Circadian and cell cycle clock systems in cancer.

The ability to cure certain cancers, and reduce the side-effects of specific anti-cancer drugs, can be greatly improved by simply giving these cancer treatments at specific times of day. How does this process work? Actually very little is known about how the biological clock, present in most cells of the body, can regulate cell division, in healthy cells as well as in tumours. This project combines the efforts of 7 groups across Europe to use a variety of approaches to explore this problem. A great deal of information is available about each process alone, clock and cell division, but little is understood about how they work together. We will create mathematical models of these processes, which will make predictions of how and when they interact. In addition, these models will make critical prediction of how drugs, as well as light, may impact upon their function. The group at UCL will provide essential raw data to help construct these models, and explicitly test the actions of drugs on healthy living cells to see if the results fit with the mathematical predictions.

There is clear clinical, as well as more limited basic science evidence that the circadian clock and the cell cycle interact. Chronotherapy has clearly demonstrated improvements for cancer cure rates and reduced side-effects. But how do these two cellular oscillators interact? This proposal aims to take a systems biology approach to look at this problem, combining the varied expertise of 7 groups across Europe. Models are being created that link these two processes, and explicit predictions will be made regarding gene rhythmicity, oscillator phase and period. Also these models will be used to predict the optimal times to apply a variety of drug and light perturbations. My group at UCL will explicitly test these predictions using our luminescent reporter cells in zebrafish, as well as provide critical kinetic data to the modelling effort. We already possess luminescent reporter cell lines containing constructs for period1, bmal1, cry1a as well as cyclin B1 and 6-4 photolyase. Using a 96 well plate format, and Packard Topcount Luminometers we will be able to follow gene expression over many days - exploring the timing of critical events between both the circadian clock and the cell cycle oscillator. This ability to follow both processes in parallel puts us in a unique position to be able to manipulate one system and see immediately the consequences on the other biological oscillator. These types of dynamic, high-resolution data are critical for the success of the modelling components of this project. The C5Sys program as a whole is broken into a series of workpackages with clear and explicit aims. These are outlined in considerable detail in the Case for Support. WP1 and WP3 explicitly compare the clock-cell cycle interactions in healthy tissues (WP1) versus malignant cell types (WP3). Representing the first such large scale comparison of altered cell function. WP2 forms the core of this proposal as the mathematical/systems biology hub of this effort.

Circadian rhythms, or the biological clock is a topic that has caught the interest of the general public in a significant way. The reasons for this are readily apparent, as almost all aspects of human behaviour, physiology and cell biology are controlled by the clock. The idea of biological time is easily accessible to everyone. We all sleep for approximately a third of our lives, and most people can relate to getting drunk more easily at lunchtime than in the evening. This topic is, therefore, frequently discussed in newspapers, online sites and TV documentaries. This fact is especially true for this project, the interaction between the clock and cell division. Everyone is concerned with the treatment of diseases such as cancer, and the idea of improving this by simply giving drugs at the best time of day is very compelling. The general public understands that peoples' lives can be saved by simply using our current resources and technology more efficiently. We are confident that this project will be well received with this in mind. A critical part of our research is appropriate dissemination of data and public engagement. In the case of projects like this we have found this a relatively small problem. The issues are quite simple, and easily accessible to the general public. This is true not only for adults, but also children and politicians, and we have found our work very accessible as an educational tool to explore basic aspects of evolution, and molecular biology. The issue simply remains how to best publicize the effort. Obviously, we intend to publish results in the usual peer reviewed scientific journals. Gene sequences etc. will be deposited in the appropriate databases. For a more general audience, the project will be discussed on our own lab web page, but also through UCL's media resources and communications/Press Office, as well as the media offices of the BBSRC. Several times each year I give general outreach talks to high school level students on this topic, from within the UK and also Europe. Interest levels are always high. This joint project will also contain specific outreach plans that are outlined in Form 2. The long-term clinical impact of this basic science project is clear; a fundamental understanding of how to improve cancer treatment with timed drug application. This can only be achieved through collaborative basic science projects of this kind, bringing together a range of scientists with very different expertise. The use of a mathematical modeling approach also broadens the impact of this proposal by incorporating an even wider audience of computer science, and modeling people.