A multiscale model for collagen alignment in wound healing

It is thought that collagen alignment plays a significant part in scar tissue formation during dermal wound healing. We present a multiscale model for collagen deposition and alignment during this process. We consider fibroblasts as discrete units moving within an extracellular matrix of collagen and fibrin modelled as continua. Our model includes flux induced alignment of collagen by fibroblasts, and contact guidance of fibroblasts by collagen fibres. We can use the model to predict the effects of certain manipulations, such as varying fibroblast speed, or placing an aligned piece of tissue in the wound. We also simulate experiments which alter the TGF-β concentrations in a healing dermal wound and use the model to offer an explanation of the observed influence of this growth factor on scarring

Cancer modelling: Getting to the heart of the problem

Paradoxically, improvements in healthcare that have enhanced the life expectancy of humans in the Western world have, indirectly, increased the prevalence of certain types of cancer such as prostate and breast. It remains unclear whether this phenomenon should be attributed to the ageing process itself or the cumulative effect of prolonged exposure to harmful environmental stimuli such as ultraviolet light, radiation and carcinogens (Franks and Teich, 1988). Equally, there is also compelling evidence that certain genetic abnormalities can predispose individuals to specific cancers (Ilyas et al., 1999). The variety of factors that have been implicated in the development of solid tumours stems, to a large extent, from the fact that ‘cancer’ is a generic term, often used to characterize a series of disorders that share common features. At this generic level of description, cancer may be viewed as a cellular disease in which controls that usually regulate growth and maintain homeostasis are disrupted. Cancer is typically initiated by genetic mutations that lead to enhanced mitosis of a cell lineage and the formation of an avascular tumour. Since it receives nutrients by diffusion from the surrounding tissue, the size of an avascular tumour is limited to several millimeters in diameter. Further growth relies on the tumour acquiring the ability to stimulate the ingrowth of a new, circulating blood supply from the host vasculature via a process termed angiogenesis (Folkman, 1974). Once vascularised, the tumour has access to a vast nutrient source and rapid growth ensues. Further, tumour fragments that break away from the primary tumour, on entering the vasculature, may be transported to other organs in which they may establish secondary tumours or metastases that further compromise the host. Invasion is another key feature of solid tumours whereby contact with the tissue stimulates the production of enzymes that digest the tissue, liberating space into which the tumour cells migrate. Thus, cancer is a complex, multiscale process. The spatial scales of interest range from the subcellular level, to the cellular and macroscopic (or tissue) levels while the timescales may vary from seconds (or less) for signal transduction pathways to months for tumour doubling times The variety of phenomena involved, the range of spatial and temporal scales over which they act and the complex way in which they are inter-related mean that the development of realistic theoretical models of solid tumour growth is extremely challenging. While there is now a large literature focused on modelling solid tumour growth (for a review, see, for example, Preziosi, 2003), existing models typically focus on a single spatial scale and, as a result, are unable to address the fundamental problem of how phenomena at different scales are coupled or to combine, in a systematic manner, data from the various scales. In this article, a theoretical framework will be presented that is capable of integrating a hierarchy of processes occurring at different scales into a detailed model of solid tumour growth (Alarcon et al., 2004). The model is formulated as a hybrid cellular automaton and contains interlinked elements that describe processes at each spatial scale: progress through the cell cycle and the production of proteins that stimulate angiogenesis are accounted for at the subcellular level; cell-cell interactions are treated at the cellular level; and, at the tissue scale, attention focuses on the vascular network whose structure adapts in response to blood flow and angiogenic factors produced at the subcellular level. Further coupling between the different spatial scales arises from the transport of blood-borne oxygen into the tissue and its uptake at the cellular level. Model simulations will be presented to illustrate the effect that spatial heterogeneity induced by blood flow through the vascular network has on the tumour’s growth dynamics and explain how the model may be used to compare the efficacy of different anti-cancer treatment protocols

Mathematical models in physiology

Computational modelling of biological processes and systems has witnessed a remarkable development in recent years. The search-term (modelling OR modeling) yields over 58000 entries in PubMed, with more than 34000 since the year 2000: thus, almost two-thirds of papers appeared in the last 5–6 years, compared to only about one-third in the preceding 5–6 decades.\ud \ud The development is fuelled both by the continuously improving tools and techniques available for bio-mathematical modelling and by the increasing demand in quantitative assessment of element inter-relations in complex biological systems. This has given rise to a worldwide public domain effort to build a computational framework that provides a comprehensive theoretical representation of integrated biological function—the Physiome.\ud \ud The current and next issues of this journal are devoted to a small sub-set of this initiative and address biocomputation and modelling in physiology, illustrating the breadth and depth of experimental data-based model development in biological research from sub-cellular events to whole organ simulations

The Virtual Physiological Human: Ten Years After

Biomedical research and clinical practice are struggling to cope with the growing complexity that the progress of health care involves. The most challenging diseases, those with the largest socioeconomic impact (cardiovascular conditions; musculoskeletal conditions; cancer; metabolic, immunity, and neurodegenerative conditions), are all characterized by a complex genotype–phenotype interaction and by a “systemic” nature that poses a challenge to the traditional reductionist approach. In 2005 a small group of researchers discussed how the vision of computational physiology promoted by the Physiome Project could be translated into clinical practice and formally proposed the term Virtual Physiological Human. Our knowledge about these diseases is fragmentary, as it is associated with molecular and cellular processes on the one hand and with tissue and organ phenotype changes (related to clinical symptoms of disease conditions) on the other. The problem could be solved if we could capture all these fragments of knowledge into predictive models and then compose them into hypermodels that help us tame the complexity that such systemic behavior involves. In 2005 this was simply not possible—the necessary methods and technologies were not available. Now, 10 years later, it seems the right time to reflect on the original vision, the results achieved so far, and what remains to be done

Policy needs and options for a common approach towards modelling and simulation of human physiology and diseases with a focus on the virtual physiological human.

Life is the result of an intricate systemic interaction between many processes occurring at radically different spatial and temporal scales. Every day, worldwide biomedical research and clinical practice produce a huge amount of information on such processes. However, this information being highly fragmented, its integration is largely left to the human actors who find this task increasingly and ever more demanding in a context where the information available continues to increase exponentially. Investments in the Virtual Physiological Human (VPH) research are largely motivated by the need for integration in healthcare. As all health information becomes digital, the complexity of health care will continue to evolve, translating into an ever increasing pressure which will result from a growing demand in parallel to limited budgets. Hence, the best way to achieve the dream of personalised, preventive, and participative medicine at sustainable costs will be through the integration of all available data, information and knowledge

DCC Case Study: Integrative Biology

Computer simulation organ functions based on models offers the potential to increase researchers’ understanding of the causes of medical conditions such as heart disease and to work towards developing new drugs and treatments to combat these illnesses. The main aim of the Integrative Biology (IB) project is to realise this potential by developing multi-scale models - spanning the range from genes to whole organs - and to provide data management features for its disparate users including the sharing of data in a secure infrastructure, and enabling the storage and re-use of simulation outputs

INSPIRE: A European training network to foster research and training in cardiovascular safety pharmacology

Safety pharmacology is an essential part of drug development aiming to identify, evaluate and investigate undesirable pharmacodynamic properties of a drug primarily prior to clinical trials. In particular, cardiovascular adverse drug reactions (ADR) have halted many drug development programs. Safety pharmacology has successfully implemented a screening strategy to detect cardiovascular liabilities, but there is room for further refinement. In this setting, we present the INSPIRE project, a European Training Network in safety pharmacology for Early Stage Researchers (ESRs), funded by the European Commission's H2020-MSCA-ITN programme. INSPIRE has recruited 15 ESR fellows that will conduct an individual PhD-research project for a period of 36 months. INSPIRE aims to be complementary to ongoing research initiatives. With this as a goal, an inventory of collaborative research initiatives in safety pharmacology was created and the ESR projects have been designed to be complementary to this roadmap. Overall, INSPIRE aims to improve cardiovascular safety evaluation, either by investigating technological innovations or by adding mechanistic insight in emerging safety concerns, as observed in the field of cardio-oncology. Finally, in addition to its hands-on research pillar, INSPIRE will organize a number of summer schools and workshops that will be open to the wider community as well. In summary, INSPIRE aims to foster both research and training in safety pharmacology and hopes to inspire the future generation of safety scientists

LifeTime and improving European healthcare through cell-based interceptive medicine

Here we describe the LifeTime Initiative, which aims to track, understand and target human cells during the onset and progression of complex diseases, and to analyse their response to therapy at single-cell resolution. This mission will be implemented through the development, integration and application of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during the progression from health to disease. The analysis of large molecular and clinical datasets will identify molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. The timely detection and interception of disease embedded in an ethical and patient-centred vision will be achieved through interactions across academia, hospitals, patient associations, health data management systems and industry. The application of this strategy to key medical challenges in cancer, neurological and neuropsychiatric disorders, and infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade

General report & recommendations in predictive, preventive and personalised medicine 2012: white paper of the European Association for Predictive, Preventive and Personalised Medicine

This report is the collective product of word-leading experts working in the branches of integrative medicine by predictive, preventive and personalised medicine (PPPM) under the coordination of the European Association for Predictive, Preventive and Personalised Medicine. The general report has been prepared as the consortium document proposed at the EPMA World Congress 2011 which took place in Bonn, Germany. This forum analyzed the overall deficits and trends relevant for the top-science and daily practice in PPPM focused on the patient. Follow-up consultations resulted in a package of recommendations for consideration by research units, educators, healthcare industry, policy-makers, and funding bodies to cover the current knowledge deficit in the field and to introduce integrative approaches for advanced diagnostics, targeted prevention, treatments tailored to the person and cost-effective healthcare

Systems Science and the Art of Interdisciplinary Integration

Systems sciences address issues that cross-cut any single discipline and benefit from the synergy of combining several approaches. But interdisciplinary integration can be challenging to achieve in practice. Scientists with different disciplinary backgrounds often have different views on what count as good data, good evidence, a good model, or a good explanation. Accordingly, several scholars have reported on challenges encountered in interdisciplinary settings. This chapter outlines how some of the challenges play out in systems biology where disciplinary ideals and domain-specific practices sometime collide. We focus on tensions arising due to differences in epistemic standards between modellers with a background in physics or systems engineering, on one hand, and experimenters with a background in molecular biology on the other. We propose that part of the problem of interdisciplinary integration can be understood as the result of unfounded “disciplinary imperialism” on both sides, in which standards from one discipline are uncritically applied to new domains without recognition of other valid or complementary perspectives. Addressing and explicating the disciplinary background for the different views can help facilitate interdisciplinary collaboration in science and improve science education