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Lesser Strives for More

Don’t let Cammie Lesser’s surname fool you; this up-and-coming young scientist is all about doing and achieving more—not less. A postdoctoral fellow on the cusp of starting her own lab, Lesser over the past decade has earned both an M.D. and a Ph.D., won a prestigious Howard Hughes Medical Institute (HHMI) award and pioneered the use of yeast as a model system for divining the roles of bacterial virulence proteins as they attack mammalian cells. She managed these achievements while still finding time for trekking in parts of Asia, touring Europe, smacking softballs deep into center field and kicking up powder on the ski slopes.

Lesser’s can-do style showed up early in her career planning. "I decided at the ripe young age of 20 to do both degrees," she recalls. "At that time I was thinking I’d be a researcher and yet I was intrigued by this idea of how the human body works. I thought a general education in medicine would expose me to questions that would be interesting to explore."

Lesser’s training and research have covered a wide gamut, encompassing infectious disease, molecular biology, patient care and more. Yet it all overlapped, she says. Her Ph.D. thesis research—pinpointing an elusive factor responsible for defining a key 5´ cleavage site during RNA processing—may seem removed from bacterial interactions with their target host cells. Even so, that earlier work involving yeast genetics that set the stage for Lesser’s work on the yeast surrogate of bacteria-host cell interactions, which she has developed in collaboration with Samuel Miller lab at the University of Washington, Seattle.

Lesser’s doctoral research also demonstrated the tenacity that has fueled her many achievements. She spent about six years in Christine Guthrie’s lab at the University of California, San Francisco, trying to ascertain the mechanism of intron recognition in yeast. "We conducted genetic screens over and over again and never found the answer," she says. "I was ready to quit and say, ‘I’m just going to be a doctor; I’m not cut out for this!’" Despite the frustrations and urgings from others to abandon the project, Lesser doggedly stuck with it till she reached the answer, helped in part by findings from another lab. Her report on the subject published in Science in 1993 was picked as a "hot paper" by The Scientist.

"Experiences like that make you a lot more willing to hang in and try to answer questions—and hopefully know when to drop them," she reflects. "I think it made it easier to do [the subsequent yeast-pathogen model] project knowing that I had some inclination for when things were going the right way and when they were going wrong."

Lesser’s interest in virulence proteins was stoked by her six years of clinical work following the completion of her Ph.D. research. She worked as a physician specializing first in internal medicine and then in infectious diseases, an activity she continues today, spending about 10% of her time caring for patients.

The idea of using yeast as a surrogate for mammalian cells to determine the roles of bacterial proteins during infection combined Lesser’s experience in yeast genetics with Miller’s expertise in bacterial type III secretion systems. Both admit that the project represented a risk at the outset. "We were going out on a limb a little" to suggest that yeast cells could stand in for more complex mammalian cells to yield clues on how virulence proteins operate, Lesser says. But, as Miller says, "Cammie always had complete faith in the yeast system. I give her credit for really believing in the idea and putting it into practice. She figured out all the mechanics of how to do it."

Lesser says it was simply a matter of following logical leads. "It isn’t clear if pathogenic bacteria evolved type III secretion systems specifically to infect higher eukaryotic cells or if these systems initially were designed to combat molds or other organisms that the bacteria are in contact with in the environment. Nevertheless, we assumed that in many cases bacterial virulence proteins would target basic cellular processes conserved among all eukaryotes."

Her confidence in the system was boosted by news in late 1999 that she had been tapped as a recipient of an award from the HHMI Postdoctoral Research Fellowships for Physicians program, as well as grants from Pfizer and the Infectious Diseases Society of America. "I was very happy to see that people were interested in what we were trying to do because it was a stretch," she says. "People in bacteriology don’t usually think of yeast as being relevant to mammalian pathogenesis, so it was nice to see that others thought it was a good idea or were at least willing to fund it so we could see if it really would work."

Some scientists remain skeptical about the applicability of the yeast surrogate. "We haven’t gone the whole nine yards yet and found any novel roles for proteins," Lesser concedes. However, this yeast work is sparking plenty of interest among other scientists, several of whom have asked to use the team’s plasmids.

"There were people who said, ‘oh, we thought about doing that but weren’t sure whether it would work so we never did it,’" Lesser says. She supposes that she is simply willing to take on somewhat uncertain projects if they have potential for significant results. "This system offers an alternative, complementary approach to study the functions of bacterial virulence proteins," she says. "I’m just glad to have had a role in developing this new approach."

Christine Stencel
Christine Stencel is a communications manager and science writer at ASM.