Wellcome Sanger Institute

Lee Group

Malaria Parasite Drug Resistance

Marcus Lee’s group is interested in the molecular basis of drug resistance in the human malaria parasite Plasmodium falciparum, and in developing molecular genetics tools to interrogate gene function in this important pathogen.

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.

Research Areas

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 6 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 prioritize compounds that may have novel mechanisms of action or that antagonise the generation of resistance.

Developing molecular genetics approaches to interrogate gene function

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. We are exploring ways of adapting the RNA-guided CRISPR/Cas system for genome editing and gene regulation in the parasite.

Core team

Photo of Dr Katharina Boroviak

Dr Katharina Boroviak

Senior Staff Scientist

Photo of Dr Sophie Adjalley

Dr Sophie Adjalley

Postdoctoral Fellow

Photo of Krittikorn Kümpornsin

Krittikorn Kümpornsin

Postdoctoral Fellow

Photo of Mr Gareth Girling

Mr Gareth Girling

Advanced Research Assistant

Photo of Dr Frank Schwach

Dr Frank Schwach

Senior Computational Biologist

Photo of Emma Fern Carpenter

Emma Fern Carpenter

Wellcome PhD Student

Photo of Hannah Jagoe

Hannah Jagoe

PhD Student

Photo of Megan Ansbro

Megan Ansbro

PhD Student

Previous team members

Photo of Dr Chuan Cao

Dr Chuan Cao

Postdoctoral Fellow

Photo of Dariya Nikitin

Dariya Nikitin

Advanced Research Assistant

Photo of Asli Akidil

Asli Akidil

Advanced Research Assistant

Photo of Hannah Bruce

Hannah Bruce

Advanced Research Assistant

Partners

We work with the following groups

External

Bill and Melinda Gates Foundation

We are part of the Malaria Drug Accelerator (MalDA) Consortium, funded by the Bill and Melinda Gates Foundation. The MalDA consortium is composed of 13 members, and aims to identify new antimalarial targets.

External

Tres Cantos Open Lab Foundation

We are funded by the Tres Cantos Open Lab Foundation on a project to identify new liver-stage drug targets.

External

Medicines for Malaria Venture

Medicines for Malaria Venture (MMV) are funding a project to use drug resistant parasites to profile new antimalarial candidates.

External

BBSRC

The Biotechnology and Biological Sciences Research Council (BBSRC) funds an iCASE studentship in our lab to develop methods for rapid identification of drug mode-of-action.

 

Publications

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