Dr Marcus Lee | Group Leader

Lee, Marcus

Marcus Lee is 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 my 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 prioritization of future therapeutic targets and gain fundamental biological insights into critical parasite pathways.

A key bottleneck in the historical interrogation of drug resistance mechanisms has been the ability to manipulate the parasite genome. Establishing the causality of given phenotypes relies on the precise query of distinct resistance-associated alleles.

We are developing new molecular genetics approaches that harness CRISPR/Cas to apply systems-level analysis to parasite fitness and drug tolerance. In this work we collaborate closely with the labs of Julian Rayner and Oliver Billker. Our work also directly complements genome-wide association studies that have identified candidate loci involved in emerging drug resistance and clinical treatment failure.

Publications

  • Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase.

    Paquet T, Le Manach C, Cabrera DG, Younis Y, Henrich PP et al.

    Science translational medicine 2017;9;387

  • A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.

    Sonoiki E, Ng CL, Lee MC, Guo D, Zhang YK et al.

    Nature communications 2017;8;14574

  • UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes.

    Lim MY, LaMonte G, Lee MC, Reimer C, Tan BH et al.

    Nature microbiology 2016;16166

  • A broad analysis of resistance development in the malaria parasite.

    Corey VC, Lukens AK, Istvan ES, Lee MC, Franco V et al.

    Nature communications 2016;7;11901

  • CRISPR-Cas9-modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs.

    Ng CL, Siciliano G, Lee MC, de Almeida MJ, Corey VC et al.

    Molecular microbiology 2016;101;3;381-93

  • A novel multiple-stage antimalarial agent that inhibits protein synthesis.

    Baragaña B, Hallyburton I, Lee MC, Norcross NR, Grimaldi R et al.

    Nature 2015;522;7556;315-20

  • CRISPR-mediated genome editing of Plasmodium falciparum malaria parasites.

    Lee MC and Fidock DA

    Genome medicine 2014;6;8;63

  • Targeting Plasmodium PI(4)K to eliminate malaria.

    McNamara CW, Lee MC, Lim CS, Lim SH, Roland J et al.

    Nature 2013;504;7479;248-253

  • Site-specific genome editing in Plasmodium falciparum using engineered zinc-finger nucleases.

    Straimer J, Lee MC, Lee AH, Zeitler B, Williams AE et al.

    Nature methods 2012;9;10;993-8

  • Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery.

    Meister S, Plouffe DM, Kuhen KL, Bonamy GM, Wu T et al.

    Science (New York, N.Y.) 2011;334;6061;1372-7

  • Spiroindolones, a potent compound class for the treatment of malaria.

    Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B et al.

    Science (New York, N.Y.) 2010;329;5996;1175-80

  • Plasmodium falciparum Sec24 marks transitional ER that exports a model cargo via a diacidic motif.

    Lee MC, Moura PA, Miller EA and Fidock DA

    Molecular microbiology 2008;68;6;1535-46

  • Sar1p N-terminal helix initiates membrane curvature and completes the fission of a COPII vesicle.

    Lee MC, Orci L, Hamamoto S, Futai E, Ravazzola M and Schekman R

    Cell 2005;122;4;605-17

  • Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase.

    Paquet T, Le Manach C, Cabrera DG, Younis Y, Henrich PP et al.

    Science translational medicine 2017;9;387

  • A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.

    Sonoiki E, Ng CL, Lee MC, Guo D, Zhang YK et al.

    Nature communications 2017;8;14574

  • UDP-galactose and acetyl-CoA transporters as Plasmodium multidrug resistance genes.

    Lim MY, LaMonte G, Lee MC, Reimer C, Tan BH et al.

    Nature microbiology 2016;16166

  • CRISPR-Cas9-modified pfmdr1 protects Plasmodium falciparum asexual blood stages and gametocytes against a class of piperazine-containing compounds but potentiates artemisinin-based combination therapy partner drugs.

    Ng CL, Siciliano G, Lee MC, de Almeida MJ, Corey VC et al.

    Molecular microbiology 2016;101;3;381-93

  • A broad analysis of resistance development in the malaria parasite.

    Corey VC, Lukens AK, Istvan ES, Lee MC, Franco V et al.

    Nature communications 2016;7;11901

  • Profiling the Essential Nature of Lipid Metabolism in Asexual Blood and Gametocyte Stages of Plasmodium falciparum.

    Gulati S, Ekland EH, Ruggles KV, Chan RB, Jayabalasingham B et al.

    Cell host & microbe 2015;18;3;371-81

  • A novel multiple-stage antimalarial agent that inhibits protein synthesis.

    Baragaña B, Hallyburton I, Lee MC, Norcross NR, Grimaldi R et al.

    Nature 2015;522;7556;315-20

  • (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium.

    Jiménez-Díaz MB, Ebert D, Salinas Y, Pradhan A, Lehane AM et al.

    Proceedings of the National Academy of Sciences of the United States of America 2014;111;50;E5455-62

  • KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission.

    Kuhen KL, Chatterjee AK, Rottmann M, Gagaring K, Borboa R et al.

    Antimicrobial agents and chemotherapy 2014;58;9;5060-7

  • N-aryl-2-aminobenzimidazoles: novel, efficacious, antimalarial lead compounds.

    Ramachandran S, Hameed P S, Srivastava A, Shanbhag G, Morayya S et al.

    Journal of medicinal chemistry 2014;57;15;6642-52

  • CRISPR-mediated genome editing of Plasmodium falciparum malaria parasites.

    Lee MC and Fidock DA

    Genome medicine 2014;6;8;63

  • Targeting Plasmodium PI(4)K to eliminate malaria.

    McNamara CW, Lee MC, Lim CS, Lim SH, Roland J et al.

    Nature 2013;504;7479;248-253

  • An integrated strategy for efficient vector construction and multi-gene expression in Plasmodium falciparum.

    Wagner JC, Goldfless SJ, Ganesan SM, Lee MC, Fidock DA and Niles JC

    Malaria journal 2013;12;373

  • Wherever I may roam: protein and membrane trafficking in P. falciparum-infected red blood cells.

    Deponte M, Hoppe HC, Lee MC, Maier AG, Richard D et al.

    Molecular and biochemical parasitology 2012;186;2;95-116

  • Site-specific genome editing in Plasmodium falciparum using engineered zinc-finger nucleases.

    Straimer J, Lee MC, Lee AH, Zeitler B, Williams AE et al.

    Nature methods 2012;9;10;993-8

  • Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery.

    Meister S, Plouffe DM, Kuhen KL, Bonamy GM, Wu T et al.

    Science (New York, N.Y.) 2011;334;6061;1372-7

  • Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue.

    Adjalley SH, Johnston GL, Li T, Eastman RT, Ekland EH et al.

    Proceedings of the National Academy of Sciences of the United States of America 2011;108;47;E1214-23

  • Spiroindolones, a potent compound class for the treatment of malaria.

    Rottmann M, McNamara C, Yeung BK, Lee MC, Zou B et al.

    Science (New York, N.Y.) 2010;329;5996;1175-80

  • A method for rapid genetic integration into Plasmodium falciparum utilizing mycobacteriophage Bxb1 integrase.

    Adjalley SH, Lee MC and Fidock DA

    Methods in molecular biology (Clifton, N.J.) 2010;634;87-100

  • Genomewide analysis reveals novel pathways affecting endoplasmic reticulum homeostasis, protein modification and quality control.

    Copic A, Dorrington M, Pagant S, Barry J, Lee MC et al.

    Genetics 2009;182;3;757-69

  • Plasmodium falciparum Sec24 marks transitional ER that exports a model cargo via a diacidic motif.

    Lee MC, Moura PA, Miller EA and Fidock DA

    Molecular microbiology 2008;68;6;1535-46

  • Arresting malaria parasite egress from infected red blood cells.

    Lee MC and Fidock DA

    Nature chemical biology 2008;4;3;161-2

  • Inhibiting endoplasmic reticulum (ER)-associated degradation of misfolded Yor1p does not permit ER export despite the presence of a diacidic sorting signal.

    Pagant S, Kung L, Dorrington M, Lee MC and Miller EA

    Molecular biology of the cell 2007;18;9;3398-413

  • Molecular mechanisms of COPII vesicle formation.

    Lee MC and Miller EA

    Seminars in cell & developmental biology 2007;18;4;424-34

  • Sar1p N-terminal helix initiates membrane curvature and completes the fission of a COPII vesicle.

    Lee MC, Orci L, Hamamoto S, Futai E, Ravazzola M and Schekman R

    Cell 2005;122;4;605-17

  • Cell biology. BAR domains go on a bender.

    Lee MC and Schekman R

    Science (New York, N.Y.) 2004;303;5657;479-80

  • Multiple cargo binding sites on the COPII subunit Sec24p ensure capture of diverse membrane proteins into transport vesicles.

    Miller EA, Beilharz TH, Malkus PN, Lee MC, Hamamoto S et al.

    Cell 2003;114;4;497-509

  • Ceramide biosynthesis is required for the formation of the oligomeric H+-ATPase Pma1p in the yeast endoplasmic reticulum.

    Lee MC, Hamamoto S and Schekman R

    The Journal of biological chemistry 2002;277;25;22395-401

  • The solution structure of C1-T1, a two-domain proteinase inhibitor derived from a circular precursor protein from Nicotiana alata.

    Schirra HJ, Scanlon MJ, Lee MC, Anderson MA and Craik DJ

    Journal of molecular biology 2001;306;1;69-79

  • Identification and characterization of a prevacuolar compartment in stigmas of nicotiana alata

    Miller EA, Lee MC and Anderson MA

    The Plant cell 1999;11;8;1499-508

  • Structure of a putative ancestral protein encoded by a single sequence repeat from a multidomain proteinase inhibitor gene from Nicotiana alata.

    Scanlon MJ, Lee MC, Anderson MA and Craik DJ

    Structure (London, England : 1993) 1999;7;7;793-802

  • A novel two-chain proteinase inhibitor generated by circularization of a multidomain precursor protein.

    Lee MC, Scanlon MJ, Craik DJ and Anderson MA

    Nature structural biology 1999;6;6;526-30

Lee, Marcus
Marcus's Timeline
2015

Joined Wellcome Trust Sanger Institute

2010

Associate Research Scientist at Columbia University Medical Center

2007

Moved to Columbia University Medical Center with David Fidock

2005

NIH NRSA Postdoctoral Fellowship with David Fidock at Albert Einstein College of Medicine

2000

Human Frontier Science Program Postdoctoral Fellowship with Randy Schekman at University of California Berkeley

1999

Awarded PhD from University of Melbourne, on the study of plant defense proteins with Marilyn Anderson