Professor Marcus Lee
Biological Chemistry and Drug Discovery, School of Life Sciences
Marcus Lee received his Ph.D from the University of Melbourne, and subsequently undertook postdoctoral training in the laboratory of Dr. Randy Schekman at the University of California Berkeley where he used yeast genetics and biochemical reconstitutions to study the biophysical basis for membrane curvature during vesicle formation. During this time, he became interested in the unique biology of the malaria parasite and joined the lab of Dr. David Fidock at Columbia University Medical Center to focus on uncovering mechanisms of resistance to novel antimalarial compounds. Marcus established his independent research group in 2015, joining the Malaria Programme at the Wellcome Sanger Institute as Group Leader. Marcus moved to the University of Dundee in 2023, where he is Professor of Parasite Molecular Genetics.
We are interested in the molecular basis of drug resistance in the human malaria parasite Plasmodium falciparum, and in developing molecular genetics approaches to interrogate gene function.
An individual malaria infection can be driven by more than 100 billion parasites at the peak of the disease cycle. Over the course of a chronic infection, the parasite has the potential to mutate at rates that suggest an enormous capacity to develop vast genetic diversity. This latent variability has troubling implications for the ease with which the parasite might develop immunity to drug treatment, both current and future. In the field, clinical resistance can take as little as a year to develop or can accrue over decades.
One of our longstanding research interests has been to understand the mechanisms available to the parasite to develop resistance, which often comes at a cost in terms of fitness in the absence of drug pressure. We hope to guide the development and prioritisation of future therapeutic targets and gain fundamental biological insights into critical parasite pathways.
Understanding the molecular basis for drug resistance
Antimalarial drug resistance is one of the most significant challenges facing malaria control, and resistance has developed to every major drug released to date. To identify new drugs, several large-scale screening campaigns have tested over 8 million compounds in cell-based screens against the blood stage of P. falciparum, yielding thousands of chemically diverse active drug scaffolds. However, a major challenge is to leverage these compounds to identify targets that are either particularly vulnerable to perturbation, or refractory to resistance.
We are developing platforms that permit the rapid analysis of multiple aspects of antimalarial compound action, including the identification of potential targets or mechanisms of resistance, cross-resistance profiles, and fitness costs associated with resistance. This will allow us to prioritise compounds that may have novel mechanisms of action or that antagonise the generation of resistance.
We are also interested in understanding the influence of genetic background on the development of drug resistance and the maintenance of parasite fitness.
Developing molecular genetics approaches to interrogate gene function
Of the >5000 genes in the genome of the malaria parasite, a sizable number have unknown function and lack homologs outside of Plasmodium species. A deeper understanding of their roles and essentiality would provide biological insight as well as suggest new therapeutic targets.
Advances in our ability to manipulate the parasite genome will be critical to any systematic investigation of Plasmodium biology. These applications include the in-depth validation of new drug targets and detailed biological investigation of specific genes or gene families. In addition, we are interested in developing tools for performing unbiased genetic screens, in the hope of assigning roles to the large number of parasite genes of unknown function, including lncRNAs about which little is known. We are exploring ways of adapting the RNA-guided CRISPR/Cas system for genome editing and gene regulation in the parasite.
The Lee group are focused on understanding antimalarial drug resistance and the validation of new drug targets.