E X PE R IM ENT A L CE LL R ES E AR CH 319 (2013) 1240–1246

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/yexcr

Review Article

Predicting the future: Towards symbiotic computational

and experimental angiogenesis research

Katie Bentleya,b,n, Martin Jonesa, Bert Cruysc,d

a
Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK
b
Computational Biology Laboratory, CVBR, Beth Israel deaconess Medical Center, Harvard Medical School, Boston MA 02215 USA
c
Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, Vesalius Research Center, KU Leuven, Belgium
d
Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven B-3000, Belgium

article information abstract

Article Chronology: Understanding the fundamental organisational principles underlying the complex and multi-
Received 24 November 2012 layered process of angiogenesis is the mutual aim of both the experimental and theoretical
Received in revised form angiogenesis communities. Surprisingly, these two fields have in the past developed in near
1 February 2013 total segregation, with neither fully benefiting from the other. However, times are changing and
Accepted 2 February 2013 here we report on the new direction that angiogenesis research is taking, where from well-
Available online 13 February 2013 integrated collaborations spring new surprises, experimental predictions and research avenues.
Keywords: We show that several successful ongoing collaborations exist in the angiogenesis field and
Computational modelling analyse what aspects of their approaches led them to achieve novel and impactful biological
Interdisciplinary insight. We conclude that there are common elements we can learn from for the future, and
Angiogenesis provide a list of guidelines to building a successful collaborative venture. Specifically, we find
Prediction that a near symbiosis of computation with experimentation reaps the most impactful results by
Simulation close cyclical feedback and communication between the two disciplines resulting in continual
refinement of models, experimental directions and our understanding. We discuss high impact
examples of predictive modelling from the wider, more established integrated scientific
domains and conclude that the angiogenesis community can do nothing but benefit from
joining this brave new, integrated world.
& 2013 Elsevier Inc. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1241
Towards predictive modelling in angiogenesis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1241
Predictive biological modelling can have high impact . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1242
What is the secret to achieving high impact biological insight through predictive modelling? . . . . . . . . . . . . . . . . . . . . . . 1242
Towards a unified, predictive modelling mindset . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1242
Symbiotic approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1242

n
Corresponding author.
E-mail address: kbentley@bidmc.harvard.edu (K. Bentley).

0014-4827/$ - see front matter & 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.yexcr.2013.02.001
 EX PE R IM ENT A L CE LL R ES E AR CH
Simple focused, but extendable models. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1243
Quantitative data/image analysis greatly improves the symbiotic process . . . . . . . . . . . . . . . . . . . . . . . . . . 1244
Discussion and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1244
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1245
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1245
Introduction
The goal of biology, be it theoretical or experimental, is to study
complex living systems and understand their fundamental
principles of organisation and generation. Biology is, however,
inherently noisy with variables that are hard to control. More-
over, in vivo information is often difficult to extract and analyse.
Data often comes in many disjointed forms: static images,
global rather than cellular protein analysis, whole organ level
functional descriptions or single pathway in vitro biochemistry.
As a result, details can remain disconnected and important
underlying mechanistic behaviours can evade discovery. Com-
putational modelling can enable us to ‘‘join the dots’’ and
integrate our disparate knowledge of signalling pathways,
cell/tissue level dynamics and the ever changing cell environ-
ment to attempt to fully understand how and why a biological
process unfolds as it does.
Angiogenesis is a prime example of a hugely complex, multi-
scale, adaptive process with intricate temporal and spatial
dynamics. Multiple subcellular, cellular and multicellular
mechanisms occur in tandem, constantly adapting to the ever
changing environment to generate the new tubular structures
capable of supporting and optimising blood flow: actin
dynamics in migrating cells, cell rearrangement, lumen forma-
tion and ultimately plexus remodelling to name but a few [1].
Indeed, this special issue itself captures the breadth and
diversity of mechanisms contributing to the process. Computa-
tional approaches, if applied correctly, can hugely aid the
detangling of this complexity and fuel the discovery of the
general, underlying principles.
However, computational modelling is not new, nor is the fact
that computation can aid the understanding of biological complex-
ity. A host of excellent reviews already exists, covering this issue in
a wide range of biological domains [2–5] as well as specifically
covering the large number of theoretical angiogenesis models that
have already been developed [6–8], most recently with an impor-
tant focus on the role of incorporating experimental data along
with model development [9]. However, as pointed out in Ref. [10],
still there is hesitation on how best to exploit this powerful tool
and, indeed, whether to facilitate integration at all.
Here, we aim to address this hesitation. We will show first
that real progress can be made by combining forces, and that a
common theme of ‘‘successful examples’’ of biological model-
ling is that not only are they integrated, but clear testable
predictions from the model, and constant feedback throughout,
have been essential design principles of the research pro-
gramme. We conclude that simply handing over an experi-
mental data set to a modeller will not likely yield the most
predictive modelling results; we must work together. High
impact has been achieved in other fields, and is on the horizon
already for the angiogenesis field. Thus we postulate that the
time is ripe for the field of angiogenesis to sew more predictive
seeds through iterative, integrated modelling in order to suc-
cessfully reap new biological understanding.
319 (2013) 1240–1246 1241
Towards predictive modelling in angiogenesis
Mathematical/computational models take a long time to build, as
does confidence in the approach. Before full integration with
experimentation could be achieved, models were mainly built on
theoretical grounds with the aim of illustrating that the process
could even be modelled [11–13]. This was an important first step
that stimulated a surge in angiogenesis modelling, which has seen an
increasing incorporation of experimental data over time [14–19].
Now we can see that the field has developed still further; a small
pocket of fully integrated, joint ventures are emerging where
modellers work side by side with experimentalists, or, indeed, indi-
viduals are trained in both sides of the trade [20–25]. This heralds a
move in a positive direction for the angiogenesis field, catching up, as
we will show, with other fields where this level of integration has
existed for much longer. We will discuss two such examples,
particularly notable for their predictive and iterative nature.
Starting from one-compartment models for breast tumour
tissue [26] and skeletal muscle [27], the Popel group generated
a whole-body pharmacokinetic model consisting of three differ-
ent compartments: normal, diseased (e.g. tumour) and vascular
[28]. Two vascular endothelial growth factor A (VEGF) isoforms
(the freely diffusible VEGF-121 and the matrix bound VEGF-165),
VEGF-receptor 1 and 2 and their co-receptors (Neuropilin-1 and
2) are integrated in the model. This allowed them to investigate
the distribution of free and bound VEGF, which is hard to assess
experimentally, in exercising as well as pathological conditions.
One of this model’s predictions is that the higher plasma VEGF
levels in cancer patients compared to healthy individuals may be
caused by a change in the vascular permeability of the cancer
patient’s healthy tissue [28]. In the next phase, the model was
extended to study the mode of action of the anti-VEGF agent
bevacizumab and more specifically its accompanying counter-
intuitive increase in plasma total VEGF level in treated patients
[29]. The model predicted that the working mechanism of
bevacizumab is to deplete the tumour VEGF levels rather than
the plasma VEGF levels. By adding tumour cells, muscle fibres
and by sequentially integrating newly measured experimental
data they further refined their model [30]. Upon every newly
added parameter, they compared the obtained model with the
prior one. In the next step, they investigated the influence of
several parameters on the model output. In this way, they were
able to make predictions on the role that the (1) tumour
microenvironment, (2) anti-VEGF binding properties, (3) density
of VEGF receptors and co-receptors on tumour cells, (4) VEGF
secretion rate and the secreted VEGF-isoform ratio and (5)
tumour lymphatics play in the therapeutic potential of an anti-
VEGF agent. Finally, their results raise interesting questions
regarding the use of VEGF isoform expression and/or interstitial
VEGF concentration as predictive biomarkers to tune the anti-
VEGF therapy better for a specific patient [30]. In their most
recent instantiation of the model, the applicability of isoform-
specific anti-VEGF agents was investigated [20]. The specific
targeting of the VEGF-121 isoform was predicted to reduce the
1242 E XP E RI ME N T AL C E L L RE S E AR CH
unbound VEGF in the tumour and thus could be a candidate with
therapeutic potential.
A second example is the iterative evolution of a cell-centred
model that started from a simple experimentally-based model of
tip/stalk cell selection via Notch signalling, built to understand
the basic mechanisms that regulate sprouting under normal and
pathological conditions [31]. Several new predictions were made
based on the unexpected, emergent behaviours that the simula-
tions generated, in particular the regular selection of branch
spacing was predicted to be disrupted under pathologically high
VEGF conditions and to give rise to abnormal synchronous Notch
oscillations, potentially explaining the abnormal sprouting that
occurs in high VEGF pathologies such as cancer. This model was
then extended to simulate cell migration and anastomosis, with
close inclusion of in vivo zebrafish sprouting data during model
development, giving rise to a new set of predictions concerning
(1) the mechanism of anastomosis, (2) the instability of tip/stalk
fate selection as the branching network structure changes under
loop formation, (3) as junctions become irregular and (4) the
robustness of pathological oscillations due to the positive feed-
back of cell migration, leading to potential therapeutic insights
[32]. Later, extended versions of this model predicted that (1)
loss of the deacetylase Sirt1, which affects the timing of Notch
regulated gene expression, would lead to a sparser vessel net-
work due to low-level oscillations in Notch. This not only exactly
matched the phenotype found in Sirt1 mutant mouse retinas but
also provided the first mechanistic explanation and consideration
of temporal influences on the emergence of this phenotypic
manifestation [33] and (2) VEGFR3/VEGF-C signalling may
directly affect filopodia dynamics and the cells ability to move
in a persistent manner, with preliminary validation in the
zebrafish intersegmental vessels [34]. A recent unexpected
experimental observation was made that cells are in fact highly
dynamic in the sprout, constantly shuffling and rearranging their
positions. The model was then overhauled to include and
investigate this new behaviour. These model refinements in light
of new data then created a surge in new insights and predictions.
Principally, Notch signalling may be involved in regulating cell
rearrangement behaviour [22,35].
Predictive biological modelling can have high impact
There is a surprisingly high level of hesitation in the angiogenesis
field to trust modelling. Perhaps one way to encourage integra-
tion is proof by example. Modelling is integral and fundamental
to many other disciplines and has led to great advances in
science. The best and most longstanding example of this is the
role that modelling plays in physics, where it is ubiquitous (in
fact, the distinction between theoretical and experimental phy-
sics is frequently blurred). One of the most significant results in
physics in recent years has been the discovery of the famous
Higgs boson. Its possible mass range was predicted by the
theoretical ‘‘Standard Model’’. The Large Hadron Collider at CERN
was built and in 2012 the elusive particle was finally discovered
[36,37]. This stands as a huge testament to what can be achieved
when theoreticians and experimentalists combine forces, food
for thought for the angiogenesis community.
Already in the wider world of biological modelling there are
countless examples of excellent integrated research [38–43]. In
319 (2013) 1240–1246
particular, Sawai et al. experimentally proved Levine’s prediction
of a positive feedback loop on cAMP excitability in the aggrega-
tion of Dictyostelium discoideum (slime mould) cells, a mechan-
ism now fundamental to our understanding of slime mould [41].
In a similar way Shankaran et al. found the mechanism of
oscillations in the MAPK pathway by combining mathematics
and experiments [39]. They compared two previously published
model predictions on MAPK oscillation mechanisms and found
only one of them to match their experimental data. Hence, their
model was able to point towards the most probable oscillation
cause and as such had an explanatory role.
The applicability and dependability of predictive models is
further exemplified by their increasing use in governmental
decisions in such important areas as disease control policies
and drug discovery [44–47]. During the 2001 foot-and-mouth
disease outbreak in the UK, different predictive models were
developed in near real-time to estimate the impact of confining
strategies on the evolution of the epidemic [47]. Ferguson et al.
devised a simple deterministic model, consisting of ordinary
differential equations, that accurately predicted the policy’s
effects on the spatial evolution on the disease and as such guided
the governmental control policy.
What is the secret to achieving high impact biological
insight through predictive modelling?
Considering these examples of validated, predictive modelling
across the variety of fields discussed, we can begin to identify
common features that led to their success.
Towards a unified, predictive modelling mindset
Modelling should not be viewed as simply a method for
corroborating experimental results. Although obviously this is
an important step in the development and calibration of a
predictive model, it has too often been the end result of
angiogenesis models and arguably over time has led to a loss
of confidence in in silico approaches’ potential for driving
research forward.
However, it takes two to tango. A concerted effort and
commitment will be needed on both sides to move the angio-
genesis field towards achieving the kind of integrated success
seen in the wider biology field. Modellers need to have a more
unified direction and only develop and publish models that give
rise to new predictions, but equally experimentalists need to
commit to actually test and explore the model predictions.
Symbiotic approach
From the angiogenesis examples given, it is clear that constant,
open communication channels between the two disciplines is
key. Though it has often been noted that models must be
integrated with experimentation, simply providing a modeller
with an experimental dataset will not yield the best results. The
realism and, therefore, predictive capacity of a model will
increase as the level of integration and communication with
experimentalists increases. Indeed, if we push this idea to its
limit, the ideal scenario for developing a highly predictive model
is to totally immerse the modeller within the experimental
environment and vice versa. Indeed, the importance of the
experimentalist also taking the time to understand the model-
ler’s perspective and toolsets should not be underestimated;
 EX PE R IM ENT A L CE LL R ES E AR CH
crucial and unique contributions to a models’ design subtleties,
leading to greater predictive power, can possibly only be devised
by the theoretically-inquisitive experimentalist. From the given
examples a two-way education process in the other’s discipline
during research was a key component to their success.
We will dub this Holy Grail of integration the ‘‘symbiotic’’
approach; see Fig. 1. Symbiosis was originally defined as ‘‘The
living together of unlike organisms’’—by Heinrich Anton de Bary
in 1879. It is defined as a process continually in flux where the
feedback from one to the other provides a mutual benefit and
creates a larger system greater than the sum of its parts. This
then is perhaps the perfect analogy. A crucial component to the
examples given is the cycles of iterative refinement with close
integration between modelling and experimentation. Indeed, this
is the essence of the generalised scientific process, to continually
refine and investigate, building and evolving our model view of
the world. It should never be expected that a theory or model is
built that is totally right at the outset; science is a process of
refinement. It is then simply a natural next step, in the
technological age, to implement this process with the rigour
and temporal simulation capacity of the computer.
Feedback is a crucial aspect that maintains, but also can be
exploited by, a successful symbiosis. As well as the obvious
benefit of including new data in iterations in the model, experi-
mental design itself is also an important aspect of the scientific
process. Without some guidance as to the most potentially
fruitful avenues to pursue, we can be left searching around in a
vast parameter space that may contain many dead ends. The
symbiotic approach can generate unlikely and potentially
Fig. 1 – Symbiotic approach: the model and our
understanding, evolves through iterative cycles where
continual feedback drives both model refinement and directs
optimised experimental design. Fundamental to this
approach is the open, continual communication and
education between the disciplines throughout, represented by
the flow of ideas through a dashed ‘‘membrane’’ between the
disciplines. This is enhanced, where possible, by existing and
working in the same physical location and publishing in
shared journals and conferences.
319 (2013) 1240–1246 1243
accurate predictions meaning experimental design itself can be
overhauled in new directions, requiring development of new
tools and techniques, but with great new insight that may never
have occurred otherwise.
Returning to the example of integration of theory and experi-
mentation in physics, we can learn that other factors may also
contribute to the success of the field. Theoreticians and experi-
mentalists traditionally inhabit the same spaces, both literally in
terms of academic buildings, and also in the sense of generally
sharing the same journals and conference circuits. This extension
of the symbiotic approach to the workplace and dissemination of
results is largely missing from modern biology and it would
appear that it could only enhance the science if such a metho-
dology were employed more widely. The examples in angiogen-
esis of successfully predictive models indeed employed this
spatially symbiotic arrangement, though together we must tackle
reducing the publication/conference segregation that currently
exists.
Simple focused, but extendable models
The models exemplifying success here all exploited a simple and
extendable design principle; a clear biological question and
desire to be predictive on that specific question has kept the
model free of excessive elements and parameters that can
confuse/detract from question in hand. Too often, undirected,
overly complex models are created with too many features
modelled at once to be able to control variables and make
concise predictions on single components or mechanisms’
dynamics. Thus, if we actually follow the first principle, to have
clear questions and predictions in mind, then designing the
simplest model to achieve this aim should naturally enhance
the model’s predictive capacity.
It is clear that simpler qualitative models can still be informa-
tive in the initial absence of quantitative data. Models are, by
definition, simplifications of the system being studied. Even
extreme simplifications can be instructive and are frequently
used in physics for example, with approximations such as
spherical symmetry, point particles and so on. Such models
may not provide robust quantitative data, but the qualitative
behaviours and sensitivity analysis on them can be a vital
starting point for building more realistic models and directing
new quantitative experiments to find those values that can
subsequently be included to produce robust numerical data
and testable predictions.
Thinking in a bottom–up manner naturally leads to emergent
and extendable models and is evident from many of the examples
above [31,32,38,40,41]. Bottom-Up or generative models are
approaches that use simple building blocks representing the
lowest level elements in the model only, such as molecular
interactions. These elements are then allowed to interact by a
stated set of rules, usually in a spatially coherent way, to then
generate emergent behaviours at a higher level above, only evident
to the observer of the simulation and not governed by rules
themselves, e.g. cellular context behaviours defined by molecular
interactions below. These models are well characterised to gen-
erate dynamics that are far more complex than their simple set of
underlying rules might suggest and the dynamics they produce
are often ‘emergent’, i.e., impossible to predict ab initio. See Fig. 2
for a schematic.
1244 E XP E RI ME N T AL C E L L RE S E AR CH 319 (2013) 1240–1246

Fig. 2 – Schematic of the Bottom–Up, emergent modelling approach. (A) Assumptions of the model, built on experimental data
and understanding, are written in as rules that govern the interactions of the lowest level components in the model. The
simulation of these rules of local interaction of small components over time gives rise to higher level dynamics of the system as a
whole, observable but not directly programmed in. These emergent behaviours can then either be used against existing data
to validate the assumptions at the level below, or as new predictions. Model refinement and extensions are easily incorporated as
new or revised interaction rules/components. (B) Biological representations of the different levels are depicted, respectively
from bottom to top: intracellular components, a few interacting cells and an established vascular network. Fluorescence
microscopy images supplied by Eleonora Lapi (CRUK London, CNIO Madrid) and electron microscopy image supplied by Lucy
Collinson (CRUK London).

Further advantages of the Bottom–Up approach are that firstly

it is generally far easier to extend the model by simply adding
additional interactions or components, as and when experimen-
tal data reveal new phenomena. Secondly, the framework is
much more closely aligned with our current understanding of
how complex cellular behaviours arise, from the interaction of
many simple components, and hence is more palatable to
experimentalists, breaking down the communication barriers
and aiding the flow of information needed. This type of model-
ling could represent a ‘‘Rosetta Stone’’ and will engender a
common language that will allow more effective communication
and a tightening of the integration between model and
experiment.
Quantitative data/image analysis greatly improves the symbiotic
process
It is often said that a model is as good as the experimental data
that contributes to its development. The closer we can get to
reliable quantitative information to feed into the model the
better. In order to incorporate new experimental findings back
into models effectively, it is worth exploiting computation to
build quantitative analysis tools to extract meaningful and
rigorous numerical information from the experiments, leading
to a greater synergy between the model and experiment
[22,38,39]. Indeed, given the complex morphological nature of
the angiogenesis process there is a real need for development of
tailored computational image analysis to link our mechanistic
understanding to quantitative read-outs on network growth and
function. Already work has begun in this area, ripe to build on in
the future [48–53].
Discussion and conclusions
We have provided a short overview of the potential computa-
tional modelling holds for angiogenesis by considering what has
made collaborations impactful in other fields, and made the few
that have so far emerged in the computational angiogenesis
field successful. Model predictions can be invaluable for finding
new and unexpected understanding as Scianna et al. conclude
with regard to their model’s predictions: ‘‘Even though it is
possible to form a post hoc explanation of each solution’s
effectiveness, it is unlikely that these solutions would have
been manually discovered’’. The list of common elements that
led to the novel insight we have discussed are summarised
below:
1) Unify computational angiogenesis towards predictive model-
ling on specific scientific questions.
a. Commitment from modellers to make predictions.
b. Commitment from experimentalists to test predictions.
2) Move towards a symbiotic research approach.
a. Communication: open constant, two way communication
channels between modeller and experimentalist.
b. Feedback: exploit the two way feedback for iterative
model refinement and optimised experimental design.
3) Design simple, focused but extendable models.
a. Avoid over complexity and parameterisation in the model:
less is more.
b. Exploit Bottom–Up, generative approaches for their intui-
tive, emergent and extendable qualities.
 EX PE R IM ENT A L CE LL R ES E AR CH
4) Develop automated quantitative data/image analysis methods.
a. Greatly enlarge the quantitative datasets that can feed into
the model.
a. Gain novel insight by improving the resolution and
accuracy of observation.
When considering all these factors, the one that perhaps gets
the least praise, but deserves the most credit, for generating novel
insights is the integral, mutual education that occurs during a
successful, symbiotic collaboration. A serious, continual commu-
nication effort on both sides drives one to rethink and more fully
understand their position, potentially of much greater and lasting
value than the simple exchange of raw data that might be
misguidedly construed as ‘‘integration’’. After all, scientific insight
comes as much from the mind as from the microscope. The
interested reader is directed to an excellent illustration and
discussion of this aspect of the process by Drubin et al. [54].
Ultimately, the evolving model and our understanding is more a
reflection of how successful and deep the communication has
been to drive the accuracy and design of the underlying assump-
tions, than just on the level of data that has been incorporated.
There are however, limitations and challenges ahead even for
close collaborations, which we will have to solve and overcome
together. It is notoriously difficult to find precise measures with
which to compare and evaluate both natural and simulated
vascular network structures, due to their plastic and variable
patterning from case to case. Levels of acceptable evaluation differ
between experimentalists and theoreticians. For example it may be
sufficient in a purely experimental paper to say there is a
difference between a control and mutant retina, however this
needs to be quantified and broken down into specific morpho-
metric elements to make generation and evaluation of a simulated
mutant possible. Measures can be either functional or morpholo-
gical, i.e. changes in tissue perfusion and growth of tumours fed by
the vessels or defined by number of branch points, vessel
diameters etc. All of these however, rely, as we have noted, on
improving our development of precise imaging and image analysis.
Another challenge is to be respectful of, and plan in advance to
marry up, the time differences between work in the experimental
and theoretical worlds. Often computational models are expected
to be built overnight, whereas the careful development of a fully
integrated working model can actually take many years, and
needs continual refinement and interaction with the experimen-
talist during development. Equally, theoreticians entering the
experimental world for the first time are unlikely to appreciate
the painstaking, and often nail-biting time it can take to establish
and repeat experiments. To avoid long periods waiting on data for
the modelling or frustration that models aren’t producing instant
results, it is worthwhile to create realistic timelines, explain the
time consuming elements of the work carefully to the other
discipline, and if possible show them the process. In this way both
sides can plan the project timeline appropriately.
Overall, we conclude that the goal of computational angiogen-
esis should be to use the symbiotic and prediction-motivated
modelling approaches to create groundbreaking models that give
novel biological insight. As postulated by Kitano [2]: ‘‘It is not
inconceivable that the U.S. Food and Drug Administration may one
day mandate simulation-based screening of therapeutic agents,
319 (2013) 1240–1246 1245
just as plans for all the high-rise building are required to undergo
structural dynamics analysis to confirm earthquake resistance.’’
This statement became reality when the FDA approved the cardiac
models of Noble, Hunter and colleagues [3,46] for drug testing.
Thus if we may be so bold as to predict the future, a brave new
world is ahead if both the theoretical and experimental branches
of the angiogenesis community truly embrace, anastomose if you
will, and let the creativity and ideas flow.
Acknowledgments
BC is funded by the Institution of Research and Innovation (IWT).
MJ is funded by a Cancer Research UK fellowship. KB is funded by
Cancer Research UK and the Leducq Foundation ARTEMIS Trans-
atlantic Network Grant. Thanks to Dr Bill Hanage, Harvard School
of Public Health, for insight on predictive modelling in the
epidemiology field.
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