In science developing a theory provides the most efficient route to new treatments and technologies. Over a long period our lab has been testing and developing a new theoretical perspective on complex cellular behaviour. Our target is the immune system, but our theories apply equally to blood cell development and cancer biology.
Our theory begins by noting striking differences in behaviour among similar, even cloned, cells. Traditionally viewed as ‘biological variation’ we are now confident cells take advantage of randomising systems as a means of coding for, and allocating, cells to different tasks. We use this idea to create quantitative probabilistic models of the cell and from that starting point extrapolate to complete complex dynamic systems. We inform the developing framework by experiments such as video microscopy to catch single T and B cells in the act of making decisions and modifying their behavior.
Our models are now mature and accurate enough to serve as the framework for investigations into:
Australia, University of Western Australia, BSc (Hons)
Australia, Australian National University, PhD
2014, Eureka prize, Australian Museum (with Nutt, Tarlinton, Corcoran)
2012, Burnet Oration Medal, Australasian Society of Immunology (ASI)
2009, Honorary Professorial Fellow, The University of Melbourne
2008, Derrick Rowley Medal, Australasian Society of Immunology
Feb-July 2007, International Travelling Fellowship: SFI E.T.S. Walton Visitor Award, National University of Ireland, Maynooth
Member, HFSP Council of Scientists, 2022-
Member, National Health and Medical Research Council Academy, 2012
Member, National Health and Medical Research Council project review panel, 2010 – 2011
Member, Career Development Award Ranking panel, National Health and Medical Research Council, 2004 – 2007
President (elected), Australasian Society of Immunology, 2005 – 2006
Vice President (elected), Australasian Society of Immunology, 2003 – 2004
Cheon H, Kan A, Prevedello G, Oostindie SC, Dovedi SJ, Hawkins ED, Marchingo JM, Heinzel S, Duffy KR, Hodgkin PD. Cyton2: A Model of Immune Cell Population Dynamics That Includes Familial Instructional Inheritance. Front Bioinform. 2021 Oct 26;1:723337. doi: 10.3389/fbinf.2021.723337. PMID: 36303793; PMCID: PMC9581048.
Horton MB, Cheon H, Duffy KR, Brown D, Naik SH, Alvarado C, Groom JR, Heinzel S, Hodgkin PD. Lineage tracing reveals B cell antibody class switching is stochastic, cell-autonomous, and tuneable. Immunity. 2022 Oct 11;55(10):1843-1855.e6. doi: 10.1016/j.immuni.2022.08.004. Epub 2022 Sep 14. PMID: 36108634.
Horton MB, Prevedello G, Marchingo JM, Zhou JHS, Duffy KR, Heinzel S, Hodgkin PD. Multiplexed Division Tracking Dyes for Proliferation-Based Clonal Lineage Tracing. J Immunol. 2018 Aug 1;201(3):1097-1103. doi: 10.4049/jimmunol.1800481. Epub 2018 Jun 18. PMID: 29914887.
Heinzel S, Binh Giang T, Kan A, Marchingo JM, Lye BK, Corcoran LM, Hodgkin PD. A Myc-dependent division timer complements a cell-death timer to regulate T cell and B cell responses. Nat Immunol. 2017 Jan;18(1):96-103. doi: 10.1038/ni.3598. Epub 2016 Nov 7. PMID: 27820810.
Hodgkin PD. Modifying clonal selection theory with a probabilistic cell. Immunol Rev. 2018 Sep;285(1):249-262. doi: 10.1111/imr.12695. PMID: 30129201; PMCID: PMC6446824.
Marchingo JM, Prevedello G, Kan A, Heinzel S, Hodgkin PD, Duffy KR. T-cell stimuli independently sum to regulate an inherited clonal division fate. Nat Commun. 2016 Nov 21;7:13540. doi: 10.1038/ncomms13540. PMID: 27869196; PMCID: PMC5121331.
Marchingo JM, Kan A, Sutherland RM, Duffy KR, Wellard CJ, Belz GT, Lew AM, Dowling MR, Heinzel S, Hodgkin PD. T cell signaling. Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion. 2014 Science 346: 1123-1127 PMID: 25430770.
Dowling MR, Kan A, Heinzel S, Zhou JH, Marchingo JM, Wellard CJ, Markham JF, Hodgkin PD. Stretched cell cycle model for proliferating lymphocytes. Proc Natl Acad Sci U S A. 2014 Apr 29;111(17):6377-82. PMID: 24733943.
Hawkins ED, Turner ML, Wellard CJ, Zhou JH, Dowling MR, Hodgkin PD. Quantal and graded stimulation of B lymphocytes as alternative strategies for regulating adaptive immune responses. Nat Commun. 2013;4:2406. PMID: 24009041.
Duffy KR, Wellard CJ, Markham JF, Zhou JH, Holmberg R, Hawkins ED, Hasbold J, Dowling MR, Hodgkin PD. Activation-induced B cell fates are selected by intracellular stochastic competition. Science. 2012 Jan 20;335(6066):338-41. PMID: 22223740.
Duffy KR, Hodgkin PD. Intracellular competition for fates in the immune system. Trends Cell Biol. 2012 Sep;22(9):457-64. PMID: 22727035.
Hawkins ED, Markham JF, McGuinness LP, Hodgkin PD. A single-cell pedigree analysis of alternative stochastic lymphocyte fates. Proc Natl Acad Sci U S A. 2009 Aug 11;106(32):13457-62. PMID: 19633185.
Hawkins ED, Turner ML, Dowling MR, van Gend C, Hodgkin PD. A model of immune regulation as a consequence of randomized lymphocyte division and death times. Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5032-7. PMID: 17360353.
Kallies A, Hasbold J, Tarlinton DM, Dietrich W, Corcoran LM, Hodgkin PD, Nutt SL. Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J Exp Med. 2004 Oct 18;200(8):967-77. PMID: 15492122.
Hasbold J, Corcoran LM, Tarlinton DM, Tangye SG, Hodgkin PD. Evidence from the generation of immunoglobulin G-secreting cells that stochastic mechanisms regulate lymphocyte differentiation. Nat Immunol. 2004 Jan;5(1):55-63. PMID: 14647274.
The development of mathematical models of the T and B cell adaptive immune response has developed rapidly over the last several years and the probabilistic principles for codifying modules of cellular behavior have proved increasingly successful. All members of the lab work either with, or on improving such models directly. New resources are being developed as software for the immunology community. Experiments to inform the models and to test predictions are made from single cell tracking, from cell division and differentiation tracking and from fate mapping performed both in vitro and in vivo.
Team members: Evan Thomas, Ken Duffy (National University of Ireland).
There is still much to learn about the normal biology of both T and B lymphocytes in the immune response. We are particularly keen to understand how cells add signals together and adjust to changing levels and combinations of the many different cytokines and costimuli on offer during an immune challenge. To reveal this ‘cellular calculus’ we measure cell behavior, at single cell and population level to learn the rules of addition and to predict the net outcomes. The effects of drugs and genetic manipulations on modular components of the cell are also being measured with the aim to develop a principle for predictive immunotherapy and in silico drug screening.
The model team – Su Heinzel, Michelle Ruhle, Melissa Biemond, Evan Thomas
Our principles of cellular calculus and single cell behavior have been developed using model systems. We are asking whether the same principles operate for people and the quantitative methods we have developed could help stratify and screen for genetic deficiencies and susceptibilities. Importantly we aim to identify how multiple small quantitative changes in cellular circuits can add up to powerful immune disorders such as autoimmunity. Our first target is to examine Common Variable Immunodeficiency and move from there to more complex immune disorders.
Team members: Vanessa Bryant, Su Heinzel and Charlotte Slade