Jonathan M. Irish, Ph.D.
Assistant Professor of Cancer Biology
Assistant Professor of Pathology, Microbiology and Immunology
740B Preston Research Building
2220 Pierce Avenue
Nashville, TN 37232-6840
Jonathan M. Irish, Ph.D. is Assistant Professor of Cancer Biology and Pathology, Microbiology and Immunology at Vanderbilt University. The Irish Lab uses new tools and computational approaches to do basic and translational research in human cancer and immunology.
A specialty of the Irish lab is tracking and targeting rare populations of cells in human tissues. Close collaborations between the Irish lab and clinicians in the VICC enable Irish lab members to bring patient biopsy samples directly from the bedside into the laboratory for analysis by 'next generation' research techniques. For example, using mass cytometry Irish lab members can detect and characterize every cell in a patient's biopsy sample -- including cancer cells, immune cells, and stem cells. Dr. Irish is leading the development of mass cytometry at Vanderbilt, one of the first 15 institutions worldwide to acquire the technology. The long term goal of the Irish lab is to use single cell approaches and new knowledge of biology to detect disease earlier, create safe and effective new therapies, and to monitor and guide personalized medicine.
Ultimately, by better understanding biological systems which control cell biology in healthy and diseased contexts, we can learn to program cells to become therapeutic agents or target malignant signaling events to specifically kill cancer cells.
The Irish lab is grateful for outstanding support from the VICC, including the VICC Young Ambassadors, a passionate group of volunteers and advocates dedicated to fighting cancer by supporting research:
The goal to study control of signaling networks in healthy and malignant cells forms the basis of an NIH/NCI R00 grant that supports the Irish lab (5R00CA143231-04).
Research Background and Training
Dr. Irish received his Ph.D. from the Cancer Biology program at Stanford for studies in the laboratory of Dr. Garry Nolan, Ph.D., and previously earned B.S. degrees in Chemistry, Biochemistry, and Biology from the University of Michigan. For his postdoctoral fellowship, Dr. Irish worked with Dr. Ronald Levy, M.D., at Stanford until founding his lab at Vanderbilt in 2012. Together with Nolan lab alumni Dr. Nikesh Kotecha and Dr. Peter Krutzik, Dr. Irish created Cytobank, a big data analytics platform used by thousands of researchers worldwide to manage, analyze, and share data from high dimensional single cell research.
During his Ph.D. research with Dr. Nolan, Dr. Irish created a new technique to measure signaling responses in individual cancer cells and applied it to the study of leukemia patient clinical outcomes (Cell 2004). An advantage of this single cell approach is that signaling can be characterized in rare populations of cancer cells and contrasted with the bulk cancer cell population or with tumor-infiltrating non-malignant cells.
In his postdoctoral research with Dr. Levy, Dr. Irish applied this 'single cell signaling profiles' technique to dissect B cell signaling in follicular lymphoma (Blood 2006) and healthy B cell development (J Immunol 2006). This project culminated in the identification of new type of lymphoma B cell termed lymphoma negative prognostic (LNP) cells. LNP cells are closely associated with progression to aggressive disease and lower overall survival (PNAS 2010). With collaborators, Dr. Irish has now shown that LNP cells exist in other B cell cancers (BMC Cancer, Br J Haematol 2012), are distinguished by a set of genetic driver mutations (Blood 2013), and suppress tumor infiltrating T cell signaling via PD-1 (Blood 2013).
Single cell systems biology for translational cancer and immunology research
My background is in cancer biology, cell signaling, immunology, and computational biology. A central goal of my research at Vanderbilt is to understand how changes at the single cell level alter signaling in healthy cells and lead to therapy resistant populations in human diseases.
In addition to making discoveries at the frontier of human genetics and immunology, I aspire to use knowledge of cell signaling to create therapeutic technologies and to guide clinical decisions. In the long term, great potential exists to detect disease earlier and to tailor a patient's therapy to the biological alterations detected in the cells of their disease. By better understanding biological systems which control development and cell-cell interactions in healthy and diseased contexts, we can learn to program cells to become therapeutic agents or target malignant signaling events to specifically kill cancer cells.
I aim to foster a diverse and exciting research atmosphere in my lab by recruiting students working on integrative, interdisciplinary projects. I'm especially interested in training students whose projects will combine elements of:
- basic cancer biology or immunology
- computational & systems biology
- pharmacology & drug screening
- clinical translational research
- new technology or techniques
- primary human samples
My experimental approach has focused on measuring signaling events in individual cells from primary tissues, including human tumors. Before coming to Vanderbilt, I trained at Stanford University with Garry Nolan and Ronald Levy. There I created a new approach that measures signaling in individual cancer cells and applied it to the study of acute myelogenous leukemia patient clinical outcomes (Cell 2004). An advantage of this single cell approach is that signaling can be characterized in rare populations of cancer cells and contrasted with the bulk cancer cell population or with tumor-infiltrating non-malignant cells. I later applied this technique to healthy B cells (J Immunol 2006) and malignant B cells in follicular lymphoma (Blood 2006). In follicular lymphoma, signaling identified a subset of tumor B cells that were present at diagnosis only in patients with a lower overall survival (p < 0.0001) and that increased over time as the patient's cancer progressed (PNAS 2010). Systems biology tools we created to manage and analyze single cell signaling data were critical to this work (Curr Protoc Cytometry 2010).
Key technologies in my laboratory include phospho-specific flow cytometry (phospho-flow) and mass cytometry. Phospho-flow combines lineage and phospho-specific antibodies to measure intracellular signaling in individual cells (Nature Reviews Cancer 2006). Mass cytometry is a next generation analytical flow cytometry technology capable of measuring 34+ features of individual cells - a dramatic leap forward from the present technology, which routinely measures only 3 to 8 features per cell. The form of single cell proteomics enabled by mass cytometry provides unique opportunities for mechanistic understanding of signaling in primary tumors and healthy human tissues.
My laboratory is also interested in computational biology, bioinformatics, and modeling and develops tools for our research that:
1) Identify and compare individual cells in heterogeneous primary tissue samples
2) Are cloud based and connected to online tools and communities
3) Capture key experiment annotations and relate them to the raw data files
4) Integrate pathway modeling and visualization tools into the data analysis wor
- Green, MR, Gentles, AJ, Nair, RV, Irish, JM, Kihira, S, Liu, CL, Kela, I, Hopmans, ES, Myklebust, JH, Ji, H, Plevritis, SK, Levy, R, Alizadeh, AA Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma. Blood, 2013.
- Myklebust, JH, Irish, JM, Brody, J, Czerwinski, DK, Houot, R, Kohrt, HE, Timmerman, J, Said, J, Green, MR, Delabie, J, Kolstad, A, Alizadeh, AA, Levy, R High PD-1 expression and suppressed cytokine signaling distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood, 2013.
- Blix, ES, Irish, JM, Husebekk, A, Delabie, J, Tierens, AM, Myklebust, JH, Kolstad, A Altered BCR and CD40 signalling are associated with clinical outcome in small lymphocytic lymphoma/chronic lymphocytic leukaemia and marginal zone lymphoma patients. Br J Haematol, 2012.
- Blix, ES, Irish, JM, Husebekk, A, Delabie, J, Forfang, L, Tierens, A, Myklebust, JH, Kolstad, A Phospho-specific flow cytometry identifies aberrant signaling in indolent B-cell lymphoma. BMC Cancer, 12(1), 478, 2012.
- Irish, JM, Myklebust, JH, Alizadeh, AA, Houot, R, Sharman, JP, Czerwinski, DK, Nolan, GP, Levy, R B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progression. Proc Natl Acad Sci U S A, 107(29), 12747-54, 2010.
- Kotecha, N, Krutzik, PO, Irish, JM Web-based analysis and publication of flow cytometry experiments. Curr Protoc Cytom, Chapter 10Unit10.17, 2010.
- Houot, R, Goldstein, MJ, Kohrt, HE, Myklebust, JH, Alizadeh, AA, Lin, JT, Irish, JM, Torchia, JA, Kolstad, A, Chen, L, Levy, R Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion. Blood, 114(16), 3431-8, 2009.
- Hammer, MM, Kotecha, N, Irish, JM, Nolan, GP, Krutzik, PO WebFlow: a software package for high-throughput analysis of flow cytometry data. Assay Drug Dev Technol, 7(1), 44-55, 2009.
- Kotecha, N, Flores, NJ, Irish, JM, Simonds, EF, Sakai, DS, Archambeault, S, Diaz-Flores, E, Coram, M, Shannon, KM, Nolan, GP, Loh, ML Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates. Cancer Cell, 14(4), 335-43, 2008.
- Irish, JM, Anensen, N, Hovland, R, Skavland, J, BÃ¸rresen-Dale, AL, Bruserud, O, Nolan, GP, Gjertsen, BT Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53. Blood, 109(6), 2589-96, 2007.
- Van Meter, ME, DÃaz-Flores, E, Archard, JA, PasseguÃ©, E, Irish, JM, Kotecha, N, Nolan, GP, Shannon, K, Braun, BS K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells. Blood, 109(9), 3945-52, 2007.
- Irish, JM, Czerwinski, DK, Nolan, GP, Levy, R Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells. Blood, 108(9), 3135-42, 2006.
- Irish, JM, Czerwinski, DK, Nolan, GP, Levy, R Kinetics of B cell receptor signaling in human B cell subsets mapped by phosphospecific flow cytometry. J Immunol, 177(3), 1581-9, 2006.
- Irish, JM, Kotecha, N, Nolan, GP Mapping normal and cancer cell signalling networks: towards single-cell proteomics. Nat Rev Cancer, 6(2), 146-55, 2006.
- Krutzik, PO, Irish, JM, Nolan, GP, Perez, OD Analysis of protein phosphorylation and cellular signaling events by flow cytometry: techniques and clinical applications. Clin Immunol, 110(3), 206-21, 2004.
- Irish, JM, Hovland, R, Krutzik, PO, Perez, OD, Bruserud, Ã˜, Gjertsen, BT, Nolan, GP Single cell profiling of potentiated phospho-protein networks in cancer cells. Cell, 118(2), 217-28, 2004.
- Armstrong, JS, Steinauer, KK, Hornung, B, Irish, JM, Lecane, P, Birrell, GW, Peehl, DM, Knox, SJ Role of glutathione depletion and reactive oxygen species generation in apoptotic signaling in a human B lymphoma cell line. Cell Death Differ, 9(3), 252-63, 2002.
- B.S., B.S., and B.S., Chem. - University of Michigan, 1998
- Ph.D. - Stanford University, 2004
- Fellowship - Stanford University, 2011