Developing a powerful computer model of inflammation

Research investigating the cell migration involved in inflammation, the first part of the innate immune response, typically involves the use of zebrafish due to their cost and ease of use over mammalian models. Using a mathematical approach, Juliane Liepe, Imperial College London, who has this week been awarded an NC3Rs David Sainsbury Fellowship, plans to develop a computer model of cell migration to better understand this process and reduce the need for zebrafish in future research. Dan Richards finds out more.

Juliane Liepe

“Scientists from all fields need to be aware of the possible methodologies that can be used to investigate a certain research question. Many techniques are already available and will be developed further in the future, but only their application makes them powerful tools.”

Why did you apply for the NC3Rs fellowship?

I have always been fascinated by how much we can learn by applying mathematical and computational tools in immunology. The possibility to use very abstract tools in a very practical research field such as immunology can help us to gain the maximum information out of data collected from experiments. The idea to use this principal in order to reduce the number of necessary animal experiments in research motivated me apply for the NC3Rs David Sainsbury fellowship.

What do you plan to investigate during your fellowship?

My project will study signalling processes that are related to the innate immune response. After an injury, parts of the immune system are activated; specific immune cells leave the blood vessels and migrate through the tissue to the side of the injury. I will investigate the migration of these immune cells, more specifically macrophages and neutrophils, which are the first layer of defence of the immune system in humans. It is still not fully understood – which signals drive cells towards the injury, how these cells migrate and what the cells do once they reach the site of injury are all open questions.

To answer these questions I will analyse cell migration data from zebrafish, which is a well-established animal model to study the innate immune system. In particular, I will develop data processing algorithms and analysis tools to investigate cell migration tracks.
I will finally compare the signalling pathway in zebrafish to the pathways in other species, such as mouse or human. In this way we will be able to extrapolate the gathered knowledge across species.

Why is this research important?

This project will serve as an example of how we can use computers and mathematical modelling in order to study a complex biological system. I plan to demonstrate how we can apply theoretical and computational methods to better inform how animal experiments are carried out as well as to reduce and avoid them altogether. For example, the model developed during this project will provide a platform to exclude uninformative experiments based on in silico analysis. This in turn reduces the amount of necessary animal experiments in a study. In a clinical trial, in silico prediction experiments can be used to reduce the risk for the test person.

While my project will focus on immune cell migration in zebrafish, the results and developed methodologies will be helpful to better understand cell migration. Other related studies include cancer cell migration, bacterial chemotaxis or even animal movement. This project will help to improve the technologies and optimise the workflow in these areas.

What are the advantages of mathematical modeling in preclinical research?

A mathematical model is important in daily lab work when planning new experiments. Indeed, most experiments can first be done in silico and then performed on real animal models after an optimisation of the experimental procedures; this will mean that we have more informative experiments. Bearing this in mind, the computer model serves as a platform to reduce the cost of the experiments and the unnecessary use of animals or human specimens. In addition, the mathematical model provides an alternative approach to wet lab experiments and it links findings from a range of studies together into a whole system.

What impact will the outputs of your research have in your lab, and for the use of zebrafish in research?

This project will provide a comprehensive set of tools for researchers to further study migration processes in zebrafish embryos, which have so far proven to be an ideal model of cell migration, but also to study similar processes in other species.

From a more computational point of view, the developed advanced statistical tools and image-processing tools will help my colleagues in other projects, which are currently prominent in Imperial College London’s Theoretical Systems Biology Group. There is also a general need to make these tools and algorithms accessible to the wider scientific community.

You are putting quite a big emphasis in your fellowship on communicating this work to both scientific and public audiences, why is that?

The communication between both biologists and computer scientists has the potential for new insights from data compared to the way such analyses were performed in the past. Scientists from all fields need to be aware of the possible methodologies that can be used to investigate a certain research question. Many techniques are already available and will be developed further in the future, but only their application makes them powerful tools. So far, computational methods especially, are poorly communicated outside of the expert audience.

Additionally, I think it is very important to introduce research fields to the public. ‘Systems biology’ research is still unknown to most people and I would like to demonstrate how practical and relevant theoretical and computational work can be.

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