New approach to preventing malaria transmission holds promise
Alexandra Probst, PhD ’25, loves conducting basic biology research in the lab—and knowing that her work could have real-world impact. Slated to graduate in May from the Harvard Griffin Graduate School of Arts and Sciences, Probst is in Harvard T.H. Chan School of Public Health’s Biological Sciences in Public Health (BPH) program. She’s been part of a team using an innovative approach to develop compounds that can prevent malaria transmission by targeting the parasite inside the mosquitoes responsible for passing the disease to people. [Read the press release on the study.]
Q: How did you get into the field of public health?
A: I took a little bit of a meandering path. When I went to the University of Washington for my undergraduate degree, I knew I wanted to get involved in infectious disease research, but initially had an opportunity in a totally different area of biology. My first research experience was fieldwork on Mount St. Helens, documenting ecological recovery after its eruption and comparing different tools to measure plant growth. This work really cemented my interest in the act of research and writing up findings, but I wanted to refocus on research that was more relevant to human health.
I was majoring in microbiology and had actually been interested in parasites before college. I did a project on them in high school, and thought they were crazy—their biology is just absolutely unlike other eukaryotic organisms [those whose cells have a membrane-bound nucleus], and it was fascinating learning how they adapt to and take advantage of their host. While taking microbiology and public health courses, I became more interested in making an impact on human health with my research. I wound up working in the labs of two infectious disease experts during college. In Chris Fox’s lab I worked on vaccine development for a variety of infectious diseases. Then I worked in Alexis Kaushansky’s lab studying the malaria parasite in the liver—and totally just fell in love with malaria as a field. Both of those experiences definitely shaped my interest in doing basic science research, but with a focus on its health applications.
When I applied to PhD programs, the BPH program fit my research interests. I’m surrounded by people who are focused on public health for everyone, and that motivation ends up informing the basic biology research that I do.
Q: What was your PhD research project?
A: I’m co-mentored by Dyann Wirth and Flaminia Catteruccia in the Department of Immunology and Infectious Diseases, who both focus on malaria research, but from two different angles. Dyann’s lab looks at antimalarial drug discovery and development, and Flaminia’s lab focuses on malaria parasite development in mosquitoes. My project took elements from both of those research areas. Working with my colleagues in Dyann and Flaminia’s labs, I identified antimalarial drug compounds that can kill the parasite during its development in the mosquito, as a way of preventing mosquito infection—and therefore preventing transmission to people.
Currently, insecticide-treated bed nets are one of the main ways that we prevent malaria transmission—by having both a physical barrier for whoever’s sleeping under them, and the insecticide to kill the mosquitoes so that other people in the community won’t be bitten. But there are really high rates of insecticide resistance among mosquito populations—over 80% of malaria-endemic countries have reported it. Resistance is a serious problem that jeopardizes the efficacy of the bed nets, so our idea is to add an antimalarial drug to them. That way, when an insecticide-resistant mosquito lands on a bed net, it won’t be killed by the insecticide but it would still take up the antiparasitic drug, which would kill the parasites within the mosquito. As a result, it would no longer be able to transmit infection.
We started our experiments with an initial library of drug compounds that had previously been described to have antimalarial activity, and that we thought would work well in mosquitoes. We screened over 80 compounds by pipetting them one at a time onto mosquitoes and found 22 that significantly reduced parasite infection. We then took successful compounds from that screen and tested them in a landing assay, which involved coating a surface with a compound, then letting mosquitoes land on top to see if the compound could get inside via leg contact. Based on those results, we focused on one promising class of compounds called quinolones. We collaborated with chemists in Mike Riscoe’s lab at Oregon Health and Science University to improve both the compounds’ uptake into mosquitoes’ legs and antiparasitic activity. Mike’s team ultimately synthesized two compounds that we found had even better efficacy at inhibiting mosquito-stage parasite development.
Q: What are the next steps for the project?
A: We are beginning to make early bed-net-like prototypes. In our original landing assay, we had our drug basically evenly dispersed on a surface. It’s wonderful that mosquitoes can pick up the drug in that scenario, but a bed net is a plastic polymer net, a three-dimensional surface. It also needs to be treated at very high heat to be manufactured. We’re working with Mike’s lab and also with polymer chemists at the Southwest Research Institute to make early prototypes, where we melt the two active compounds at high heat and infuse the compounds into the plastic bed net prototype. Right now we don’t have the capacity to actually knit the plastic into a net, but our collaborators can press the polymer into a flat film that we can then use in landing assays to confirm that the compounds still work. We have found that the compounds work extremely well—which means that they have the chemical properties necessary to work effectively when the plastic is formed into actual bed nets.
In the next couple of years, we plan to work with collaborators in Ethiopia. Together with Fitsum Tadesse’s research group at the Armauer Hansen Research Institute, we’re building experimental huts that are typically used to test insecticide-treated bed nets, and we will be able to test our antimalarial-treated bed nets there. The experiments will let us measure net effectiveness in a natural environment that better takes into account mosquito behavior compared to the lab.
Our initial experimental hut trial site in Ethiopia is well suited to capture both parasite and mosquito diversity—the two most common species of malaria parasites worldwide are both present at this site, and there are multiple mosquito species as well. We also plan to test the bed nets at other geographical sites in the future to further assess if the nets work with different types of parasites and mosquitoes.
Q: What are your future career plans?
A: I want to stay in academic research. I love doing research—I enjoy the problem-solving aspect of it, the day-to-day of coming into the lab and working with my hands. The malaria research community is so strong and is a wonderful community to be part of in Boston, in the U.S., and internationally. I think that there’s a lot of space for academic research to be at the forefront of new malaria control approaches. Malaria is a disease that impacts some of the poorest communities in the world, but you don’t get a lot of traditional pharmaceutical company investment in basic research, so academic work is really critical to push the boundaries of our understanding of this disease and develop new tools to fight it.
Quick hits
Q: What’s a hobby you enjoy?
A: I am really into rock climbing. I competed in high school and college, which was very fun. Now I do both indoor and outdoor climbing—indoors for day-to-day practice, but when the weather looks nice, there’s so much beautiful climbing outdoors.
Q: Do you have any favorite places to climb outdoors?
A: There’s Farley Ledges in western Massachusetts, and a bunch of places in New Hampshire and Vermont. I’ve gone bouldering and sport climbing with friends throughout the years at different places around here, and it’s such a nice way to explore the area—especially on a crisp New England fall day!