Project Success Stories - Multi-scale modelling in healthcare
Plaque build-up in the coronary artery could mean that the heart is not getting enough oxygen, and that there is a risk of a blocked artery, which could lead to a heart attack. The standard procedure for addressing this condition is angioplasty, which involves mechanically widening a narrowed or obstructed blood vessel. Doctors then crack this plaque open in order to restore blood flow, though the cleared artery is often not strong enough to remain open without some support. A stent is inserted, which basically sits in the artery, ensuring it is kept open. The patient then has a wound inside the artery that needs time to heal. In most cases tissue will grow around the stent and the patient will be able to lead a healthy life. However, in about 10% of such cases, things go wrong when unwanted tissue forms inside the artery. This condition is called in-stent restenosis (ISR): the development of neointimal tissue which has the potential to block the artery. Once this happens, follow-up treatment may be required. Addressing this problem was the driving force for the project 'Complex automata simulation' (Coast), an EU-funded project to build a framework for multi-scale, multi-science simulations. The goal of the project was not to improve medical care per se, but rather to develop a complex automaton (CxA) capable of simulating and synthesising complex mathematical models at a wide range of scales, from 'molecule to man'. 'The Coast project is about multi-scale modelling or MSM,' says Alfons Hoekstra, professor of computational science at the University of Amsterdam and coordinator of the Coast project. 'About 10 years ago, we realised that in science, biology and healthcare, we are used to studying systems at a certain scale, say at a certain magnification of our microscopes. We zoom in to see organs, tissues, cells and try and understand our bodies at separate scales. Since the unravelling of the human genome, we've been able to analyse from the molecular level up to the level of man; these are complex processes that happen at different scales,' he explains. Better understanding of ISR ― and ultimately finding a better treatment ― was used as an example of a challenging multi-scale biomedical application to validate whether a framework for multi-scale, multi-science simulations is achievable. 'This whole Coast project is being driven by ISR,' says Mr Hoekstra. 'It is a very challenging application. It involves all the different variants of multi-scale couplings you can think of.' To study exactly how the body works, scientists could try to simulate every cell in the body, and all proteins in the cells, to find out what happens. The problem is that no computer in the world is capable of achieving this goal. Therefore, one solution is to treat things at a coarser scale, say in bigger blocks. But then researchers would not get all the information they need to analyse a process. The idea behind Coast was to do both: create large-scale and small-scale simulations running at the same time and somehow couple them. Achieving this has been the core of the EU-funded project. So while Coast had a specific objective relating to ISR, it also attempted to answer the broader question of whether a model can be used to simulate a number of parts of the body and enable interdisciplinary cooperation. Using some muscle In order to deal with all these multi-scale couplings, the project team developed a computational tool called 'Multiscale coupling library and environment' (Muscle) for the simulation of multi-scale models. And in order to study ISR, the team identified and constructed individual single-scale models of the biological and physical sub-processes involved. Muscle then integrated these complex interactions according to their distinct temporal and spatial scales. 'On all these MSMs, you usually have single-scale models available,' says Mr Hoekstra. 'They are just there. You want to glue them together, and Muscle provides that glue. The scale separation map then provides a pictorial demonstration to help biologists organise their knowledge and by organising all this, Coast also becomes a qualitative modelling tool.' Muscle is also an open source project, and is available for researchers to use. The framework developed by the Coast project was used to try and learn more about ISR. 'Our simulations now allow us to test hypotheses related to simple questions, such as "why does ISR start, and why does it stop?"', says Mr Hoekstra. This hypothesis testing will then inform the biologists to conduct new experiments. Such simulation-guided experimentation should then lead to a deeper understanding of ISR. The virtual physiological human The focus by Coast on ISR feeds in to a much broader research target: the development of a virtual physiological human (VPH) model. This concept is currently receiving lots of ICT funding, and a large network of excellence has already been developed. With the help of EU funding, Europe has developed a very strong VPH community. The VPH is a methodological and technological framework that will enable collaborative investigation of the human body as a single complex system. The VPH will be made up of integrated computer models of the mechanical, physical and biochemical functions of a living human body. 'The whole VPH vision is very challenging from an ICT perspective,' says Mr Hoekstra. 'This is where ISR fits in ― as one VPH application. The VPH community is pushing these ideas along. I believe VPH is part of this "health for ICT vision", and we're starting to see a merging of these groups.' Mr Hoekstra reckons there are about 15 or so EU-funded VPH projects currently active. 'There is lots of interest in this, creating models to understand human physiology and improve human health,' he says. 'It can be summed up in two phrases: from molecule to man, or from DNA to disease.' It is within the VPH community that the groundwork laid by Coast can now best be exploited. This is where real uptake in ICT research has been occurring. 'The point is that the models have been validated,' says Mr Hoekstra. 'Coast has ended, but there are follow-up projects. The 'Medical devices design in cardiovascular applications' (Meddica) project, for example, is about improving medical devices: artificial heart valves, stents, etc.' The future Mr Hoekstra believes that the Coast project has got researchers to the point where they can really begin to make a difference in multi-scale modelling and applications in human health. 'It is now time to broaden the application to other systems, not just coronary,' he says. 'Coast was not discussed with companies, but Meddica will be. We are in a position now to team up with companies and discuss our findings. Previously, we weren't quite there.' A new project, due to start in October 2010, with completion scheduled for 2013, aims to find the best computers on which to run multi-scale models, using paradigms developed by Coast. It will involve coupling computers throughout Europe, and tying together disparate disciplines such as fusion researchers, those working with nanomaterials, hydrologists, and the VPH.