Modelling
Cellular Interactions - the "Middle-Out" approach
The software agent is an intuitively natural
computational representation of a real world entity.It is applicable to any system where
emergent behaviour arises as a result of the complex
interactions between many individuals, and is particularly
appropriate in the case of modeling biological tissues where
tissue behaviour is an emergent property of physical and
biochemical interactions between individual cells, and between
cells and their micro-environment.
At the simplest level, the observed
behaviour of the real-world cells can be represented by simple
logical rule sets that determine the responses of individual
software agents to various stimuli(e.g. rules can represent
apoptosis (death), change in morphology or progression through
the cell cycle in response to a sensed biochemical signal).However, where additional
detail is required, models can be extended "downwards" to
incorporate sub-models of mechanisms that determine changes in
cell phenotype (e.g. signalling pathways) or "upwards" to
produce continuum level properties. Hence the agent-based
representation of the cell is a natural starting point for
"middle-out" modelling.
I have worked in this area since 2001, when
I was employed as a post-doctoral Research Associate on the
EPSRC Platform Grant which ultimately resulted in
The
Epitheliome Project
.
My more recent research interests include
developing agent-based models epithelial cells at the
individual level, focusing on:
-
The role of
cell contact-mediated pathways in determining cell
phenotype
- The interaction of sub-populations of "social" (normal) and "anti-social" (genetically mutated) cells.
-
Understanding cellular
heterogeneity and how small differences in certain
intracellular signals may influence cell phenotype
(e.g. see here)
-
Integrating
agent-based models with continuum based mechanical
models to study remodeling processes in tendon (see below).
-
Understanding how
interactions of sperm cells with the
oviduct
(fallopian tube) may affect
fertilisation.
All
the above involve close interactions with laboratory-based
cell biologists.
Scratch wound closure of layer of bladder cellsI.
In
vitro (laboratory experiment) and
II
Computer
Simulation using
The Epitheliome
at a)
0 hours, b) 3 hours c) 6 hours and d) 9 hours after
wounding. Blue cells are in G1 or G2 phase of the cell
cycle, pink cells in M phase, green cells in S phase and
yellow cells in G0 (quiescent).
SELECTED PUBLICATIONS
Walker, D.C. and Southgate, J. (2009), The
virtual cell--a candidate co-ordinator for
'middle-out' modelling of biological systems.
Brief Bioinform, 10(4):450-61
Link
via PubMed
Walker DC,
Walker DC, Hill G, Wood
SM, Smallwood RH, Southgate J (2004) Agent-based
computational modeling of epithelial cell
monolayers: predicting the effect of exogenous
calcium concentration on the rate of wound
closure, IEEE Transactions in NanoBioscience 3
(3) pp153-163
Link
via White Rose
Walker, D.C., Southgate J, Hill G.,Holcombe M.,
Hose D.R., Wood S.M., MacNeil S., Smallwood R.H.
(2004) The
Epitheliome: modelling the social behaviour of
cells, Biosystems 76 (1-3) pp 89-100
Link
via White Rose
PRIMAGE
PRedictive In-silico Multiscale Analytics to support cancer personalized diaGnosis and prognosis, Empowered by imaging biomarkers
EU Ho2020 funded project
The aim of this project is to combine imaging and biomarker data with state of the art computational modelling in order to predict patient-specific outcomes for neuroblsatoma, a devastating childhood cancer. We are working towards developing an agent-based model of a neuroblastoma tumour, with initial conditions and parameters informed by patient-derived data. This model will be deployed in our highly optimised FLAME GPU environment. By integrating our model with those of other project partners we aim to predct the growth of the tumour, or its response to treatment.
This
project commenced 1st December 2018.
USFD co-investigator: Dr Paul Richmond Dr Paul Richmond
USFD Post-Doctoral Research Associate: Dr Kenneth Wertheim Dr Kenneth Wertheim
USFD Research Software Engineer: Robert Chisholm Robert Chisholm
More information relating to this project is available on the PRIMAGE website here
THE
VIRTUAL TENDON
- a multi-scale
computational model of dynamical tissue remodelling
Tendons are tough, flexible pieces of connective tissue that connect muscles to the skeleton allowing them to efficiently convert muscular force into movement.We aim to produce a computational model which can be used as a tool to understand how normal tendon reacts in different mechanical environments, and also how things can go wrong, leading to disease or compromised healing. Unlike existing models, we propose to represent the dynamic process of tissue modelling, including mechanical behaviour of the tissue matrix, as well as intercellular signalling and cell response. This will involve the integration of continuum finite element models with agent-based models of cellular behaviour. We will validate each component of the model against experimental data to ensure its accuracy and relevance.
Once developed, the model
could be tailored to represent tissue from particular
patient groups, e.g. differing in gender or age. Ultimately,
we would hope that the predictive power of this method will
be able to identify combinations of factors that might be
beneficial or detrimental to connective tissues and that the
patient might benefit from this computational approach, as
has already been achieved in cardiac medicine.
representing various aspects of remodelling from the macroscopic mechanical
properties to cellular signalling
Grant Holders: Dr Dawn Walker (PI),
Prof Rod Hose (CI), Senior Lecturer, Academic Unit of Medical Physics, Department of Cardiovascular Science, School of Medicine and Biomedical Sciences, University of Sheffield http://www.shef.ac.uk/medicine/staff/hose.html
Dr Andy Scutt (CI), Senior Lecturer, Academic Unit of Bone Biology, Department of Human Metabolism, School of Medicine and Biomedical Sciences, University of Sheffield
Grant period 1/9/09-31/8/12
Funding
Body
Arthritis
Research UK
A Combined in vitro
and in virtuo Multi-scale Approach to Understanding
Calcium Signalling as a Signature and Integrator of
Cellular Response
Although cells are autonomous, they function within highly ordered communities or tissues, with sophisticated mechanisms for sensing, communicating and delivering an integrated response. For instance, it has been observed that mechanical stretch or wounding of tissues results in a wave of elevated intracellular calcium emanating from the point of stimulation, preceding the onset of proliferation or migration of individual cells, the summative effect of which is closure of the wound. Preliminary experiments on human urothelial monolayers suggest that the temporally varying calcium signature “seen” by each individual cell will determine the nature of its response.
Biological cells are not
identical in terms of their gene/protein profile, neither do
they exist in a homogeneous environment. However, biological
systems are generally robust in that as a population, they
will respond to a stimulus in a predictable fashion, even
though the responses of individuals within that population
may vary. Hence understanding the differences that arise
from relatively small levels of heterogeneity, in contrast
to those associated with significantly different cell
phenotypes (e.g. proliferative versus differentiated) is critical, and
may play an important role in the wider understanding of
growth regulation in biological tissues.
This project involves a closely integrated and
iterative process of computational model development
(Sheffield) and laboratory-based cell biology (York)
in order to understand how external signals to a cell
frequently trigger a calcium signal that is then translated
into a cell response. In
particular, we want to understand how effectively one signal
(calcium) can trigger a multitude of different responses at
the cellular level.
Biological Processes that will be modelled during
this project
Publications
Appleby PA, Shabir S, Southgate J, Walker D.
Cell-type-specific modelling of intracellular calcium
signalling: a urothelial cell model. J R Soc Interface. 2013
Jul 17;10(86):20130487 pdf
Shabir S, Cross W, Kirkwood LA,
Pearson JF, Appleby PA, Walker D, Eardley I, Southgate J.
Functional expression of purinergic P2 receptors and
transient receptor potential channels by the human
urothelium. Am J Physiol Renal Physiol. 2013 Aug
1;305(3):F396-406.
article
Appleby P A, Shabir S, Southgate J,
Walker DC A theoretical model of cytosolic calcium elevation
following wounding in urothelial cell monolayers. Journal of
Physics: Conference Series 410 ISSN1742-6596 pdf
P. A. Appleby, S. Shabir, J. Southgate and D. Walker (2012) " The impact of selection bias when examining individual cells from whole-field images" Proc. 10th Int. Symp. on Computer Methods in Biomechanics and Biomedical Engineering. pdf
Image analysis software
We have produced a Matlab based
image analysis approach that we have used to provide a
semi-automated method of:
i) segmenting individual cells from
a series of immunofluorescent timelapse images
ii) automatically extracting the cytosolic calcium profile
(amplitude of calcium signal over time)
A zip file containing the relevant
Matlab function, with instructions for use, is available here
A description of this algorithm is
available in:
P. A. Appleby, S. Shabir, J. Southgate and D.
Walker (2012) "
The impact of selection bias when
examining individual cells from whole-field images" Proc.
10th Int. Symp. on Computer Methods in Biomechanics and
Biomedical Engineering. pdf
PLEASE TAKE A MOMENT TO
READ THIS DISCLAIMER
Please note that this code is made available on the
understanding that it will be used for research purposes
only
NOT for commercial purposes. It has been
optimised
for and tested on the sets of images
collected in this project only and may need
re-parameterisation for use on other datasets.
The authors accept no liability associated with use of
this code and will not be in a position to help with
debugging or other issues relating to its reuse.
Any use or further development of this code resulting in
a publication should acknowledge both the authors and this
project
.
Grant Holders:
Dr Dawn Walker (PI -
University of Sheffield), Professor Jenny Southgate (PI –
Jack Birch
Unit of Molecular Carcinogenesis, Department of
Biology, University of York
)
Research Staff:
Dr Peter Appleby,
Research Associate, Department of Computer
Science
Dr Saqib Shabir, Research Associate, Department of Biology, University of York
Grant period 1/9/10-31/8/13
Funding
Body
– The Wellcome Trust
Finite Element Modelling
of the Electrical Properties of Epithelial Tissue
This work formed the basis of my
Ph.D. and was carried out with
Medical
Physics and Clinical Engineering, University of Sheffield,
U.K.
The introduction of Pap Smear testing for cervical cancer
has significantly reduced the number of deaths from this
disease in developed countries. However, the screening
process remains subjective and the laboratory analysis
required is time consuming and expensive. The development of
a quick, cheap and objective screening method for this
disease, and other epithelial cancers which are currently
diagnosed by biopsy (e.g. bladder cancer, oesophageal
cancer) is therefore desirable.
It has long been known the biological tissue conducts
electrical current differently at different frequencies.
This is a result of the arrangement of individual cells
within the tissue. Electrical Impedance spctroscopy, or EIS
is a technique whereby a very small electrical current is
passed through the tissue, and the electrical impedance, or
resistance, is measured at different frequencies. When
impedance is plotted against frequency, a characteristic
curve known as an impedance spectrum is obtained. Clinical
trials carried out in Sheffield have shown that differences
between impedance spectra obtained from normal and
precancerous (CIN) tissue are as significant as those
obtained from analysing Pap smear tests.
Pencil probe used to collect electrical
impedance measurements in clinic, and cartoon showing
pattern of changes in the cervical epithelium from
normal, through Cervical Intraepithelial Neoplasia (CIN)
to invasion of the underlying stroma.
In order to obtain a better
understanding of the reasons for the different properties of
normal and precancerous cervical tissue, and the optimise
the design of the four electrode probe used to collect data,
I constructed finite element models of the structure of
normal cervical epithelium, and epithelium at various stages
of precancerous development, and used these to predict the
pattern of current flow and voltage distribution arising
from given input currents. In order to include effects
arising from subcellular structures, such as the cell
nucleus, it was necessary to build two hierarchies of model
- the first being a cellular level model that included
features such as extracellular space, cell membranes and
nuclei, and the second incorporating the averaged properties
of volumes of cells with different morphologies (e.g.
superficial layer cells as opposed to basal cells). This
explicit modelling of the cellular nature of the tissue
demonstrated that the current flow (and hence sensitivity to
morphological changes) is determined primarily by the
distribution of extracellular space in a tissue, with both
the stroma and the surface fluid layer having significant
effects on the electrical impedance properties.
More recently, I have been using FE models to predict the
effect of increasing tissue hydration associated with the
onset of labour, and have also modelled changes associated
with carcinoma of the bladder.
Finite
element meshes of a) a single epithelial cell and b) the
macroscopic tissue model
PUBLICATIONS
Walker D C, Smallwood R H,
Keshtar A, Wilkinson B A, Hamdy F C, Lee J Modelling the
electrical properties of bladder tissue - quantifying
impedance changes due to inflammation and oedema
Physiological Measurement 26 (3) 251-268 (2005).
Link
via IOP
Walker D.C., Brown
B.H., Blackett A.D., Tidy J. and Smallwood R.H.
Walker
D C, Brown. B. H., Smallwood R H, Hose D R, Jones D M
(2002)
Walker D C, Brown. B. H, Hose D R,
Smallwood R H
Jones D, M, Smallwood R H, Hose D R, Brown
B H, Walker D C (2003)
Walker D.C. (2001) Modelling the Electrical Properties
of Squamous Epithelium Ph.D. Thesis, University of
Sheffield, U.K.
pdf
COAST
COmplex Automata Simulation Technique (EU FP6
funded project)
This 3 year
project commenced 1st September 2006. The project was lead
by Dr Alfons Hoekstra, University of Amsterdam. Lead
investigators in the UK were Drs Pat Lawford and Rod Hose,
Department of Medical Physics, University of Sheffield.
The
aim of this project was to develop a formal computational
modelling framework for simulating biological phenomena
across a number of time and length scales, using restenosis
of coronary arteries following stenting as an exemplar
clinical problem.
More information relating to this project is available here
PUBLICATIONS
Caiazzo
A, Evans D, Falcone J, Hegewald J, Lorenz E, Stahl B,
Wang D, Bernsdorf J, Chopard B, Gunn J, Hose R,
Krafczyk M, Lawford P, Smallwood R, Walker D, Hoekstra
A
A Complex
Automata approach for in-stent restenosis:
Two-dimensional multiscale modelling and simulations
.
Journal of Computational Science (2011).
Link
via ScienceDirect
Evans DJ, L.P., Gunn J,
Walker D, Hose DR, Smallwood RH, Chopard B,
Krafczyk M, Bernsdorf J, Hoekstra A., The
application of multiscale modelling to the
process of development and prevention of
stenosis in a stented coronary artery. Philos
Transact A Math Phys Eng Sci, 2008. 366(1879):
p. 3343-60.
Link via
PubMed
Computational Modelling of
Sperm Behaviour in a 3D Virtual Oviduct
NOTE: The following
text is adapted from Mark Burkitt's Ph.D. thesis abstract
(currently undergoing minor revisions).
The processes by which individual sperm cells
navigate the length and complexity ofthe female reproductive
tract and then reach and fertilise the oocyte are fascinating.
Numerous complex processes potentially inuence the movement of
spermatozoa within the tract, resulting in a regulated supply
of spermatozoa to the oocytes at the site of fertilisation.
Despite signi cant differences between species, breeds and
individuals, these processes converge to ensure that a
sucient number of high quality spermatozoa reach the oocytes,
resulting in successful fertilisation without a signi cant
risk of polyspermy. Computational modelling provides a useful
method for combining knowledge about the individual processes
in complex systems to help understand the relative
significance of each factor.
In this project, the first agent based computational model of
sperm behaviour within the oviductal environment has been
created. A set of accurately scaled 3D virtual models of
the oviductwere combined with an agent based model of sperm
movement. Sperm were modelled as individual cells with a set
of behavioural rules de fining how they interact with their
local environment and regulate their internal state.
The model has been used to investigate the signi cance of the
oviductal environment on the regulation of sperm distribution
and progression to the site of fertilisation, and how changes
to that environment alter the distribution.
PUBLICATIONS
Computational modelling of maternal interactions with
spermatozoa: potentials and prospects. Burkitt M, Walker D,
Romano DM, Fazeli A. Reprod Fertil Dev. 2011;23(8):976-89.
Link via
PubMed
Constructing
Complex 3D Biological Environments from Medical Imaging
using High Performance Computing. Burkitt M, Walker D,
Romano DM, Fazeli A.
IEEE/ACM
Trans Comput Biol Bioinform. 2011.
Link via
PubMed
This is a Ph.D.
project recently completed by Mark Burkitt.
Co-supervisors were
Dr
Daniela Romano
(Department of Computer Science) and
Dr Alireza
Fazeli
(Department of Reproductive Medicine)