Bridging systems biology and advanced computing, to realise multi-scale biological modelling.

The life sciences are in the midst of an unparalleled expansion, so much that the 21st-century has been termed "the century of biology". This interchange Fellowship will recruit the experience from a world-leading centre for computational science, EPCC, personified by Alastair Hume one of its senior software architects, to build a long-term partnership that maintains the U.K.'s advantage at the forefront of Biology. Such expertise is urgently required, because mathematical and computational modelling is the next driver of progress for a broad and growing swathe of life science research.

The publication of a ground-breaking "whole-cell" model (Karr et al., 2012) has galvanised this research in the field of Systems Biology, by representing the function of every gene in a (very simple) cell. This landmark in multi-scale modelling bridges from the genome to cell function. Physiological models already exist that span from cellular to organ and organism level, not only in the pioneering mammalian heart model but also in the plant-level models of crop science. Thus the "whole-cell" model is a crucial step towards a link from genotype to phenotype or from genome sequence to clinical traits. The plant models link even further, to the field scale and to larger agricultural and ecological models that routinely contribute to crop and climate forecasting.

The whole-cell model's authors are among many to stress that biologists must collaborate with computer scientists in data curation, model integration, accelerated computation and data analysis (Macklin et al.). Standards and software must constantly evolve to keep pace. Working, exemplar models are essential to specify the next-generation solutions. Researchers at SynthSys are using the "whole-cell" exemplar model and developing models for more complex cells. SynthSys was established by BBSRC and EPSRC as one of six UK Systems Biology centres, to focus on modelling cell and molecular biology. Andrew Millar's group has developed a whole-plant Framework Model of Arabidopsis growth, building on this major BBSRC investment. It is not only one of the very few exemplars that can be used to specify future computational infrastructure, but is also supporting a growing link from fundamental Systems Biology to Crop Science.

We are privileged to work with Alastair Hume, who ideally meets the urgent needs of our current research. Hume has over 20 years' experience in software development in industry and academia. While working at EPCC over the last 14 years, he has led the design and implementation of scalable data integration, processing and analysis systems for a variety of research fields ranging from astronomy to environmental modelling and prediction. In the recent EU BonFIRE project, for example, he led a team of up to 20 software developers working on future cloud computing.

Hume has already demonstrated his potential in joint, pilot projects with SynthSys and he is now poised to make a long-term contribution. The Fellowship is essential to realise that interdisciplinary conversion, allowing him to train in systems biology including an internship at the EBI, to engage with the broader systems biology modelling community, as well as addressing demonstration projects in three areas. Our multiscale models explicitly aim to link researchers from different scientific backgrounds, who must work together to provide the data, the modelling components and validation experiments. The Fellowship will provide time for this crucial networking, in the UK and USA, and with our partners at Rothamsted Research and Simulistics Ltd.

This Fellowship will allow SynthSys and EPCC jointly to link our work to international leaders in both computational resources and in biological modelling, creating a commanding position for the U.K.'s research and Alastair Hume in particular, at the nexus of three fast-moving areas: plant systems biology, cyber-infrastructure and multi-scale crop modelling.

This proposal will engage and adapt the skills of a software architect with 20 years' experience, Alastair Hume, to the modelling of complex biological systems. Multi-scale, whole-organism models have transformative potential and have just become achievable in Systems Biology. SynthSys has developed the leading example for Arabidopsis. These models emphasise computational challenges, requiring expert informaticians who understand biological modelling. Hume has already contributed to several informatics projects with biological researchers, attracting him to this emerging area. His broad skills and experience could clearly meet this community's growing computational needs. However, the short-term joint projects allow no time for the immersion, training and community engagement that are required for him to lead the provision of advanced tools for biological modelling.

Therefore, firstly, Hume will develop a broader understanding of systems biology modelling, through formal training and an internship at EBI, including multi-scale, whole-plant modelling. Secondly, Hume will engage with the relevant research communities to understand the scientific questions being asked, the methods being adopted, the computational infrastructure required, and to build a collaborative network with current providers. Finally, by the development of demonstration systems Hume will contribute tools and services that will support ongoing research in multi-scale modelling, with a view to generally-applicable results fostered through interaction with crop and ecosystem modelling, via Rothamsted Research, Simulistics Ltd and Millar's international network. The overall aim is that by combining the acquired skills and knowledge with his existing skill set, Hume will play a key role between EPCC and SynthSys, realising the advanced computing infrastructure required to support "digital organism" research for many years to come.

The Fellowship will develop the skills of Alastair Hume, allowing him to become a leading contributor to the emerging generation of complex biological models, and in particular their informatics infrastructure. This research is at the "bleeding edge" of current capabilities, where new technical challenges in the research methodology require an effort comparable to the underlying biological research. This Fellowship will help to bring this area to the leading edge, where it can inform progress broadly across biology and biotechnology. Thus the prime beneficiaries will be the resource providers who can re-use our results and the modellers whose work is facilitated, and these are inevitably in the academic communities.

In addition to the academic work, contract modelling offers commercial income, both in SynthSys and to our partners in Simulistics Ltd, with corresponding benefits to our clients in biotechnology and ecosystem management, respectively. Millar's work with Mendel Biotechnology Inc was published (Pokhilko et al., 2011) and contributed to his current models, for example. The new tools will allow us to model more complex systems, more efficiently, adding realisable commercial value to the dual-expertise of our staff and for client firms. Incorporating these features into future versions of Simulistics' Simile software will likewise increase its value.

The broadest benefits are expected from the applications of future, improved models both to the understanding of natural systems and their engineering in synthetic biology. Model simulations might become key educational tools, facilitating interactive training by collating the knowledge and understanding across multiple biological specialisms, without students needing to understand how the models were generated or simulated. This would be particularly easy to implement for focussed areas in a commercial setting, for example specialised training by a biofuel company on just the biological systems of interest for their production system. More widely, 'whole-cell' models are widely expected to allow a new generation of microbial re-engineering, for bioremediation, biofuel or fine chemical production, and future applications in stem cell research. In this case, the model is crucial to allow a rational 'design' stage of the Synthetic Biology production cycle. SynthSys, the Edinburgh Genome Foundry and their commercial partners are well placed to contribute, for example through our proposed BBSRC Synthetic Biology Research Centre.

In the context of ag-biotech, there is growing interest in precision agriculture (albeit from a small base of current users), especially following recent work in 'prescriptive planting' (noted even in The Economist, 2014), including acquisitions by Monsanto and other major players. The heart of these precision systems is a model that integrates soil, yield, and agronomic data into crop growth predictions. The models are proprietary, and presumably based on statistical descriptions. There is interesting potential in future for our work to make a mechanistic link from the genome sequences of crop varieties to the field traits relevant in these models. This could create a new commercial niche in technology provision, contributing to enhance UK economic competitiveness.