Commentary

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Moving beyond the genome with computer

modeling
Patrik Christen*,1
1
Institute for Biomechanics, ETH Zurich, Zurich, Switzerland
*Author for correspondence: patrik.christen@hest.ethz.ch

“Once personalized computer simulations can provide the appropriate models and explanations
to model biological and mechanical processes, we will be able to move beyond genome-based
personalized medicine, enabling better use of the valuable medical data. ”

First draft submitted: 27 August 2017; Accepted for publication: 25 January 2018; Published online:
16 May 2018

Keywords: adolescent idiopathic scoliosis • Boolean network • cellular automaton • complexity science • computer
modeling • finite element analysis • medical data diversity • personalized computer simulation

Background
Personalized or precision medicine has been defined as treatments targeted to the needs of individual patients based
on genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish patients with similar clinical
presentations [1]. Despite this broad definition and the general recognition that many different characteristics and
factors influence a patient’s pathophysiology, so far personalized medicine mainly focuses on treatments exclusively
based on the genome. However, in many cases, disease development and treatment effects are characterized and
influenced by a multitude of factors including more than one genomic and other ‘omics’, such as proteomics and
metabolomics, as well as environmental, behavioral, and psychosocial factors [2].
Adolescent idiopathic scoliosis (AIS) is an example of such a disease. It is not only characterized by a lateral
curvature of the spine but also by numerous and diverse other characteristics and factors including systemic low bone
mass and several abnormal levels of metabolic serum biomarkers [3]. It affects 1–4% of adolescents, predominantly
females. AIS limits the quality of life and in severe cases repeated invasive surgery of the spine is necessary [3]. It is
currently not possible to predict curve progression based on genetic or any other factors. Prognosis would be of great
value to be able to time therapy and surgery. Bracing has been shown to decrease the risk of curve progression [4]
and thus may be used in a preventive manner in patients predicted to be at risk from curve progression. The lack
of prognostic factors can be attributed to our limited understanding of AIS and its complexity as indicated by its
multifactorial nature. Although data on these disease characteristics and influence factors are often available, they
are only partially considered in diagnosis, prognosis, and treatment.

Medical data
Medical data are very diverse. Improved and novel measurement techniques can assess an individual patient’s
physiology in ever increasing detail in space and time, generating large volumes of highly diverse data. Technological
improvements include, for example, rapid progress in genome sequencing techniques [5], improved [6] and more
extensive [7] biomarker analysis, digitized patient record analysis [8], and advanced imaging techniques and image
analysis methods [9]. In addition, there is a trend toward mobile monitoring where patients gather data themselves,
for example, using health apps on smart phones and watches [10–13]. In AIS, data as diverse as gene expression
profiles, metabolic serum biomarkers, high-resolution computed tomography images, and physical activity scores
have been gathered in longitudinal clinical studies [14]. Medical data therefore capture multiple pathophysiological
characteristics and influence factors in individual patients providing an opportunity for personalized medicine to
move beyond the genome. This is sorely needed for the diagnosis, prognosis, and treatment of many diseases, not
only AIS, but it simultaneously poses an enormous data integration challenge.

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Computer modeling
Computer modeling potentially provides an interface and a way of integration for these diverse medical data.
Computer models including molecule, cell, tissue, and organ levels provide an interface for medical data, measured
at these levels in the patient [15]. If such a model can be built, it becomes possible to perform personalized simulations
of medical outcomes months, years, and even decades before the actual event. Based on the patient’s medical data,
this would allow, for example, to simulate virtually the effects of certain treatment options in the patient. Simulations
could be run by clinicians during consultation, but also by patients on mobile devices informing them when to visit
a physician. An AIS patient at risk of curve progression could be identified at a stage when bracing is still possible to
avoid invasive surgery. Although there are currently almost no such personalized computer simulations to support
physicians for better diagnosis, prognosis, or treatment, they are widely used elsewhere. In engineering, one would
not build a car or an airplane without computer models. They also have become indispensable in science, where
multiscale computer models of complex biomolecules even led to a Nobel Prize in Chemistry in 2013 [16].

Modeling limitations & possible solutions

Modeling limitations are currently hindering the success of computer modeling in medicine. One of the most
serious limitations is that the models usually have too many parameters, which are not measurable in patients [17]
and that the available medical data are not necessarily represented by model parameters – a mismatch between
required model input and the available data. Additionally, the models are often very specific and are only capable
of simulating certain aspects of a patient’s biology, disallowing the integration of the diversity of data present in
medicine. In particular, biological models exist for different biological levels such as the gene and cell levels. Not
only do these isolated models generally not account for interactions between biological levels, they also disregard
mechanical forces; although it is known that most if not all cells respond to mechanical loading and thus are
mechanosensitive [18]. These problems of disregarding multiple biological levels and mechanical loading could be
tackled by simplifying models through the abstraction and coupling of specific models, therefore bridging the gap
between biological levels and the gap between biological and mechanical models. Discrete computer models from
complexity science are particularly well suited for building simple models as they model space and time only at
discrete spatial locations and time points but are still able to capture complex behavior. Instead of modeling the
exact behavior and concentration of signaling molecules in a continuous model, discrete models from complexity
science such as Boolean networks [19–21] consider their components only as either being true or false and thus, for
example, active or inactive at discrete time points. The behavior emerges from the interaction of the individual
components [22] and does not require specification of unknown concentration values, but still allows interactions in
molecular regulation and cellular signaling to be captured. Structural data could be modeled with discrete models
from complexity science as well, for example, with cellular automata [23]. They simulate changes in a certain spatial
domain – in this case the tissue – that is divided into equally sized elements referred to as cellular automaton cells.
Each discrete element of the cellular automaton is updated with local rules considering neighboring elements, for
example, increasing the tissue density if a certain molecule is present. It has been shown that such simple local rules
can produce very complex behavior [22,23]; again without specifying this behavior explicitly. Coupled with a network
model such as a Boolean network, cellular automata would thus not only model molecular and cellular effects on
structural data but also provide a model that interfaces the medical data. Furthermore, numerical methods such as
the finite element analysis for tissue mechanics calculations [24] are well suited for coupling with cellular automaton
models as it is possible to build them based on the same discretization of the spatial domain. A cellular automaton
cell could be regarded as an element of the finite element analysis. Therefore, cellular automaton potentially allows
bridging the gap between isolated biological models of various levels by coupling with network models capturing
biological interactions, as well as bridging the gap between biological and mechanical models through coupling
with numerical methods.
Another limitation of computer modeling in medicine is the lack of validation, due to the difficulty of gathering
suitable clinical data in many cases. This limitation is particularly severe if the computer models rely on parameters
that are not possible to measure in patients, as mentioned above. In addition, even if model parameters can be
linked to a measurement, limitations remain, especially if only a single measurement is performed. For example,
measuring a certain hormone level in the blood is affected by many factors including the time point and spatial
location of the sample. Longitudinal studies are therefore essential for generating validation data at several time
points and, in the best-case, also spatial locations in the patient. Blood samples could be taken at several time points
and at the spatial location of interest to monitor local changes in molecular and cellular processes. Time-lapse in

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 Moving beyond the genome with computer modeling Commentary

vivo imaging – the application of in vivo imaging of the same region at several time points – might be performed
capturing structural changes of tissues over time [25]. Such longitudinal biomarker and image data would serve as
valuable validation and input data to personalize computer models.
Furthermore, in particular the lack of explanations of fundamental disease mechanisms is preventing the success
of computer modeling in medicine. Our understanding of diseases and even treatments are often limited to
certain symptoms and effects while an explanation of the underlying pathophysiological mechanisms remains
fragmental or unknown. Biological and medical research have been very successful, uncovering more and more
details about diseases, especially regarding the role of specific genes and other ‘omics’ components. However,
formulating explanations of disease mechanisms might require adopting a more epistemological approach that is
improving current explanations through the continuous process of generating and testing hypotheses [26]. New
hypotheses of disease mechanisms could be guessed at or conjectured by ‘bold guessing’. They could be scrutinized
in ‘Gedankenexperiments’ and then tested against observations from clinical studies and animal experiments with
computer models. Current computer methods, particularly machine learning, are powerful tools to discover patterns
in data but they are not capable of coming up with explanations. For this, we rely on our cognitive capabilities [26].
Computer modeling and personalized computer simulations cannot come up with explanations either, but they
allow to virtually implement conjectured hypotheses and can test their predictions against observations providing
a valuable tool in guiding us in formulating explanations.

Current developments
We are working on the matching of model parameters with the diversity of medical data through the coupled
modeling of biological and mechanical processes from different biological levels with discrete computer models
from complexity science, the generation of longitudinal in vivo data in patients for model validation, as well as the
explanation of disease mechanisms. In a first prototype [27] that couples a cellular automaton with Boolean network
models and finite element analysis, we successfully simulated AIS-related bone loss by integrating individual AIS
patient data including high-resolution computed tomography bone images, physical activity scores and metabolic
serum biomarkers. The core of the model builds a cellular automaton constructed from the image data. Each voxel
of the image is forming a discrete element of the cellular automaton. The local rule of the cellular automaton
updates the bone density with time and is determined by a Boolean network of bone metabolism present in each
cellular automaton element. The network consists of the metabolic serum biomarkers and their action on the bone
cells. The model implements the assumption of mechanical bone adaptation, which states that the continuous bone
removal and addition by bone cells is triggered by mechanical loading. This assumption has been corroborated in
mice [28] and humans [9] using time-lapse in vivo imaging [23] and interestingly has been investigated and confirmed
with a computer model coupling biological and mechanical processes [29]. Mechanical tissue loading is calculated
using finite element analysis of models built from the image data. The implementation of this prototype led
to realistic bone loss predictions in AIS and indicated that this bone loss is related to some disruption of the
mechanoregulation, that is the mechanical regulation, of bone cells.
In a next step, to explore and test different hypotheses of AIS disease mechanisms, the prototype still needs
to be extended to more biological factors in the Boolean network to capture the multifactorial nature of AIS.
For example, some studies reported low vitamin D and calcitonin serum levels in young females with AIS [30].
They are the subject of current investigations and may lead to a better understanding of AIS and guide us in
conjecturing an explanation of the fundamental mechanisms of AIS. Finally, we want to provide a computer model
for a personalized prognosis of curve progression and testing of personalized treatment options including bracing.

Conclusion
However, we have not yet arrived at this point. Modeling limitations must be addressed and longitudinal in vivo
data in patients need to be gathered first. Maybe even more challenging is that we need to come up with better
explanations of disease mechanisms. Once personalized computer simulations can provide the appropriate models
and explanations to model biological and mechanical processes, we will be able to move beyond genome-based
personalized medicine, enabling better use of the valuable medical data. This will not only allow the prediction of
disease development and treatment options, but also extend our understanding of disease mechanisms and thus
help to develop better treatments.

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Commentary Christen

Financial & competing interests disclosure

This work was supported by the Holcim Stiftung for the Advancement of Scientific Research. The author has no other relevant
affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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