My research focuses on three main topics, click below to find out more.
Can we slow the evolution of drug resistance?
Drug resistant pathogens, also known as 'superbugs', threaten the success of medical procedures that we have come to take for granted. New drugs are difficult and expensive to develop. While we await the development of new drugs, can we use the principles of evolutionary ecology slow the evolution of drug resistance?
Drug resistance, like any trait, arises in an ecological context - in an environment where drugs are present, drug resistance gives microbes a competitive advantage over their susceptible relatives (which, after all, killed by drugs!). Yet in the absence of drugs, drug resistance is often associated with costs and resistant microbes lose in competition with their susceptible competitors. I found that the we can manipulate ecological interactions between parasites to prevent emergence of superbugs. I identified a nutrient that drug resistant parasites require more of than their susceptible competitors and demonstrated that it mediates competition between drug -susceptible & -resistant parasites. I then showed limiting that nutrient can prevent the emergence of drug resistance. Importantly, resource limitation does not kill resistant parasites outright, rather it makes them lose in competition with susceptible competitors. This work demonstrates that a sublethal intervention can thwart drug resistance, opening up new, much-needed avenues for drug discovery. Thus, we showed that evolutionary ecology could help to slow down the evolution of drug resistance & might even get the drying-up drug development pipeline flowing again.
Key papers: Wale et al. Proc R Soc. 2017; Wale et al. PNAS 2017
Collaborators & coauthors: The Read Group (Penn State), Troy Day (Queen's University Canada).
Most of us imagine the immune response as an army of cells, hunting & killing parasites. Yet, killing an enemy population is not the only way to limit its growth; restricting access to resources with a can also be effective. Elucidating the defense strategies the host employs to fight off infection is essential for understanding the evolution of parasite counter-defenses. It will also help to understand 'who' (parasite vs. host). causes disease & thus 'who' to target treatment at.
Combining novel mathematical modeling approaches & experiments, we quantified the strategies the host uses to combat malaria infections. In the early stage of infection the host kills parasites, as we might expect but it also targets the red blood cells, in which malaria parasites live & reproduce. Specifically, the host employs a 'siege' & 'scorched earth' strategy: cutting off the supply of red blood cells (RBCs) and destroying them outright. In so doing, the host causes the vast majority anemia (the major symptom of malaria infection) but also reduces parasite reproduction by almost 25%. In the late stage, we found the host employs a hitherto unrecognized RBC-directed defense strategy, which we dub `juvenilization'. As the host pumps RBCs back into the bloodstream, enabling it to recovering from anemia, it simultaneously increases the removal rate of RBCs. By thus increasing the turnover of cells it prevents further parasite reproduction.
Future work will focus on developing predictive models of infection dynamics, as derived from simple 'rules' of immune system deployment that this analysis revealed.
Key papers: Wale et al. (2019) PNAS
Collaborators & coauthors: Aaron King (UMich), The Read Group (Penn State).
Breaking down defenses: how does the host control an infection?
as of 2018.
Collecting Daphnia, the host of Spiro. in the field.
A healthyDaphnia (bottom) & a Daphnia at the terminal stage of Spirobacillus infection (top)
What are the causes & consequences of color variation in a virulent parasite?