Dr Stephen Brown

Steve Brown

SRSF Manager
Department of Biomedical Science
The University of Sheffield
Western Bank
Sheffield S10 2TN
United Kingdom

Room: Alfred Denny B2 226/7 Labs
Telephone: +44 (0) 114 222 3690
Email: stephen.brown@sheffield.ac.uk

SRSFlogo

General

Brief career history:

  • 2008-present: University of Sheffield (Biomedical Sciences), Sheffield RNAi Screening Facility Manager (SRSF)
  • 2004-2008:  University of Manchester (Faculty of Life Sciences), MRC Career Development Fellowship
  • 2004: University of Cambridge (Pathology), Post-Doctoral research
  • 1997- 2003: University of Cambridge (Zoology), Post-Doctoral research
  • 1997: University of Nottingham, PhD 

Research interests

Functional genomics, siRNA genome screens, drug screening, cell models of Human disease.

Professional activities

  • Founding member and co-organiser of the UK RNAi and Functional Genomics Group (London, 2011-)
  • Founding member and co-organiser of the Stem Cell Phenotyping Consortium (2014-)
  • EMBO Practical Course Tutor; High-throughput RNAi and Data Analysis (2010)
  • SRSF Symposium co-organiser (Sheffield, 2010)
  • Guest Editor of Seminars in Cell and Developmental Biology (2008) 
  • MRC Career Development Fellowship Award 2004-2008

Full publications

Research

Functional Genomics and RNAi Screening

  • Many diseases have an unknown or poorly defined molecular diagnosis. There is a need to identify the molecular nature of these orphan diseases and the changes these mutations cause to cells and tissues.
  • The Sheffield RNAi Screening Facility uses robotics and automated systems to leverage RNAi/small molecules and genome editing tools to identify novel biological and disease candidates.
  • I use Drosophila and Human cell models of disease. In particular, I use normal, cancer and Human embryonic stem cells. Recently we have been growing 3D tumour spheroids for screening.
  • I collaborate with Dr. Xiubo Zhao using self-assembling nano-peptides, Dr. Ivana Barbaric and Dr. Paul Gokhale investigating miR regulation of Human embryonic stem cells and Dr. Martin Zeidler identifying new members of the JAK/STAT signalling pathway.

I have managed over 50 RNAi library screens for both UK and international scientists. My laboratory uses both automation (robotics) and molecular cell biology to identify genes involved in disease. I am also involved in teaching Masters and PhD students in the art of “Functional Genomics”.

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Funding

  • Fabrication of antibody functionalized silk fibroin micro-well arrays using reactive inkjet printing for circulating tumour cell capture. Dr. X. Zhao (Chem Eng) and Dr. S. Brown
  • Engineering and Physical Sciences Research Council. Nov 2016 - Oct 2019 (£333,657)
Teaching

Undergraduate and postgraduate taught modules

Level 1:

  • BMS109 1st year Tutor
  • BMS110 Research Topics in Biomedicine

Level 3:

  • BMS349/BMS359 Extended Library Project

Masters (MSc):

  • BMS6011 The Biotech and Pharmaceutical Industry
  • BMS6014 Genomic Approaches to Drug Discovery
  • BMS6012 3D Tissue Culture and Genome Editing
  • BMS6013 Small Molecule and Functional Genomic Screening
  • MSc Genomic Approaches to Drug Discovery (module leader)
Opportunities

Postgraduate PhD Opportunity

Bacterial-associated oncogenesis: Investigating the typhoid toxin of the persistent intracellular pathogen Salmonella Typhi in oncogenesis

Co-supervisor:

Background

The human intracellular bacterial pathogen Salmonella enterica serovar Typhi (S.Typhi) causes systemic typhoid fever resulting in 27 million cases of disease and 200,000 deaths each year. S.Typhi is a stealth pathogen and a hallmark feature is its ability to also establish persistent chronic infections in the gall bladder where the pathogen is associated with causing cancer. Oncogenesis is exacerbated in humans carrying gene mutations that predispose individuals to gall bladder cancer. This is relevant to public health, as a link between infection and tumour development may result in personalised therapeutic protocols.

How S.Typhi persists in host cells and promotes oncogenesis is not known. S.Typhi initiates infections by injecting virulence proteins into mammalian host cells to direct uptake and replication within intracellular Salmonella-containing vacuoles (SCVs). From its intracellular niche, S.Typhi secretes the typhoid toxin into the extracellular milieu where it enters target host cells. Once inside the cell the toxin traffics to the nucleus where it reprogrammes cell cycle progression, causes DNA damage and manipulates cellular signalling through nuclease and ADP-ribosylase activities. Recent evidence shows that typhoid toxin mediates establishment of persistent infections in animal hosts, and persistence underlies S.Typhi-associated tumour development.
Project

The mechanisms by which typhoid toxin manipulates cells to drive persistent infections are not understood, and the significance of the toxin to S.Typhi’s stealth virulence strategy and bacterial-associated oncogenesis has not been addressed. The PhD project will investigate these research questions using purified toxin derivatives and infection models in combination with the latest advances in molecular cell biology, fluorescence microscopy, and automated high-throughput screening technologies.

The student will join the laboratory of Dr. Daniel Humphreys (first supervisor) at the Department of Biomedical Science (BMS), University of Sheffield. The project will establish assays to study mammalian cells intoxicated with typhoid toxin using molecular, biochemical, genetic and fluorescence imaging approaches. In particular, how the toxin perturbs nuclear functions in cells predisposed to oncogenesis during S.Typhi infection will be examined using high resolution using structural resolution microscopy at the Wolfson Light Microscopy Suite at the BMS.
Having established the project foundations an RNAi screen will be developed with Dr. Steve Brown (third supervisor) at the RNAi Screening Facility, University of Sheffield.

The PhD student will be trained to use robotics and automated microscope systems to perform high-throughput RNAi screens aimed at identifying host genes required for cellular manipulation by the typhoid toxin.

Finally, the student will use Salmonella infection models, intoxication and cell transformation assays to investigate the significance of genes identified in the screen on pathogen persistence and the generation of bacterial-associated oncogenic phenotypes. These project components will be developed in the laboratories of the first supervisor and the second supervisor, Dr. Anjam Kahn, at the University of Newcastle.

To combat typhoid fever we need to understand the hijack mechanisms employed by S.Typhi to cause disease. By bringing together researchers from the University of Sheffield and the University of Newcastle, three areas of expertise will be combined to provide excellent scientific training and exposure to a broad range of techniques in a project of enormous biomedical significance. 

References

  1. Humphreys D*. Singh V, Koronakis V*. (2016). Inhibition of WAVE Regulatory Complex activation by a bacterial virulence effector counteracts pathogen phagocytosis. Cell Reports. 17(3):697-707. PMID: 27732847.
  2. Humphreys D, Davidson AC, Hume PJ, Makin LE, Koronakis V. (2013) Arf6 coordinates actin assembly through the WAVE complex, a mechanism usurped by Salmonella to invade host cells. Proceedings of the National Academy of Sciences of the United States of America. 110(42):16880-16885. PMID: 24085844
  3. Humphreys D, Davidson AC, Hume PJ, Koronakis V. (2012) Salmonella SopE and host GEF ARNO cooperate to recruit and activate WAVE to trigger bacterial invasion. Cell Host & Microbe 11, 129-39. PMID: 22341462
  4. Smith, K., Humphreys, D., Hume, P.J., and Koronakis, V. (2010) Enteropathogenic Escherichia coli recruits the cellular inositol phosphatase SHIP2 to regulate actin-pedestal formation.
    Cell Host & Microbe 7, 13-24. PMID: 20114025

Further information about this project can be found on our PhD Opportunities page:

PhD Opportunities

Selected publications

Journal articles