MODERATOR: Denis Noble, CBE, FRS, FMedSci, MAE, Professor Emeritus; Co-Director of Computational Physiology, Department of Physiology, Anatomy, and Genetics, University of Oxford
Sui Huang, Professor, Institute for Systems Biology
Sui Huang, MD, PhD, obtained his doctorates in medicine and in molecular biology at the University of Zurich in 1995, working interferon-g. After 12 years as postdoctoral fellow and faculty at Harvard Medical School in Boston, where he studied cell fate decisions and tumor angiogenesis, he was recruited to the University of Calgary in 2007 and worked alongside Stuart Kauffman on gene regulatory networks and cancer therapy (=exiting the cancer attractor) before joining the Institute for Systems Biology in Seattle in 2011. Sui Huang demonstrated that cell types are attractor states in high-dimensional gene expression space, and subsequently showed cell state instability preceding cell fate decisions. His current laboratory at ISB combines single-cell omics technologies and theory of non-linear dynamical systems to better understand non-genetic mechanisms of tumor progression and an intrinsic limitation of cancer treatment: cancer treatment so often backfires…
Title: Non-genetic plasticity and Lamarckian Dynamics of Tumor Progression: What does not make me, makes me stronger”
Abstract: The idea that the genotype maps in a deterministic 1:1 fashion to phenotype has long dictated evolution biology, as well as cancer biology. Accordingly, cancer progression is driven by a somatic Darwinian evolution of cells that accumulate mutations and undergo selection. In reality, the link between genetic mutation and cancer is much looser. For, one genome can produce thousands of stable and inheritable phenotypes, most prosaically manifest in the diversity of cell types of the metazoan body. A cell of a distinct types sits at the bottom of the valleys in Waddington’s epigenetic landscape. This familiar picture is more than a metaphor because it explains phenotypic variability (“plasticity”) in the absence of genetic alterations by grounding it in the mathematical principles of gene regulatory network dynamics. In this talk I will propose how the departure from the rigid 1:1 genotype-to-phenotype mapping prompts us to rethink evolution, notably somatic evolution of the neoplastic cell in the development of therapy resistance. Theory and experiments that I will present suggest that treatment either kills the cell, or if not, will induce a stemness state in the non-killed (but stressed) cells, and make them more resilient – manifesting a symmetry-breaking bifurcation. Such treatment-induced resistance corresponds to a Lamarckian scheme of tumor evolution (without genetic mutations). But it is perhaps more fittingly described with Nietzsche: “What does not kill me makes me stronger
Dr. Jean-Jacques Kupiec (Centre Cavaillès de l’Ecole Normale Supérieure – Paris)
Dr. Kupiec, proposed in 1983 a cell differentiation model based on stochastic gene expression. Since then, he has developed this model and has published a series of articles and books on the subject.
Title: Stochastic gene expression, cell differentiation and cancer
Abstract: Cells associate to form multicellular living beings through, on the one hand, stochastic gene expression and, on the other hand, interactions with their internal environment which stabilize them. This model allows for testable predictions that were verified. Notably, it predicts a surge in gene expression variability preceding cell differentiation. Computer simulation experiments show that, in this frame, a living being is an equilibrium state between the intrinsic variation of cells and their interaction with the internal environment, and that the cause of cancer is a disturbance of this equilibrium.
Kupiec, J.J. A probabilist theory for cell differentiation, embryonic mortality and DNA C-value paradox. Spec. Sci. Technol. 6(5):471-478, 1983. (Republished in 2020 in Organisms: Journal of Biological Sciences, vol. 4, no. 1, pp. 80-85.)
Kupiec J.-J. A Darwinian theory for the origin of cellular differentiation. Mol. Gen. Genetics. 255: 201-208, 1997
Kupiec J.-J. The Origin of Individuals. World Scientific Publishing. 2009.
Heams T. Approche endodarwinienne de la variabilité intercellulaire de l’expression génétique, 2004 Thèse de doctorat sous la direction de J.-J. Kupiec – Paris, Institut national d’agronomie
Laforge, B. et al., 2005. Modeling embryogenesis and cancer: an approach based on an equilibrium between the autostabilization of stochastic gene expression and the interdependance of cells for proliferation. Progress Biophys. Mol. Biol. 89: 93-120.
Richard A et al. Single-Cell-Based Analysis Highlights a Surge in Cell-to-Cell Molecular Variability Preceding Irreversible Commitment in a Differentiation Process. PLoS Biol. 2016 Dec 27;14(12):e1002585. doi:10.1371/journal.pbio.1002585.
Moussy A et al. Integrated time-lapse and single-cell transcription studies highlight the variable and dynamic nature of human hematopoietic cell fate commitment. PLoS Biol. 2017 Jul 27;15(7):e2001867. doi: 10.1371/journal.pbio.2001867
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