My research focuses on three main topics, click below to find out more.
Can we slow the evolution of drug resistance?
Drug resistant pathogens are not killed by the antimicrobial drugs we use to treat infections. These 'superbugs' threaten the success of medical procedures that we have come to take for granted. New drugs are difficult and expensive to develop, so much so that the rate that new drugs appear on the market has fallen in recent times. Can we use the principles of evolutionary ecology to buy us time and 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.
My PhD work focused on identifying how drug sensitive and drug resistant malaria parasites compete inside the host's body, with the goal of developing a new, evolution-proof way to stop the emergence of drug resistance. We found a nutrient that malaria parasites require for optimal growth, showed that drug resistant parasites require more of this nutrient than their susceptible competitors and demonstrated that it mediates competition between drug -susceptible & -resistant parasites. Drawing on classical ecological ideas, we used this information to develop a new way to prevent the emergence of drug resistance. We showed that when resistant parasites are more hungry for a nutrient than susceptible parasites, 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, buying time for drug development, and 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).
Breaking down defenses: how does the host control an infection?
Asked to imagine 'the immune response', most of us would probably call to mind an army of soldier-like cells, hunting & killing parasites. Yet, killing an enemy is not the only way to limit its growth; restricting access to resources with a 'siege' or 'scorched earth' strategy can also be effective. Understanding which defense strategies the host employs, and when, is important if we are to understand the defenses that parasites evolve in response. Moreover, this will help us understand 'who' (parasite vs. host). causes disease; crucial if we are to know 'who' to target our treat at and maximize its efficacy.
Combining novel mathematical modeling approaches & experiments, we used a simple accounting scheme to elucidate which strategies the host uses to combat infection. In the early stage, the host employs a 'siege' & 'scorched earth' strategy: cutting off the supply of RBCs & actively destroying them. In so doing, the host is responsible for th emajority of the anemia (the major symptom of infection) but also reduces parasite reproduction by almost 25%.
Key papers: Wale et al. (2019) PNAS
Collaborators & coauthors: Aaron King (UMich), The Read Group (Penn State).
In the field, collecting Daphnia, the host of S.cienkoswkii.
The symptoms of infection with S. cienkowskii:
top - a Daphnia infected with 'Spiro''; bottom - an uninfected Daphnia.
What are the causes & consequences of color variation in a virulent parasite?
Spirobacillus cienkoswkii ("Spiro") is a lethal bacterial pathogen of Daphnia, a herbivorous crustacean that plays an important role in lake food webs. Despite being first described in the late 1800s, and turning its hosts a striking red color, this bacteria had gone unstudied in the laboratory...until now.
Having worked out how to grow Spiro in the laboratory & described color variation among infected hosts in the lab & field, I am developing the Daphnia-Spiro system as a model system with which to investigate how ecological forces outside of the host (e.g. predators, light) interact with in-host stresses (e.g. immunity) to shape parasite traits, using color as the trait of interest. In addition to elucidating the basic biology of the pathogen - what does Spiro's life cycle look like? How does it transmit between hosts? - I am investigating:
i. the cause & evolutionary role of the distinctive colorful symptom of infection. What molecules cause the infected host to change color? Is the host or parasite responsible for this 'blushing' & what (if any) adaptive purpose does it serve?
ii. the impact of Spiro's symptoms on predator-prey interactions & hence parasite ecology & evolution. (How) does Spiro infection alter the perception of Daphnia hosts by predators & therefore their susceptibility to predation? What is the downstream impact of altered predator-prey interactions on parasite transmission & trait evolution?
Key papers: Wale et al. (2019) Ecology
Collaborators & coauthors: Team Spiro - a team of fantastic undergraduate researchers who work with me (currently, Clare Freimark). Kristel Sanchez (Duffy lab graduate student, UMich), Sherman lab (UMich), Becky Fuller (U. Illinois), Sonke Johnsen (Duke U.)