A Linear Systems Toolkit for Biology
Lead Research Organisation:
University of York
Department Name: Biology
Abstract
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Technical Summary
We have developed a tool set from Engineering to identify the causal connections in biological networks. We use linear time invariant (LTI) models to describe the dynamic relationships in biological systems based on analysis of time series datasets. The LTI models describe causal relationships in the network and have predictive power concerning the dynamical system. We have used LTI modelling successfully to describe the circadian clock of Arabidopsis.
We wish to build on this advance by developing a new approach based on the Nu gap metric, which identifies the causal changes in a network in response to stimulation or perturbation, (e.g. pharmacological agents or genetic mutation). The Nu gap identifies those connections that are altered by measuring the degree of change in the LTI models that describe those connections. Identification of those network connections that have changed in response to treatment allows follow up studies to be focused exclusively on the affected nodes that represent primary candidate gene targets.
Our preliminary studies demonstrate the utility of our approach. LTI modelling and Nu gap analyses of circadian transcriptomes of Arabidopsis has identified the target for the metabolite nicotinamide in the circadian clock and we have confirmed the mathematical prediction through experimentation.
We will develop LTI modelling with Nu gap analysis both theoretically and practically. We will apply Nu gap analysis to circadian datasets obtained both from model systems that are well understood and from crop plants in which circadian networks are not fully understood. We will use LTI modelling coupled with Nu gap analysis to investigate transcriptional responses to pharmacological and genetic. We will extend the utility of the LTI modelling with Nu gap analysis by incorporating non-transcriptional data. Theoretical developments will attempt to extend the power of Nu gap analysis to non-linear models.
We wish to build on this advance by developing a new approach based on the Nu gap metric, which identifies the causal changes in a network in response to stimulation or perturbation, (e.g. pharmacological agents or genetic mutation). The Nu gap identifies those connections that are altered by measuring the degree of change in the LTI models that describe those connections. Identification of those network connections that have changed in response to treatment allows follow up studies to be focused exclusively on the affected nodes that represent primary candidate gene targets.
Our preliminary studies demonstrate the utility of our approach. LTI modelling and Nu gap analyses of circadian transcriptomes of Arabidopsis has identified the target for the metabolite nicotinamide in the circadian clock and we have confirmed the mathematical prediction through experimentation.
We will develop LTI modelling with Nu gap analysis both theoretically and practically. We will apply Nu gap analysis to circadian datasets obtained both from model systems that are well understood and from crop plants in which circadian networks are not fully understood. We will use LTI modelling coupled with Nu gap analysis to investigate transcriptional responses to pharmacological and genetic. We will extend the utility of the LTI modelling with Nu gap analysis by incorporating non-transcriptional data. Theoretical developments will attempt to extend the power of Nu gap analysis to non-linear models.
Planned Impact
Impact statement
WHO WILL BENEFIT?
(1) Academic scientists interested in circadian rhythms, crop biology, stress physiology of plants and systems biologists in all organisms
(2) Industrial scientists interested in generating crop varieties with enhanced stress tolerance and those using systems tools for gene and drug discovery.
(3) Research staff.
(4) The general public.
HOW WILL THEY BENEFIT?
(1) We will ensure wide dissemination and use of the Nu gap in systems biology. (a) We will organise a one day training course in Nu gap techniques at Cambridge for doctoral and pre-doctoral scientists. We have requested funds to support travel and subsistence for up to 20 participants. We will advertise the Nu gap training course through our contact networks, the Cambridge Networks Network, UKPSF, GARNet and Engineering and Systems Biology message boards. Materials associated with the training course will be made available via our websites. (b) We will present our research at the following conferences; IEE Conference on Decision and Control, the International Conference on Systems Biology and other appropriate meetings. These will also be used to advertise the Nu gap training course. (c) We will ensure maximum impact by publishing our research in a timely manner. The applicants have a track record of publishing in high impact journals and widespread dissemination.
(2) Industrial scientists will benefit because we will develop a new STEM tool that allows identification of the causal changes in biological systems that occur in response to stimulation. We envisage that this will have utility in both the agricultural and pharmaceutical industries. In agriculture the Nu gap might be implemented to identify candidate genes for breeding programmes. In the pharmaceutical industry Nu gap could be exceptionally powerful in identifying drug targets and may offer considerable advantage compared to correlative tools currently in use. We will use our current relationships with industrial partners at Bayer Crop Science and Microsoft Research to attract industrially-based scientists to the Nu gap training course.
(3) The PDRA will gain considerable benefit from being employed on the project. This will include training in circadian systems and linear modelling tools. The training in the specialist control theory approaches will place the PDRA in a good position for a further career in academia or the pharmaceutical, agricultural, financial or engineering industries. PDRAs from the Webb laboratory have had excellent career advancement. All BBSRC-funded PDRAs in the Webb laboratory have obtained publications in Science or Nature and eight former members of the Webb laboratory have obtained Faculty positions. The PDRA will gain considerable experience on helping develop and deliver the Nu gap training course and associated material.
(4) The general public will benefit from outreach activities at the Department of Plant Sciences, Cambridge. During Science Week numerous interactive and more formal displays on aspects of plant biology and research are presented and 7,000 visit the Plant Sciences displays on 'Science Saturday' which will include dissemination of findings from this project. We take every opportunity to publicise our findings, Dr Webb has appeared on Radio interviews (e.g. BBC Farming Today) and his recent findings have been summarised in media outlets as diverse as the Financial Times and Comedy Central's Colbert Report. It is hoped in the long term that the public will benefit from food security generated from the novel agricultural products that arise from our findings. Whilst recognising that in any field of study the translation rate from laboratory finding to industrial product is always low, we make every effort with our industrial partners (Bayer Cropscience) to translate our findings for public benefit. We are currently registering IP on one of our discoveries.
WHO WILL BENEFIT?
(1) Academic scientists interested in circadian rhythms, crop biology, stress physiology of plants and systems biologists in all organisms
(2) Industrial scientists interested in generating crop varieties with enhanced stress tolerance and those using systems tools for gene and drug discovery.
(3) Research staff.
(4) The general public.
HOW WILL THEY BENEFIT?
(1) We will ensure wide dissemination and use of the Nu gap in systems biology. (a) We will organise a one day training course in Nu gap techniques at Cambridge for doctoral and pre-doctoral scientists. We have requested funds to support travel and subsistence for up to 20 participants. We will advertise the Nu gap training course through our contact networks, the Cambridge Networks Network, UKPSF, GARNet and Engineering and Systems Biology message boards. Materials associated with the training course will be made available via our websites. (b) We will present our research at the following conferences; IEE Conference on Decision and Control, the International Conference on Systems Biology and other appropriate meetings. These will also be used to advertise the Nu gap training course. (c) We will ensure maximum impact by publishing our research in a timely manner. The applicants have a track record of publishing in high impact journals and widespread dissemination.
(2) Industrial scientists will benefit because we will develop a new STEM tool that allows identification of the causal changes in biological systems that occur in response to stimulation. We envisage that this will have utility in both the agricultural and pharmaceutical industries. In agriculture the Nu gap might be implemented to identify candidate genes for breeding programmes. In the pharmaceutical industry Nu gap could be exceptionally powerful in identifying drug targets and may offer considerable advantage compared to correlative tools currently in use. We will use our current relationships with industrial partners at Bayer Crop Science and Microsoft Research to attract industrially-based scientists to the Nu gap training course.
(3) The PDRA will gain considerable benefit from being employed on the project. This will include training in circadian systems and linear modelling tools. The training in the specialist control theory approaches will place the PDRA in a good position for a further career in academia or the pharmaceutical, agricultural, financial or engineering industries. PDRAs from the Webb laboratory have had excellent career advancement. All BBSRC-funded PDRAs in the Webb laboratory have obtained publications in Science or Nature and eight former members of the Webb laboratory have obtained Faculty positions. The PDRA will gain considerable experience on helping develop and deliver the Nu gap training course and associated material.
(4) The general public will benefit from outreach activities at the Department of Plant Sciences, Cambridge. During Science Week numerous interactive and more formal displays on aspects of plant biology and research are presented and 7,000 visit the Plant Sciences displays on 'Science Saturday' which will include dissemination of findings from this project. We take every opportunity to publicise our findings, Dr Webb has appeared on Radio interviews (e.g. BBC Farming Today) and his recent findings have been summarised in media outlets as diverse as the Financial Times and Comedy Central's Colbert Report. It is hoped in the long term that the public will benefit from food security generated from the novel agricultural products that arise from our findings. Whilst recognising that in any field of study the translation rate from laboratory finding to industrial product is always low, we make every effort with our industrial partners (Bayer Cropscience) to translate our findings for public benefit. We are currently registering IP on one of our discoveries.
Organisations
People |
ORCID iD |
Seth Davis (Principal Investigator) |
Publications
Avello PA
(2019)
Heat the Clock: Entrainment and Compensation in Arabidopsis Circadian Rhythms.
in Journal of circadian rhythms
Barros KA
(2020)
Diurnal patterns of growth and transient reserves of sink and source tissues are affected by cold nights in barley.
in Plant, cell & environment
Hargreaves J
(2018)
Wavelet spectral testing: application to nonstationary circadian rhythms
Hargreaves J
(2018)
Clustering Nonstationary Circadian Rhythms using Locally Stationary Wavelet Representations
in Multiscale Modeling & Simulation
Hargreaves J
(2019)
Wavelet spectral testing: Application to nonstationary circadian rhythms
in The Annals of Applied Statistics
Oakenfull RJ
(2017)
Shining a light on the Arabidopsis circadian clock.
in Plant, cell & environment
Perea-García A
(2016)
Modulation of copper deficiency responses by diurnal and circadian rhythms in Arabidopsis thaliana.
in Journal of experimental botany
Philippou K
(2020)
Chemical Perturbation of Chloroplast-Related Processes Affects Circadian Rhythms of Gene Expression in Arabidopsis: Salicylic Acid Application Can Entrain the Clock
in Frontiers in Physiology
Philippou K
(2019)
Physiological and Genetic Dissection of Sucrose Inputs to the Arabidopsis thaliana Circadian System.
in Genes
Ronald J
(2019)
Focusing on the nuclear and subnuclear dynamics of light and circadian signalling.
in Plant, cell & environment
Ronald J
(2017)
Making the clock tick: the transcriptional landscape of the plant circadian clock.
in F1000Research
Rubin MJ
(2017)
Circadian rhythms vary over the growing season and correlate with fitness components.
in Molecular ecology
Saini R
(2019)
Circadian oscillator proteins across the kingdoms of life: structural aspects.
in BMC biology
Shin J
(2017)
The metabolic sensor AKIN10 modulates the Arabidopsis circadian clock in a light-dependent manner.
in Plant, cell & environment
Sánchez-Villarreal A
(2018)
AKIN10 activity as a cellular link between metabolism and circadian-clock entrainment in Arabidopsis thaliana.
in Plant signaling & behavior
Description | Work progresses to harness an understating of the barley circadian clock. |
Exploitation Route | Data is being use to develop LTI and Nu-gap models. |
Sectors | Agriculture Food and Drink Education Environment Manufacturing including Industrial Biotechology |
Title | Data from: Circadian rhythms vary over the growing season and correlate with fitness components |
Description | Circadian clocks have evolved independently in all three domains of life, suggesting that internal mechanisms of time-keeping are adaptive in contemporary populations. However, the performance consequences of either discrete or quantitative clock variation have rarely been tested in field settings. Clock sensitivity of diverse segregating lines to the environment remains uncharacterized as do the statistical genetic parameters that determine evolutionary potential. In field studies with Arabidopsis thaliana, we found that major perturbations to circadian cycle length (referred to as clock period) via mutation reduce both survival and fecundity. Subtler adjustments via genomic introgression of naturally occurring alleles indicated that clock periods slightly >24 hrs were adaptive, consistent with prior models describing how well the timing of biological processes is adjusted within a diurnal cycle (referred to as phase). In segregating recombinant inbred lines (RILs), circadian phase varied up to two hours across months of the growing season, and both period and phase expressed significant genetic variances. Performance metrics including developmental rate, size, and fruit set were described by principal components (PC) analyses and circadian parameters correlated with the first PC, such that period lengths slightly >24 hrs were associated with improved performance in multiple RIL sets. These experiments translate functional analyses of clock behavior performed in controlled settings to natural ones, demonstrating that quantitative variation in circadian phase is highly responsive to seasonally variable abiotic factors. The results expand upon prior studies in controlled settings, showing that discrete and quantitative variation in clock phenotypes correlate with performance in nature. |
Type Of Material | Database/Collection of data |
Year Produced | 2017 |
Provided To Others? | Yes |
URL | https://datadryad.org/stash/dataset/doi:10.5061/dryad.th8b5 |
Description | BBC Radio Interview (York) |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | BBC - York; Yorkshire Farming interview on 06 November 2015, aired 08 November 2015. Question and answer program on how seasonal changes impact barley and wheat growth. |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.bbc.co.uk/programmes/p02fqk6w |
Description | Cellular imaging for primary school students |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Activity engaging children on STEM aspects of their natural world. Discussion on imaging and microbiology. |
Year(s) Of Engagement Activity | 2017 |
Description | Festival of ideas presentation and tent for public engagement |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Circadian exhibition at the York Festival of Ideas - Tick Tock |
Year(s) Of Engagement Activity | 2016 |
URL | http://yorkfestivalofideas.com/2016/ |
Description | Plant sciences interaction for primary school students |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Using diverse plants, primary children conducted experiments with barley, pea and cress to test the effects of light and temperature on growth. A presentation on "the beginnings of life" added to that in a context of a seed and an egg. |
Year(s) Of Engagement Activity | 2018 |
Description | School visit (Pocklington School) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | School visit (Pocklington School) |
Year(s) Of Engagement Activity | 2021 |
Description | Syngenta meeting on pre-breeding |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Meeting with Syngenta on pre-breeding of barley and B. rapa. |
Year(s) Of Engagement Activity | 2020,2021 |
Description | The Gatsby Plant Science Summer School 2015 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Undergraduate students |
Results and Impact | Ran undergraduate tutorials on plant metabolism within the United Kingdom Plant Sciences Federation, which was organized by The Gatsby Foundation termed The Gatsby Plant Science Summer School 2015 |
Year(s) Of Engagement Activity | 2015 |
URL | http://www.slcu.cam.ac.uk/outreach/gatsbyplants |