Integrative Cell Models – Bridging Microbial Physiology and Systems biology

Organizers: Vitor Martins dos Santos, Frank Bruggeman, Vincent Danos, Diego Oyarzun, Peter Swain, Andrea Weiße

Originally, we thought of cellular regulation merely in terms of the molecular mechanisms underpinning point-to-point information flows. But growing evidence now points to the major impact that global trade-offs in the physiology of cells have on the execution of sub-cellular processes.

Predictive models in systems biology need to incorporate these new insights and take into account global physiological effects alongside the sub-cellular processes to understand the emergent behaviour of cells. For this to happen, a prerequisite is to measure and quantitatively understand the deep couplings between a cell and its various processes. The associated experiments and the new insights will be guided by and rely on the currently existing cell models. The broad ambition of this workshop was to chart the landscape of available cell models, their underpinning concepts, and associated tools, and to promote the further development and use of these models. The specific goals were to:

1. Gather the experts who pioneered different approaches to integrative cell modelling and form a European cell-model community.

2. Harvest the available cell models and identify the salient variables that determine the cellular physiology and globally impact sub-cellular processes.

3. Plan the development of a cell model standard to serve as a ‘plug-and-play’ environment to integrate models of sub-cellular processes.

The workshop proceeded successfully as per the programme on the workshop website. The sessions included talks by both experimentalists and modellers, and across different fields, focusing on one specific area per day, and were followed by afternoon break-out sessions. The break-out sessions formed an important part of the meeting, fostering the interactions among participants and allowing them to concentrate the discussions around specific topics underlying the current challenges/bottlenecks. Speakers and participants jointly decided on break-out topics based on the questions triggered by the lectures and subsequent questions-and-answers. Each break-out group summarized the main conclusions of the brainstorm and these were presented to all other groups in a general session at the end of the afternoon.

Overall, participants discussed the state-of-the-art, key bottlenecks and future perspectives for cell models, and they debated on how to build upon and overcome them. Participants, presentations and discussions covered the many required disciplines from theoretical/biological conceptual underpinnings in microbial metabolism and physiology, to the mathematical aspects necessary to building cell models, to the more pragmatic aspects of existing and future computational and experimental tools. A recurring topic of discussion was the philosophic divide between ‘minimal’ models to address specific problems and novel ‘holistic’ approaches aimed to provide general tools and repositories of knowledge. This divide was not fully overcome, but the workshop helped in bringing both parties closer and appreciate the respective other’s objectives.

Participants jointly decided on a spontaneous change of programme dedicating one of the afternoon sessions to voluntary short talks by participants. This session gave a broad overview of the diverse research related to cell modelling and led to further discussions. During the last session of the week, the main directions, bottlenecks and potential solutions, as well as perspectives were discussed in plenary. It was jointly planned to place these discussions on a perspective/opinion/trending paper to be submitted to a journal of impact within the area. The editor of the journal Molecular Systems Biology was contacted and responded positively to the concept. The tentative layout of the potential paper agreed at the meeting is shown below.

As an outcome of the meeting, several participants teamed up to organise further events such as the 2016 Summer School on whole-cell models (http://www.wholecell.org/school-2016 organised by 2 participants and including 4 other participants as speakers), and a course on multi-algorithm whole-cell modelling paired with a course on mechanistic cell modelling (http://tinyurl.com/cri-2016-wc & http://tinyurl.com/cri-2016-mechcell organised by 3 participants).

The Lorentz Center provided an excellent venue to hold this workshop allowing organizers and participants to solely focus on the science and giving space for both plenary and small discussions.

PAPER LAYOUT

1. Why context-dependence, both for models and experiments? examples

2. Coarse- and fine-grain as examples of the same process;

3. Coarse-grain modelling; data needed;

4. Fine-grain modelling; data needed;

5. Interfacing between different granularities;

6. Organization of community;

Frank Bruggeman (Vrije Universiteit Amsterdam, NL)

Vincent Danos (University of Edinburgh, UK and École Normals Supérieure, FR)

Vítor Martins dos Santos (Wageningen UR, NL)

Diego Oyarzún (Imperial College London, UK)

Peter Swain (University of Edinburgh, UK)

Andrea Weiße (University of Edinburgh, UK)