Focusing on What's Important

By Roshni Mitra Chintalapati

"I never wanted to do anything that I didn't commit to and do well—as well as I possibly could." These words from Sandra Schmid, chair of the Department of Cell Biology at The Scripps Research Institute, reflect the passion and tenacity she brings to her many endeavors—her work in the lab, her family life, and her mentorship of the next generation of scientists.

Schmid works in the field of Cell Biology, the study of the important machinery that controls the development, function and demise of a cell, providing crucial insights into why diseases, like cancer, cystic fibrosis, mental retardation, and cardiac dysfunction, develop and how they can be treated. With the mapping of the complete human genome and new tools like proteomics, sophisticated microscopy, and robotics, together with classical techniques like genetics, biochemistry, and molecular biology, the cell biology field is rapidly expanding its horizons and producing fascinating insights into the workings of our body.

Within this larger field, Schmid focuses on the study of endocytosis, the mechanism by which a cell takes up nutrients and other factors such as growth hormones and immune complexes. Over the course of her career, Schmid has made several major scientific contributions—including the first in-depth characterization of a major cell organelle of endocytosis, the endosome; the development of a novel biochemical "perforated-cell" assay that faithfully imitates the events of receptor-mediated endocytosis; and the characterization of a key regulator protein of endocytosis, dynamin, and construction of numerous mutants of this protein, which either speed up the endocytic process or slow it down. These discoveries have helped other cell biologists in the field move ahead with their research.

Tackling Unknowns

Born in Vancouver, British Columbia, Schmid was raised in a "science-friendly" home where both her parents actively encouraged her interest. The young Schmid was quickly recognized by many lecturers at her high school for the in-depth questions she bombarded them with and they encouraged her to continue her education in cell biology, which she did at the University of British Columbia.

At the time Schmid entered a Ph.D. program at Stanford University, the study of endocytosis was a fledgling field with a lot of unproven hypotheses. This posed an immediate challenge to her to "crack the code" and provide hard-core evidence about the mechanistics of this seemingly highly regulated process. As part of the Rothman lab, Schmid began tackling some of the unknowns in the field.

Many of the transactions between the cell and its environment are executed by special membrane transport vesicles, which are coated by the protein, clathrin. This portion of the membrane then grows as a coated pit, which pinches off into the inside of the cell cytoplasm. Once the coated vesicle reaches its destination within the cell, it is uncoated to reveal the contents. Schmid's 1985 thesis was on an ATPase critical for the uncoating of the coated vesicles, which is now characterized as HSC-70, a chaperone (helper) molecule involved in protein folding and unfolding reactions.

Schmid was then drawn to Ira Mellman's lab at Yale University for her postdoctoral research, where studies on the endosome as a novel and controversial organelle had just commenced. The endosome is now known as the central organelle in intracellular trafficking and sorting of internalized receptors and ligands. Schmid was the first to provide hard biochemical evidence for the existence of two distinct subpopulations of endosomes, early and late, with distinct roles in endocytic trafficking.

"I've been very fortunate in having good mentors," she says, "'Good' in that they taught me how to do science in a serious way."

Schmid was recruited as an assistant professor to Scripps Research in 1988 by the late Norton B. Gilula, and was appointed full professor in January 2000. During that time, she extensively worked out the function of another protein, dynamin, in the formation of the coated pits by developing several mutants of the protein, and was the first to define the role of dynamin as a key regulator in clathrin-mediated endocytosis.

A Meeting Ground

Now, over 18 years later, Schmid is appreciative of all that Scripps Research has provided. "There aren't many places where you only have one thing to do—research!" She also sees the institute as a great meeting ground for researchers from different areas of science to come together and collaborate, which can take a research program in different directions.

And that's exactly what is happening to Schmid's research. Defne Yarar, a senior postdoc in Schmid's lab, is collaborating with Associate Professor Clare Waterman-Storer's group to start a unique area of research involving live cell microscopy-based assays to study endocytosis. This approach, which allows researchers to directly study single events of formation and pinching off of coated pits without having to rely on indirect biochemical studies, has opened up a whole set of new questions about how endocytosis really works.

Another area of study that Schmid is excited about is work with Associate Professor Gaudenz Danuser in computational biology. Danuser's approach to understanding cellular processes is to look at thousands of events simultaneously and then to develop sophisticated computational tools to categorize these events into different classes and kinetic behaviors. From these behaviors new hypotheses about the mechanics of the process can be generated. She good-naturedly laughs and acknowledges that this approach has taken some adjustment as she is used to looking at one thing at a time and breaking it down.  

A third totally new strategy Schmid is employing in her research on dynamin combines biophysics and structural biology. She believes this will help to shed light on dynamin as a mechanochemical enzyme in membrane fission. Again, in collaboration with Scripps Research colleagues, she plans to employ cryo- and x-ray crystallography, as well as site-directed fluorescent probes for FRET-based assays to show conformational changes, assembly, and interactions of dynamin in the clathrin-coated pits of biological membranes.

Advancing the Field

In addition to contributing through her own research, Schmid has helped build structures that will continue to advance Cell Biology well into the future.

For one, she has left her mark on the field's journals. Schmid served on the editorial boards of Trends in Cell Biology, The Journal of Cell Biology, and The FASEB Journal, and was appointed editor-in-chief of Molecular Biology of the Cell in 2004. She also launched a new journal, Traffic, along with Frances Brodsky, Mark Marsh and the late Thomas Kreis, which focuses exclusively on intracellular membrane trafficking.

Why a new journal? Schmid, like many of her colleagues, had the experience of getting back manuscripts from Cell and Science with a statement that they should be sent to a more specialized journal—a euphemism, Schmid says, for something not so good! So, Schmid wanted a specialty journal that really held up to high standards, run by scientists who do not abdicate important scientific decisions to people untrained in the field. Traffic is among the leading journals in cell biology – remarkable for a journal focused on a single topic.

In addition, Schmid has contributed to mentoring the next generation of cell biologists. Postdocs and graduate students at Scripps Research should now be familiar with Schmid's seminars on time management and successful postdoctoral training, which have reached hundreds of postdocs at Scripps Research and other institutes and associations like Burnham, Salk, UCSF, UCLA, and the American Society for Cell Biology.

Schmid is also committed to one-on-one mentoring, especially encouraging graduate students and postdocs to look at the fundamental question of whether they really have the passion and commitment to be on the academic track in science. "Science today is highly competitive," Schmid says, "[although] it's not as competitive as many other fields. In professional athletics, for instance, the top 1-2% make it, while in science, it is the top 20%." Nevertheless, these are statistics that Schmid believes individuals beginning a career in science should take seriously, especially since there are many other career options for those with a biology Ph.D.

Mastering Time Management

Another issue Schmid feels strongly about is the position of women in science. Although unaware of experiencing gender bias in establishing her own career, she feels she has become a feminist over time. There is solid scientific evidence, she says, that women are under-appreciated for what they do; women tend to undervalue themselves and men tend to overvalue themselves. For instance, the same grant gets a higher score with a man's name on it than when there is a woman's name on it. Hence, men and women can't simply be treated in the same way. "We should be female-proactive," Schmid states.

Which brings us to the question of how Schmid has managed to balance an exemplary career with a fulfilling family life—a feat that tends to be more difficult for women. Part of the answer lies in Schmid's talent for time management.

"I've always liked doing more than one thing at a time. As a kid, I was a musician, athlete and scholar and all those things were important to me. As each required a certain commitment, in order to fulfill them all, I had to think ahead and plan and organize my day, week, and month."

Schmid is in the lab by 8 AM and leaves by 7 PM. When her children were young, she never worked at night or over the weekends. She managed this by implementing her time management matrix of working on important things before they become urgent, prioritizing her tasks, planning and organizing her day, week, and month, engaging other people to help, and staying focused exclusively on science as long as she is in the lab. She also sits and eats her lunch at her desk, as she exemplified by nibbling on crackers and tuna while doing the interview for this story.

Once home, she completely leaves lab responsibilities at the lab, opens a bottle of wine, checks her personal email, watches a game on TV, and spends quality time with her family.

Schmid attributes her ability to be able to get ahead in her career to the complete understanding she has with her husband. Schmid met and married Bill Balch, now a professor at Scripps Research, during her graduate years at Stanford. "I am very lucky to have a husband who really believes in what I am doing and has enough confidence in his own ability and his own career not to be threatened," she says. Everything from how they dealt with having children to how they take care of the house has involved sharing responsibilities, giving them both time to develop successful careershelping to free her up for her work.

Her love for her children is evident in the glowing words with which she describes their manifold interests. Her son, Jeremy, now a freshman in college, is interested in history and philosophy, but is also taking chemistry and physics in college. Her daughter, Katie, is an artist, writes songs and poetry, and sings "with a beautiful voice."

"My kids understand that I am passionate about my work," Schmid says. "If I had to choose between taking care of them and work, then it would be their needs, no question about it. But I don't have to choose. They understand that my work is important, too—it is the other thing I get a lot of satisfaction from.

Send comments to: mikaono[at]scripps.edu

Sandra Schmid, chair of the Scripps Research Department of Cell Biology, has advanced the study of endocytosis, the mechanism by which a cell takes up nutrients and other factors.

The Schmid lab investigates the cell biology and biochemistry of clathrin-coated vesicle formation, among other topics.

The Schmid-Balch family.