have similar tales of meeting the chemical biologist with certain plans for their future, only to have them upended in a matter of minutes.

“She has a very unique style of leadership,” says Chaitan Khosla, a chemical engineer who recruited Bertozzi from Berkeley to Stanford. When pushed to define what makes her unique, Khosla chuckles. “I’ve known Carolyn very well for many years—our careers more or less paralleled each other’s,” he says, taking a long pause. “I’ve been trying to figure this out myself every time we sit in a meeting.”

Khosla has a few theories, though. “I think she listens very carefully and makes connections very quickly.” But there’s also a more ephemeral quality that Khosla says he rarely encounters. “She’s got a personal touch that makes people feel like they want to be with her, they want to see her succeed, they want to do what they can to enable her vision.”

Even as Bertozzi’s lab came out with tool after tool to make it easier for scientists to explore and exploit our cells’ sugary canopies, translating that information into actual diagnostics or therapies was further off.

The scientific and technical reasons why carbohydrates don’t get the same love as proteins, lipids, and nucleic acids are many, but Bertozzi likes to point out one foundational issue: glycoscience was traditionally not part of the core science curriculum in college or even graduate school, meaning many basic facts about sugar structures are beyond most scientists’ reach.

She offers an example: from a high school biology student to a Nobel laureate, many people can rattle off the four letters in DNA and might even be able to recite all 20 amino acids that make up proteins. “But if I ask how many building blocks are in your glycans? I guarantee you no Nobel laureate at Stanford knows this basic information.” (The answer, by the way, is nine.)

It made pushing ideas out of the lab tough. At Berkeley, Bertozzi did start two companies, Redwood Bioscience and Enable Bioscience, based on her knowledge of controlling the placement of glycans on proteins.

But she began to feel restless. “I kind of felt at Berkeley that I had reached some sort of plateau in what we were doing,” she says. “It was great for basic science and really great for chemistry because the graduate students are top notch. But it was really hard for me to think about how to translate [ideas] to the clinic.”

Bertozzi says she first noticed other institutions’ more translational mind-set during joint retreats between Berkeley and the University of California, San Francisco. “When the UCSF people would talk, it was, like, medicinal chemistry,” she says. “It really struck me, year after year. We were doing probe development and new imaging platform technologies, and they were trying to make drugs.”

Her awareness of the divergence became more acute about a decade ago, when her lab began exploring Siglecs, a family of 14 proteins that decorate the surfaces of immune cells and look for glycans capped with a sugar called sialic acid. (Siglec is shorthand for “sialic acid–binding immunoglobulin-like lectins.”)

Think of a cell surface as a page of braille, with glycans as the raised dots, Bertozzi says. The Siglecs are like fingers, gently traveling over the page in search of a specific pattern. When one brushes against a pattern it recognizes, the immune cell that it’s on reacts: it might kill an invader or a host cell gone awry, send for help, or do nothing at all.

For a good 50 years, researchers had noticed changes in glycan patterns on the surfaces of cancer cells. The field had come up with all sorts of ideas to explain their existence—theories Bertozzi deems “hocus-pocus crap.”

In a series of papers, Bertozzi showed what the shift in glycosylation really meant. Cancer cells were in fact decorating themselves with those sialic acid glycans, which were arranged in a pattern that Siglecs interpreted as “do nothing.”

If the concept of a cancer cell hiding behind a “do nothing” molecule sounds familiar, it should: a class of cancer immunotherapies called checkpoint inhibitors works on an analogous system in immune cells called T cells. When a T-cell receptor called PD-1 binds to its partner, PD-L1, on a cancer cell, the immune cell lets the cancer cell pass by. The scientists who discovered this process received the 2018 Nobel Prize in Physiology or Medicine. Approved drugs like Merck & Co.’s Keytruda prevent that connection by binding to PD-1, while others, like Roche’s Tecentriq, bind to PD-L1. Blinders removed, the immune cells can go on to kill the cancer cells.

Bertozzi had begun contemplating ways to disrupt the Siglec–sialic acid interaction when Khosla called from Stanford. He had been given carte blanche to hire 20 faculty members for a new institute to be called ChEM-H (short for Chemistry, Engineering, and Medicine for Human Health). He wanted that group to include a few senior people who would play leadership roles and provide broader visibility for the nascent venture. Would Bertozzi ever leave Berkeley?

Stanford had tried to recruit Bertozzi twice before. Twice, she’d said no.

But this time was different. Khosla told her he was trying to convince Peter Kim to join the institute, too. At the end of his decade-long stint as research chief of Merck, Kim had resurrected a cast-off antibody that went on to become Keytruda. With her Siglecs program top of mind, Bertozzi reasoned, “What better person to help guide my thinking?”

She also harbored a twinge of regret for not making bold moves earlier in her career. When Broad Institute of MIT and Harvard was conceived, its leadership tried to convince her to move back to her hometown of Boston to join. “Somehow I turned that down, which is quite stunning now that I say that,” Bertozzi says with a smile.

In mid-2015, Bertozzi moved her family about an hour away and opened her lab at Stanford. Her very first project there was to design a method for stripping the sialic acids away from the end of the glycans on cancer cells.

The move to Stanford started a new chapter in Bertozzi’s already-storied career. Her first year there, she and Paul Crocker, the glycoimmunologist who discovered Siglecs, cofounded Palleon Pharmaceuticals to develop antibody-sialidase conjugates that would act as glycoimmune checkpoint inhibitors.

In the less than 5 years since then, Bertozzi has started four more companies. In 2017, she joined the board of Eli Lilly and Company, and last year Versant Ventures signed her on to be an exclusive adviser.

Bertozzi attributes her entrepreneurial fervor to the natural collaborations that bubble up at Stanford in a way they didn’t at Berkeley. For example, colleagues from the medical school who hear about the resident glycoscientist will reach out with an intriguing glycan-encoding gene they came across when screening for drug targets.

And new kinds of students are flocking to her lab—ones who have different backgrounds and are more therapeutically inclined. Marie Hollenhorst, for example, came to Bertozzi after completing her PhD in enzymology and clinical training in internal medicine. For her postdoc, Hollenhorst wanted to explore clotting disorders. It turns out that sialic acids coat the surfaces of platelets. In Bertozzi’s lab, Hollenhorst is trying to figure out the machinery that platelets use to make sialoglycans, with an eye toward hijacking that machinery to control the length of time the blood cells linger in the body.

Bertozzi made her move at a time when the biotech industry was ripe for the types of discoveries coming out of her lab. Stuart Schreiber, a cofounder of the Broad Institute, says today’s insights about human biology “don’t point to the traditional path for drug discovery.” Venture investors and drug companies are getting comfortable with the idea that biology is messy; simple kinase inhibitors or antibody drugs of the past are making way for molecules that might look odd and behave with more complexity.

Indeed, Bertozzi’s entrepreneurial work reflects that messy, complex approach to new therapies. Her companies are working on technologies including a new generation of antibody-drug conjugates, rapid diagnostics, and glycoproteomics.

Her most recent biotech firm, Lycia Therapeutics, came together with lightning speed. It converges a novel observation in a hot field, her track record, and one of her passions—open-access publishing.

In March 2019, Bertozzi’s group plonked a paper onto the preprint server ChemRxiv about a new class of molecules called lysosome-targeting chimeras, or LYTACs. The work was a new twist on protein degradation, a way of driving disease-causing proteins to the cellular trash bin. Much work in protein degradation focuses on constructing bifunctional small molecules that use one end to tether to a protein and the other to grab an enzyme that helps tag the protein for breakdown in the proteasome.

Drug developers are excited by the idea that degraders can eliminate proteins they’ve found impossible to shut down with conventional small molecules. But there’s a catch: current degraders can get rid of only proteins hanging around inside cells.

Bertozzi’s LYTACs expand that range to extracellular proteins. The concept is relatively simple: an antibody is engineered to express a glycan that steers a protein of choice to be internalized by the lysosome, a cellular component chock full of degradative enzymes. It created an immediate stir. The paper showed the method could effectively break down—in cells, at least—some well-known cancer and cardiovascular disease drug targets.

Bertozzi says she put the LYTACs paper on the preprint server mainly because she planned to talk about the work at a conference and wanted the audience to have a reference point. Almost immediately, pharma companies and investors reached out to her. “Clearly there was an appetite for this, which I didn’t fully understand at the time,” she says.

Versant Ventures, which had previously enlisted Bertozzi as an adviser for a different firm, ended up licensing the technology to become the basis of Lycia. The company came together even before the publication has made it into a peer-reviewed journal—a sequence of events Bertozzi seems almost giddy about. She’s a strong advocate for making research freely available, and in 2014 she signed on as editor in chief of the open-access journal ACS Central Science, published by C&EN’s parent organization, the American Chemical Society.

For its part, Versant saw a chance both to explore what it views as a cornerstone of an extracellular degradation company and to bring Bertozzi in as an adviser. “The opportunity to partner with her is broader than just her initial publication,” says Versant managing director Clare Ozawa. “She’s a very broad thinker.”

Bertozzi’s role in pushing glycoscience forward is undeniable, but colleagues and peers are quick to stress the broader impact of the scientists she’s trained. As her life gets busier, she remains dedicated to raising new generations of glyco evangelists.

“She’s had this constant focus on next-generation chemical biologists, and that’s really helped propel the team,” Broad’s Schreiber says. “I see that in my own lab—the impact of Carolyn.”

Everyone mentions Bertozzi’s special knack for explaining messy biological and chemical concepts in simple terms, a skill she has passed down to her students. Manuscripts aren’t just sent back and forth or edited anonymously in Google Docs. Bertozzi works one on one with students, demanding they read their papers aloud, “sentence by sentence, and then paragraph by paragraph,” Prescher recalls. “You couldn’t just read it normally at her computer, you had to ‘read it with gusto.’ I still do that to this day.”

In her assistant professor days, those marathon sessions could last until the wee hours of the morning. Now with a wife and three kids, Bertozzi avoids late nights, but graduate students still marvel over the weekly two-hour midday chunks she schedules for paper writing.

“The first time, the whole thing gets rewritten,” says Kayvon Pedram, a fifth-year student in Bertozzi’s group. “But then the second or third time you’re writing a paper, you’ve got a feel for how to do it correctly. She does this amazing thing where she can make a very complicated set of results or hypotheses really digestible and simple.”

Bertozzi is also passing on soft skills that define a certain kind of leader—one that is creative and demanding but also present and caring.

Yes, she’s the scientific slide trombone in a sea of trumpets and clarinets, but it’s about more than the research. “She’s very generous with her time and energy,” Pedram says. “If you ask Carolyn what she thinks about a certain problem, she will put her full attention on that question, and her full knowledge, to answer it to her best ability.”

That might sound touchy-feely, but many students, colleagues, and peers echo a similar sentiment: after talking to Bertozzi, you simply feel better about your science.