Timothy Mitchison
We work on fundamental questions of how cells are spatially organized applied problems in pharmacology and drug development. We ask how systems comprising microtubules, binding proteins and motors self-organize to promote cell division in frog eggs using microscopy and biochemistry. We work on the pharmacology of microtubule-targeting drugs, and to development new drug that combat cancer and inflammation by modulating innate immunity.
Harvard Medical School, Department of Systems Biology
Alpert Building, Room 541B
200 Longwood Ave.
Boston, MA 02115
Tel: 617-432-3805
Email: timothy_mitchison@hms.harvard.edu
Website: http://mitchison.hms.harvard.edu/
Lab Size: Between 10 and 15
Summary
The Mitchison group has long been interested in fundamental mechanisms by which cells use for physically organization and movement. Our main focus is on dynamic organization of the microtubule cytoskeleton, in particular during cell division. We use eggs of the frog Xenopus laevis as a model to study this problem and also as an example of an extremely large cell, where the scaling gap between molecular and cellular processes becomes extreme. We analyze microtubule-based organizing mechanisms by microscopy, image analysis and biochemistry, often taking advantage of egg extracts that reconstitute complex processes ex vivo. In the pharmacology area we are working on how microtubule- and mitosis-targeting drugs kill cancer cells, in particular how the important anti-cancer drug taxol works to promote tumor regression in man. We are also developing small molecules that activate tumor-resident macrophages by mimicking viral infection, and cause an innate immune attack of the cancer.
Publications
Li L, Yin Q, Kuss P, Maliga Z, Millán JL, Wu H, Mitchison, TJ. (2014). Hydrolysis of 2'3'cGAMP by ENPP1 and design of non-hydrolyzable analogs. Nature Chemical Biology. In press.
Laughney AM, Kim EU, Sprachman MM, Miller MM, Kohler RH, Yang KS, Orth JD, Mitchison TJ, Weissleder R (2014). Single-cell intravital microscopy reveals a nanotherapeutic strategy to reverse MDR-mediated resistance to the microtubule inhibitor eribulin. Science Transl Med. In press.
Krukenberg KA, Jiang R, Steen JA, Mitchison TJ. (2014). Basal Activity of a PARP1-NuA4 Complex Varies Dramatically across Cancer Cell Lines. Cell Rep. pii: S2211-1247(14)00672-X. NIHMS ID: NIHMS622462.
Tang Y. (2014). A one-step imaging assay to monitor cell cycle state and apoptosis in mammalian cells. Curr Protoc Chem Biol, 6(1):1-5. PMCID: PMC4016950.
The bacterial cell division proteins FtsA and FtsZ self-organize into dynamic cytoskeletal patterns. Loose M, Mitchison TJ. Nat Cell Biol. 2014 Jan;16(1):38-46.
Anticancer Flavonoids Are Mouse-Selective STING Agonists. Kim S, Li L, Maliga Z, Yin Q, Wu H, Mitchison TJ. ACS Chem Biol. 2013
Imaging burst kinetics and spatial coordination during serial killing by single natural killer cells. Choi PJ, Mitchison TJ. Proc Natl Acad Sci U S A. 2013 Apr 16;110(16):6488-93.
Growth, interaction, and positioning of microtubule asters in extremely large vertebrate embryo cells. Mitchison T, Wühr M, Nguyen P, Ishihara K, Groen A, Field CM. Cytoskeleton (Hoboken). 2012 Oct;69(10):738-50.
Deformations within moving kinetochores reveal different sites of active and passive force generation. Dumont S, Salmon ED, Mitchison TJ. Science. 2012 Jul 20;337(6092):355-8.