For as long as she can remember, Luísa Figueiredo has been drawn to the small things—“the things we could not see,” she says. As a young girl, she was fascinated by an expensive book that her mother, a chemistry teacher, kept on a high shelf. Its glossy pages carried colorful illustrations of molecules. “My mom would take it from the shelf and look at it with me. And I had to be very careful,” Figueiredo recalls. “I think because it was unreachable, it attracted my attention.”
Now, as a group leader at the Institute of Molecular Medicine in Lisbon, Figueiredo is still drawn to problems that are just out of reach. Her research centers on the mystery of how parasites vary their surface proteins to evade detection by their hosts’ immune systems. That interest took hold when Figueiredo was an undergraduate majoring in biochemistry at the University of Porto. She traveled to London as part of the European Union’s Erasmus Exchange Program and took a course in molecular parasitology at Imperial College. “I really enjoyed the course, and by the end, I decided I wanted to do a Ph.D. in that area,” Figueiredo says.
She chose to study the molecular biology of the malaria parasite with mentor Artur Scherf at the Pasteur Institute in Paris and earned her doctorate in 2002. Although she enjoyed working with the malaria parasite, she grew frustrated with the lack of tools available for doing functional genetic studies in that organism. When searching for postdoctoral positions, she decided to switch her focus to Trypanosoma brucei, the parasite responsible for infecting millions of people with African sleeping sickness.
T. brucei is a well-characterized, experimental system that is amenable to functional studies. It covers itself with millions of copies of one type of antigen—a strategy that Figueiredo likens to wearing a coat of one particular color. The parasites change their display of surface antigens—and hence the color of the coat—frequently in an attempt to slip past the host’s immune system. Immune defenses, on the other hand, soon learn to recognize the parasite’s disguise and make antibodies against it. However, it would be inefficient for the parasites to cycle through their limited number of antigen “colors” too quickly.
As a postdoctoral fellow at The Rockefeller University with professor George Cross, Figueiredo began unraveling the molecular mechanisms behind T. brucei’s coat-changing process, known as monoallelic expression. She discovered a protein that T. brucei needs so that it can show just one type of antigen on its surface while keeping more than 2,000 variants silent. Without that protein, the parasite expresses more than one surface protein—essentially putting on a multicolored coat.
The way the parasite’s DNA is packaged into its chromosomes affects expression of the genes for these antigens, called variant surface glycoproteins, or VSGs. The DNA packages, known as chromatin, are “important in determining which gene is active and how to keep the other ones silent, but we don’t really know exactly how this works,” Figueiredo says. “That’s what we are trying to understand.”
Figueiredo plans to use her HHMI support to pursue two complementary strategies to identify the chromatin factors that activate or silence the different VSG genes. The first is a traditional approach: looking at genes that alter chromatin in other organisms and then interfering with those genes in T. brucei to see what happens.
The second, more ambitious method focuses on developing a genetic screen—a method commonly used in other model systems. By creating a library of DNA sequences for all possible genes and using them to turn off genes in the parasite, Figueiredo hopes to identify genes that have an effect on the parasite’s VSG coat. The key will be to look for parasites that express two VSGs instead of only one when a certain gene is depleted.
“It’s probably going to be more difficult because we’re going into territories that people have not explored before, but we hope that it will pay off,” Figueiredo says. “It may actually take us to a new direction that is not chromatin. We think that this unbiased approach might reveal new things we would not have thought of otherwise.”