Thinking like a mosquito

Using technology to control insect-borne diseases

by Austin Price | August 21, 2019

The most deadly animal in the world today is a miniscule flying insect—the mosquito. In the United States these insects aren’t much more than a backyard nuisance, but around the globe they transmit yellow fever, dengue, Zika, chikungunya and malaria. The World Health Organization estimates that mosquitoes account for millions of deaths each year. Malaria alone kills an estimated 2.7 million people annually. 

Professor Eva Harris is leading a research culture that couples technological innovation with what she calls a “renaissance approach” to studying infectious diseases. Harris says biologists must think like epidemiologists, statisticians like ecologists—all while harnessing technology tools to control and survey mosquito-borne diseases. 

“You have to look beyond just the biology,” Harris says. “You have your human aspect and you have your viral aspect, but you also have your mosquito aspect.”

This approach defines Berkeley Public Health’s approach to vector-borne diseases. In the labs of Harris and Professor John Marshall, a biostatistician implementing genomic innovations to control mosquito vectors, faculty and students are using cutting-edge technology and building on transdisciplinary research. 

Technology is providing tools to understand disease-carrying mosquitoes—helping to crack the code of their ecology and movements, investigate the behavior of the pathogens they transmit, and discover how to survey and control them. In essence, technology allows researchers to get to the mosquito level of these diseases. 

Or, as the late world-renowned Professor William Reeves told his students: To survey and control a mosquito, you must think like one.

From chasing bugs to ground-breaking discoveries

Yellow fever and dengue had existed for centuries before scientists identified mosquitoes as the vehicle for transmission. Then in 1881, Cuban physician Carlos Finlay presented his mosquito-as-vector theory during the International Sanitation Conference, singling out Aedes aegypti—a mosquito species that would come to be known as the “yellow fever mosquito”—as the culprit. This same species would later prove to be the transmitters of chikungunya and Zika virus. 

Over half a century later, epidemiology pioneer Reeves coined the term “arbovirology,” from arthropod-borne virology. Reeves told oral historian Sally Smith Hughes that his academics were driven by his interest in “chasing bugs in my spare time.”

When Reeves earned his PhD in entomology from UC Berkeley in 1943, Aedes aegypti were infecting American soldiers stationed at Pearl Harbor with dengue. The army had a vested interest in hiring entomologists to control insect-borne diseases among the troops, and Reeves got the call to serve. 

When Zika came along, there wasn’t just one question. There was what I like to call the zillion Zika questions.

Reeves knew mosquitoes. He knew how to survey them and control the diseases they spread. As a PhD candidate, he cultured his own population of mosquitoes and used them to transmit isolated strands of western equine encephalitis, thus proving that thousands of horses across the western United States were dying due to mosquito bites. This discovery enabled public health officials in the 1940s to effectively target a key source of disease transmission and better control these widespread outbreaks. As part of the Armed Forces Epidemiological Board, Reeves combined his entomological survey techniques with epidemiology and set the stage for technological innovations in studying infectious diseases. 

When he joined the Berkeley Public Health faculty in 1949, Reeves refined his techniques for surveying mosquitoes, including using carbon dioxide and light to trap them and using a fluorescent dust to mark and track them. His methodology for colonizing, controlling and surveying mosquitoes was groundbreaking. In 2001, when a dead crow in New York City signaled the start of the West Nile Virus epidemic in the United States, the Centers for Disease Control and Prevention (CDC) contacted then-retired Reeves for help. Dr. Roy Campbell, a former student and chief of the surveillance and epidemiology activity of the CDC’s Arboviral Diseases Branch, says Reeves’s research from a half-century earlier provided “a roadmap for understanding West Nile virus.”

Reeves’s seminal work, involving the intersection of technology, entomology and epidemiology, forms the cornerstone for studying infectious diseases—and research leaders like Harris and Marshall are continuing this tradition today. 

Applying science to the real world

“I always had this drive that I wanted to use science in the real world,” says Harris. When she was at Harvard in the 1980s, physicians traveled to communities affected by arthropod-borne and infectious diseases, but bench scientists typically stayed in the lab. At that time it wasn’t clear to Harris how she could bridge this gap as a molecular biologist.

Then as a UC Berkeley graduate student, Harris began organizing workshops in Nicaragua to introduce scientists to polymerase chain reaction—a technique of amplifying and replicating DNA, often referred to as “molecular photocopying.” This technology makes diagnosing and identifying vector-borne diseases possible. “Polymerase chain reaction is actually quite simple in concept,” says Harris. “And very powerful.” In 1997, she received a MacArthur Fellowship in part for bringing this technology to Nicaragua. 

While in Nicaragua, Harris was also first exposed to dengue. “I didn’t know what it was,” she says. “I didn’t know how to spell it. I didn’t know it was a virus. But I knew it was a big public health problem.”

Since joining Berkeley Public Health’s faculty in 1998, much of her career has been devoted to this disease. Harris has multiple active research projects concerning various aspects of dengue, from its microbiology to the social implications of its spread in certain populations. The science of each virus is a spectrum, she says, from molecular biology to the sociopolitical aspects of the disease. For that reason, her lab includes a wide range of researchers from various disciplines, from molecular virologists to social epidemiologists.

In 2015, Harris’s transdisciplinary lab pivoted from dengue to Zika following the outbreak and epidemic that originated in Brazil. “When Zika came along, there wasn’t just one question,” says Harris. “There was what I like to call the zillion Zika questions.” 

Within months of the outbreak, she had projects on the ground that would go on to explain multiple aspects of the virus, such as how Zika affects a developing fetus and, when the epidemic hit Nicaragua, how many people there were eventually infected.

Harris also directs the Center for Global Public Health and runs the Sustainable Sciences Institute, an institute committed to Harris’s longtime mission of bringing innovative technology to communities with limited resources—bridging the gap between bench science and public health. Harris has introduced diagnostic technology to more than 25 countries in Africa and Latin America.  

Bringing gene-editing technologies to the battlefield

Marshall, like Harris and Reeves, comes from a hard-science background. As an undergraduate in New Zealand, he studied laser physics and molecular biology. He then earned a PhD in mathematics from UCLA. “When you do applied mathematics, you can apply it to high-energy physics, or hedge funds if you want to, or climate change,” he says. “Or to any number of diseases and epidemics.”

Today Marshall works to control mosquito-borne diseases by targeting the insects themselves—using technology to modify their genetics. Developed by UC Berkeley faculty Jennifer Doudna, the CRISPR-Cas9 method marks a significant—some say, revolutionary—step in genome-editing technology. Marshall says that CRISPR’s technology turns “a haphazard, random process” into “a precise, almost digital process.” 

Across campus from Doudna, he applies this and other gene-editing technologies to mosquitoes. Marshall models strategies for using genetically modified mosquitoes: studying how these insects can be released, used effectively and then removed at the end of a trial.

At UCLA, Marshall worked with ecologist Charles Taylor, who proposed that gene editing insects could combat wide-scale disease transmission. One method involves releasing genetically modified, sterile mosquitoes into a population of disease-carrying mosquitoes. This stunts the insects’ reproduction, thereby reducing their population and ability to transmit diseases. Another method involves introducing genes into mosquito populations that disrupt the insects’ ability to transmit diseases—a process made significantly easier with technology like CRISPR.

Engaging community support to save lives

Before coming to Berkeley Public Health, Marshall spent a year in Mali gauging the local people’s interest in using genetically modified mosquitoes to help combat the spread of malaria. He also co-organized biosafety workshops to create a regulatory framework for safely releasing these insects. Marshall learned that many Malians were receptive to this life-saving technological approach.

“At the time I was doing my PhD, two children were dying every minute in sub-Saharan Africa from malaria,” says Marshall. “Now it’s one child every minute, as a result of bed nets and antimalarial drugs.” With nearly a billion people in sub-Saharan Africa, the distribution of mosquito nets and medicine goes only so far. Marshall believes gene-editing technology has the potential to finish the job.

Harris and Marshall continue to build on Reeves’s work, making new discoveries about arboviruses and working with countries like Nicaragua, Mali and elsewhere. They are bringing the latest technological advances to the “renaissance approach” of infectious diseases. 

Solutions to health problems, Harris explains, are multi-faceted and don’t come only from the mind of a microbiologist or the technology used in labs. Testing for antibody-dependent enhancement in dengue is one thing. Developing a plan to reuse old tires, where standing water collects and mosquitoes breed, is another. “If you do all this work across the whole transdisciplinary approach,” she says, “then you can really see the whole disease.”