Professor Ben Simons
Tracing stem cell fate in development, maintenance and disease
Laboratory: Gurdon Institute. Departmental Affiliation: Physics
Ben has a background in theoretical condensed matter physics. Having obtained his PhD at the Cavendish Laboratory in Cambridge researching high temperature superconductivity, he undertook post-doctoral research in quantum mesoscopic physics at MIT and NEC Research Inc. in Princeton. In 1994 he transferred to a Royal Society Research Fellowship and was appointed to a Lectureship at Imperial College before moving to the Cavendish Laboratory in 1995. In 2002, he was promoted to a Chair in Theoretical Condensed Matter Physics. In 2011, Ben was appointed to the Herchel Smith Chair in Physics. His research is supported by grant income from EPSRC, MRC, and the Wellcome Trust with whom he holds a Senior Investigator Award.
Human Frontiers Science Program, Wellcome Trust
Lineage labelled intestinal crypts and villi in mice
With a background in theoretical condensed matter physics, my group is using concepts from non-equilibrium statistical physics and mathematics to address the fate behaviour of stem and progenitor cells in the development, maintenance and regeneration of tissues and factors leading to their dysregulation in diseased states. In particular, we have combined long-term lineage tracing studies using transgenic animal models with static marker-based assays to resolve strategies of stem cell self-renewal in the maintenance of epithelial tissues, including mammalian brain, epidermis, intestine, lung and testis. Our studies have emphasized the role of stochastic fate decisions in the regulation of stem cell fate, questioning the nature of stem cell identity, and offering new perspectives on stem cell regulation. Lately, we have extended these approaches to study the development of adult tissues, from the specification of pseudo-stratified neuroepithelia (retina and cortex) to the patterning of the heart.
To develop this program, we are extending this approach to study the development of ductal tissues, including the liver, lung, mammary epithelium, pancreas and prostate. At the same, we are collaborating with partner labs to address the cellular basis of tumour initiation using the clonal activation of oncogenic mutations or the action of carcinogens. We are also making use of genetic lineage tracing approaches to study the process of remyelination in spinal cord.
Finally, we are working with colleagues at the Sanger and Babraham to develop statistical approaches to address single cell transcriptional and epigenetic profiling data, with the aim of resolving the factors controlling symmetry breaking and cell fate specification in the developing mouse embryo.
Roberta Azarelli, Silvia Benito, Juergen Fink, Philip Greulich, Edouard Hannezo, Chris Hindley, David Jorg, Teresa Krieger, Crystal McClain, Jamie McGinn, Steffen Rulands, Magdalena Sznurkowska, Hinal Tanna, Julia Tischler
In adults, many tissues such as epidermis, blood, and gut undergo routine and constant turnover. The maintenance and repair of such tissues relies upon stem cells. As with embryonic stem cells, tissue stem cells are defined by their capacity to self-renew and to differentiate into the more specialised cell types. However, in contrast to embryonic stem cells, tissue stem cells must achieve a perfect balance between proliferation and differentiation. Resolving the mechanisms of balance represent one of the defining questions of stem cell biology. To address this question, most studies focus on the identification of molecular regulatory factors. However, such factors are rare and often unspecific. By exploiting methods of population dynamics and statistical physics, we have shown that, in homeostasis, stem cells must follow simple and restricted patterns of fate, which impart characteristic signatures in the size distribution of surviving clones. We are using this general methodology to explore the pattern of tissue maintenance in normal adult tissues, and to address the mechanisms of dysregulation in disease, cancer and aging.
- Gao P, Postiglione MP, Krieger TG, Hernandez L, Wang C, Han Z, Streicher C, Papusheva E, Insolera R, Chugh K, Kodish O, Huang K, Simons BD, Luo L, Hippenmeyer S, Shi S-H. Deterministic progenitor behavior and unitary neuron production in the neocortex. Cell (2014). 159, 775-788 PMCID:PMC4225456
- Hara K, Nakagawa T, Enomoto H, Suzuki M, Yamamoto M, Simons BD, Yoshida S. Mouse spermatogenic stem cells continually interconvert between equipotent singly isolated and syncytial states. Cell Stem Cell (2014). 14, 658-672 PMCID:PMC4010676
- Ritsma L, Ellenbroek SIJ, Zomer A, Snippert HJ, de Sauvage FJ, Simons BD, Clevers H, van Rheenen J. Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo live imaging. Nature (2014) 507, 362-365; PMCID:PMC3964820
- Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C. Defining the mode of tumour growth by clonal analysis.Nature (2012). 488, 527-530. PMID:22854777
- Simons BD, Clevers H. Strategies for homeostatic stem cell self-renewal in adult tissues. Cell (2011). 145, 851-862. PMID:21663791