Seeking immunity

B Y - P A U L - K A R R

UGA's new Center for Tropical and Emerging Global Diseases is taking aim at infections and parasites that kill 17 million people worldwide each year

In earnest, three-week stretches, Bolyn Hubby hunches over a microscope in a tiny lab above a medical clinic in Buenos Aires. Downstairs, patients—some of whom are dying from a variety of tropical diseases—offer samples of their blood. Hubby diligently applies test vaccines developed at UGA to drop after drop of infected blood, hoping to find a glimmer of acquired resistance—a clue in someone's blood that might point the way to a successful vaccine.

"This is what I always wanted, to be involved directly with people suffering from the disease," says Hubby, a UGA doctoral candidate in cellular biology from Savannah who also studies anthropology. "To combine what I do in the lab with actual contact with these people is a tremendous opportunity."

It is also the motivating force behind UGA's new Center for Tropical and Emerging Global Diseases. Directed by cellular biologist Rick Tarleton (see photo at right and sidebar on p. 31), the center brings the work of UGA scientists from a variety of disciplines to bear on some of the world's most devastating diseases.

Infections and parasites contribute to one-third of all human deaths each year—a staggering 17 million, mostly in lesser-developed nations. Malaria alone kills 3 million people, many of the victims younger than 10. Yet tropical parasitic diseases historically haven't received as much scientific attention as other diseases, in part because they usually occur in nations with inadequate resources to find cures and vaccines. Scientists still have much to learn about the biology of these conditions. That's why research at the Center for Tropical and Emerging Global Diseases is focused on basic science, examining the underlying biology of infections—the building blocks of defense against disease.

"There are very few success stories with this tropical disease. We'd like to see that change."—Rick Tarleton


Chagas is caused by parasites carried by kissing bugs, which people come in contact with in the tropical rainforests.

Top of page: Tarleton, who will direct the new center, has spent more than 20 years researching a parasitic protozoan that causes a tropical disease called Chagas, which kills 50,000 people a year—and may be invading the U.S.

In the case of Hubby's work in Argentina, she and her colleagues have found some promising signs that the vaccines that worked for mice back home in a UGA lab may work for people, too. But it may take many years of these sorts of confirmations—not just one person's success—to make conclusions about a vaccine. There will be no dramatic ending to the quest, no single drop of blood that touches off the celebration—which makes Hubby's efforts all the more important. "Much of what we do, in research, is for the future," she says. "It takes time and a lot of effort."

NIH GRANT WILL CREATE RESEARCH UNIT

Contributing to the effort is a $3.3 million grant from the National Institutes of Health, which will enable UGA researchers to establish a tropical disease research unit. The University is one of just four national recipients of NIH's tropical disease awards, which are granted only once every five years.

The grant helps Tarleton's team arm itself with sophisticated equipment to combat malaria, as well as such tongue-twisting infections as leishmaniasis, schistosomiasis, cryptosporidiosis, and lymphatic filariasis. His first target, however, is a parasitic protozoan he knows all too well—one he has been pursuing for more than 20 years now, throughout his undergraduate and professional life.

Trypanosoma cruzi is a tiny microbe that is transmitted to animals and humans through the feces of kissing bugs—a class of insects also known as reduviid. These bugs, relatives of stinkbugs and wheelbugs, come into contact with people in the thatched huts of the tropical forests. The result is Chagas (pronounced SHA-gus), a debilitating, often fatal illness most prevalent in South America—and one for which there is no known cure or vaccine.

"There are very few success stories with this tropical disease," says Tarleton. "We'd like to see that change."

HE'S GOT GAME
A college basketball injury forced Rick Tarleton into the lab, where he became a cellular biologist and a world-class medical researcher

Rick Tarleton was never a threat to make the NBA, but it was his love of basketball that led him indirectly to a career in medical research. Playing in an intramural game as an undergraduate at Wake Forest, he blew out his knee.

"I couldn't do anything but study when I was laid up with my knee injury," says Tarleton, director of UGA's Center for Tropical and Emerging Global Diseases. "I loved biology, so I found the most dynamic researcher at Wake at the time, Ray Kuhn. He was working with the T. cruzi parasite."

Now considered the world's leading expert in T. cruzi research, Tarleton is a proponent of what he calls "right science." Which is another way of saying that he rejects the stereotypical narrowing of information inherent to many research projects and instead studies subjects broadly.

"If you reduce your research to a specific gene and then after several years you're wrong, your ego can get wrapped up in it," says Tarleton, who is sitting amongst piles of paper arranged so that only he can interpret the makeshift filing system. "Not many people are willing to study broadly because it is uncomfortable to go into such levels of complication. But if you know nothing about something, you have to leave all information open—and to do the right science, you have to go beyond what makes you comfortable."

Tarleton came to UGA in 1984 to teach and research cellular biology. From the beginning, he was part of a cadre of researchers who benefited from the University's natural strengths in tropical disease research.

"UGA has always had strong vet, poultry science, zoology-ecology, and a strong history in parasitology," says Tarleton. "We are also at an advantage because we have no medical school and, therefore, can track diseases that are not of the first priority or immediate necessity in an American hospital—like tropical diseases."

In December 1998, after Tarleton had done the initial legwork, President Adams approved a proposal to establish the Center for Tropical and Emerging Global Diseases, of which there are fewer than 10 in the U.S.

"To put on paper what already existed in theory meant we could compete, officially, for resources, training grants, faculty spots, and building space so that we can share information faster and easier," says Tarleton, who notes that top researchers will come to UGA because of its ability to offer better packages and more stimulating colleagues.

Recent hires bear that out: immunologist Julie Moore, bioinformatics and computational biology specialist Jessica Kissinger, and cellular biologist Boris Striepen.

"The center provides a stimulating intellectual environment," says Striepen, whose specialty is the cell biology of parasite responsible for life-threatening encephalitis in AIDS patients. "And with generous support from the Georgia Research Alliance, the center provides access to state-of-the art research equipment." But Striepen adds: "Frankly, Rick Tarleton is the reason I came to UGA. He is an outstanding scientist, and he has been a wonderful mentor for me."

In an office with a bird's eye view of Sanford Stadium, Tarleton invokes a football metaphor when asked how far tropical disease research has come and why the CTEGD'swork is so vital:

"We're on our own 10-yard line. When I started, you put a parasite in an animal and then figure out why it died. Now the box is a little more transparent. We can now take cells from an animal or human and isolate and determine what they are doing. But we're just now accumulating the tools to scratch the surface."

—Alex Crevar (AB '93)

The Centers for Disease Control and Prevention in Atlanta estimates that 20 million people worldwide are infected with Chagas, also known as American trypanosomiasis, and that 50,000 more die each year. The symptoms—heart enlargement and breathing problems are the most common ones—may not show up for 10-20 years. But when they do, they can be serious.

Chagas has worked its way to the U.S. in recent years through immigrants, says Tarleton, and "is almost certainly being transmitted here through the blood supply." It even exists, in small numbers, in Georgia.

To combat it, scientists have experimented with breeding techniques that neutralize the pathogens while they still reside in the insects that transmit them. But integrating genetically altered insects into wider natural populations is a daunting—perhaps impractical—goal that may never be achieved.

And recent findings indicate that a Chagas sufferer is harmed by the cumulative effects of small amounts of the parasite that remain in the body. That's why disease researchers like Tarleton keep working to find two vaccines: one that would arm the body against the parasite to ward off infection, and another that would provoke an immune response in victims and rid the body of the organism early enough to avoid cardiac problems. It's tedious work.

Tarleton's team is trying several approaches. One of the most promising appears to be DNA gene delivery, where cocktails of specially selected DNA are injected directly into an infected person's muscle or skin. If the mix is just right, the body's immune system will be stimulated to produce the proper response and fight off the disease.

However, finding the right mix is as difficult as it is crucial. T. cruzi contains at least 10,000 genes; experience leads Tarleton to believe the right combination would contain perhaps 20-30 pieces of those 10,000.

It seems an impossible task. Yet several new technologies are speeding the hunt. One uses random cocktails of the T. cruzi's DNA, which contain every possible bit of protozoan DNA. These cocktails are injected into mice, which are then injected with T. cruzi.

It requires several painstaking months to tell which mice have become infected and which have developed immunity. If a particular mixture seems to generate immunity more often than not, lab technicians like Bolyn Hubby will subdivide it and run its pieces through more tests. Later, when good candidates are identified through repeated vaccine trials, researchers sequence the specific genetic code.

"Over the course of a year," says Tarleton, "you can conceivably sift through tens of thousands of genes this way."

CENTER WILL PROVIDE GLOBAL OUTREACH

Tarleton's lifelong pursuit to find a vaccine for Chagas disease is important, but it's just one part of what the Center for Tropical and Emerging Global Diseases is working on around the globe. Liaisons with clinics and labs in Argentina, Ghana, Kenya, Guatemala, Mali, and Brazil keep fresh data flowing to Athens, where UGA researchers can focus an extensive array of technology on the problem. You can't walk into or phone a centralized CTEGD office, but collectively it has the resources of a powerful disease-research facility.

"Like many 'centers,'" says Tarleton, "this one involves a lot of people instead of a single location. It's more of a virtual center." But it has a large reach, stretching around South Campus to involve eight core investigators plus a cadre of research associates in arts and sciences, veterinary medicine, and agricultural and environmental sciences.

Tarleton's lab alone involves some 15 researchers working in several different areas of the labyrinthine Biological Sciences Building. Then there are various other researchers, each with his or her own set of assistants.

UGA is one of just four national recipients of NIH's tropical disease awards, which are granted only once every five years


The Trypanosoma cruzi parasite, shown in muscle tissue, causes the debilitating and often fatal Chagas disease, named after the scientist who discovered its cause in 1909.

As computers on the sixth floor of Biological Sciences spit out, analyze, and compare peptide sequences of T. cruzi, researchers in a basement lab—recently converted from a loading dock—array its DNA or print images of brightly colored fluorescent cells and gels. Tarleton's lab is yet another complication of beakers, test tubes, machinery and a special room where live pathogens are grown in incubators; safety devices are mandatory here. Another researcher works in borrowed space, waiting for a permanent home.

The Centers for Disease Control, the Medical College of Georgia, and the Emory Vaccine Center all have signed on to assist in various capacities. The most important of those partners is probably the CDC, which brings a wealth of experience in epidemiology—the long-term studies of disease factors and patterns. The CDC also has an extensive network of field sites in the tropics, and several of their researchers are now UGA adjunct faculty.

MORE COLLABORATIONS AHEAD

Tarleton's next challenge well involve increased collaborations. The center might join forces with animal disease specialists such as UGA ecology professor Peter Daszak, as well as institutions such as the World Health Organization and NIH, to study the interaction between diseases, including HIV.

"The impact of HIV on other pathogens is becoming an issue," says Tarleton. "As HIV continues to gain in its impact on developing countries, it's going to increase the problems that parasitic and opportunistic infections cause. We've seen people who have carried Chagas for 10-20 years, doing alright. Suddenly, they get HIV and the next thing you know they're dead from an overwhelming parasitic infection."

To do broader work like this, the center's wish list doesn't include high-tech equipment; the Georgia Research Alliance already has funded some equipment. But it does include a dedicated space that would centralize its scattered research operations, plus additional staff to do the investigating.

"We hope to build expertise and have as many representatives of different areas and parasites as we can," says Tarleton. "What we've tried to do with the center is not focus on any one parasite or set of approaches. We're trying to get people who work in a variety of areas and cover as much of the field as we can."


A similar version of this story ran in UGA's Research Reporter. For more information, go to www.uga.edu/ctegd.

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