Department of Biochemistry University of Oxford Department of Biochemistry
University of Oxford
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Department wins prestigious BBSRC strategic grant for cell cycle work

Biochemistry researchers Bela Novak and Francis Barr, together with colleagues in Oxford, London and the University of Sussex, have won £3m for a BBSRC Strategic LoLa grant.

A mammalian cell undergoing cell division showing DNA (blue) and microtubules (red)

A mammalian cell undergoing cell division, with DNA in blue and microtubules in red (Click to enlarge)

The grant, one of only five awarded, will bring together the group of world-class experimentalists and cell cycle modellers to address fundamental questions about cell cycle controls in mammalian cells.

Strategic LoLaS (Longer and Larger Grants) support integrated research projects requiring long timescales, extensive resources and/or multidisciplinary approaches. They must involve internationally leading research teams and address critical research challenges.

Professor Novak explains that the impetus for the project came from the increasing desire to bring a quantitative component into cell cycle studies.

'I had many requests from cell cycle researchers to do quantitative analysis, and was already collaborating or planning to collaborate with some of these groups. I wanted to take the work further and look systematically at each of the critical transition points in the cell cycle.'

He adds that traditional biologists sometimes comment that because we do not know all the components of the cell cycle, it is premature to embark on this type of work. But he considers that now is the right time to attempt such an ambitious project.

'It's timely because we do know quite a bit. The biological literature provides lots of pieces of the puzzle. We have to try and put this together and build a coherent picture and then challenge that picture.'

He argues that we do not need to know all the components to build up a picture because it is the overall function in this complex network, comprised of evolutionary well-conserved regulators, that is most important. The team's work will be based on this approach: testing the design principles seen in single-celled organisms - that all transitions between cell cycle stages behave in a switch-like manner - in human cells.

Illustration showing the sequential activation of bistable switches at the critical transition points during mammalian cell cycle progression

Illustration showing the sequential activation of bistable switches at the critical transition points during mammalian cell cycle progression

The five groups participating groups, Ulrike Gruneberg (The Dunn School, Oxford), Helfrid Hochegger (University of Sussex) and Chris Bakal (Institute of Cancer Research) in addition to Bela Novak and Francis Barr, are well suited to the task. Each has expertise in one of the critical transition points of the cell cycle and will study their component as part of the complete cell cycle. Bringing the work together will involve an iterative cycle of mathematical modeling and experimental testing and verification, using state-of-the-art live-cell imaging and biochemistry.

In this way, Professor Barr says, the team aims to create a more quantitative description of the key events of the entire cell cycle and use this to generate a systematic understanding of how the components link together.

He highlights that the work is also important because, unlike the majority of research on the cell cycle, it does not focus on cancer or disease cells and dissection of a defective cell cycle component.

'It's important that we are not working with tumour cells,' he explains. 'We will use a normal diploid human cell line for all our experiments, so rather than working back from findings in a tumour cell, we are starting with normal cells and learning from them.' One of the first tasks of the team will be to standardise the materials they will use, such as the cell line.

He points out that this approach will have additional benefits. 'Part of the design of the project is to develop ways of working so that anyone can reproduce an experiment at any site. We will generate and share reagents so that Bela's group can take the experimental data and know that they are robust and comparable between labs.'

'This will also be valuable to other researchers because along the way we will learn what the problems are in trying to get reproducibility, and develop ways of dealing with these. This is where modelling is important because it will highlight discrepancies that arise and help us design experiments. By bringing together and coupling more tightly the experimental and theoretical components, we hope to identify issues and learn what to do to address them.'

Effective communication between the researchers on the project will be essential. Each of the five groups will have one postdoc and there will be regular interaction to ensure that there are no communication barriers between modellers and experimentalists.

Taking on the challenge of building up a quantitative understanding of the entire cell cycle, if successful, could help researchers in many ways. By providing the framework for other activities, it could lead to the identification of better targets for the design of tumour therapies.

In the announcement of the five successful projects by the BBSRC, Greg Clark, Minister for Universities, Science and Cities, commented: 'This funding will support world-leading research teams in Sheffield, Kent, Manchester, Glasgow and Oxford to address research gaps in bioscience for the benefit of the UK.

'From harnessing the sun’s power for better biofuel production to investigating how to reduce costs for British sheep farmers, these research projects supported by almost £16m from government will help to find long-term solutions to some of our biggest challenges in areas like health, energy and agriculture.'










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