Mathematics of Biological Systems: Modelling, Data & Analysis
Lead Research Organisation:
University of Warwick
Department Name: Mathematics
Abstract
To predict and preventing diseases such as cancer, diabetes and AIDS we need to do more than identify the components that make up the machinery of cells and tissues. We must also understand how these components interact to produce normal and pathological behaviour. Since the interactions between genes, transcripts, proteins, metabolites and cells are complex and dynamics, mathematical modelling and analysis will be needed for their understanding. Moreover, there is a rapidly growing number of powerful technologies that probe gene expression and the abundance and spatial distribution of metabolites and proteins. These produce huge amounts of data and require the development of new mathematical and statistical methods. This and the associated experimental design problems pose considerable mathematical and statistical challenges.This work will be developed in a number of biological areas chosen with the expectation that results obtained for these are likely to be generalisable. These include circadian clocks, photoperiodism, immunology of T cells, plant development (flowering), the control of apoptosis (cell suicide) and replication, and bacterial signalling. The research involves extensive collaboration with experimental groups and will be carried out in a multidisciplinary context involving mathematical and physical scientists as well as biologists and clinicians.
People |
ORCID iD |
| David Rand (Principal Investigator) |
Publications
Adamson A
(2016)
Signal transduction controls heterogeneous NF-?B dynamics and target gene expression through cytokine-specific refractory states.
in Nature communications
Akman OE
(2008)
Isoform switching facilitates period control in the Neurospora crassa circadian clock.
in Molecular systems biology
Akman OE
(2010)
Robustness from flexibility in the fungal circadian clock.
in BMC systems biology
Ashall L
(2009)
Pulsatile stimulation determines timing and specificity of NF-kappaB-dependent transcription.
in Science (New York, N.Y.)
Costa M
(2013)
Inference on periodicity of circadian time series
in Biostatistics
Domijan M
(2011)
Balance equations can buffer noisy and sustained environmental perturbations of circadian clocks.
in Interface focus
Domijan M
(2016)
PeTTSy: a computational tool for perturbation analysis of complex systems biology models.
in BMC bioinformatics
Domijan M
(2015)
Using constraints and their value for optimization of large ODE systems.
in Journal of the Royal Society, Interface
Finkenstädt B
(2008)
Reconstruction of transcriptional dynamics from gene reporter data using differential equations.
in Bioinformatics (Oxford, England)
Harper CV
(2011)
Dynamic analysis of stochastic transcription cycles.
in PLoS biology
| Description | To understand biological systems, to predict and prevent diseases such as cancer and diabetes and to address issues such as food security and the climate change we need to do more than identify the components that make up the machinery of cells, tissues and organs. We must also understand how these components interact to produce normal and pathological behaviour and how they interact with the environment. Since the interactions between genes, transcripts, proteins, metabolites and cells are complex and dynamic, mathematical modelling and analysis is needed for their understanding. Moreover, there are increasingly powerful technologies that probe gene expression and the abundance and spatial distribution of metabolites and proteins. These produce huge amounts of data and require the development of new mathematical and statistical methods. This and the associated experimental design problems pose considerable mathematical challenges. It is now widely accepted that a systems approach is needed and that the best way to deliver this is in multidisciplinary teams in which experimentalists and theoreticians work together. To achieve this a number of substantial systems biology projects in the key areas of the fellowship were developed through collaborations with leading experimental groups, and we resourced these projects by obtaining very substantial grant funding. One of the areas developed was circadian rhythms and chronobiology, an area that is increasingly important in terms of basic science, clinical and medical priorities, food security, and climate change. It is important in shaping medical treatment, providing new targets for drug development, and yielding insight into the inter-relatedness of various disease processes and circadian rhythms. Moreover, oncologists have come to realize that the effectiveness and severity of side effects of chemotherapies can vary dramatically based upon the time of day of their administration. A cross-Europe projects called C5Sys that is co-coordinated by Rand and an oncologist, directly addresses this. The relevance to climate change arises from the fact that the clock plays a key role in regulating the plant's response to temperature changes. The ROBuST project which involves teams from 4 UK universities addresses how this works. In this work the mathematical understanding of the design principles behind clocks developed during the fellowship provides crucial theoretical tools. Also highly relevant to food security and climate change is the highly successful PRESTA project that has developed new mathematical techniques for the prediction of regulatory interactions between genes and has discovered many new genes involved in plant stress. Cellular signalling and decision-making was another particularly productive area. One of the most important questions in biology is how the information from extracellular signals is accurately transmitted within cells in order to ensure appropriate cellular responses. Moreover, the discovery that some of the most important cellular signalling systems show oscillatory dynamics has fundamentally shifted the way such things are understood. We have studied several systems including the particularly important NF-kappaB system that plays a key role in controlling inflammation and in different contexts has differing effects on cell death and cell division. The key question we have studied in a number of papers is how the oscillatory dynamics of this system determine the different patterns of gene expression and cell fate that are observed. The challenges presented by the huge quantity, diversity and heterogeneity of biological data was another key theme. Without the development of analytical tools to organise data and interpret it we will be lost, sightless in a morass of incomprehensible data. To address this challenge we have developed and used a range of novel statistical estimation tools and data analysis algorithms. The work carried out during this fellowship substantially achieved all of the original objectives. Several substantial systems biology projects were developed and to support these grant funding of over £20m was obtained by Rand and his collaborators. These resulted in a significant number of high impact publications in journals such as Science, Nature, PNAS, Cell, PLoS Biology, & Molecular Systems Biology and a number of high profile lectures such as the AstraZeneca Lecture at ICSB2010. The ideas generated will drive Rand's research for at least the next 5 years. A range of new mathematical and statistical tools were developed and used in these projects, including tools for model development and analysis, sensitivity analysis, experimental design and optimisation, statistical estimation of parameters, data management and processing, and pipelines for analysis of various forms of biological data. Many of the developments addressed highly challenging mathematical tasks and have produced interesting conjectures and lines of enquiry for mathematical research. Multidisciplinary teams were developed around the projects and within the Warwick Systems Biology Centre (WSB). The fellowship strongly supported Rand's scientific leadership of WSB which has developed an outstanding multidisciplinary scientific environment with a very strong USP: the use of Warwick's strength in the Mathematical Sciences and multidisciplinary research to address key challenges in the Life Sciences by building multidisciplinary teams that use the power of advanced modelling and analysis to enhance their biological and biomedical research. The University has appointed 11 staff to the Centre, more than £27m of the University's grant funding since 2006 has had a WSB PI and the Centre continues to expand. A strong contribution to training was made through Rand's scientific leadership with others of the associated EPSRC/BBSRC funded Doctoral Training Centre. To date 44 students from a broad range of backgrounds have been trained in both experimental and theoretical aspects of systems biology and experience shows that because of their quality and multidisciplinary training such students are highly attractive to both industry and academia. Important results were obtained in areas such as the following : Circadian clocks: A general mathematical approach to design principles was developed and this has been applied to a broad range of problems such as temperature compensation, photoperiodism, tracking multiple phases, and robustness to internal noise and external environmental fluctuations. The new idea of flexibility that was introduced in these papers has now become a global theme of the circadian community. The new understanding generated by this approach has strongly contributed to the planning of experiments and was a key component of the £5m ROBuST SABR grant funded by BBSRC and in two other clock oriented grants. NF-kappaB Signalling: In papers in Science and PNAS we designed experiments and models to predict the structure of the input pathway and the role of A20 feedback and we showed that the frequency of the NF-kappaB oscillations determines differential gene expression, that the role of the IkappaBepsilon feedback loop is to optimally increase the heterogeneity of the later oscillations and that this heterogeneity provides population robustness. Gene transcription: In a recent paper in PLoS Biology we use mathematical analysis of imaging timeseries to reconstruct detailed statistics of the transcription process for the medically important prolactin gene. This paper has attracted a lot of attention and we believe it is a groundbreaking piece of work opening up a new area. Statistical estimation: In a series of papers we have developed a broad range of statistical estimation techniques for estimating parameters and other quantities of interest from biological timeseries data such as that from imaging, microarrays, and rtPCR. |
| Exploitation Route | They papers produced have large numbers of citations and the results have been incorporated and should ciontinue to be incorporated into the systems biology approach used now within heath, biology and industry. |
| Sectors | Agriculture, Food and Drink,Healthcare,Pharmaceuticals and Medical Biotechnology |
| URL | http://www.davidrand.co.uk |
| Description | BBSRC Grouped |
| Amount | £1,251,543 (GBP) |
| Funding ID | BB/F003498/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2007 |
| End | 11/2011 |
| Description | BBSRC Grouped |
| Amount | £654,256 (GBP) |
| Funding ID | BB/G005699/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2008 |
| End | 02/2012 |
| Description | BBSRC Grouped |
| Amount | £654,256 (GBP) |
| Funding ID | BB/G005699/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | BBSRC Grouped |
| Amount | £790,698 (GBP) |
| Funding ID | BB/F022832/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | BBSRC Grouped |
| Amount | £394,094 (GBP) |
| Funding ID | BB/G01227X/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2009 |
| End | 02/2013 |
| Description | BBSRC Grouped |
| Amount | £792,832 (GBP) |
| Funding ID | BB/F005814/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | BBSRC Grouped |
| Amount | £394,094 (GBP) |
| Funding ID | BB/G01227X/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | BBSRC Grouped |
| Amount | £223,204 (GBP) |
| Funding ID | BB/H021051/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2010 |
| End | 09/2013 |
| Description | BBSRC Grouped |
| Amount | £3,764,063 (GBP) |
| Funding ID | BB/F005806/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | BBSRC Grouped |
| Amount | £223,204 (GBP) |
| Funding ID | BB/H021051/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | BBSRC Grouped |
| Amount | £1,251,543 (GBP) |
| Funding ID | BB/F003498/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | BBSRC Grouped |
| Amount | £704,042 (GBP) |
| Funding ID | BB/F005261/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | |
| Description | BBSRC Grouped |
| Amount | £790,698 (GBP) |
| Funding ID | BB/F022832/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2008 |
| End | 03/2013 |
| Description | BBSRC Grouped |
| Amount | £246,768 (GBP) |
| Funding ID | BB/I004521/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 07/2010 |
| End | 06/2013 |
| Description | BBSRC Grouped CCCC |
| Amount | £246,768 (GBP) |
| Funding ID | BB/I004521/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 07/2010 |
| End | 06/2013 |
| Description | BBSRC SABR |
| Amount | £792,832 (GBP) |
| Funding ID | BB/F005814/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2008 |
| End | 04/2014 |
| Description | BBSRC SABR |
| Amount | £704,042 (GBP) |
| Funding ID | BB/F005261/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2008 |
| End | 10/2013 |
| Description | BBSRC SABR |
| Amount | £3,764,063 (GBP) |
| Funding ID | BB/F005806/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2008 |
| End | 04/2014 |
| Description | EPSRC |
| Amount | £243,956 (GBP) |
| Funding ID | EP/G021163/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2009 |
| End | 08/2011 |
| Description | EPSRC Responsive Mode |
| Amount | £356,217 (GBP) |
| Funding ID | EP/P019811/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 04/2017 |
| End | 04/2020 |
| Description | MathSys CDT |
| Amount | £3,700,000 (GBP) |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2015 |
| End | 09/2023 |
| Description | Wellcome Trust, The |
| Amount | £177,880 (GBP) |
| Funding ID | 091688/D/10/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2010 |
| End | 09/2015 |
| Description | European Associated Laboratory between France and United Kingdom "Personalising Cancer Chronotherapy through Systems Medicine" |
| Organisation | National Institute of Health and Medical Research (INSERM) |
| Department | DR2 INSERM |
| Country | France |
| Sector | Public |
| PI Contribution | Clinical and mathematical expertise in the area of Cancer Chronotherapy. |
| Collaborator Contribution | Clinical research, clinical and biological data in areas associated with cancer. |
| Impact | Substantial exchange of clinical data and analysis of this data. |
| Start Year | 2016 |
| Title | PeTTSy (Perturbation Theory Toolbox for Systems) |
| Description | This is a GUI based Matlab toolbox which implements a wide array of techniques for the perturbation theory and sensitivity analysis of large and complex ordinary differential equation based models. |
| Type Of Technology | Webtool/Application |
| Year Produced | 2015 |
| Impact | Has enabled analysis of complex dynamics of big systems that was not possible before. |
| URL | http://www2.warwick.ac.uk/fac/sci/systemsbiology/research/software/ |
| Title | ReTrOS: Reconstructing Transcription Open Software |
| Description | Matlab based software to reconstruct transcription profiles e.g. from time-course (LUC-, GFP- etc) imaging data. Written in Matlab 2009b, and distributed with test data. A paper on this has now been published: 123. Giorgos Minas, Hiroshi Momiji, Dafyd J Jenkins, Maria J Costa, David A Rand and Bärbel Finkenstädt. ReTrOS: A MATLAB Toolbox for Reconstructing Transcriptional Activity from Gene and Protein Expression Data. BMC Bioinformatics (2017) 18:316 DOI 10.1186/s12859-017-1695-8. |
| Type Of Technology | Webtool/Application |
| Year Produced | 2010 |
| Impact | Mainly used by biological community. |
| URL | http://www2.warwick.ac.uk/fac/sci/systemsbiology/research/software/ |
| Description | Invited Lecture. Clocks & signals. Human Circadian Rhythms: Developing a Multi-Oscillator Framework. Lorentz Center, Leiden, The Netherlands. July 2015. |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Facilitated collaboration with experts (including clinicians) in sleep and sleep pathologies and has led to new research projects. |
| Year(s) Of Engagement Activity | 2015 |
| Description | Keynote Lecture. 2016 Information and Decision-Making in Dynamic Cell Signaling. IEEE International Conference on Bioinformatics and Biomedicine, Shenzhen, China. December, 2016. |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | Enabled contact/collaboration with professional/industry keen to collaborate in the bioinformatics are and enabled me to get over to them the new opportunites that recent mathematical developments allow. |
| Year(s) Of Engagement Activity | 2016 |
| Description | Open Evening panel discussion and questions Did you know chemotherapy can be less toxic based on the time of day it's delivered? |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | Open Evening panel discussion and questions Did you know chemotherapy can be less toxic based on the time of day it's delivered? that we organised as part of our recent international scientific meeting Medicine in the 4th Dimension. Experts from Cancer, Sleep, Circadian Biology and Mathematics chaired by a scientific journalist. |
| Year(s) Of Engagement Activity | 2016 |