Image credit: Wellcome Sanger Institute
At the end of July 2023, Dr Marcus Lee and his research group will finalise the move of their Malaria Parasite Drug Resistance programme to the University of Dundee, where he is now Professor of Parasite Molecular Genetics.
Antimalarial drugs have been the major contributor to decreased deaths from malaria and have become a cornerstone of control efforts. However, the evolution and spread of resistance to frontline antimalarials represents a serious the public health emergency, and underscores the urgent need to identify new targets and a range of new drugs to target the malaria parasite. Understanding the mechanisms by which malaria parasites develop resistance can help to guide the development and prioritization of future therapeutic targets and provide fundamental insights into critical parasite pathways.
When Marcus Lee joined the Wellcome Sanger Institute in 2015, he established a research group to focus on identifying new antimalarial compounds and developing tools to manipulate the Plasmodium falciparum genome, enabling the basic biology of the parasite and the mechanisms responsible for drug resistance to be characterised.
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Marcus Lee's research group at the Wellcome Sanger Institute in 2020
Large-scale cell-based screening campaigns have tested over 8 million compounds against the blood stage of P. falciparum, yielding thousands of chemically diverse active drug scaffolds. However, prioritization of compounds that may have novel mechanisms of action or that are not easily amenable to the generation of resistance can be challenging.
The Lee group therefore developed new molecular genetics approaches that harness CRISPR/Cas to enable rapid systems-level analysis of antimalarial compound action, including the identification of potential targets or mechanisms of resistance, cross-resistance profiles, and fitness costs associated with resistance.
Their novel tools have enabled in-depth validation of new drug targets and detailed biological investigation of specific genes or gene families. In addition, they use these tools to perform 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. The group also explore ways of adapting the RNA-guided CRISPR/Cas system for genome editing and gene regulation in the parasite.
“The genetic tools that Marcus and his lab have developed during his time at Sanger are game-changing for studying malaria parasite biology and for understanding whether and how resistance to their new drug candidates might emerge. Marcus has been an invaluable member of the Parasites and Microbes programme over the last 8 years, and took the lead in establishing and setting the tone for our International Faculty programme. Recognised by all to be an exemplary Sanger citizen, he brought unbridled energy and enthusiasm in addition to his deep knowledge and expertise. It has been a pleasure to work alongside Marcus and his team and I look forward to seeing much more from them all in the years to come.”
Professor Nick Thomson,
Group Leader and Head of the Parasites and Microbes programme
Moving to the University of Dundee provides an ideal opportunity for the Lee group to interact more closely with like-minded researchers in the Dundee Drug Discovery Unit and the wider Wellcome Center for Anti-Infectives Research who focus on developing new drugs for parasitic diseases.
Before joining Sanger, Marcus received his PhD from the University of Melbourne, Australia, where he studied plant defence proteins. He subsequently undertook his postdoctoral training, first in yeast cell biology with Randy Schekman at the University of California Berkeley, and subsequently with David Fidock at Columbia University Medical Center, where he worked on mechanisms of resistance to novel antimalarial compounds.
“Drug resistance is one of the major problems facing global malaria control and we urgently need new drugs to replace those that are currently being lost to resistance. During his time at Sanger, Marcus created an innovative repertoire of novel experimental genetic tools to identify new antimalarial targets and speed up the drug development process. He is now taking those tools to the ideal destination, the world-leading programme at the University of Dundee which is focussed on developing new therapies for malaria and other neglected tropical diseases. Marcus was also an absolute joy to work with, a genuinely supportive and kind colleague who influenced many careers during his time at Sanger, and I look forward to collaborating with him for many years to come.”
Professor Julian Rayner,
Director of Cambridge Institute for Medical Research; Director Wellcome Connecting Science; Honorary Faculty (and former Senior Group Leader) in the Parasites and Microbes Programme.
All members of the Parasites and Microbes programme and wider Sanger Institute extend their thanks to Marcus and the members of his research group past and present, and wish them well in the next stages of their research in Dundee.
