Microbiologists Without Borders
Jeff Griffiths and Matthew Waldor approach their research, which includes the study of waterborne diseases like cholera, through a global lens.
Matthew Waldor's laboratory hums with activity. The clanking of test tubes mingles with the voices of goggle-clad graduate and post-doctoral students chatting with each other across the aisles.
"I have a fairly big lab," says Waldor, MD, MPH, director of the Tufts School of Medicine's M.D./PhD program and Associate Professor of Molecular Biology and Microbiology. "It's a challenge—a fun challenge—to learn how to give the different people in my lab who are at very different stages of their scientific development the best help."
Living up to challenges—and even having fun while doing so—is something at which Waldor is adept. Since starting at Tufts nine years ago, he has made major strides in understanding the ways in which two disease-causing organisms—enterohemmorhagic E. coli (also known as E. coli 0157) and Vibrio cholerae—infect humans.
According to Waldor, E. coli 0157 – first identified two decades ago – is a major cause of both diarrheal disease and renal (kidney) failure in the United States. Vibrio cholerae, the other diarrheal pathogen studied by Waldor's group, causes cholera, a disease so fast-acting that without treatment, death can take place within several hours.
Cholera is far less common stateside than E. coli 0157, as there hasn't been an outbreak in the U.S. since 1911. But the disease's effects are still devastating in regions of the world where the proper medical treatment isn't available: according to Medicins San Frontieres/Doctors Without Borders, cholera outbreaks occur in about 60 countries every year. With an eye on developing vaccines for the illness, Waldor's research could go a long way in helping to reduce that number.
'A Web of Organisms'
"There's beauty in the way the world works," says Jeff Griffiths, MD, PhD, director of the Global Health Division of the Tufts School of Medicine's Department of Public Health and Family Medicine and an expert in the realm of diarrheal disease. "One of the appealing things about the biological sciences is that one can appreciate how complex and beautiful the world is through an understanding of the subtleties in the way that things like infectious diseases work."
Griffiths has devoted his career to studying parasitic organisms from a standpoint that encompasses science, medicine and public health, as well as economics and the environment. His experiences in medical school and his infectious disease training showed him that all of these realms are closely interlinked.
"Infectious diseases are a really interesting way to gain insight into complex things," Griffiths elaborates. "There are some infections where a parasite might have three different hosts and have to adapt to three completely different systems in order to survive. It's remarkable that anything could actually do that." A degree of awe enters his voice. "And not only do it, but succeed at it, and persist for hundreds, if not millions, of years."
Over the course of his career, Griffiths has found his work taking on broader implications.
"I came to understand that we really live in a web of organisms, and that many of the things I was interested in—parasitology, what used to be called 'tropical medicine' [and is now frequently termed global health], infectious diseases—involved looking at people in an environment, and then looking at the environmental influences around them," he says. "A person might study a disease like malaria or tuberculosis or diarrheal disease, which is important, but the big picture is that the thing that eradicates those diseases is poverty reduction."
Griffiths is putting those understandings to work in Ecuador, where he is using a grant from the National Institutes of Health (NIH) to study respiratory and diarrheal diseases in the Latin American nation as they pertain to geographic location and air pollution.
"One of the ways to get the political class interested in fixing these problems it is to make it clear that they're a problem for everybody, and that you can't be protected from them simply by having a high wall around your house," he explains.
Stopping the Spread
When Waldor discusses the discoveries his lab has made while working on E. coli 0157 and Vibrio cholerae, his enthusiasm and appetite for discovery is—pardon the pun—infectious.
"When E. coli 0157 grows inside us, it makes a toxin that gets absorbed and damages the blood vessels and causes some other serious side effects," he explains, gesturing with his hands to illustrate the process.
Past research had indicated that the toxin is encoded by a bacteriophage, a virus that infects bacteria. But Waldor and his team have found that certain antibiotics can activate the phage and prompt it to create toxin.
"And that can explain the clinical observation that antibiotics can sometimes worsen the course of 0157 disease," he proclaims.
Waldor's cholera work has followed a somewhat similar trajectory. "Interestingly, like E. coli 0157, we discovered that the toxin of cholera which is responsible for severe diarrhea of cholera is also encoded in a bacteriophage, which we call the cholera toxin phage, or CTX phage," he says. "So we're studying similar issues, like when that phage gets turned on, does that also increase the production of the toxin?" (He adds that with cholera, "that doesn't really seem to be the case.")
That may be due to the cholera phage's unique DNA makeup (it's double rather than single-stranded, like most toxin phages) and behavior. "A former MD-PhD student [at Tufts] who's now a resident in the radiation-oncology program found that unlike other phages and viruses that integrate into the chromosome of the bacteria, the CTX phage instead just has a site in its genome that's recognized by a host genome," he says.
Waldor's lab also studies the way antibiotic resistances are transmitted from strand to strand of Vibrio cholerae – work that has great relevance for the areas where cholera treatments are needed.
"We've discovered, actually," he explains, "that certain antibiotics promote the transfer of this antibiotic resistance transfer element. So if we could give substances or compounds that would inhibit this element along with those antibiotics, that would prevent the spread of these resistances." Waldor’s work is supported by the prestigious Howard Hughes Medical Institute.
"Infectious disease," says Jeff Griffiths (left), "has always been a way that I could integrate my interest in the developing world as well as the developed world; that I could address the major health problems of people living in other countries."
Like Waldor, whose research was originally focused only on Vibrio cholerae and not E. coli 0157, Griffiths has seen his interests evolve since he started at Tufts in 1988. "Then, all of my research was at a very molecular level," he says. "Now, much more of my work is epidemiology—I'm much more interested in the effects of the infection on populations of people, and how to prevent people from getting the infection by eliminating the exposures."
To that end, Griffith has involved himself "very heavily" in the public policies surrounding water-borne diseases: he's on the National Drinking Water Committee for the United States and the Science Advisory Board of the Environmental Protection Agency. "I bring a public health perspective to the issue of contaminants that might be spread via water," he says.
The roots of Griffiths' commitment to effecting change as well as conducting research can be traced back to his childhood in South America and the Caribbean, where the "poverty and injustice" he witnessed prompted his interest in exploring the issues affecting those populations.
"Infectious disease," he says, "has always been a way that I could integrate my interest in the developing world as well as the developed world; that I could address the major health problems of people living in other countries."
With one of his most recent and most challenging endeavors, Griffiths is addressing those major health problems in a big way—by working toward developing a heat-stable measles vaccine. Though measles is "a forgotten disease" within the U.S., it still kills between a half million and a million people per year, mostly in developing nations.
"It's typical of Tufts that people from different faculties and different backgrounds are able to get together to work on this," Griffiths says of the project, which involves the Feinstein International Famine Center at the Friedman School of Nutrition Science and Policy and Jeff Mariner of the Cummings School of Veterinary Medicine. And it's typical of Griffiths to understand the great significance of his work.
"If we do succeed in developing a heat-stable measles vaccine, and it's used for getting rid of measles, that will without question be the most important thing I ever do in my life," Griffith says soberly. "You have to keep plugging away on things. You have to take chances, and sometimes in academia it's hard for people to take chances. But I think that's what you have to do."
Twists and Turns
Like Griffiths, Waldor makes a habit of branching out into uncharted areas—for example, the intricacies of the unusual Vibrio cholerae genome. "You think of bacteria as having one chromosome, but Vibrio cholerae has two, and there's been very little attention paid to bacteria with divided genomes like that," he says.
Ever the proud professor, he notes how former MD/PHD student Elizabeth Egan, now a pediatrics intern at Children's Hospital, uncovered some of the unusual replicating behavior in the chromosomes, while current MD/PhD student Michael Fogel is studying how the chromosomes segregate.
"It's challenging but fun to try to think of the best 'next step;' to think of ways to approach problems that we can articulate but are not really sure how to solve," Waldor says.
Indeed, part of what makes his and Griffiths' work so exciting—a word both scientists use to describe the field of infectious disease—is the fact that when one problem is "solved," its "solution" tends to uncover another.
"Usually, you find that every time you think you answer a question," muses Griffiths, "the answer poses several more."
Profile written by Patrice Taddonoio, Class of 2006
Patrice Taddonio, a native of Holland, Pennsylvania, is an English major and a communications and media studies minor. Currently the Tufts Daily's head features editor, she interned with the Improper Bostonian magazine during her sophomore year, and worked as a temporary text editor with the Associated Press at last July's Democratic National Convention. A member of the Class of 2006 and a songwriter, Taddonio has also performed on guitar and vocals at on-campus venues and at Boston-area benefits.
Homepage photo by Getty Images (Animals in Niger are watered from a cholera-infected pool in August 2005). Griffiths photos by Melody Ko, University Photographer. Waldor photos by Aaron Schutzengel (A'07).
This story originally ran on Oct. 31, 2005