SCIENCE/TECHNOLOGY
January 31, 2000
Volume 78, Number 5
CENEAR 78 5 pp. 26-35
ISSN 0009-2347

Bertozzi: Infectious In Her Enthusiasm

One of the congratulatory cards Carolyn R. Bertozzi received after her MacArthur fellowship was announced shows a shark fin ripping through an asphalt road. The message: "You're a tough act to follow." If there's any downside to working with Bertozzi, some people say it's the fact that she's so good.

"I worry that after working with Carolyn I might be disappointed with other people I'll work with," says Youngsook Shin, a postdoc from South Korea who's a member of Bertozzi's research group in the chemistry department at the University of California, Berkeley.

"I've heard other professors say she's a superstar," says Lara K. Mahal, a fifth-year Ph.D. student. That can be daunting because it can make one "feel like how in the world are you ever going to" be as good as she is?

Bertozzi [Photos by Maureen Rouhi]

If Bertozzi had wanted, she could have become a successful musician with her natural talent for music. "She has an amazing ear for music," says her older sister Andrea, a professor of mathematics at Duke University. "Even when we were really young and starting to play the piano, she would listen to records, pick out the tunes, and play them on the piano."

Bertozzi also has the looks, the stance, and the charisma of a music star. But science proved to be a stronger pull than music, perhaps because Bertozzi grew up in a home where science was part of the routine.

Her father, William, is a professor of physics at Massachusetts Institute of Technology. When Andrea, Carolyn, and younger sister Diana (now an occupational therapist practicing in New Jersey) were growing up in Lexington, Mass., the conversations at home were mostly about what their father was doing. He also used to bring items from the physics lab for the children to play with, such as the 20-lb magnet to which they at times stuck the family cat through its metal collar.

Bertozzi won awards for compositions and accompanying musicals during her high-school years, and she sang and played keyboards for a heavy-metal band called Bored of Education during her college years at Harvard University. Her father says he may have counseled her that music is a difficult career, requiring not only talent but also luck, and that many musicians end up poor and hungry.

Yet, "from my perspective, there was no overt effort to steer her toward science," William says.

"As a child, Carolyn was so versatile that she could have been superior in anything," says her mother, Norma. Norma even thought Bertozzi might go into literature or history, especially after she aced a junior high school English honors course. The teacher announced each year that he gives only one A, and "everyone was pushing to be that A student," Norma recalls. Bertozzi wrote an essay about Joseph Conrad's novel, "Heart of Darkness," that the teacher, Norma says, singled out. Bertozzi got the A that year.

At 33, Bertozzi is one of chemistry's young stars. Her rapid rise testifies to her creativity, determination, and indefatigable enthusiasm. In naming her a fellow in 1999, the MacArthur Foundation cited, among other things, her research on chemical remodeling of cell surfaces and its potential use in understanding how cells work and in detecting and treating diseases.

At UC Berkeley, where Bertozzi is an associate professor of chemistry, she is in command of labs that occupy more than half the space in the eighth floor of Latimer Hall. In these labs, 30 graduate students, undergrads, and postdocs are figuring out the roles of carbohydrates on cell surfaces, the metabolic processes that lead to elaborate glycosylated macromolecules on the cell surface, and ways to interfere with these processes to generate new information on the cell surface.

Bertozzi didn't even intend to be a chemist. At Harvard, Bertozzi was originally a biology major who was, at best, indifferent to chemistry. Organic chemistry changed her mind. She found it "elegant, internally consistent, and beautiful in how it converges on a core of fundamental principles," she says. Organic chemistry also appealed to her because the molecules are visually pleasing and can be thought of as having personalities. "Molecules have intrinsic energy, just like people," she says. "Some people are very reactive, some are inert. The same goes for molecules. It made sense to me."

Bertozzi also was inspired by how the organic chemistry course was taught. When she took the course, the lecturers were chemistry professors David A. Evans and George M. Whitesides, both of whom, she says, are superb educators--clear, dynamic, and passionate about what they do. "Both also have a global view of chemistry and how it fits into the world we live in, its role in the economy, in health and medicine, in industry," Bertozzi states.

As an undergrad, she couldn't get into the labs of the prominent synthetic organic chemists at Harvard, including E. J. Corey, Evans, and Whitesides. So she did the next best thing that would keep her in organic chemistry: She joined the physical organic chemistry lab of Joseph J. Grabowski, who in 1987 was an assistant professor at Harvard. He is now an associate professor of chemistry at the University of Pittsburgh.

Grabowski asked her to build a photoacoustic calorimeter, an instrument that measures heat deposition into a solution after photoexcitation of molecules. "I knew nothing of photochemistry, lasers, or computer programming," Bertozzi says. "But it sounded cool, so I said, 'Why not?' "

The experience focused her interest in pursuing a Ph.D. degree. Grabowski was in the early stages of his career, and she saw what that was like. She enjoyed the lab culture, the team aspects, and burning the midnight oil working on a problem or talking to colleagues. It was fun, she says.

Grabowski also was very proactive about her education, urging her to write an undergraduate thesis on the photoacoustic calorimeter project. He thought she had a chance of winning the Harvard thesis competition, which she did. Grabowski also advised her on fellowships to go after and graduate schools to consider, and provided a good role model with his professionalism and respectful treatment of students. "I have a lot to thank him for," Bertozzi says.

For her Ph.D. at Berkeley, Bertozzi chose to work with Mark D. Bednarski, who in 1988 was a new assistant professor there. Bertozzi had known him from Harvard, where he did postdoctoral research with Whitesides. He was young, enthusiastic, and full of creative ideas, and Bertozzi thought "it would be fun" to work with an assistant professor again, "to build a lab from scratch."

But three years into Bertozzi's graduate work, Bednarski was diagnosed with colon cancer. As a result, says Bertozzi, "he had an epiphany about his life and career objectives and decided he wanted to be a physician." He left Berkeley and went to Stanford University Medical School.

During her final year in graduate school, Bertozzi operated in the absence of an adviser and did things Ph.D. students don't usually do--such as negotiating with journal editors and acting as de facto adviser to a few other people in Bednarski's lab. Other Ph.D. students might have found the situation discouraging, but Bertozzi, typically, shrugs it off, saying, "Students at Berkeley don't need a lot of guidance."

An adviser is supposed to open doors, help launch the careers of new Ph.D.s, and write letters and make phone calls on behalf of students. Bertozzi received little of that kind of assistance. "I'm sure there were times when I could have benefited from having someone to throw some weight around--to help you get the award you need to be recognized, to suggest your name for something, to send postdocs your way, knowing that you need to recruit people and you're too young to be well known."

Yet it all worked out. "I had ideas for experiments, and I've done what I wanted to do without being concerned about names," she says. "But chemistry is a tough profession. Without the support of colleagues, it can be that much harder."

Bertozzi's research is at the chemistry/biology interface, using chemistry, especially organic synthesis, to answer fundamental questions in biology. She rounded out her training by doing a postdoctoral stint with Steven D. Rosen, a cell biologist at the University of California, San Francisco, immersing herself "in an environment where I could see how biologists think about, identify, and approach problems; learn their techniques; and meet people in the field."

Bertozzi meets with Saxon during a Sunday evening in her office.

The experience was eye-opening, she says. "I learned a lot of science--what we know, what we don't know, why some areas are so difficult, what techniques are missing." She became familiar with the biological literature and learned how to criticize it. And she realized that, unlike in organic chemistry where groups tend to operate independently, in biology communication among groups studying different facets of the same system is imperative. "It doesn't work to be secretive," she says.

Work in the Bertozzi labs ranges from development of new reactions to studies with animals to test whether chemistries with cells grown in vitro can work in living organisms. The goal is understanding and control of the cell surface.

The cell surface harbors a bewildering array of molecules that cells use to perceive and respond to their environment. Most are proteins or lipids conjugated to oligosaccharides. By exploiting the promiscuity of oligosaccharide biosynthetic pathways--that is, their tolerance to unnatural substrates--Bertozzi and coworkers have shown that cells can be made to display unusual functional groups on their surfaces.

In 1997, Bertozzi, Mahal, and postdoc Kevin J. Yarema showed how cells can be coaxed to express ketone groups on the surface by tricking the sialic acid pathway into using as a substrate an unnatural sugar containing a ketone group. And because sialic acid is overexpressed on tumor cells, tumor cells also overexpress the ketone in the unnatural substrate. The proliferation of ketones can be used to differentiate tumor cells from normal cells and thus may provide a basis for early diagnosis and treatment of tumor cells.

Once the ketone is on the surface, "you can build on it," Bertozzi says. Through chemistry that's specific only to ketones, various agents--including viruses, toxins, drugs, and magnetic resonance imaging contrast agents--can be attached to cells, or complex molecules that are difficult to prepare in the lab by total synthesis, such as glycoproteins, can be made.

Pharmaceutical and biotechnology companies "spend a lot of money to obtain well-defined glycosylation patterns on large recombinant proteins," such as erythropoietin or thrombopoietin, she explains. "Now we can design the oligosaccharides so that we can chemically elongate them with anything we want and obtain a homogeneous product."

With second-year Ph.D. student Eliana Saxon, Bertozzi has developed a second handle for cell-surface chemistry. A future publication will describe how cells can be made to express azides so that azide-phosphine chemistry can be carried out on the cell surface. "The great thing is that this chemistry is chemically orthogonal [indifferent] to the ketone chemistry," she says. "You could have azides in some biopolymer and ketones in some other biopolymer, simultaneously do reactions on both groups, and really start to build towns and cities on the cell surface."

Just as Bertozzi is excited by the possibilities of her research, those working with Bertozzi often describe their environment as exciting. "It is a great place to learn," says Michael J. Grogan, the latest postdoc to join the group. "You have chemists, biologists, and people with different types of expertise all in one place, and they are willing to take the time to teach each other."

Bertozzi herself projects excitement, energy, and passion that some find irresistible. For example, ignoring advice that working with a new professor would be suicidal, Kendra G. Bowman, a fifth-year Ph.D. student, says her decision to join Bertozzi "was visceral." Mahal and George A. Lemieux, a fourth-year Ph.D. student, both also say gut feelings had much to do with their choice to work with Bertozzi.

She exudes the conviction of a preacher seeking converts. Saxon, for example, says she originally was interested only in organic synthesis. Bertozzi "pretty much sold me on the biology end of it," she says. "She made me believe that the work she is doing is interesting and that anybody who knew anything would want to be working on it. I believe that."

Bertozzi discusses a point with an undergraduate student during a lecture break.

In the Bertozzi labs, people do what they want to do. "You don't feel that there's any experiment that you can't do," Lemieux says. "If for some reason I wanted to target plutonium to cells, and I could convince Carolyn that this experiment would be interesting, she'd let me do it."

And Bertozzi will find a way to make it happen even if it can't be done in her labs. For example, Chris L. de Graffenried, a second-year Ph.D. student, needed to do confocal microscopy to image the location of sulfotransferases in the Golgi apparatus of cells. No one in the group had used this technique, and Bertozzi does not have the equipment. So she arranged for de Graffenried to work with Carolyn Larabell, a microscopist and staff scientist at Lawrence Berkeley National Laboratory. "We feel that we can do anything because we know that she's always there for us, bringing in the money, doing what needs to get done for the research group to work," de Graffenried says.

"If I can afford it, I have to let the students do what they want to do," Bertozzi says. (The budget for her current group is $1.2 million annually, and she says she's always on the verge of being broke.) "The goal is to train people to be independent minded, creative, proactive. The way to keep their energy level up is to let them do what they want. It's much more fun for them."

Once in a while, Bertozzi reins in things, such as when a grant renewal is coming up, when she's concerned that a student might be scooped on a project, or when a project is not working. But her students know it's for their benefit.

"I think many students feel an intrinsic antagonism toward their advisers," Bowman notes, referring to a perception among some Ph.D. students that their work mainly benefits their advisers. "I've always felt that Carolyn wants me to get data so I can write a great paper or I can give a great talk because it's in my interest, not hers."

Some people think of Bertozzi as a superstar. Some think she's superhuman. "I've seen her on almost no sleep," de Graffenried says. "It's very hard sometimes to keep up with her." In fact, Bertozzi may have slowed down a bit since the early days when she was setting up her own lab from scratch with her first recruits, Bowman and Mahal, while also finishing her own postdoctoral work. "In those days, we were practically living" in the lab, Mahal says. Now Bertozzi does not work in the lab anymore, but her accessibility to her group and the attention she gives to each member are undiminished.

When C&EN visited Bertozzi last fall, one of the items in her schedule was a 9 PM meeting with her group to listen to Saxon practice her graduate research seminar. This rehearsal happened on a day when Bertozzi drove to San Francisco in the morning to give a lecture at a glycobiology conference, returned to Berkeley at noon, then drove back to San Francisco in the early evening to have dinner with a collaborator she was meeting for the first time.

Bertozzi arrived about a half-hour late. At the end of Saxon's 25-minute talk, her immediate remark was, "That was superb." Then she followed with comments about enunciation, spelling, and grammar; a slide-by-slide critique; and a reminder to Saxon to slow down. It was almost 11 PM when the group dispersed.

She gives the same kind of close attention to everyone.

Bertozzi "has a deep-seated commitment to students," says her colleague, chemistry professor Robert G. Bergman. "She really goes out of her way to help. She's very unselfish." Her students, too, often mention Bertozzi's generosity. Bowman and Mahal both say it's something they hope to emulate in their own careers.

If the timing is right, Bertozzi can be very funny, too, Mahal assures C&EN. "She's perfectly professional until 11 PM. After that, if you catch her, she's very different. She hangs loose, she tells great stories, she impersonates people."

But if people can mention only one thing about Bertozzi, most likely it will be her enthusiasm. "She has an enthusiasm for science that infects everyone she interacts with, from faculty colleagues to undergraduates," another colleague, chemistry professor Paul A. Bartlett, says. Sitting in Bertozzi's organic chemistry lecture for nonchemistry majors at UC Berkeley's G. N. Lewis Auditorium, this reporter observed that infectious quality.

She is kinetic, working the lecture hall like a talk-show host, moving up and down the aisles and once in a while approaching members of her audience to get a reaction to whatever "pretty wild" or "cool" concept she has just explained. She speaks with a clear voice, using precise organic chemistry terms as she must, but liberally injecting expressions that sophomores immediately relate to, such as "That's a no-brainer" or "Check this out."

And she always tries to make the chemistry relevant by giving real-world examples. In this particular lecture, part of which is about methods for synthesizing ethers, she showed pictures of "cool-looking" ethers--okadaic acid and palytoxin--explaining where they came from, why researchers are interested in them, and how it took years of work to prepare them in the lab.

"Anybody who has seen her lecture is blown away by her enthusiasm," Bergman says. "She can explain a complicated phenomenon in a way that is clear and that makes it evident why it's important, whether it's carbohydrate chemistry related to her research or bonding between small molecules in a beginning organic chemistry course."

Talking about how she tries to motivate undergrads, Bertozzi says: "I try to bring all the enthusiasm I feel for the subject and just let it all hang out. Sometimes they laugh at me." Youth also is an advantage, she says, "although as I get older, that will go away. If you're young, students feel they can talk to you more openly. And they are not afraid to ask the 'stupid' questions. I never make them feel stupid, not intentionally anyway. I do my best to treat them with respect."

Bertozzi hopes to bring this same enthusiasm to public schools more often than she has been able to do in the past. When she's invited to give scientific demonstrations or to just talk about careers in science, often she can't accept for lack of time. That's because she takes consulting jobs to supplement her income. "If I didn't do that," she says, "it would be difficult to live in the Bay Area."

At present, she and her partner of 11 years, Cynthia A. Williams, rent a two-bedroom house. And because Williams is still studying to become a nurse-midwife, Bertozzi has been the sole support of the two of them for the past three years. "I have worried about how we're going to live here," Bertozzi says. "Because of the computer industry, public university professors have been priced out of the housing market."

With the MacArthur fellowship, Bertozzi is now turning down consulting opportunities and using the resulting free time to go out to public schools. It's her way of giving back to the community and helping to ensure that there will always be enough talented people to do science.

"If we want to keep the pool of scientists at the highest level, the time to intervene is probably in junior high school," she says. She thinks teenagers who may be interested in scientific careers must be steered in that direction in junior high school so that they can prepare by building a strong foundation in math and science during high school.

"Intellectually, a lot of kids have ruled out any interest in science by the time they get to college. Often it's because they weren't encouraged earlier on," she says. "If you can get them interested and motivated in junior high school, I think that will be manifested in colleges in the number of science majors."

Bertozzi is "up to her eyeballs," as her father puts it, with chemistry, which easily takes up 80 hours of her time every week. "But a lot of it I don't perceive as work," she says, while driving to the glycobiology conference in San Francisco. "I don't have to give this talk this morning. But why not? It's fun.


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