Carolyn Bertozzi: Glycan Chemist

By | June 1, 2016

Carolyn Bertozzi
Anne T. and Robert M. Bass Professor of Chemistry Stanford University
Investigator, Howard Hughes Medical Institute
LINDA A. CICERO/STANFORD NEWS SERVICE
I was one of three girls, and when we were asked in school what we wanted to be when we grew up, and other kids said doctor or fireman, we each said ‘medium-energy nuclear physicist,’” laughs Carolyn Bertozzi, whose father was a professor of applied physics at MIT in Boston. “As early as I remember, he would talk about how, when we grew up, we were going to be nuclear physicists,” recalls the Stanford University chemistry professor. As little kids, she and her sisters donned MIT T-shirts and attended summer day camp there. “That was the difference between us and the other kids, especially the girls. I was born in the mid-1960s at a time when women were catastrophically underrepresented in science and actively discouraged from higher education,” she says. Bertozzi’s own mother had put herself through secretarial school instead of attending college because “her parents were not supportive, thinking [college] was a waste of money.” Bertozzi’s parents sent her and her sisters—a younger sister is an occupational therapist, and an older sister, Andrea, is an applied math professor at UCLA—a clear message: “Go to college, get a PhD in science, have your own career, be independent,” Bertozzi recounts.

Bertozzi enjoyed high school biology, but was not particularly drawn to other sciences. She entered Harvard University in 1984, initially majoring in biology. She had been recruited to play soccer and originally wanted to major in music. “I played keyboard in jazz and heavy metal bands.” But Bertozzi had also followed in her older sister’s footsteps, joining math teams in junior high and high school. “I mostly did whatever my sister did, because I didn’t have a better idea,” she says.

Thinking she might go to medical school, Bertozzi took the required organic chemistry course as a sophomore and something clicked: “Organic chemistry turned out to be my thing. I loved how you could see the three-dimensional molecules—their shapes and behaviors—and that there were just simple, beautiful core principles that let you rationalize really complicated sequences of events. I loved that you could look at molecules and predict what would happen, and when your predictions were good, you could engineer and make new molecules no one had made before.” Bertozzi switched to a major in chemistry and has never looked back.

Here, she talks about how to get over a fear of technology, how she made cold calls to learn biology from experts, and the gut feeling that helped her avoid bad career advice.

Bertozzi Blossoms

No fear. At Harvard, Bertozzi did undergraduate research in a physical chemistry lab, where she constructed a photoacoustic calorimeter—an instrument that measures heat deposition into a solution following the photoexcitation of molecules. She was accepted into a graduate research program for women at Bell Labs in New Jersey that included a pregraduate internship there and a PhD fellowship award to pursue a graduate degree at an institution of her choice. At Bell, Bertozzi studied the kinetics of electron transfer on various surfaces with Christopher Chidsey, now her colleague at Stanford. “I learned that you didn’t need to be intimidated by instruments. I became fearless about taking a wrench to a back panel and digging in the electronics. I also learned the fundamental way instruments work, no matter the instrument: how you set it up to initiate a process, collect a readout, digitize it into data you can analyze,” she says.

“I had no concept of social media until a year ago December. Every day, I am learning what you can do with that platform.”
 

Going out west. Bertozzi grew up in Lexington, Massachusetts, and had never been on an airplane until her West Coast tour of schools—Caltech, Stanford, and the University of California, Berkeley—after she had already been accepted into all three graduate chemistry programs. The trip won her over to the Golden State: “It seemed so foreign to me: the landscape where you can see for miles, the smells, the weather, the architecture. My student host [at Berkeley] picked me up from my hotel on a motorcycle and we drove over the Bay Bridge to a club in San Francisco. That really wowed me.” As she began her graduate career at Berkeley in 1988, Bertozzi finally got to pursue research in organic chemistry, the subject she had fallen in love with in college. The chemistry department at Berkeley was just beginning to develop the field that is now called chemical biology, then known as bio-organic chemistry.

She chose to work with Mark Bednarski, who had recently set up his own lab, and began to synthesize stable analogs of carbohydrates that interacted with bacterial and viral receptors that promote immune attack. Because the chemistry department had little crosstalk with the life-sciences departments, Bertozzi and her labmates made cold calls to immunology labs to get advice on biology techniques and concepts. “This was before the Internet. You couldn’t easily search for people on this big campus, so we would just go floor by floor in a building looking for immunologists.” During her third year, her advisor was diagnosed with colon cancer, decided to leave his faculty position, and enrolled in medical school. Bertozzi and two other students “convinced the department that we should be left to finish our projects as we wished. There was money in the bank from Mark’s grants and we were able to spend those resources down,” she recalls. Most of Bertozzi’s papers were completed during this time, including work showing that the galactosphingolipid analogs she had synthesized bound to the gp120 protein of HIV-1. “It was an unusual experience. At the time it was like, ‘Poor us, our boss quit,’ but now I think back and realize how much I developed during that period and what a perspective it gave me on what is important in life.”

Biology 101. As she was wrapping up her PhD, Bertozzi reasoned that, to have an impact on the field of biology, she needed to be at the leading edge of biology, “not just reading about it from a distance.” At the time, in 1992, researchers had just discovered the selectin family of adhesion receptors, molecules found on the surface of endothelial cells and lymphocytes that direct immune cells to sites of tissue damage to generate inflammation. The finding had pushed glycobiology from a small, niche research topic into the mainstream, says Bertozzi, as the selectins were host targets for developing anti-inflammatory drugs. Bertozzi seized the opportunity to sell her chemistry skills to a selectin researcher as an entrée into a biology laboratory. In the 1990s, chemists joining biology labs were still a rare phenomenon. “To have a carbohydrate synthesis chemist apply for a postdoctoral position in a cell biology lab was considered truly bizarre,” she says. Bertozzi joined the University of California, San Francisco (UCSF), lab of Steven Rosen, one of the few biologists who even granted her an interview.

Bootleg research. Bertozzi proposed synthesizing putative glycans that could bind to L-selectin to help identify the molecule’s natural ligands. Rosen’s lab knew a few generalities about ligands that could bind to the receptor. Using radiolabeling, the lab had figured out that the L-selectin–interacting glycoprotein was sulfated, had sialic acid side chains, and also fucose. But the details of the carbohydrate structures were still beyond their reach and “it was clear that the carbohydrate was the business part of this glycoprotein,” Bertozzi explains. It was a race to figure out what the exact sugar molecules were. “I didn’t realize how competitive the field was.” Rosen wanted her to get started right away, so she began to make potential carbohydrate ligands while still completing her PhD. In 1994, after joining Rosen’s lab, Bertozzi published a paper identifying GlyCAM-1 as one of the ligands for L-selectin.

Busy Bertozzi

Quick transition. Only one year into her postdoc, Chidsey, Bertozzi’s former Bell advisor who had recently joined the chemistry faculty at Stanford University, convinced her to apply there for a faculty position as a chemical biologist.  She found out Berkeley was also looking to hire and applied there as well. “I think Steve [Rosen] thought I was out of my mind. In immunology, a postdoc is often a six year commitment and there I was, a year into it, with no papers, talking about faculty jobs! It was unusual for biology but not for chemistry,” says Bertozzi, who received offers from both universities and chose to return to Berkeley.  

Building new tools. At Berkeley, Bertozzi’s research took many new directions while continuing to focus on enzymes that produce L-selectin ligands. But her lab became most known for figuring out how to image cell-surface glycans using what is now called bio-orthogonal chemistry—a term coined by Bertozzi to describe chemical reactions that neither interact nor interfere with the biological system under study. The idea to build tools to visualize cell-surface glycans came to her while in Rosen’s lab. Studying glycosylation on the surface of cells, the lab had no way to know whether certain glycans were expressed or changed their abundance under different conditions. “Meanwhile, there were genetic reporter systems like GFP fusions that enabled imaging of proteins in cells. I remember thinking it would be so great to image sugars like that,” says Bertozzi.

Bertozzi’s lab went on to develop such methods. First her team demonstrated the ability to engineer sialic acids on cell-surface glycans with chemical handles that allowed the addition of affinity probes such as biotin or fluorescent probes for imaging, and also held promise for such applications as cancer-drug targeting. Then the lab developed the first truly bio-orthogonal reaction: the Staudinger ligation, which incorporated azides—functional groups that are biologically inert—into cells in living mice. Because the initial reaction was rather slow under physiological conditions, the lab then developed a biocompatible copper-free azide-alkyne cycloaddition chemistry, a reaction now often referred to as copper-free click chemistry. The inspiration for the reaction came to her while she was on a plane writing a lecture for a sophomore organic chemistry class, says Bertozzi. The lab has since used the technology to visualize the expression and trafficking of cell surface glycans in vivo during zebrafish embryonic development.
    
Clinical applications. Bertozzi’s lab also works on Mycobacterium tuberculosis, and has shown that the bacterium produces sulfated molecules that modulate its interaction with human host cells. “This tuberculosis project crossed paths with a sugar-imaging study. We figured out that we could use metabolic labeling as a potential point-of-care diagnostic for detection of tuberculosis in patient sputum samples. One of my students is going to Africa to do field testing of the method we developed.” The lab has also begun to study how glycans and glycoproteins are perturbed in tumors. In 2014, in collaboration with Valerie Weaver’s lab at UCSF, Bertozzi’s group showed that the glycoprotein and polysaccharide coating on epithelial cells—called the glycocalyx—increases in thickness and stiffness as a tumor evolves, and that this physical alteration enhances cancer cell fitness.

Bertozzi Broadcasts

A recent move.  After 19 years at Berkeley, Bertozzi moved to Stanford in 2015 to help create an institute named ChEM-H which denotes Chemistry, Engineering, and Medicine for Human Health. Bertozzi is one of 20 new faculty who will ultimately be hired for the integrated, interdisciplinary center. “I am now equally comfortable at tuberculosis and immunology conferences as at chemistry ones. I love the human health–centered environment here,” she says.

Boys club. “In the 1980s, the chemistry community, especially the organic chemistry community, was not particularly inclusive of women. Organic chemistry has its own unique culture and was dominated by large labs with influential professors who didn’t think women could contribute in a meaningful way. That was the sense I got as an undergraduate. Graduate classes were about 10 percent women. But at Berkeley, as a student, I thought that I at least had a shot. It was a bigger department and graduate program, so even though women were no better represented as a proportion, at least the absolute numbers were higher.”

Bad advice. “When deciding on a postdoc, I was getting advice from other senior professors, since my advisor was gone. Their message was, ‘If you want to be a professor yourself or work in a top company, you will need brand-name faculty backing you up.’ They gave me a list of people it would be prudent for me to work for. That was the counseling I got: If I wanted a faculty position working at the interface of chemistry and biology, I had better go work for someone who had a track record of placing people in top academic jobs. This gave me a queasy feeling in my stomach. I remember thinking, ‘Why should some professor I have never met have that much power over my life? That doesn’t seem right. Shouldn’t I have that power over my life?’ It seemed strange to choose an advisor on that basis rather than, say, based on how excited I was about their scientific interests. When I thought about the problems those suggested labs were working on, I just couldn’t get excited about them, at least not as much as I was about the discovery of the selectins.”

A voice on social media. Since becoming the editor in chief of the American Chemical Society’s new journal ACS Central Science, Bertozzi has been active on Twitter with a goal of elevating the visibility of chemistry “beyond the boundaries of the chemistry community,” she explains. “I had no concept of [social media] until a year ago December. Every day, I am learning what you can do with that platform. I started following other journals and was never so up to date on the literature in my life. I had to write an editorial for our April issue on the status of women faculty in chemistry departments and asked on Twitter what I should discuss. Tons of people sent suggestions, so now I am basically crowdsourcing my editorial!” 

Greatest Hits

  • Introduced the concept of metabolic engineering for imaging glycans in cells, zebrafish embryos, and mice without disturbing natural functions
  • Founded the field of bio-orthogonal chemistry, which has led to many enabling technologies within and beyond the field of glycobiology, including methods for site-specific antibody-drug conjugation that have been translated to commercial settings
  • Invented a nanoscale cell-injection system, using carbon nanotubes to deliver molecules into cells
  • Developed a new method for point-of-care diagnosis of tuberculosis
  • Discovered new avenues for cancer immune therapy that target tumor-specific glycosignatures

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Comments

July 2, 2016

Nice to see this field grow and be respected. I personally would like to see more of a look at glycans and lectins and a potential role for coping with antibiotic resistance.

 

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