Mathematical Modelling in Biomedicine: A Primer for the Curious and the Skeptic

Abstract

In most disciplines of natural sciences and engineering, mathematical and computational modelling are mainstay methods which are usefulness beyond doubt. These disciplines would not have reached today's level of sophistication without an intensive use of mathematical and computational models together with quantitative data. This approach has not been followed in much of molecular biology and biomedicine, however, where qualitative descriptions are accepted as a satisfactory replacement for mathematical rigor and the use of computational models is seen by many as a fringe practice rather than as a powerful scientific method. This position disregards mathematical thinking as having contributed key discoveries in biology for more than a century, e.g., in the connection between genes, inheritance, and evolution or in the mechanisms of enzymatic catalysis. Here, we discuss the role of computational modelling in the arsenal of modern scientific methods in biomedicine. We list frequent misconceptions about mathematical modelling found among biomedical experimentalists and suggest some good practices that can help bridge the cognitive gap between modelers and experimental researchers in biomedicine. This manuscript was written with two readers in mind. Firstly, it is intended for mathematical modelers with a background in physics, mathematics, or engineering who want to jump into biomedicine. We provide them with ideas to motivate the use of mathematical modelling when discussing with experimental partners. Secondly, this is a text for biomedical researchers intrigued with utilizing mathematical modelling to investigate the pathophysiology of human diseases to improve their diagnostics and treatment.

Keywords: biomathematics; computational drug discovery; computational modelling; data-driven mathematical modelling; mathematical oncology; scientific method; systems biology.

Figure 1

Science employs different types of models to represent natural systems. Let us suppose that we are interested in investigating the properties and potential vulnerabilities of a melanoma metastasis (here, the “natural system”, visualized with MELC microscopy as in Ostalecki et al. 2017 [1]). One can represent the natural system with a semantic model, that is, the verbalization in natural language of the key compounds and processes as well as the hypotheses about a melanoma micrometastasis. Under some simplifying assumptions, a melanoma metastasis can be studied with lab bench models. For example, if one is interested in the interplay between cancer and immune cells, it is possible to co-culture tumor cells with relevant types of immune cells in vitro, like in Vescovi et al. 2019 [2]. In most cases, an alternative option is mathematical models, that is, sets of parametric equations that encode the key properties of metastasis and the hypotheses. The mathematical model is the basis for computational simulations to design experiments or to formulate or explore hypotheses like in Santos et al. 2016 [3].

Figure 2

Sketch of the Einstein-grade scientific method (grey boxes) and the place that mathematical modelling occupies in it (blue boxes): the photograph of Albert Einstein is modified from the photo “Albert Einstein colorized” by Michael W. Gorth as stored in Wikimedia (CC-BY-SA-4.0, accession date: 10.08.2020; https://commons.wikimedia.org/wiki/File:Albert_Einstein_colourised_portrait.jpg).

Figure 3

The modelling workflow in biomedicine: during model derivation, the biological knowledge and hypotheses about the studied system are encoded in a mathematical model. In model calibration, quantitative experimental data are added to characterize the mathematical model and to give values to the model parameters. In model validation, the ability of the model to make predictions is assessed by judging the agreement between new quantitative data and equivalent simulations of the calibrated model. In model analysis, a validated model is used to investigate the system using computer simulations or other tools like stability analysis.

Figure 4

BIC pen-like mathematical models: prioritizing the purpose of the model instead of its detailedness. BIC pens look like the simplest and cheapest ballpoint pen one can buy, but their apparent simplicity conceals features conceived to optimize them in economic, ergonomic, and safety terms. In Santos and coworkers 2016 [3], a similar strategy was followed to build a mathematical model accounting for anticancer dendritic cell (DC) vaccination composed of only two ordinary differential equations, far simpler than other published models [41]. (A) Simplicity in design: BIC pens have a characteristically simple hexagonal structure; this apparently naïve choice significantly reduces the material consumption of the pen and minimizes the required space for storage. An important aspect to consider in DC vaccine modelling is the bioavailability of the cells after their injection. There are much elaborated models describing this process [42], but for our purpose, it was sufficient to model DC bioavailability with a cyclic piecewise linear function that mimics the known overall behavior of injected DCs. (B) Mathematics behind design principles: compared to standard circular pens, BIC pens hardly roll on the surface of a table. This feature was explicitly desired when drafting their design. In Santos et al., we wanted a simple enough model that was still able to mimic the interaction between the tumor and both innate and adaptive immunity; to this end, the model contained two nonlinear kinetic rates in a single equation, which are still able to mimic the basics of the interplay between the tumor and the two branches of immunity. (C) Ability to solve problems: in the end, simplicity has to be reconciled with effectiveness. The design of a BIC pen, for example, integrates more characteristics like minimizing the risk of suffocation when swallowing the cap. The predictions made in Santos et al. (2016) in terms of which phenotypic features sensitize the tumor to the therapy were aligned with patient data from clinical trials; furthermore, the model predicted alternative phenotypes that promote therapy resistance. The figures about DC vaccine modelling are adapted from Santos et al. 2016 under the conditions of an open access publication (CC BY 4.0). The figures about the BIC pen were inspired by the content of the webpage www.bicworld.com. Fight by doing: A route map to good mathematical modelling in biomedicine.