Infectious disease researcher Flaminia Catteruccia is searching for novel ways to control mosquitoes that rely less on brute force and more on a deep knowledge of the organism’s biology
September 23, 2016 – Mosquitoes have threatened human health for centuries. By virtue of the insects’ capacity to ferry pathogens, ancient scourges like malaria as well as emerging infections such as Zika can persist and spread. Yet throughout much of our uncomfortable co-existence with these miniscule pests, the strategies for battling them can be summarized simply: Kill ’em.
“There was this pervasive belief that mosquitoes could actually be eliminated with insecticides,” explains Flaminia Catteruccia, associate professor of immunology and infectious diseases at Harvard T.H. Chan School of Public Health and an expert in mosquito biology. “So, there was little if any research into their biology—if you can kill them, why should you study them?”
Because of that thinking, investment in mosquito-oriented research languished, stifling discovery and dissuading scientists from entering the field. But in the 1990s, it became clear that insecticides could not be the sole means of mosquito control: Resistance to insecticides was surging, limiting their effectiveness. Also in the 1990s, powerful genetic tools, honed in the fruit fly Drosophila melanogaster, were first tried out in mosquitoes. These tools, which allowed researchers to manipulate the mosquito genome, opened up new avenues of research and attracted young, passionate students to the field.
“It was a new era,” recalled Catteruccia, who began her graduate studies during this heady time, working on Anopheles mosquitoes, which transmit malaria. “There were very few researchers working in the field, so there were massive opportunities. It was really exciting.”
In some ways, that excitement is even more palpable now, as scientists, government agencies, and funders recognize the power of fundamental research on mosquitoes to propel new ways to control infectious diseases. Indeed, Catteruccia and her colleagues are recent beneficiaries of this enthusiasm.
In recognition of her team’s impressive accomplishments in mosquito biology, in September Catteruccia was named a Faculty Scholar by the Howard Hughes Medical Institute, the Bill & Melinda Gates Foundation, and the Simons Foundation. The five-year award, part of a brand-new program launched jointly by the three philanthropies, intends to fuel scientific innovation by supporting outstanding early-career scientists. These days, junior faculty members face formidable challenges, particularly as the scientific funding climate grows increasingly uncertain—which means more time spent grant-writing and less time dreaming up bold new experiments. Catteruccia is among 84 investigators selected as Faculty Scholars and winnowed from a field of more than 1,400 applicants nationwide.
Malaria, mosquitoes, and genomes
Catteruccia was not always drawn to study mosquitoes, or even malaria, the disease that now garners the lions’ share of her attention. As an undergraduate in her native Italy, she was interested in the physical sciences, including physics and chemistry, as well as mathematics. She chose to pursue a degree in chemistry because in her mind, it offered the surest path to employment post-graduation. Indeed, her instincts proved true: After completing her degree in 1992, she was immediately offered a position at a pharmaceutical company in Italy. But she refused it.
“If I took the job, I’d go straight into industry, and I imagined myself doing the same thing for the next 40 years,” she said. “I wanted to stay in academia and explore different opportunities.”
So she accepted a research fellowship at the University of Rome to study infectious diseases, specifically malaria. Despite her limited background in biology, Catteruccia found the work inspiring. She worked alongside some of the giants in malaria research—trailblazing scientists who were not only unlocking the biology of the malaria parasite, but also the malaria mosquito, which bites and then transfers the parasite to its human host.
A year and a half later, Catteruccia began graduate studies at Imperial College London in the United Kingdom. She worked with her colleagues to pioneer new tools to manipulate the Anopheles mosquito genome, creating the first robust system to modify the DNA that mosquitoes pass on to their offspring (also known as “the germline”). Their landmark work, published in the scientific journal Nature, enabled scientists to begin dissecting the function of individual genes in the mosquito, especially their roles in malaria transmission.
After earning her Ph.D. in 2000, she continued to create and apply genetic tools that fueled basic biological studies of the malaria mosquito and also sparked efforts to control them using genetic approaches. But tool development was not her true passion. So when she began her own laboratory at Imperial College London in 2007 and later at the University of Perugia in Italy, Catteruccia delved even deeper into biological questions.
“By learning more about the malaria mosquito—its own biology as well as how the parasite develops inside it—we can come up with new solutions for disease control. It’s basic biology with a very keen eye for translation.”
In 2010, while attending a conference on the biology of malaria mosquitoes, Catteruccia met Dyann Wirth, Richard Pearson Strong Professor of Infectious Diseases and chair of the Department of Immunology and Infectious Diseases at Harvard Chan School. Wirth was looking to recruit a stellar mosquito biologist to her department to complement its deep expertise in malaria parasite biology.
But Catteruccia was not looking for another position, though the thought of moving to the U.S. intrigued her. “If Harvard invites you to come give a seminar, of course you go,” she said. “I immediately fell in love with the place—the research, the different departments, how open everyone was about their work, and how exciting the science was.”
“We were fortunate to be able to attract Flaminia to Harvard,” said Wirth. “Mosquito biology is critical to understanding vector-borne infections, and her work is at the cutting-edge. It is important not just for understanding and potentially preventing malaria transmission, but has far-reaching implications for the other mosquito-borne diseases such as Zika.”
In 2011 she was offered a position as associate professor in the School’s Department of Immunology and Infectious Diseases. When Catteruccia shared the news with members of her lab, she expected maybe one or two would choose to move with her. Instead, all of them did. “We came as a group, and it’s been a really exciting adventure for all of us.”
Now, some five years later, the lab has blossomed. With a team of 15 postdocs, graduate students, and technical staff, they are at the bleeding edge of malaria mosquito research. By combining her own group’s expertise with the know-how of her Harvard Chan school colleagues as well as collaborators at MIT and the Broad Institute, Catteruccia has achieved some game-changing synergies.
“There are very few groups in the world that can grow malaria parasites in a dish and at the same time preserve their infectivity, feed those parasites to mosquitoes, and then analyze parasite development within the mosquito,” she explained. “The beauty of this unique collaboration is that we can effectively complete the malaria life cycle—looking not just at the mosquito stages of the disease, but the complete biological picture, spanning both mosquitoes and humans.”
By harnessing these and other capabilities, her group is working on multiple fronts to answer a fundamental question: Can they unravel the biology of the malaria mosquito and, at the same time, discover ways to break the devastating cycle of malaria infection?
One area of Catteruccia’s research that has received significant media attention over the last year concerns gene drives—pieces of DNA that can be inserted into a mosquito’s genome and then quickly spread through an entire population. By hooking these gene drives up to specific genes, such as those encoding antimalarial factors, for example, it may be possible to interfere with malaria transmission—without killing the mosquitoes.
Another key line of inquiry in Catteruccia’s lab addresses reproduction. Like humans, female mosquitoes do most of the heavy lifting when it comes to propagating the species. Framed in biological terms, female mosquitoes must nourish their developing eggs, and human blood—which they gulp down when they bite—provides an ideal source of nutrients.
That got Catteruccia thinking: Does the parasite exploit this availability of resources—that is, the nutrients from blood—for its own development? “It’s sort of a simple idea, but no one had really looked,” she said.
So her team began to explore the idea a few years ago. They looked at different substances in the malaria mosquito that can also impact malaria parasites, and they homed in on a hormone that plays essential roles in the female mosquito reproductive cycle. Using a chemical that mimics this hormone, Catteruccia and her colleagues observed major effects not only on the mosquito, but also on parasite development: The mosquitoes survive, although the females are made sterile, and they can no longer transmit disease—similar to the goals of Catteruccia’s work with gene drives.
Further work is needed, both in the laboratory and in field studies, to extend these results. Nevertheless, Catteruccia and her team are optimistic. “Even though we are basic biologists, everyone in the lab is very excited about the prospect of translating basic research into real-world tools for malaria control,” she said. “This is the first example from my lab of how we might actually use knowledge we generate in the laboratory to interfere with malaria transmission in the field. And the important thing is we are not aiming to kill the mosquito, but simply change its physiology—and do so with minimal effects on the environment.”
She added, “This is why we work on infectious diseases—because we want to have an impact.”
photo: Aubrey LaMedica