Statistical modelling of in vivo immune response dynamics in zebrafish to multiple stimuli

Zebrafish embryos are optically transparent and allow us to visualize biological processes in real time. Here we will study how the innate immune response deals with different threats to the fish's health. In particular we will study the response to wounding and to cancer in the fish. In both cases cells of the immune response system are drawn to the wound site or the location of the tumor/cancer cell and determining the precise way in which this is achieved is one of the fundamental aims of our research. We will use a combination of microscopy and mathematical modelling in order to understand how the immune system senses and responds to such stimuli. We will reconstruct mechanistic models that capture how cells react and reach decisions from the observed data. To this end we will also develop new statistical and computational tools. These will allow us to analyze the complex data generated over the course of this project. We are very interested in how cells make decisions and how we can guide such behaviour. To this end we will also selectively interfere with and probe molecular interaction networks that affect directly how the immune cells respond to stimuli and move towards their target.
Mathematical models will, crucially, also allow us to assess how the immune response is regulated if it receives more than one stimulus. This is a completely unsolved problem but one of great fundamental and biomedical importance: for example surgery is still one of the important therapeutic approaches against many cancers and our initial analyses have shown that wounding (surgery) and cancer affect cells of the innate immune response differently.
More generally, this research will develop a platform that can be applied also in other contexts, where we want to analyze biological processes inside living organisms. Such investigations will benefit greatly from the statistical, computational and image analysis tools and protocols that are developed as part of this research.

For technical reasons biological processes have in the past predominantly been studied in isolation from each other and often only from a single perspective or on a single spatial but also temporal) scale: e.g. the levels of molecules or cells. For the vast majority of biological, biotechnological and biomedical problems, however, it is easy to recognize that the underlying processes span more than just a single scale. Our research will tackle this fundamental problem and develop zebrafish as a model system to study such intrinsically multi-scale problems.

In the proposed research project we will apply an integrated experimental-theoretical framework to study fundamental processes related to immune signalling in zebrafish. In particular we propose to develop novel statistical and computational analysis suitable for multi-scale problems where cellular decision making processes affect the organism-wide dynamics. This type of problem is exemplified by immune response signalling processes; here we will study these using a combination of experimental and theoretical approaches and study how wounding and cancer in zebrafish embryos affect cells of the innate immune response system. We will characterize the response to single stimuli as well as combinations of stimuli (two wounds and wound+cancer) and develop and probe mechanistic models for immune response dynamics. We will then use small molecule inhibitors to block key-kinases believed to modulate immune cell behaviour to study the phenotypic effects of such molecular interventions at the whole-organism level.

Multi-scale problems are all-pervasive in biology and especially in biomedical research. The biggest immediate and mid-term impact of this research is the development of an integrative framework for the quantitative analysis of in vivo systems. There is tremendous scope for applying such tools in fundamental and applied biological and biomedical research. Zebrafish are also a natural model organism to study biological processes of relevance aquaculture and commercial fish-breeding.

Other application areas include:
pharmacology and in vivo drug screening
tissue engineering and stem cell biology
regenerative medicine

To maximize short-term impact we will release software in a suitable licensing framework that will allow easy and free access to academic stake-holders. The commercial scope for such software will be explored with the Imperial College Technology Transfer office.

In the medium term we will also discuss the application of the immunological findings of our research with fisheries researchers and stakeholders in the aquaculture and food industries. Understanding how the immune system in wish works will have implications for drug treatment and other disease prevention schemes in this sector. We already have good working relationships with the Food Standards Agency and the Foundation for Science and Technology; both of these organizations offer idea fora to engage with commercial stake-holders.

In addition we will address the distinct lack of individuals trained and conversant in both computational and laboratory techniques. The need for such individuals in academia and industry is likely to increase. But a suitable trained individual will be able to lead innovative new research programmes and it is one of our essential aims to aid the RAs to become recognized researchers at the wet/dry interface of systems biology. We believe that the named RA has great potential to become a future research leader and the proposed research project will form an important milestone in her career progression.