For Tufts' Ralph Isberg and Joan Mecsas, getting a close look at bacteria that are linked to infections like Legionnaire's disease—and even the bubonic plague—is all in a day's work.
Back in 1984, while working in a lab at Stanford, Ralph Isberg went out on a limb. The microbiologist hung tight to his unconventional approach to studying the interactions between pathogenic (disease-causing) organisms and their host cells.
He believed that by examining the phenotype—the observable traits of an organism resulting from the relationship between that organism's genetic makeup and its environment—he could find clues into why certain bacteria were able to invade mammal cells.
"In the field of bacterial pathogens, that wasn't the attitude," explains Isberg, who was then working on the bacterium Yersinia pseudotuberculosis. "They didn't think you could chase things that way.
But Isberg did. "I told people in the lab I was going to do it, and they said, 'Good luck—it's not going to work. Why don’t you try something else?'"
They were wrong: Isberg's approach did work, and it went on to dramatically change the field of pathogenesis—the study of disease origins—by shedding light on how bacteria infiltrate their host cells. Since then, open-mindedness has been the name of the game for Isberg. Since coming to Tufts in 1986, the Tufts professor made a point of pursuing what he gleefully calls his "crazy ideas" about researching Yersinia pseudotuberculosis (which causes gastroenteritis and is common in Scandinavian countries) and Legionella pneumophila (which causes Legionnaire's disease).
Like Isberg, Microbiology Assistant Professor Joan Mecsas spends a lot of time getting up close and personal with Yersinia pseudotuberculosis—a fact that might seem frightening, given its close relationship to Yersinia pestis, the bacteria that causes the bubonic plague. But she doesn't sound at all scared to be working with something so closely tied to what's known as the Black Death. In fact, she sounds downright enthusiastic.
"I chose to work on Yersinia pseudotuberculosis because it's very close to pestis," she explains. "This way, we can learn something about pestis without worrying about the high virulence it has for humans."
Mecsas and Isberg talking with students in the lab.
Mecsas was drawn to the pathogen for another reason: its "very cool" biology. It has an intricate relationship with its host that made it "exactly what I wanted to study." Since coming to Tufts in 1999, Mecsas has uncovered a great deal about those complex interactions, with her lab focusing on the role of proteins secreted by Yersinia called Yops, which help determine its infectious properties.
"The Yops can do a lot of different things to cell cultures, but we really didn't know what they were doing during infection in different tissues," Mecsas says. This is key because way the bacterium affects the organism depends on which tissues it infects.
Studying this at the microbiological level as well as in animal models has led Mecsas to some unexpected conclusions. "One of the most surprising things is that if we get infection at multiple sites [across the body], like the spleen and liver, we also have drastic changes in the GI tract," she explains. "So we really have to look at what's going on in all the organs rather than one specific organ."
Mecsas's research has significant practical implications for developing vaccines and testing therapeutics. She is collaborating with other Tufts faculty who are working on agents that can be tested using the animal model of infection.
"We're really understanding how this organism subverts the immune response," notes Mecsas—something that, not too long ago, was a mystery.
Before Isberg got to work on it, Legionella pneumophila was also a mystery. The bacteria employs some nifty trickery in order to infect its host. So Isberg decided to unravel the way Legionella pulls the wool over its host cells' eyes. "We think Legionella, when it goes in, hijacks material from [a component of the cell called] the endoplasmic reticulum and sets up immediate communication with the host cell's membrane."
This line of communication is facilitated by the distribution of proteins, the nature of which makes it tough to throw an effective wrench in Legionella's growth. But the challenge has made Isberg, who is also a Howard Hughes Medical Institute investigator, all the more eager to find ways to stymie Legionella's spread.
"There's a protein called LidA that we're really interested in, because it affects the movement of vesicles [membranous pouches containing Legionella] from the endoplasmic reticulum throughout the cell," he says. "It turns out it does exactly that, tethering the vesicles so they aren't moving through the normal pathway."
And Isberg surmises that anchoring itself in the endoplasmic reticulum might not be the wisest move for Legionella. "The way in which host cells can recognize foreign matter through the immune system also uses endoplasmic reticulum. So although it looks like it's good for the bug to [travel throughout the cell using the] endoplasmic reticulum, the host may be taking advantage of it as well, to limit the infection in some way." Sort of like a bank robber parking the getaway car at the police station.
In studying the microorganism’s interplay with the host cell, Isberg has developed a scientific outlook that goes far beyond what's beneath the microscope. "I'm a microbiologist, which means I work with bacteria," he says. "But by working with bacteria, we've come understand how certain facets of a whole organism work."
'Directions You Didn't Expect'
Since Mecsas came to Tufts, her research has led her down unanticipated paths, both through application of her training and collaborations with colleagues. "I'm doing things that I didn't anticipate five years ago," she explains.
Mecsas has taken full advantage of the possibilities for synergy on campus. "There are several of us who are trained as microbiologists, but are now really moving into the host and learning about the host—and learning about it from the perspective of the infection, rather than the perspective of an immunologist," she says. "And it's been fantastic to be here, because there's a couple of people doing that independently and coming together."
Students, says Mecsas and Isberg, are another valuable component of the Tufts experience.
"Some of the things that my students have done and the results that they get, I just wouldn't have predicted at all," Mecsas says. "And it's incredibly pleasing to watch graduate students develop into mature scientists and go their independent ways. That's a real thrill."
"All of the success I've had at Tufts has been because I had good students and post-doctoral fellows," echoes Isberg. "They push the system into areas in which I never thought I wanted to work."
But he pushes them, too, encouraging them to take the same sorts of chances he took while he was a budding scientist.
"I was so naïve, you know?" he reflects, referring to his 1984 discovery on pathogenesis. "One of the lessons I've taken from this experience is that the most naïve students have actually been able to do the most interesting experiments"—Isberg chuckles mischievously, his eyes lighting up—"because it's hard to talk other people into doing them."
It's those unforeseen discoveries that drive these researchers. "It's very interesting and very exciting," notes Mecsas, "to see an idea that you've formulated really bloom and go in directions that you didn't expect."
Profile written by Patrice Taddonio, Class of 2006
Patrice Taddonio graduated with a degree in English and a minor in communications and media studies.
Photos by Jodi Hilton for Tufts University
This story originally ran on July 17, 2006.